2024 ESC Guidelines for the management of chronic coronary syndromes: Developed by the task force for the management of chronic coronary syndromes of the European Society of Cardiology (ESC) Endorsed by the European Association for Cardio-Thoracic Surgery (EACTS)

Classes of recommendations

Table 2

Levels of evidence

The experts of the writing and reviewing panels provided declaration of interest forms for all relationships that might be perceived as real or potential sources of conflicts of interest. Their declarations of interest were reviewed according to the ESC declaration of interest rules, which can be found on the ESC website (http://www.escardio.org/guidelines) and have been compiled in a report published in a supplementary document with the guidelines. Funding for the development of ESC Guidelines is derived entirely from the ESC with no involvement of the healthcare industry.

The ESC Clinical Practice Guidelines (CPG) Committee supervises and co-ordinates the preparation of new guidelines and is responsible for the approval process. In addition to review by the CPG Committee, ESC Guidelines undergo multiple rounds of double-blind peer review by external experts, including members from across the whole of the ESC region, all National Cardiac Societies of the ESC and from relevant ESC Subspecialty Communities. After appropriate revisions, the guidelines are signed off by all the experts in the task force. The finalized document is signed off by the CPG Committee for publication in the European Heart Journal.

ESC Guidelines are based on analyses of published evidence, chiefly on clinical trials and meta-analyses of trials, but potentially including other types of studies. Evidence tables summarizing key information from relevant studies are generated early in the guideline development process to facilitate the formulation of recommendations, to enhance comprehension of recommendations after publication, and reinforce transparency in the guideline development process. The tables are published in their own section of the ESC Guidelines and are specifically related to the recommendation tables.

Off-label use of medication may be presented in these guidelines if a sufficient level of evidence shows that it can be considered medically appropriate for a given condition. However, the final decisions concerning an individual patient must be made by the responsible health professional giving special consideration to:

The specific situation of the patient. Unless otherwise provided for by national regulations, off-label use of medication should be limited to situations where it is in the patient’s interest with regard to the quality, safety, and efficacy of care, and only after the patient has been informed and has provided consent.
Country-specific health regulations, indications by governmental drug regulatory agencies and the ethical rules to which health professionals are subject, where applicable.

2. Introduction

The 2019 ESC (European Society of Cardiology) Guidelines for the diagnosis and management of chronic coronary syndromes introduced the term chronic coronary syndromes (CCS)¹ to describe the clinical presentations of coronary artery disease (CAD) during stable periods, particularly those preceding or following an acute coronary syndrome (ACS). CAD was defined as the pathological process characterized by atherosclerotic plaque accumulation in the epicardial arteries, whether obstructive or non-obstructive. Based on expanded pathophysiological concepts, a new, more comprehensive definition of CCS is introduced:

‘CCS are a range of clinical presentations or syndromes that arise due to structural and/or functional alterations related to chronic diseases of the coronary arteries and/or microcirculation. These alterations can lead to transient, reversible, myocardial demand vs. blood supply mismatch resulting in hypoperfusion (ischaemia), usually (but not always) provoked by exertion, emotion or other stress, and may manifest as angina, other chest discomfort, or dyspnoea, or be asymptomatic. Although stable for long periods, chronic coronary diseases are frequently progressive and may destabilize at any moment with the development of an ACS.’

Of note, ‘disease’ refers to the underlying coronary pathology, and ‘syndrome’ refers to the clinical presentation.

2.1. Evolving pathophysiological concepts of chronic coronary syndromes

Our understanding of the pathophysiology of CCS is transitioning from a simple to a more complex and dynamic model. Older concepts considered a fixed, focal, flow-limiting atherosclerotic stenosis of a large or medium coronary artery as a sine qua non for inducible myocardial ischaemia and ischaemic chest pain (angina pectoris). Current concepts have broadened to embrace structural and functional abnormalities in both the macro- and microvascular compartments of the coronary tree that may lead to transient myocardial ischaemia. At the macrovascular level, not only fixed, flow-limiting stenoses but also diffuse atherosclerotic lesions without identifiable luminal narrowing may cause ischaemia under stress;^2,3 structural abnormalities such as myocardial bridging⁴ and congenital arterial anomalies⁵ or dynamic epicardial vasospasm may be responsible for transient ischaemia. At the microvascular level, coronary microvascular dysfunction (CMD) is increasingly acknowledged as a prevalent factor characterizing the entire spectrum of CCS;⁶ functional and structural microcirculatory abnormalities may cause angina and ischaemia even in patients with non-obstructive disease of the large or medium coronary arteries [angina with non-obstructive coronary arteries (ANOCA); ischaemia with non-obstructive coronary arteries (INOCA)].⁶ Finally, systemic or extracoronary conditions, such as anaemia, tachycardia, blood pressure (BP) changes, myocardial hypertrophy, and fibrosis, may contribute to the complex pathophysiology of non-acute myocardial ischaemia.⁷

The risk factors that predispose to the development of epicardial coronary atherosclerosis also promote endothelial dysfunction and abnormal vasomotion in the entire coronary tree, including the arterioles that regulate coronary flow and resistance,^8–10 and adversely affect myocardial capillaries,^6,11–14 leading to their rarefaction. Potential consequences include a lack of flow-mediated vasodilation in the epicardial conductive arteries⁹ and macro- and microcirculatory vasoconstriction.¹⁵ Of note, different mechanisms of ischaemia may act concomitantly.

2.2. Chronic coronary syndromes: clinical presentations (Figure 1)

In clinical practice, the following, not entirely exclusive, CCS patients seek outpatient medical attention: (i) the symptomatic patient with reproducible stress-induced angina or ischaemia with epicardial obstructive CAD; (ii) the patient with angina or ischaemia caused by epicardial vasomotor abnormalities or functional/structural microvascular alterations in the absence of epicardial obstructive CAD (ANOCA/INOCA); (iii) the non-acute patient post-ACS or after a revascularization; (iv) the non-acute patient with heart failure (HF) of ischaemic or cardiometabolic origin. A further growing category (v) are the asymptomatic individuals in whom epicardial CAD is detected during an imaging test for refining cardiovascular risk assessment,¹⁶ screening for personal or professional purposes, or as an incidental finding for another indication.¹⁷ Patients may experience a variable and unpredictable course, transitioning between different types of CCS and ACS presentations throughout their lifetime.

Figure 1

(Central Illustration) Clinical presentations of chronic coronary syndrome and mechanisms of myocardial ischaemia.

ACS, acute coronary syndrome; ANOCA, angina with non-obstructive coronary arteries; CABG, coronary artery bypass grafting; CAD, coronary artery disease; CCS, chronic coronary syndrome; INOCA, ischaemia with non-obstructive coronary arteries; LV, left ventricular; LVEDP, left ventricular end-diastolic pressure; PCI, percutaneous coronary intervention; VSMC, vascular smooth muscle cell.

The clinical presentations of CCS are not always specific for the mechanism causing myocardial ischaemia; thus, symptoms of dysfunctional microvascular angina (MVA) may overlap with those of vasospastic or even obstructive large–medium artery angina. Furthermore, it is important to note that CCS doesn’t always present as classical angina pectoris and symptoms may vary depending on age and sex. Sex-stratified analyses indicate that women with suspected angina are usually older and have a heavier cardiovascular risk factor burden, more frequent comorbidities, non-anginal symptoms such as dyspnoea and fatigue, and greater prevalence of MVA than men.^18–21

2.3. Changing epidemiology and management strategies

Contemporary primary prevention,¹⁶ including lifestyle changes and guideline-directed medical therapy (GDMT), has led to a decline of the age-standardized prevalence^22,23 of obstructive epicardial coronary atherosclerosis in patients with suspected CCS.^24–28 As a consequence, the diagnostic and prognostic risk prediction models applied in the past to identify obstructive epicardial CAD in patients with suspected angina pectoris have required updating and refinement.^27,29,30 Initial use of coronary computed tomography angiography (CCTA)^31,32 for detecting and assessing epicardial coronary atherosclerosis is increasingly being adopted since it has shown similar performance to non-invasive stress testing for detecting segmental myocardial ischaemia.^33–35 Invasive coronary angiography (ICA), classically used to detect anatomically significant stenoses, has expanded to become a functional test³⁶ that includes refined haemodynamic assessment of epicardial stenoses, provocative testing for the detection of epicardial or microvascular spasm,^37–40 and a functional assessment of CMD.^41–43 Moreover, there is a growing interest in non-invasive imaging methods such as stress positron emission tomography (PET)^44,45 or stress magnetic resonance imaging (MRI),⁴⁶ which allow accurate assessment of the coronary microcirculation in a quantitative manner.

Medical therapy for CCS patients, including antithrombotic strategies, anti-inflammatory drugs, statins and new lipid-lowering, metabolic, and anti-obesity agents, has significantly improved survival after conservative treatment, making it harder to demonstrate the benefits of early invasive therapy.⁴⁷ However, revascularization can still benefit patients with obstructive CAD at high risk of adverse events, not only for symptom relief^48–52 but also to prevent spontaneous myocardial infarction (MI) and cardiac death and, in some groups, to improve overall survival^53–56 during long-term follow-up. Recently, revascularization through percutaneous coronary intervention (PCI) was shown to provide more angina relief than a placebo procedure in patients with stable angina and evidence of ischaemia, on minimal or no antianginal therapy, confirming the beneficial effects of revascularization.⁵²

The present guidelines deal with the assessment and diagnostic algorithm in patients with symptoms suspected of CCS (Section 3) and their treatment (Section 4), special subgroups of CCS patients (Section 5) and finally, long-term follow-up and care (Section 6).

2.4. What is new

The 2024 Guidelines contain a number of new and revised recommendations, which are summarized in Tables 3 and 4, respectively.

Table 3

New major recommendations in 2024

Table 4

Revised recommendations

3. Stepwise approach to the initial management of individuals with suspected chronic coronary syndrome

Managing individuals with suspected CCS involves four steps (Figure 2):

STEP 1. The first step is a general clinical evaluation that focuses on assessing symptoms and signs of CCS, differentiating non-cardiac causes of chest pain and ruling out ACS. This initial clinical evaluation requires recording a 12-lead resting electrocardiogram (ECG), basic blood tests, and in selected individuals, chest X-ray imaging and pulmonary function testing. This evaluation can be done by the general practitioner.
STEP 2. The second step is a further cardiac examination, including echocardiography at rest to rule out left ventricular (LV) dysfunction and valvular heart disease. After that, it is recommended to estimate the clinical likelihood of obstructive CAD to guide deferral or referral to further non-invasive and invasive testing.
STEP 3. The third step involves diagnostic testing to establish the diagnosis of CCS and determine the patient’s risk of future events.
STEP 4. The final step includes lifestyle and risk-factor modification combined with disease-modifying medications. A combination of antianginal medications is frequently needed, and coronary revascularization is considered if symptoms are refractory to medical treatment or if high-risk CAD is present. If symptoms persist after obstructive CAD is ruled out, coronary microvascular disease and vasospasm should be considered.

Figure 2

Stepwise approach to the initial management of individuals with suspected chronic coronary syndrome.

ANOCA, angina with non-obstructive coronary arteries; CAD, coronary artery disease; CCS, chronic coronary syndrome; CCTA, coronary computed tomography angiography; ECG, electrocardiogram; ED, emergency department; GDMT, guideline-directed medical therapy; INOCA, ischaemia with non-obstructive coronary arteries. ^aIn selected patients. ^bConsider also coronary spasm or microvascular dysfunction.

3.1. STEP 1: General clinical examination

3.1.1. History, differential diagnosis, and physical examination

Careful and detailed history taking is the initial step in diagnostic management for all clinical scenarios within the spectrum of CCS. Although chest pain or discomfort (Figure 3) is the most cardinal symptom of CCS, it must be emphasized that many patients do not present with characteristic anginal symptoms and that the symptomatology may vary with age, sex, race, socioeconomic class, and geographical location. In contemporary studies, only 10% to 25% of patients with suspected CCS present with angina with classic aggravating and relieving factors, while 57% to 78% have symptoms less characteristic of angina and 10% to 15% have dyspnoea on exertion.^33,57

Figure 3

Main CCS symptoms: angina and exertional dyspnoea.

CCS, chronic coronary syndrome.

While older studies suggested that women were more likely to experience less characteristic chest pain symptoms,⁵⁸ recent data show that anginal chest pain is equally prevalent in both men and women, albeit with slightly different characteristics.⁵⁹ Symptoms were classified as non-characteristic angina in over two-thirds of the patients of both sexes.^21,60 Of note, the absence of anginal symptoms does not preclude CCS, as it may be absent in patients with diabetes with autonomic neuropathy or in elderly patients with a very sedentary lifestyle despite very severe obstructive CAD. Of course, chest pain is not always angina (i.e. of ischaemic origin), since it can be related to non-coronary (e.g. pericarditis) or non-cardiovascular conditions.^61,62

Anginal pain symptoms have been traditionally classified as “typical, atypical, or non-anginal/non-cardiac” based on the location of the pain, as well as precipitating and relieving factors. Although angina that meets all three characteristics, with retrosternal chest discomfort provoked by exertion or emotional stress and relieved by rest or nitroglycerine, is highly suggestive of ischaemia caused by obstructive CAD, these characteristics are rarely all present when ischaemia is caused by microvascular dysfunction and vasospasm. Furthermore, patients with “typical” vs. “atypical” angina included in the PRECISE study had similar 1-year outcomes,⁵⁷ highlighting the limited prognostic value of symptom classification on typicality of angina used in obstructive CAD prediction models. Because this terminology to describe anginal symptoms no longer aligns with current concepts of CCS, it should be replaced by a detailed description of symptoms (Figure 3). It is important to thoroughly evaluate chest pain, including an objective exclusion of myocardial ischaemia caused by obstructive CAD, microvascular disease, and/or coronary vasospasm, before classifying it as non-cardiac.

The Canadian Cardiovascular Society classification is still widely used as a grading system for effort-induced angina to quantify the threshold at which symptoms occur with physical activities (Table 5). Importantly, the severity of symptoms is not well associated with the severity of obstructive CAD and appears to differ by sex. Women have more frequent angina, independent of less extensive epicardial CAD, and less severe myocardial ischaemia than men.⁶³ Angina at rest is not always indicative of severe, fixed obstructive CAD, as it may also occur in patients with transient epicardial or microvascular coronary vasospasm.

Table 5

Grading of effort angina severity according to the Canadian Cardiovascular Society

Grade	Description of angina severity⁶⁶
I	Angina only with strenuous exertion	Presence of angina during strenuous, rapid, or prolonged ordinary activity (walking or climbing the stairs)
II	Angina with moderate exertion	Slight limitation of ordinary activities when they are performed rapidly, after meals, in the cold, in the wind, under emotional stress, or during the first few hours after waking up, but also walking uphill, climbing more than one flight of ordinary stairs at a normal pace, and in normal conditions
III	Angina with mild exertion	Having difficulties walking one or two blocks or climbing one flight of stairs at a normal pace and conditions
IV	Angina at rest	No exertion is needed to trigger angina

Grade	Description of angina severity⁶⁶
I	Angina only with strenuous exertion	Presence of angina during strenuous, rapid, or prolonged ordinary activity (walking or climbing the stairs)
II	Angina with moderate exertion	Slight limitation of ordinary activities when they are performed rapidly, after meals, in the cold, in the wind, under emotional stress, or during the first few hours after waking up, but also walking uphill, climbing more than one flight of ordinary stairs at a normal pace, and in normal conditions
III	Angina with mild exertion	Having difficulties walking one or two blocks or climbing one flight of stairs at a normal pace and conditions
IV	Angina at rest	No exertion is needed to trigger angina

Table 5

Grading of effort angina severity according to the Canadian Cardiovascular Society

Grade	Description of angina severity⁶⁶
I	Angina only with strenuous exertion	Presence of angina during strenuous, rapid, or prolonged ordinary activity (walking or climbing the stairs)
II	Angina with moderate exertion	Slight limitation of ordinary activities when they are performed rapidly, after meals, in the cold, in the wind, under emotional stress, or during the first few hours after waking up, but also walking uphill, climbing more than one flight of ordinary stairs at a normal pace, and in normal conditions
III	Angina with mild exertion	Having difficulties walking one or two blocks or climbing one flight of stairs at a normal pace and conditions
IV	Angina at rest	No exertion is needed to trigger angina

Grade	Description of angina severity⁶⁶
I	Angina only with strenuous exertion	Presence of angina during strenuous, rapid, or prolonged ordinary activity (walking or climbing the stairs)
II	Angina with moderate exertion	Slight limitation of ordinary activities when they are performed rapidly, after meals, in the cold, in the wind, under emotional stress, or during the first few hours after waking up, but also walking uphill, climbing more than one flight of ordinary stairs at a normal pace, and in normal conditions
III	Angina with mild exertion	Having difficulties walking one or two blocks or climbing one flight of stairs at a normal pace and conditions
IV	Angina at rest	No exertion is needed to trigger angina

It is essential to document coronary risk factors during history taking, as they may be modifiable and will be used for the pre-test likelihood estimation of obstructive CAD. Smoking cessation counselling starts with a quantitative assessment of prior and current tobacco use to make the risk factor more evident to the patient. In addition, detailed family history looking for premature cardiovascular disease (CVD) or sudden cardiac death should always be obtained. If available, cholesterol levels help define familial hypercholesterolaemia.⁶⁴ It is also essential to assess the presence of comorbidities that affect the likelihood of CAD and overall survival. Because of their high prevalence in CCS patients, diabetes, chronic obstructive pulmonary disease, kidney disease, and peripheral and cerebral vascular disease are particularly relevant.

Recent-onset anginal symptoms with changing frequency or intensity should raise the suspicion that a coronary atherosclerotic plaque may be destabilizing. In these patients, the diagnostic algorithm recommended by the 2023 ESC Guidelines for the management of patients with acute coronary syndromes should be used to rule out an acute event.⁶⁵

When investigating suspected CCS, it is important to perform a thorough physical examination that includes BP measurement and body mass index (BMI) calculation, to assess the presence of anaemia, hypertension, valvular heart disease, LV hypertrophy, or arrhythmias. It is also recommended to search for evidence of non-coronary vascular disease, which may be asymptomatic (palpation of peripheral pulses; auscultation of carotid and femoral arteries), and signs of other comorbid conditions, such as thyroid disease, renal disease, or diabetes. This should be used in the context of other clinical information, such as the presence of cough or stinging pain, making CCS less likely. One should also try to reproduce the symptoms by palpation and test the effect of sublingual nitroglycerine to classify the symptoms.

3.1.2. Basic testing: 12-lead electrocardiogram and biochemistry

Basic testing in individuals with suspected CCS includes a 12-lead ECG, standard laboratory tests, resting echocardiography, and, in selected patients, a chest X-ray, and a pulmonary function test if dyspnoea is the main symptom. Such tests can be done on an outpatient basis.

3.1.2.1. Electrocardiogram

The paradigm of diagnosing myocardial ischaemia has, for almost a century, been based on detecting repolarization abnormalities, mainly in the form of ST-segment depressions or T wave abnormalities. Thus, the resting 12-lead ECG remains an indispensable component of the initial evaluation of a patient with chest pain.⁶⁷

A normal resting ECG is frequently recorded after an anginal attack. However, even in the absence of repolarization abnormalities, the ECG at rest may suggest CCS indirectly, through signs of previous MI (pathological Q or R waves) or conduction abnormalities [mainly left bundle branch block (LBBB) and impaired atrioventricular conduction]. Atrial fibrillation (AF) is not rarely associated with CCS.⁶⁸ ST-segment depression during supraventricular tachyarrhythmias, however, is not a strong predictor of obstructive CAD.^69–72

The ECG can be crucial for diagnosing transient myocardial ischaemia by recording dynamic ST-segment changes during ongoing angina. Vasospastic angina (VSA) should be suspected when observing typical transient ST-segment elevations or depressions with U-wave changes during an angina attack at rest.⁷³

Long-term ambulatory ECG monitoring can be considered in selected patients to detect ischaemia during anginal episodes unrelated to physical activities. ECG changes suggesting ischaemia on ambulatory ECG monitoring are frequent in women but do not correlate with findings during stress testing.⁷⁴ Ambulatory ECG monitoring may also reveal ‘silent’ ischaemia in patients with CCS, but therapeutic strategies targeting it have not demonstrated clear survival benefits.^75,76

Recommendation Table 1

Recommendations for history taking, risk factor assessment, and resting electrocardiogram in individuals with suspected chronic coronary syndrome (see also Evidence Table 1)

3.1.2.2. Biochemical tests

Laboratory blood tests identify potential causes of ischaemia (e.g. severe anaemia, hyperthyroidism), cardiovascular risk factors (e.g. lipids, fasting glucose), and yield prognostic information (e.g. renal disease, inflammation). When fasting plasma glucose and glycated haemoglobin (HbA1c) are both inconclusive, an additional oral glucose tolerance test is useful.^85,86

A lipid profile, including total cholesterol, high-density lipoprotein cholesterol (HDL-C), and triglycerides, allowing calculation of low-density lipoprotein cholesterol (LDL-C), is necessary in every person with suspected CCS to refine his/her risk profile and guide treatment.^16,64 Fasting values are needed to characterize severe dyslipidaemia or follow-up hypertriglyceridaemia,⁶⁴ but not in other situations.⁸⁷ Elevated lipoprotein(a) is a marker of cardiovascular risk, particularly early-onset atherosclerotic disease;⁸⁸ lipoprotein(a)-lowering strategies are currently being investigated in phase 3 cardiovascular outcomes trials.^89–91 Given that circulating lipoprotein(a) levels are genetically determined and do not fluctuate substantially over a lifetime,^89,91 a single measure is sufficient in persons with suspected CCS.⁹²

Renal dysfunction increases the likelihood of CAD and has a negative impact on prognosis.^93–95 Glomerular filtration rate (GFR) also impacts renally cleared drugs. It is reasonable to also measure uric acid levels, as hyperuricaemia is frequent, and may affect renal function.

If there is a clinical suspicion of CAD instability, biochemical markers of myocardial injury—such as troponin T or troponin I—should be measured, preferably using high-sensitivity assays, and management should follow the 2023 ESC Guidelines for the management of patients with acute coronary syndromes.⁶⁵ If high-sensitivity assays are employed, low troponin levels can be detected in many patients with stable angina. Increased troponin levels are associated with adverse outcomes,^96–100 and small studies have indicated a possible incremental value in diagnosing obstructive CAD,^101–104 but larger trials are needed to verify the utility of systematic assessment in individuals suspected of CCS. While multiple biomarkers may be useful for prognostication, they do not yet have a role in diagnosing obstructive CAD, but some promising results have been published.^105–108 Measuring NT-proBNP helps confirm or exclude suspected HF.

Markers of inflammation such as C-reactive protein^109–113 and fibrinogen^114–118 are predictors of an individual’s risk of CAD and can predict cardiovascular event risk in CCS patients,^99,111 but their value is limited beyond traditional risk factors.¹¹¹ However, in patients taking contemporary statins, high-sensitivity C-reactive protein (hs-CRP) was a stronger predictor for future cardiovascular events and death than LDL-C.^119,120 These patients may benefit from additional LDL-C reduction through adjunctive lipid-lowering therapies, such as ezetimibe, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition,¹²¹ inclisiran, and bempedoic acid.^122–124 Elevated hs-CRP levels in patients taking statins and PCSK9 inhibitors may indicate residual inflammatory risk that could be further reduced through inflammation modulation.^119,125,126 Experimental inhibition of interleukin-6, a pivotal factor in atherothrombosis, resulted in a marked parallel reduction of C-reactive protein and fibrinogen in patients with chronic kidney disease (CKD) and high cardiovascular risk.¹²⁷

Recommendation Table 2

Recommendations for basic biochemistry in the initial diagnostic management of individuals with suspected chronic coronary syndrome (see also Evidence Table 2)

3.2. STEP 2: Further evaluation

3.2.1. Pre-test clinical likelihood of obstructive atherosclerotic coronary artery disease

The diagnosis of CCS is based on interpreting the individual’s symptoms, balancing the impact of age, sex, risk factors, and comorbidities on the likelihood that CCS is present, and choosing the most appropriate diagnostic test to confirm the clinically suspected diagnosis. To aid diagnosis, prediction tables for obstructive CAD can be used that integrate these clinical factors and provide guidance on selecting diagnostic tests based on their capacities to rule in and rule out obstructive atherosclerotic CAD. Importantly, these models do not include the probability of ANOCA/INOCA, which always needs to be considered if symptoms persist after deferral of further testing or diagnostic testing that excludes obstructive CAD.

The tables used to estimate the likelihood of obstructive CAD as confirmed by ICA were initially based on the Diamond–Forrester approach, which considered sex, age, and angina symptoms.²⁵ However, these tables have had to be updated several times owing to the declining prevalence of obstructive CAD at invasive angiography in contemporary Western cohorts.^26,29 The overestimation of obstructive CAD prevalence has limited the utility of these tables in clinical routine and in accurately estimating the post-test likelihood of obstructive CAD by diagnostic imaging methods.^1,29,30

The 2019 ESC Guidelines for the diagnosis and management of CCS introduced the concept of clinical likelihood as a more comprehensive and individualized assessment of the probability of obstructive CAD.¹

Compared with a basic pre-test probability model, incorporation of risk factors in the basic pre-test likelihood model (based on age, sex, and symptoms) leads to improved prediction of obstructive CAD, down-classifies more individuals to very low and low likelihood of disease, and maintains high calibration.^30,139,140 The Risk-Factor-weighted Clinical Likelihood (RF-CL) model includes sex, age, angina symptoms, and number of risk factors without losing diagnostic accuracy compared with more advanced models requiring computed calculation (Figure 4).^139,141,142 The RF-CL model increases three-fold the number of subjects categorized as at very low (≤5%) likelihood of obstructive CAD compared with the ESC pretest probability (ESC-PTP) model (38% vs. 12%),¹³⁹ while predicting annualized event rates of MI and death of 0.5%, 1.1%, and 2.1% for individuals having very low, low, and moderate likelihood of obstructive CAD, respectively.¹⁴³

Figure 4

Estimation of the clinical likelihood of obstructive coronary artery disease.

CAD, coronary artery disease; RF-CL, risk factor-weighted clinical likelihood. Data derived from Winther et al.¹³⁹ The symptom score replaces the previous, potentially misleading terminology, that defined presence of three chest pain characteristics as ‘typical’ angina (here = 3 points), two of three characteristics as ‘atypical’ angina (here = 2 points), and no or one characteristic as ‘non-cardiac/non-anginal’ (here = 0–1 point). Family history of CAD is defined as 1 or more first-degree relatives with early signs of CAD (men <55 and women <65 years of age); smoking, as current or past smoker; dyslipidaemia, hypertension, and diabetes, as present at the time of diagnosis. Values in the lower panel are the clinical likelihood estimates expressed as %.

Individual adjustment of the likelihood may be necessary for individuals with severe single risk factors or comorbidities associated with an increased prevalence of obstructive CAD, which are not reflected in the RF-CL model, e.g. familial hypercholesterolaemia, severe kidney dysfunction, rheumatic/inflammatory diseases, and peripheral artery disease (PAD).

Exercise ECG testing may modify the likelihood of obstructive CAD and can be used in patients with low (>5%–15%) clinical likelihood, in whom a negative test allows reclassification to the very low (≤5%) clinical likelihood group with a favourable prognosis.¹⁴⁴ However, CCTA as a first-line diagnostic test can give more accurate information and has been associated with fewer angina symptoms during follow-up than a strategy with exercise ECG as the first investigation.^145–148 In addition, more adverse events were observed in randomized trials with an exercise ECG than with a CCTA-based diagnostic strategy.^34,146 However, exercise ECG remains clinically useful for reproducing anginal symptoms, which have a prognostic value.^149,150

In contrast to exercise ECG, visualization of calcified atherosclerotic plaque in the coronary artery significantly impacts the clinical likelihood of atherosclerotic obstructive CAD. Coronary artery calcification (CAC) can be measured using the coronary artery calcium score (CACS), which is derived from an ECG-gated non-contrast-enhanced computed tomography (CT) scan. Alternatively, the presence of CAC can be evaluated qualitatively by visually inspecting the coronary arteries on a previous non-cardiac chest CT scan, if available. The absence of CAC (CACS = 0) has a very high negative predictive value (>95%) for obstructive CAD.¹⁵¹ Of note, in younger patients, obstructive CAD is rare, but when present, a higher percentage (58% of those younger than 40 years) have a CACS of 0 compared with older patients with obstructive CAD (9% among those aged 60 to 69 years).¹⁵²

Small, randomized studies have shown that further testing can safely be deferred in patients without CAC, without increased event rates during follow-up.^146,153 Finally, in a larger prospective observational study, absence of CAC alone was sufficient to define a low-risk group with no need for further testing with improved accuracy compared with basic clinical prediction models.¹⁵⁴ The combination of CACS with the RF-CL model [CACS + RF-CL (the Coronary Artery Calcium Score-Weighted Clinical Likelihood—CACS-CL)] showed the strongest potential to effectively defer cardiac testing compared with other clinical prediction models or CACS alone (adjustment of the estimation of the clinical likelihood of obstructive CAD).^139,154 With the CACS-CL model, substantially more individuals (54%) compared with the RF-CL model (38%) were categorized as having a very low clinical likelihood of obstructive CAD in the external validation cohorts.¹³⁹ Finally, the CACS-CL model was superior to other clinical prediction models in predicting MI and death during follow-up.¹⁴³

Detection of atherosclerotic disease in non-coronary arteries with ultrasound or CT scans of, e.g. the aorta, and the carotid or femoral arteries, may increase the clinical likelihood of obstructive CAD,^155–158 and the risk for future CVD events.^159,160 However, how accurately the detection of non-coronary atherosclerotic disease impacts the likelihood estimation of obstructive CAD needs further investigation.

In general, individuals with a very low (≤5%) likelihood of obstructive CAD do not require further diagnostic testing unless symptoms persist and non-cardiac causes have been excluded. In patients with a low (>5%–15%) likelihood of obstructive CAD, the benefit of diagnostic testing is uncertain but may be performed if symptoms are limiting and require clarification. Patients with moderate (>15%–50%), high (>50%–85%), and very high (>85%) likelihood of obstructive CAD are encouraged to undergo further diagnostic testing.

By using pre-test likelihood estimates and diagnostic imaging-test positive and negative likelihood ratios, it is possible to calculate the post-test probability of obstructive CAD. Hence, pre-test likelihood estimation is useful to guide non-invasive diagnostic test strategies for detecting obstructive CAD (Section 3.3.4).

Recommendation Table 3

Recommendations for estimating, adjusting and reclassifying the likelihood of obstructive atherosclerotic coronary artery disease in the initial diagnostic management of individuals with suspected chronic coronary syndrome (see also Evidence Table 3)

3.2.2. Transthoracic echocardiography and cardiac magnetic resonance at rest

An echocardiographic study will provide important information about cardiac function and anatomy. Patients with CCS have often preserved left ventricular ejection fraction (LVEF).¹⁶⁷ A decreased LV function and/or regional wall motion abnormalities may increase the suspicion of ischaemic myocardial damage,¹⁶⁷ and a pattern of LV dysfunction following the anatomical perfusion territory of the coronary arteries is typical in patients who have already had an MI.^168,169 The detection of regional wall motion abnormalities can be challenging by visual assessment, and detection of early systolic lengthening, decreased systolic shortening, or post-systolic shortening by strain imaging techniques,^170–172 or new parameters such as global myocardial work,¹⁷³ may be helpful in individuals with apparently normal LV function but with clinical suspicion of CCS. Diastolic LV dysfunction has been reported to be an early sign of ischaemic myocardial dysfunction and may also be indicative of microvascular dysfunction.^174,175

Echocardiography can help in detecting alternative causes of chest pain (e.g. pericarditis) and in diagnosing valvular heart diseases, ischaemic HF, and most cardiomyopathies,¹⁷⁶ though these diseases may co-exist with obstructive CAD. The use of an echocardiographic contrast agent can be helpful in patients with poor acoustic windows.¹⁷⁷

Cardiac magnetic resonance (CMR) is an alternative in patients with suspected CAD when the echocardiogram (having used ultrasound contrast agent) is inconclusive.¹⁷⁸ Cardiac magnetic resonance can assess global and regional function,¹⁷⁹ and the use of late gadolinium enhancement (LGE) CMR can reveal a typical pattern of scarred myocardium in patients who have already experienced an MI.¹⁸⁰ Moreover, CMR provides information on myocardial ischaemia through the evaluation of stress-induced perfusion defects.¹⁸¹

The strongest predictor of long-term survival is systolic LV function. Hence, risk stratification through the assessment of systolic LV function is useful in all symptomatic individuals with suspected CCS. Mortality increases as LVEF declines.¹⁸² Management of patients with either angina or HF symptoms, with reduced LVEF ≤40% or mildly reduced LVEF 41%–49%, is described in Section 4.

Recommendation Table 4

Recommendations for resting transthoracic ultrasound and cardiac magnetic resonance imaging in the initial diagnostic management of individuals with suspected chronic coronary syndrome (see also Evidence Table 4)

3.2.3. Exercise electrocardiogram testing

Exercise ECG testing is low cost, does not use ionizing radiation, is widely accessible, and remains an alternative for diagnostic testing depending on local resources and individual characteristics.

The classical exercise ECG, involving graded exercise until the occurrence of fatigue, limiting chest pain or discomfort, significant ischaemic ECG changes, arrhythmias, excessive hypertension, a BP drop or after reaching 85% of the maximal predicted heart rate, has been the mainstay of the examination techniques used in clinical cardiology for assessing individuals with suspected CCS. Exercise ECG testing has a lower diagnostic performance of obstructive CAD compared with modern functional imaging and CCTA,¹⁴⁸ which, therefore, should be preferred as a first-line test in subjects with suspected CCS. Several clinical trials have confirmed that a strategy based on anatomical^{34,146,187,188} or functional imaging¹⁸⁹ simplifies the diagnosis, enables the targeting of preventive therapies and interventions, and potentially reduces the risk of MI compared with usual care based on exercise ECG. In addition, two randomized trials showed that patients reported fewer anginal complaints during follow-up when randomized to CCTA as an index investigation for stable chest pain compared with exercise ECG.^145,146

Although the Scottish Computed Tomography of the Heart (SCOT-HEART) trial favoured CCTA as first-line test in CCS, a post hoc analysis suggested that abnormal results of exercise ECG remain a specific indicator of obstructive CAD, and are associated with future coronary revascularization and risk of MI.¹⁸⁸ Exercise ECG testing with clearly abnormal results was most predictive for these outcomes; however, in a large proportion of individuals who underwent exercise ECG, particularly those with normal or inconclusive results, there was still a significant amount of unrecognized non-obstructive and obstructive CAD, which can be detected by additional CCTA imaging.¹⁸⁸ In the WOMEN trial (What is the Optimal Method for Ischemia Evaluation of Women), including low-risk symptomatic women, exercise ECG was equally effective compared with exercise myocardial perfusion scintigraphy, with a similar 2-year incidence of major adverse cardiovascular events (MACE), defined as CAD death, or hospitalization for an ACS or HF, while providing significant diagnostic cost savings.¹⁹⁰ Individuals exercising >10 metabolic equivalents with a negative exercise ECG and a low-risk Duke Treadmill Score have a good prognosis with limited need for downstream testing and revascularization.^166,191 Patients with marked ischaemia at a low workload and a high-risk Duke Treadmill Score may benefit from further anatomical or functional testing. In regions with limited access to functional imaging or CCTA, or in individuals with a low (>5%–15%) pre-test likelihood of obstructive CAD,¹⁴⁴ exercise ECG remains, therefore, useful for risk stratification and prognostication.¹⁴⁴ Particularly, in subjects with a low (>5%–15%) likelihood of obstructive CAD, a negative exercise ECG may help to down-classify patients into the very low likelihood (<5%) class, in whom further testing can be deferred.¹⁴⁴

An exercise ECG is of no diagnostic value in patients with ECG abnormalities at rest that prevent interpretation of the ST-segment changes during stress (i.e. LBBB, paced rhythm, Wolff−Parkinson−White syndrome, ≥0.1 mV ST-segment depression on resting ECG, or treatment with digitalis). In patients with known CAD, exercise ECG may be considered in selected patients to complement their clinical evaluation for assessing symptoms, ST-segment changes, exercise tolerance, arrhythmias, BP response, and event risk.

In summary, due to its low sensitivity (58%) and specificity (62%), exercise ECG testing has low diagnostic performance for the diagnosis of obstructive CAD¹⁴⁸ and should mainly be used for risk stratification.

Recommendation Table 5

Recommendations for exercise ECG in the initial diagnostic management of individuals with suspected chronic coronary syndrome (see also Evidence Table 5)

3.2.4. Chest X-ray

Chest X-ray is commonly utilized in the evaluation of patients experiencing chest pain. However, in the context of CCS, it does not yield specific information for accurate diagnosis or risk stratification. The test may provide assistance in assessing patients with suspected HF. Additionally, chest X-ray may prove beneficial in diagnosing pulmonary conditions that often co-exist with CAD, or in ruling out other potential causes of chest pain.

3.2.5. Ambulatory electrocardiogram monitoring

Ambulatory ECG monitoring can assist in evaluating patients with chest pain and palpitations. It can also help in detecting and evaluating silent myocardial ischaemia, as well as suspected VSA.^192–194

Recommendation Table 6

Recommendations for chest X-ray in the initial diagnostic management of individuals with suspected chronic coronary syndrome (see also Evidence Table 6)

Recommendation Table 7

Recommendations for ambulatory ECG monitoring in the initial diagnostic management of individuals with suspected chronic coronary syndrome (see also Evidence Table 7)

3.3. STEP 3: Confirming the diagnosis

3.3.1. Anatomical imaging: coronary computed tomography angiography

Through the intravenous (i.v.) injection of contrast agent, CCTA allows direct anatomical visualization of the coronary artery lumen and wall. CCTA offers a practical, non-invasive test, with proven diagnostic performance in detecting obstructive coronary artery stenoses when compared with ICA.^32,148

Obstructive coronary stenoses have typically been defined using visual thresholds of either 50% or 70% diameter reduction. It is accepted that not all anatomical stenoses above such thresholds, especially those of moderate (50%–69%) stenosis severity, are haemodynamically or functionally significant¹⁹⁵ or induce myocardial ischaemia.¹⁹⁶ Depending on the clinical context, it may be necessary to complement CCTA with functional data either from non-invasive imaging techniques or from invasive angiography with fractional flow reserve (FFR) (see Section 3.3.3.2), when the haemodynamic consequence of a stenosis is deemed questionable for management options.

While several earlier trials (publication date during or before 2016) reported a higher rate of downstream ICA in patients receiving CCTA compared with functional imaging,¹⁹⁷ this was no longer observed in more recent trials (publication date after 2016). Moreover, increased downstream use of invasive procedures was linked to non-adherence to guideline recommendations as these procedures were used significantly less when the guidelines were adopted.¹⁹⁸

Coronary computed tomography angiography-derived fractional flow reserve (FFR-CT) can complement CCTA by providing values of model-based computational FFR along the coronary tree. FFR-CT has shown good agreement with invasive FFR,¹⁹⁹ and has clinical utility by reducing the number of unnecessary ICA procedures.²⁰⁰ However, in patients with severe disease at CCTA, FFR-CT has less impact on patient management.²⁰¹ FFR-CT does not require pharmacological stress, additional contrast agent injection, or radiation exposure. FFR-CT, however, is not ubiquitous and depends on image quality. Nevertheless, the rejection rate is reported to be quite low in real-world data with newest-generation scanners.^202–204

3.3.1.1. Computed tomography perfusion imaging

Computed tomography perfusion imaging, performed under pharmacological stress, has been validated against several reference standards, including single-photon computed tomography (SPECT) and invasive FFR. It has shown adequate diagnostic performance in selected cohorts,^205,206 and a potential to reduce the number of unnecessary downstream invasive angiography procedures, when compared with functional tests (mostly symptom-limited exercise ECG).¹⁵³ While CT perfusion imaging could complement CCTA during the same visit, this technique requires the administration of a pharmacological stressor, contrast agent, and further patient irradiation. Imaging techniques and analysis methods are not yet widely standardized (e.g. static and dynamic imaging techniques, visual and quantitative assessment).^207–209

3.3.1.2. Prognosis, plaque features, and opportunity to improve outcomes

The SCOT-HEART trial demonstrated a small but significant decrease of the combined endpoint of cardiovascular death or non-fatal MI (from 3.9% to 2.3% during 5-year follow-up) in patients in whom CCTA was performed in addition to routine testing (exercise ECG).³⁴ In a post hoc analysis of this trial, CCTA features (low-attenuation plaque, positive remodelling, spotty calcifications, and napkin-ring sign) conferred an increased risk of death or non-fatal MI, although these plaque features were not independent of CACS.²¹⁰ Systematically evaluating adverse plaque features by CCTA can be challenging due to technical limitations (spatial resolution) and patient characteristics (calcifications).

A network meta-analysis of randomized trials suggested that diagnostic testing with CCTA was associated with clinical outcomes similar to those with functional imaging in patients with suspected stable CAD.¹⁹⁷ In another pairwise meta-analysis, CCTA showed a lower rate of MI compared with functional testing, but the absolute per cent risk difference was small (0.4%).²¹¹

In the available randomized trials comparing CCTA and functional testing (all testing a diagnostic strategy),^33,210,212 test reporting and patient management variability could in part help explain the improved outcomes observed in the CCTA arm of SCOT-HEART. In this trial, CCTA findings, including non-obstructive atherosclerosis, emphasized the need to trigger the start or intensification of medical treatment. Increased standardization in reporting CCTA to encompass key plaque features (accepting inherent limitations) will be warranted to systematically harvest prognostic information and help fine-tune risk management strategies.²¹³

3.3.1.3. Recognized pre-requisites for coronary computed tomography angiography

Generally, a slow and regular heart rate, and compliance with breath-holding instructions are necessary to achieve good image quality. This includes suitability to receive pre-medication (typically oral or i.v. beta-blockers) when needed. Kidney function and allergy to contrast agents should be assessed prior to referral. Temporal and spatial resolution remain technical limitations and can hinder precision in adjudicating coronary stenosis severity. This is most problematic in older patients with heavily calcified coronary arteries, in whom functional testing may be more appropriate than CCTA. Contemporary CT technology (64-slice technology or above) and a well-trained imaging team can help mitigate these limitations and must be considered a pre-requisite for CCTA.

Recommendation Table 8

Recommendations for non-invasive anatomical imaging tests in the initial diagnostic management of individuals with suspected chronic coronary syndrome—coronary computed tomography angiography, if available, and supported by local expertise (see also Evidence Table 8)

3.3.2. Functional imaging

3.3.2.1. Stress echocardiography

Stress echocardiography is used to detect myocardial ischaemia by assessing regional systolic wall-thickening abnormalities (RWTA) during stress. It relies on inducing myocardial ischaemia by increasing myocardial oxygen demand beyond the myocardial blood supply. Because ischaemia starts in the subendocardium, which contributes to more than 50% of systolic myocardial wall thickening, stress testing will precipitate wall-thickening abnormalities in the perfusion territory of narrowed coronary arteries. Stress modalities used to increase myocardial oxygen demand are exercise (treadmill or bicycle), or i.v. administration of dobutamine, or vasodilators (adenosine, dipyridamole, regadenoson) combined with atropine (to increase heart rate adequately—a major determinant of oxygen demand). Stress echocardiography using demand stress has provided diagnostic accuracy and risk-stratification capabilities similar to those obtained with other contemporary functional imaging testing modalities.^148,223 The advantages of stress echocardiography are that it is widely available, low-cost, can be performed and interpreted at the bedside, rapid, free of ionizing radiation, and can be repeated without safety concerns.^224–227 Although stress echocardiography is operator-dependent, which may compromise reproducibility, the technique is within reach of every cardiology department or office. Compromised image quality, especially in obese and chronic obstructive pulmonary disease subjects, is a significant limitation. RWTA may not occur if the myocardial oxygen demand increase is inadequate or if the induced perfusion abnormalities are not large enough (<10% of the myocardium), such as in mild atherosclerotic CAD or single-vessel obstructive CAD.²²⁸ As stress echocardiography relies on RWTA as a marker of ischaemia, it may under-estimate ischaemia in patients with microvascular disease not affecting the subendocardium as in ANOCA/INOCA.³⁶

Ultrasound contrast agents considerably enhance the quality of diagnostic images obtained during stress echocardiography. These microbubbles, consisting of stable gas and shells about the size and rheology of red blood cells, can pass through the pulmonary microcirculation and induce a dense opacification of the left heart chambers. The enhanced image quality and endocardial border definition by using ultrasound contrast agents markedly improve the accuracy of stress echocardiography.^229,230 Ultrasound contrast agents may be required in individuals with obesity and chronic obstructive pulmonary disease and must be used in all cases if it is evident at baseline that all segments may not be visible during stress. Passage of ultrasound contrast agents through the myocardium allows assessment of myocardial perfusion simultaneously with regional wall motion, improving the sensitivity of stress echocardiography (better detection of single-vessel and microvascular disease) and risk stratification beyond RWTA.^231–235 The use of ultrasound contrast agents during stress echocardiography for assessing regional and global LV function is strongly recommended by the European Association of Cardiovascular Imaging (EACVI) and the American Society of Echocardiography (ASE) guidelines—both class I indications. Similarly, myocardial perfusion assessment has received a class I recommendation by the EACVI and a class IIa recommendation by the ASE.^177,236 Ultrasound contrast agents are generally safe, but rare cases of anaphylactic reactions have been reported.²³⁷

Measurement of the coronary flow velocity reserve (CFVR) based on Doppler flow velocity recordings at rest and during stress in the left anterior descending (LAD) artery, and assessment of lung congestion through the visualization of B-lines on lung ultrasound, can easily be added to routine stress echocardiography procedures. In a prospective observational multicentre study, a reduced CFVR was often accompanied by RWTA, abnormal LV contractile reserve, and pulmonary congestion during stress, and showed independent value over RWTA in predicting an adverse outcome.²³⁸ The inclusion of these additional parameters in routine stress echocardiography procedures provides insights on coronary microcirculatory dysfunction.

Finally, carotid ultrasound may be performed in the same session with stress echocardiography to assess extracoronary atherosclerosis; while this does not add value for confirming a CCS diagnosis per se, it provides incremental prognostic value beyond myocardial ischaemia.^239,240

Recommendation Table 9

Recommendations for non-invasive tests in the initial diagnostic management of individuals with suspected chronic coronary syndrome—stress echocardiography, if available, and supported by local expertise (see also Evidence Table 9)

3.3.2.2. Myocardial perfusion scintigraphy—single-photon emission computed tomography

Myocardial perfusion SPECT imaging relies on the myocardial uptake and retention of a radiopharmaceutical. Technetium-99m (99mTc)-based tracers are the most commonly used radiopharmaceuticals, whereas Thallium 201 (201Tl) should be avoided as it is associated with higher radiation exposure. Myocardial perfusion SPECT produces images of regional myocardial tracer retention, which reflects relative regional myocardial blood flow (MBF). Myocardial hypoperfusion is characterized by relative reduced radionuclide tracer uptake and retention during vasodilatation or stress, compared with the uptake and retention at rest. The inherent need for a normally perfused myocardial reference territory allowing for visualization of the myocardium with relative hypoperfusion constitutes the main limitation of SPECT (and stress CMR), particularly in multivessel CAD. Coronary calcium scoring from non-contrast-enhanced CT, acquired for attenuation correction, as well as transient ischaemic dilatation (TID) and reduced post-stress ejection fraction (EF) are important non-perfusion predictors of severe obstructive CAD.

Ischaemia can be demonstrated by physical exercise or through the administration of pharmacological stressors (e.g. dobutamine) or vasodilators (e.g. dipyridamole, adenosine, or regadenoson). Pharmacological agents are indicated in patients who cannot exercise adequately or may be used as an alternative or an adjunct to exercise stress. The possibility to use physical exercise and/or different pharmacological stressors in combination with the wide-spread availability of the technique and the lack of absolute contraindications contributes to the high versatility and applicability of myocardial perfusion SPECT in clinical routine.

SPECT myocardial perfusion imaging is associated with good accuracy for the detection of flow-limiting coronary lesions,^{148,256–258} and has been shown to provide prognostic information^223,259 and to improve patient management in a randomized controlled trial (RCT).¹⁷⁸

Newer-generation SPECT cameras based on cadmium–zinc–telluride (CZT) semiconductor detector technology enable a substantial reduction in radiation dose exposure and acquisition time, as well as an increased diagnostic accuracy²⁶⁰ and absolute quantification of MBF. Hence, its diagnostic performance for multivessel CAD has improved substantially.²⁶¹ However, non-obstructive coronary atherosclerosis not linked with ischaemia remains undetected by functional testing in general.

If available, assessment of myocardial perfusion using SPECT is recommended in patients with suspected CCS with moderate or high pre-test likelihood of obstructive CAD (15%–85%) or known CCS. Importantly, if non-contrast-enhanced CT for attenuation correction is acquired, this allows for additional CAC scoring, providing important information for risk stratification even in the absence of flow-limiting coronary lesions.

3.3.2.3. Positron emission tomography-computed tomography

Similarly to myocardial perfusion SPECT imaging, PET also relies on radiopharmaceuticals. Contrary to SPECT, however, the radionuclides commonly used (i.e. ¹³N-ammonia, ¹⁵O-water, and ⁸²Rubidium) are short-lived, with half-lives in the range of minutes, requiring production of these radionuclides ad hoc for every investigation. As attenuation correction is mandatory, PET is routinely performed in combination with non-contrast-enhanced CT. Scans are performed during both rest and infusion of pharmacological stressors (e.g. dobutamine) or vasodilators (e.g. dipyridamole, adenosine, or regadenoson).

While myocardial perfusion PET-CT produces retention images depicting relative differences in regional MBF similar to those from SPECT—albeit with superior image quality and at much lower radiation dose exposure—the unique strength of PET-CT imaging is its ability to provide robust absolute quantitative measures of MBF. Measuring MBF with cardiac PET does not increase radiation or imaging time. Several measurements of MBF can be routinely obtained, including MBF during hyperaemia, MBF at rest, the MBF reserve, and the relative MBF reserve, and confer added diagnostic and prognostic value beyond relative perfusion assessment.^262,263

Quantitative measures of MBF offer the ability to assess individuals with known or suspected diffusely impaired MBF, e.g. with multivessel CAD, or microvascular dysfunction.^45,264 In general, PET-CT myocardial perfusion imaging is associated with high accuracy for detecting flow-limiting coronary lesions,^148,258,265 and has been shown to provide prognostic information.^223,262,263 In several head-to-head comparisons, PET-CT myocardial perfusion imaging outperformed other functional imaging modalities.^{257,266–269} However, whether the superiority in diagnostic accuracy leads to improved clinical effectiveness and post-test management remains to be elucidated.²⁷⁰ In a large retrospective study, a low MBF reserve measured by PET independently predicted mortality and helped identify patients with a survival benefit from early revascularization with PCI or coronary artery bypass grafting (CABG) beyond the extent of myocardial ischaemia.²⁷¹

Limitations of PET-CT arise from its limited availability compared with other imaging modalities. Furthermore, methodological heterogeneity exists, particularly regarding thresholds for abnormality of quantitative measurements. Finally, physical exercise is challenging to perform.

If available, assessment of myocardial perfusion using PET-CT is particularly recommended in obese patients (due to the high photon energy), in young patients (due to the low radiation dose exposure), and in those with known or suspected diffusely impaired MBF, e.g. those with multivessel CAD or microvascular dysfunction.²⁶⁴ Notably, the mandatory non-contrast-enhanced CT for attenuation correction allows for additional CAC scoring, providing essential information for risk stratification even in the absence of flow-limiting coronary lesions.

3.3.2.4. Cardiac magnetic resonance imaging

Aside from providing highly accurate and reproducible assessments of overall cardiac anatomy, cardiac volumes, function, and tissue characterization, CMR also offers the ability to assess myocardial perfusion, which relies on the first-pass myocardial perfusion of gadolinium-based contrast agents.

Recently, CMR methods using various parameters for quantitative MBF assessment have been introduced. However, the diagnostic performance of these parameters varies extensively among studies, and standardized protocols and software are lacking.²⁷² Therefore, visual assessment of perfusion defects is currently used in clinical practice. Myocardial perfusion imaging by stress CMR combines high spatial resolution with the absence of ionizing radiation. This has been shown to provide high diagnostic accuracy in detecting flow-limiting coronary lesions,^148,257,258 prognostic value,^{223,273–275} and improving patient management.^178,276 Pharmacological vasodilators (e.g. adenosine or regadenoson) or stressors (e.g. dobutamine) are commonly applied, as physical exercise is challenging to perform. In conjunction with a dobutamine infusion, wall motion abnormalities induced by ischaemia can also be detected.²⁷⁷ Of note, and as for all non-invasive imaging modalities used for assessing myocardial perfusion, incorporating all available imaging and non-imaging information as part of an integrative approach is mandatory. For CMR, a multiparametric protocol, including LV function and assessment of LGE along with myocardial perfusion, increases the ability to rule in or rule out obstructive CAD in suspected CCS.²⁷⁸

Coronary magnetic resonance angiography allows non-invasive visualization of the coronary arteries.²⁷⁹ However, CMR angiography remains primarily a research tool due to limitations arising from long imaging times, low spatial resolution, and operator dependency. General limitations of CMR for myocardial perfusion arise from its limited availability, the claustrophobia experienced by patients, duration of image acquisition,²⁸⁰ and possible contraindications to CMR [e.g. non-conditional pacemakers and implantable cardioverter defibrillators (ICDs)] or to gadolinium-based contrast agents (e.g. renal failure due to the potential risk of nephrogenic systemic fibrosis). Finally, and contrary to SPECT/CT or PET-CT, stress CMR does not currently provide information on presence or absence of coronary calcifications.

If available, and if no contraindications are met, stress CMR is recommended as an option in patients with suspected CCS with moderate or high (>15%–85%) pre-test likelihood of obstructive CAD or known CCS, particularly if additional information on cardiac function and tissue characterization is warranted.

Recommendation Table 10

Recommendations for non-invasive functional myocardial imaging tests in the initial diagnostic management of individuals with suspected chronic coronary syndrome—resting and stress single-photon emission computed tomography/positron emission tomography—cardiac magnetic resonance imaging, if available, and supported by local expertise (see also Evidence Table 10)

3.3.2.5. Non-invasive testing for microvascular dysfunction

Angina/ischaemia with non-obstructive coronary arteries (ANOCA/INOCA) may be caused by transient and/or sustained impairments in the supply–demand of myocardial perfusion. Functional disorders leading to ANOCA/INOCA (e.g. MVA and VSA) are more common in women than in men.^298,299 A recent meta-analysis reported an overall prevalence of MVA of 41% and VSA of 40% in selected patients without obstructive CAD.²⁹⁹ However, the true prevalence in unselected patient populations with suspected CCS remains unclear. Patients with ANOCA/INOCA have increased morbility/mortality,^300,301 impaired quality of life (QoL), and weigh on health resource utilization. Early, accurate, and preferably non-invasive diagnosis is, therefore, of importance.

The possibility of a microcirculatory origin of angina should be considered in individuals with symptoms suggestive of myocardial ischaemia and coronary arteries that are either normal or with non-obstructive lesions on CCTA or ICA. Several measurements that rely on quantifying blood flow through the coronary circulation are used to describe the function of the microvasculature to identify cases of MVA. Among the non-invasive imaging modalities, transthoracic Doppler echocardiography has been used as a non-invasive means to measure coronary blood flow but is limited to the assessment of the LAD artery and is affected by high inter- and intra-operator variability.^302,303 Furthermore, this modality cannot distinguish between impairment of coronary flow caused by epicardial CAD or coronary microcirculatory dysfunction.

A more direct and accurate microvascular function assessment is based on MBF measurement. This is commonly achieved by PET-CT myocardial perfusion imaging.²⁹⁹ PET allows for the quantification of MBF (expressed as millilitres per minute per gram of myocardium) and myocardial flow reserve (MFR). The latter reflects the magnitude of the increase in MBF that can be achieved by maximal coronary vasodilation conferred by vasodilators, such as adenosine or regadenoson. Since the microvasculature primarily determines vascular resistance, MFR measures the ability of the microvasculature to respond to a stimulus and therefore represents small vessel function. An MFR of less than 2.0 (2.5 for non-obstructive CAD) is often considered abnormal for PET.³⁰⁴ Of note, however, no definitive references are available across imaging modalities due to the moderate correlation among different MBF estimates.²⁶⁴

Recently, quantitative CMR has been proposed as an emerging technique for the assessment of microvascular dysfunction through MBF quantification but is currently limited to experienced centres.²⁷⁵ Quantitative myocardial perfusion can also be achieved by myocardial contrast echocardiography (MCE) through destruction–reperfusion imaging and analysis of the time–intensity curves from different regions of interest in the myocardium.^{231,233–235} Of note, MCE assesses capillary blood flow, and capillaries comprise 90% of the microvasculature. Measuring MBF at rest and during hyperaemia allows calculation of MBF reserve, which is associated with severity of coronary stenoses in patients with stable angina. In a meta-analysis, MBF reserve had high accuracy for predicting flow-limiting CAD.²³¹ However, in the absence of obstructive CAD, reduced MBF reserve by MCE depicts microcirculatory abnormalities. Transthoracic Doppler evaluation of the LAD artery is also used to assess coronary flow reserve (CFR) during stress hyperaemia and has prognostic value.^{238,255,305,306}

In contrast, the diagnosis of VSA ideally relies on the results of provocation tests in the catheterization laboratory through selective intracoronary acetylcholine (Ach) infusion (see Section 5.2.5.2).

It is important to note that there is only a modest correlation between the values of MBF reserve measured by different techniques and modalities.^269,305,307

3.3.3. Invasive tests

Invasive coronary angiography has undergone significant advancements over time. It is no longer just an angiographic technique that provides anatomical information about the presence of coronary atherosclerosis and luminal obstructions of the epicardial coronary arteries. It can also determine the functional consequences of these obstructions on coronary blood flow [FFR and instantaneous wave-free ratio (iFR)] by direct measurement of the coronary BP^49,308–311 or by calculating the coronary pressure drop across a stenosis based on two or more angiographic projections.³¹² Furthermore, new technologies allow measurement of CFR and microvascular resistance, and protocols have been introduced for testing the presence of coronary vasospasm.^36,39

3.3.3.1. Invasive coronary angiography

Invasive coronary angiography with available coronary pressure assessment^{49,308–311,313} is indicated in patients with a very high (>85%) clinical likelihood of obstructive CAD,¹ in particular those with severe symptoms refractory to antianginal treatment, or characteristic angina or dyspnoea at a low level of exercise^1,47 or left ventricle dysfunction suggesting extensive obstructive CAD.^{47,182,314,315}

Invasive coronary angiography/coronary pressure assessment is also indicated if non-invasive assessment suggests high event risk—e.g. CCTA shows ≥50% left main stenosis, or ≥70% proximal LAD stenosis with single or two-vessel CAD, or ≥70% proximal three-vessel CAD^{56,182,316,317}—or when any stress test shows moderate to severe inducible ischaemia³¹⁶ or when symptoms are highly suggestive for obstructive CAD. In all the above situations, ICA/coronary pressure assessment is performed for additional risk stratification^318–320 and to determine a potential revascularization approach (see Section 4.4).^{49,308,309,313}

Invasive coronary angiography/coronary pressure assessment may also be indicated to confirm or exclude the diagnosis of obstructive CAD in patients with uncertain results on non-invasive testing.³¹⁶

Given the frequent mismatch between the angiographic and haemodynamic severities of coronary stenoses, coronary pressure assessment should be readily available to complement ICA investigation for clinical decision-making.^321–326

In patients with suspected ANOCA/INOCA and an ICA/coronary pressure assessment disclosing no significant epicardial CAD, additional invasive investigations including index of microcirculatory resistance (IMR), CFR and, if necessary, invasive vasoreactivity testing using Ach (or ergonovine)³⁶ as part of a complete ‘invasive coronary functional testing’ (ICFT) can be performed.

Performing ICA is not exempt from potential complications. Given that femoral diagnostic catheterization has been associated with a 0.5%–2.0% composite rate of major complications, mainly bleeding requiring blood transfusions,³²⁷ radial access is now the standard access when possible. Radial access has been associated with reduced mortality and reduced major bleeding while allowing rapid ambulation.³²⁷ Still, the composite ICA rate of death, MI, or stroke through radial access is of the order of 0.1%–0.2%.³²⁷ The decision to perform ICA should balance benefits and risks, as well as potential therapeutic consequences, of the investigation that should be part of the process of shared clinical decision-making. Patients should be adequately informed of these aspects ahead of the procedure.

Recommendation Table 11

Recommendations for invasive coronary angiography in the diagnostic management of individuals with suspected chronic coronary syndrome (see also Evidence Table 11)

3.3.3.2. Functional assessment of epicardial stenosis severity to guide coronary revascularization

When non-invasive stress tests are inconclusive or not performed, identifying the artery responsible for ischaemia during ICA can be challenging, especially in cases with multivessel CAD or coronary stenoses of intermediate severity (typically around 40%–90% for non-left main stem stenoses or 40%–70% for left main stem stenoses by visual estimate). In such cases, recording wire-based intracoronary pressure during maximal hyperaemia to calculate FFR or at rest to measure iFR is recommended to improve risk assessment and clinical decision-making and to reduce clinical events.^318–320 This has been confirmed by large clinical outcome studies such as FAME 1,³⁰⁸ FAME 2,⁴⁹ DEFINE-FLAIR (Functional Lesion Assessment of Intermediate Stenosis to Guide Revascularisation),³¹⁰ iFR-SWEDEHEART (Instantaneous Wave-free Ratio versus Fractional Flow Reserve in Patients with Stable Angina Pectoris or Acute Coronary Syndrome),³¹¹ R3F (French FFR Registry),³¹³ and RIPCORD (Routine Pressure Wire Assessment Influence Management Strategy at Coronary Angiography for Diagnosis of Chest Pain trial).³⁰⁹ Haemodynamic relevance, as defined by FFR of ≤0.80, or iFR of ≤0.89, correlates poorly with diameter stenosis by visual assessment. In the PRIME-FFR [Insights From the POST-IT (Portuguese Study on the Evaluation of FFR-Guided Treatment of Coronary Disease) and R3F Integrated Multicenter Registries—Implementation of FFR (Fractional Flow Reserve) in Routine Practice]³²² and FAME (Fractional Flow Reserve versus Angiography for Multivessel Evaluation) study,¹⁹⁵ 31% of the 40%–49% stenoses were haemodynamically significant while only 35% of the 50%–70% stenoses were haemodynamically relevant, and of the 71%–90% stenoses, 20% were not. Only an estimated diameter stenosis of >90% predicted haemodynamic relevance with high accuracy (96% correct classification). The discordance between angiographical and functional assessment of coronary stenosis severity varies with age, presence of CMD and lesion-specific factors.^338,339 Lesions in the left main or proximal LAD are more likely to result in a significant FFR, as they supply a larger myocardial mass than those in smaller arteries. As a result, the optimal angiographic cut-off value for functionally non-significant stenosis is 43% for the left main and 55% for small vessels.³³⁹ This implies that the threshold for functional assessment for larger arteries should be set at 40% diameter stenosis.

Large management studies showed that integration of FFR to ICA is associated with treatment reclassification in 30%–50% of cases in the R3F, POST-IT, RIPCORD, and DEFINE-REAL studies.^{309,313,340,341} Subsequently, many other non-hyperaemic pressure parameters were introduced [distal coronary pressure to aortic pressure ratio (Pd/Pa), diastolic pressure ratio (dPR), relative flow reserve (RFR)], with good correlation with FFR or iFR, but without available clinical outcome data. It is interesting to note that both separate and pooled analyses of the patients included in those studies reveal that ‘FFR/iFR-based reclassification’ does not have any significant effect on the number of patients recommended for revascularization.³⁴²

Meta-analyses of the 5-year outcome of patients managed with iFR and FFR as part of the randomized DEFINE-FLAIR and DEFINE-SWEDEHEART studies have reported a 2% absolute increase in all-cause mortality in those managed with iFR.^343,344 This was not associated with any unplanned revascularization or non-fatal MI rate increase.^343,344 Although it was initially hypothesized that this mortality excess could be related to a higher proportion of ‘inappropriate’ revascularization deferral with iFR compared with FFR (50% vs. 45%),³⁴³ it is reassuring that iFR-based deferral is as safe as FFR-based deferral up to 5 years.³⁴⁵

In patients with multivessel CAD, systematic FFR measurement of all epicardial vessels has been proposed to select appropriate therapy, but recent studies (RIPCORD2 and FUTURE) did not demonstrate any clinical outcome improvement compared with angiography alone.^346,347 Therefore, intracoronary pressure measurement in patients with multivessel CAD should only be performed on intermediate lesions.

Several recent studies using either FFR or iFR suggest that the pattern of pressure drop along the coronary artery (focal vs. progressive) recorded during a pullback is important to select patients who will benefit more from PCI.^2,348–352 Longitudinal functional vessel interrogation can therefore be helpful in patients with serial lesions or diffuse CAD.

New 3D angiographically derived wireless coronary pressure parameters, such as quantitative flow ratio (QFR) or vessel fractional flow reserve (vFFR), are at different stages of clinical investigation^325,353,354 (NCT03729739) and have important features that may help to increase the use of coronary pressure measurement during ICA significantly. These technologies have indeed the unique advantage of providing both distal coronary pressure measures and a coronary pressure map along the coronary vessel without requiring the use of any pressure wire. The lack of benefits shown in some recent FFR trials demonstrates that it is not sufficient to validate such new coronary pressure indexes against FFR alone to demonstrate their clinical value, and it is important to also show benefit in a direct comparative trial vs. angiography. In that context, the results of the FAVOR III China study³⁵⁵ are important, demonstrating an improved clinical outcome in the QFR-guided group compared with the angiography-guided group, driven by fewer MIs and ischaemia-driven revascularizations.

The combined measurements of pressure and flow (measured by Doppler or thermodilution) may further reduce the number of interventions. Patients with lesions and concordant normal FFR and CFR have an excellent prognosis. Patients with lesions and discordant results between FFR and CFR have a similar prognosis to that of patients with lesions and concordant abnormal FFR and CFR, treated with PCI. Lesions with an abnormal FFR but normal CFR pertain to a good clinical outcome up to 5 years of follow-up if left untreated.^356–358 Moreover, hyperaemic stenosis resistance (HSR), by measuring the pressure gradient across a lesion divided by flow, is an excellent index for both diagnostic and prognostic purposes.^359,360 The recently introduced continuous thermodilution technique for measuring absolute coronary flow presents an alternative method for determining CFR. Additionally, this method allows for evaluation of the microvascular resistance reserve (MRR), a novel index for assessing coronary microvascular function.^361–364

Coronary flow capacity (CFC) integrates hyperaemic flow and CFR and is useful for both diagnostic purposes as well as the evaluation of the result after PCI.^365–368

Intravascular imaging techniques [e.g. intravascular ultrasound (IVUS) or optical coherence tomography (OCT)] have demonstrated good diagnostic accuracy in predicting FFR, especially in stenoses located in the left main stem.^369,370 They are reasonable options to assess left main stenosis severity and prognosis; increasing left main plaque burden was associated with long-term all-cause and cardiac mortality in patients not undergoing revascularization.³⁷¹

While coronary pressure thresholds, specifically 0.80 for FFR and 0.89 for iFR, are crucial in aiding clinical decision-making, particularly in the case of deferring revascularization when FFR/iFR exceeds the ischaemic threshold,^310,372 they must be considered alongside other parameters. These include a careful assessment of the patient’s symptoms and the results of non-invasive stress testing to determine the need for revascularization.

Recommendation Table 12

Recommendations for functional assessment of epicardial artery stenosis severity during invasive coronary angiography to guide revascularization (see also Evidence Table 12)

3.3.3.3. Assessment of microvascular dysfunction

Detailed discussion of microvascular dysfunction by invasive coronary functional testing is provided in Section 5.2.5.2. After nitroglycerine, adenosine is administered to assess endothelium-independent vasodilation [CFR, IMR, and hyperaemic myocardial velocity resistance (HMR)]. Coronary flow reserve can be calculated using bolus thermodilution (as baseline transit time divided by hyperaemic transit time) or continuous thermodilution (as the ratio of hyperaemic and resting absolute coronary flow), or Doppler flow velocity (hyperaemic flow velocity divided by baseline flow velocity).^307,378,379 The IMR is calculated as the product of distal coronary pressure at maximal hyperaemia multiplied by the hyperaemic mean transit time. Increased IMR (≥25 U) indicates microvascular dysfunction.^380,381 It is important to note that continuous thermodilution-derived measurements have shown higher reproducibility than similar measurements derived from bolus thermodilution.³⁸²

Angiography-derived index of coronary microcirculatory resistance (angio-IMR) allows microcirculation assessment without using intracoronary wires.³⁸³

3.3.3.4. Testing for coronary vasospasm

Vasoreactivity testing explores endothelium-dependent mechanisms of CMD and epicardial and microvascular vasomotor tone disorders.^36,73,384

The most established approach for coronary vasoreactivity testing is by intracoronary infusion of Ach, although other substances like ergonovine have been proposed.^384,385 The methodology is described in detail in Section 5.2.5.2.2.

3.3.4. Diagnostic algorithm and selection of appropriate tests

After estimation of the pre-test likelihood of obstructive epicardial CAD based on the RF-CL model (Figure 4 and Figure 5),¹³⁹ further diagnostic testing is dependent on the clinical scenario, general condition, QoL, presence of comorbidities, local availability and expertise for different diagnostic techniques, and importantly patient expectations and preferences (Figure 6; Table 6).

Figure 5

Adjustment and reclassification of the estimated clinical likelihood of obstructive coronary artery disease.

CACS, coronary artery calcium score; CACS-CL, coronary artery calcium score + RF-CL model; CAD, coronary artery disease; CT, computed tomography; ECG, electrocardiogram; LV, left ventricular; RF-CL, risk factor-weighted clinical likelihood.

Figure 6

Appropriate first-line testing in symptomatic individuals with suspected chronic coronary syndrome.

CAD, coronary artery disease; CACS-CL, coronary artery calcium score + RF-CL model; CCS, chronic coronary syndrome; CCTA, coronary computed tomography angiography; CMR, cardiac magnetic resonance; ECHO, echocardiography; PET, positron emission tomography; RF-CL, risk factor-weighted clinical likelihood; SPECT, single-photon emission computed tomography. ^aThe clinical likelihood of obstructive CAD should be estimated based on the RF-CL model (Figure 4). Individual adjustment of the RF-CL values is in some cases needed based on abnormal clinical finding (Figure 5) or highly suspicious symptoms. Beyond the CACS-CL no methods are validated to give accurate adjusted values to the RF-CL and the adjusted values is therefore based on clinical judgment.

Table 6

Overview of non-invasive tests used for first-line testing in individuals with suspected chronic coronary syndrome

	Main imaging target(s) in CCS	Requirements	Limitations
Anatomical imaging
CCTA	Atherosclerosis (obstructive and non-obstructive) in epicardial coronary arteries	Iodinated contrast Radiation Premedication: Beta-blockers or ivabradine for heart rate control Nitroglycerine for adequate vasodilation	Severely impaired kidney function^a Documented allergy to iodinated contrast Tachyarrhythmia refractory to beta-blockade Irradiation (especially young women)
SPECT/CT PET/CT	Atherosclerosis coronary artery calcium score	Radiation	Irradiation (especially young women)
Functional imaging
Stress Echo	LVEF and volumes		Poor Echo windows
	Wall motion abnormalities Myocardial perfusion Coronary velocity flow reserve	Performed with exercise, dobutamine and vasodilators Echo contrast to improve image quality and assess perfusion	Poor Echo windows Contraindications to stressor
CMR	LVEF and volumes		Non-CMR-compatible metal devices Severe claustrophobia
	MI (scar)	Paramagnetic contrast	Non-CMR-compatible metal devices Severe claustrophobia Haemodialysis
	Ischaemia/blood flow	Vasodilator stress + paramagnetic contrast	Non-CMR-compatible metal devices Severe claustrophobia Contraindications to stressor Haemodialysis
	Wall motion abnormalities	Inotropic stress (dobutamine)	Non-CMR-compatible metal devices Severe claustrophobia Contraindication to stressor
SPECT	LVEF and volumes Ischaemia/viability	Vasodilator or exercise stress Radioactive tracer	Contraindication to stressor Irradiation (especially young women)
PET	LVEF Ischaemia/blood flow Viability	Vasodilator stress Radioactive tracer (¹³N-ammonia, ¹⁵O-water, ⁸²Rb)	Contraindication to stressor Irradiation (especially young women)

	Main imaging target(s) in CCS	Requirements	Limitations
Anatomical imaging
CCTA	Atherosclerosis (obstructive and non-obstructive) in epicardial coronary arteries	Iodinated contrast Radiation Premedication: Beta-blockers or ivabradine for heart rate control Nitroglycerine for adequate vasodilation	Severely impaired kidney function^a Documented allergy to iodinated contrast Tachyarrhythmia refractory to beta-blockade Irradiation (especially young women)
SPECT/CT PET/CT	Atherosclerosis coronary artery calcium score	Radiation	Irradiation (especially young women)
Functional imaging
Stress Echo	LVEF and volumes		Poor Echo windows
	Wall motion abnormalities Myocardial perfusion Coronary velocity flow reserve	Performed with exercise, dobutamine and vasodilators Echo contrast to improve image quality and assess perfusion	Poor Echo windows Contraindications to stressor
CMR	LVEF and volumes		Non-CMR-compatible metal devices Severe claustrophobia
	MI (scar)	Paramagnetic contrast	Non-CMR-compatible metal devices Severe claustrophobia Haemodialysis
	Ischaemia/blood flow	Vasodilator stress + paramagnetic contrast	Non-CMR-compatible metal devices Severe claustrophobia Contraindications to stressor Haemodialysis
	Wall motion abnormalities	Inotropic stress (dobutamine)	Non-CMR-compatible metal devices Severe claustrophobia Contraindication to stressor
SPECT	LVEF and volumes Ischaemia/viability	Vasodilator or exercise stress Radioactive tracer	Contraindication to stressor Irradiation (especially young women)
PET	LVEF Ischaemia/blood flow Viability	Vasodilator stress Radioactive tracer (¹³N-ammonia, ¹⁵O-water, ⁸²Rb)	Contraindication to stressor Irradiation (especially young women)

CCS, chronic coronary syndrome; CCTA, coronary computed tomography angiography; CMR, cardiac magnetic resonance; CT, computed tomography; Echo, echocardiography; LVEF, left ventricular ejection fraction; MI, myocardial infarction; PET, positron emission tomography; SPECT, single-photon emission computed tomography.

^aPreventive measures are recommended for patients with eGFR <30 mL/min/1.73 m².³⁸⁹

Table 6

Overview of non-invasive tests used for first-line testing in individuals with suspected chronic coronary syndrome

	Main imaging target(s) in CCS	Requirements	Limitations
Anatomical imaging
CCTA	Atherosclerosis (obstructive and non-obstructive) in epicardial coronary arteries	Iodinated contrast Radiation Premedication: Beta-blockers or ivabradine for heart rate control Nitroglycerine for adequate vasodilation	Severely impaired kidney function^a Documented allergy to iodinated contrast Tachyarrhythmia refractory to beta-blockade Irradiation (especially young women)
SPECT/CT PET/CT	Atherosclerosis coronary artery calcium score	Radiation	Irradiation (especially young women)
Functional imaging
Stress Echo	LVEF and volumes		Poor Echo windows
	Wall motion abnormalities Myocardial perfusion Coronary velocity flow reserve	Performed with exercise, dobutamine and vasodilators Echo contrast to improve image quality and assess perfusion	Poor Echo windows Contraindications to stressor
CMR	LVEF and volumes		Non-CMR-compatible metal devices Severe claustrophobia
	MI (scar)	Paramagnetic contrast	Non-CMR-compatible metal devices Severe claustrophobia Haemodialysis
	Ischaemia/blood flow	Vasodilator stress + paramagnetic contrast	Non-CMR-compatible metal devices Severe claustrophobia Contraindications to stressor Haemodialysis
	Wall motion abnormalities	Inotropic stress (dobutamine)	Non-CMR-compatible metal devices Severe claustrophobia Contraindication to stressor
SPECT	LVEF and volumes Ischaemia/viability	Vasodilator or exercise stress Radioactive tracer	Contraindication to stressor Irradiation (especially young women)
PET	LVEF Ischaemia/blood flow Viability	Vasodilator stress Radioactive tracer (¹³N-ammonia, ¹⁵O-water, ⁸²Rb)	Contraindication to stressor Irradiation (especially young women)

	Main imaging target(s) in CCS	Requirements	Limitations
Anatomical imaging
CCTA	Atherosclerosis (obstructive and non-obstructive) in epicardial coronary arteries	Iodinated contrast Radiation Premedication: Beta-blockers or ivabradine for heart rate control Nitroglycerine for adequate vasodilation	Severely impaired kidney function^a Documented allergy to iodinated contrast Tachyarrhythmia refractory to beta-blockade Irradiation (especially young women)
SPECT/CT PET/CT	Atherosclerosis coronary artery calcium score	Radiation	Irradiation (especially young women)
Functional imaging
Stress Echo	LVEF and volumes		Poor Echo windows
	Wall motion abnormalities Myocardial perfusion Coronary velocity flow reserve	Performed with exercise, dobutamine and vasodilators Echo contrast to improve image quality and assess perfusion	Poor Echo windows Contraindications to stressor
CMR	LVEF and volumes		Non-CMR-compatible metal devices Severe claustrophobia
	MI (scar)	Paramagnetic contrast	Non-CMR-compatible metal devices Severe claustrophobia Haemodialysis
	Ischaemia/blood flow	Vasodilator stress + paramagnetic contrast	Non-CMR-compatible metal devices Severe claustrophobia Contraindications to stressor Haemodialysis
	Wall motion abnormalities	Inotropic stress (dobutamine)	Non-CMR-compatible metal devices Severe claustrophobia Contraindication to stressor
SPECT	LVEF and volumes Ischaemia/viability	Vasodilator or exercise stress Radioactive tracer	Contraindication to stressor Irradiation (especially young women)
PET	LVEF Ischaemia/blood flow Viability	Vasodilator stress Radioactive tracer (¹³N-ammonia, ¹⁵O-water, ⁸²Rb)	Contraindication to stressor Irradiation (especially young women)

CCS, chronic coronary syndrome; CCTA, coronary computed tomography angiography; CMR, cardiac magnetic resonance; CT, computed tomography; Echo, echocardiography; LVEF, left ventricular ejection fraction; MI, myocardial infarction; PET, positron emission tomography; SPECT, single-photon emission computed tomography.

^aPreventive measures are recommended for patients with eGFR <30 mL/min/1.73 m².³⁸⁹

In patients with severe comorbidities or severe frailty or very low QoL that all contribute to a limited life expectancy, in whom revascularization is judged to be futile, the diagnosis of CCS can be made clinically, and managed with medical therapy and lifestyle changes alone. If CCS diagnosis is uncertain in such patients, establishing a diagnosis using non-invasive functional imaging for myocardial ischaemia before treatment is reasonable.

Individual adjustment of the clinical likelihood should always be considered based on the clinical CCS scenario including ECG and echocardiography findings (Figure 5, Section 2). Further diagnostic testing can be deferred in patients with a very low (≤5%) likelihood of obstructive CAD. Based on the CACS-CL model, in patients with a low (>5%–15%) likelihood of obstructive CAD, CACS can be considered to re-estimate the likelihood of obstructive CAD.^{139,165,141,154} Further diagnostic testing can also be deferred in patients reclassified based on CACS from a low to a very low (<5%) likelihood of obstructive CAD (Figure 5).¹⁴³ Conversely, if CACS is high and there are clinical findings indicating that the RF-CL model may be under-estimating the likelihood of obstructive CAD, further diagnostic testing should be selected based on the adjusted clinical likelihood and coronary calcium burden. It is important to note that patients with a very low and low (≤15%) likelihood of obstructive CAD constitute approximately 85% of individuals with de novo symptoms suspected of CCS.^27,30,139 Most can be treated conservatively without the need for further testing as they have no stenoses or non-obstructive CAD with a very low incidence of events during long-term follow-up.^27,139,143

Individuals with a moderate or high (>15%–85%) likelihood of obstructive CAD should be referred for non-invasive anatomical or functional imaging to establish the diagnosis and assess the risk for future cardiac events. There is growing support for using CCTA as a first-line test in the group with a low or moderate (15%–50%) likelihood.^{27,31,32,139,386} Given the low prevalence of CAD in this group of patients and its high negative predictive value, CCTA is the most effective diagnostic method to rule out obstructive CAD. Moreover, besides its strength in ruling out CAD, CCTA offers direct visualization of non-obstructive CAD, which may trigger intensification of preventive measures. The use of CCTA as a first-line test is supported by large, randomized trials showing equivalence in health outcomes with functional testing³³ and even superiority compared with usual care using exercise ECG.³⁴

In patients with a very high (≥85%) clinical likelihood of obstructive CAD, symptoms unresponsive to medical therapy, or angina at a low level of exercise, and an initial clinical evaluation (including echocardiogram and, in selected patients, exercise ECG) that indicates a high event risk, proceeding directly to ICA without further diagnostic testing is a reasonable option. Under such circumstances, the indication for revascularization of stenoses with a diameter reduction of <90% should be guided by coronary pressure assessment (Figure 6; Table 6).

Functional imaging should be selected as a first line test if information on myocardial ischaemia, viability, or microvascular disease is desired. Tests for detecting ischaemia have better rule-in power compared with CCTA and therefore should be selected if there is a moderate-high (>15-85%) likelihood of obstsructive CAD. Moreover, functional imaging tests overcome the limitations of CCTA in certain groups (older patients with more extensive coronary calcifications, AF, and other situations with an irregular or fast heart rate, renal insufficiency, or iodinated contrast allergy), and avoid exposure to ionizing radiation in young individuals and in those suspected of ANOCA/INOCA (Figure 7).

Figure 7

Initial management of symptomatic individuals with suspected chronic coronary syndrome.

ANOCA, angina with non-obstructive coronary arteries; CAD, coronary artery disease; CCS, chronic coronary syndrome; CCTA, coronary computed tomography angiography; CMR, cardiac magnetic resonance; Echo, echocardiography; FFR, fractional flow reserve; ICFT, invasive coronary functional testing; iFR, instantaneous wave-free ratio; INOCA, ischaemia with non-obstructed coronary arteries; LV, left ventricular; PET, positron emission tomography; SPECT, single-photon emission computed tomography. Consider local availability and expertise, and individual characteristics when choosing non-invasive testing. Table 6 offers tips for selecting the first-line test in people with suspected CCS. ^aHigh–risk CAD: obstructive CAD at high risk of adverse events by CCTA: ≥50% stenosis of the left main stem; three–vessel disease with severe stenoses (≥70% diameter stenosis); single- or two–vessel disease including the proximal LAD with severe stenoses. Consider functional imaging or invasive investigation.

The discussion about which modality to use as a first-line test has been heavily focused on the detection of obstructive epicardial stenoses, neglecting the relatively high prevalence of non-obstructive coronary disease and ANOCA/INOCA, especially in female patients. The current rationale behind choosing a first-line test should be to assess the anatomical severity and functional consequences of coronary disease, whether obstructive or not. In this regard, PET-CT should be more frequently considered and its availability increased as it combines calcium scoring with accurate operator-independent detection of myocardial ischaemia and CMD with a low irradiation dose.⁴⁵

Individuals in the moderate likelihood group, except older men with all three CCS symptom characteristics, will have a likelihood of obstructive CAD around 20%. In these, anatomical and functional testing will each result in an intermediate positive predictive value with eventually many false positives, especially with CCTA easily overestimating stenosis severity. Sequential testing (i.e. functional testing after CCTA, or vice versa) will therefore be needed in many individuals to establish an accurate diagnosis of obstructive, ischaemia-inducing CAD (Figure 8). Sequential or combined anatomical and functional testing is also useful for the non-invasive diagnosis of ANOCA/INOCA.⁴¹ Moreover, combined testing, e.g. combining CCTA and PET, may result in improved prognostication of CCS patients.³⁸⁷

Figure 8

Ruling in and ruling out functionally significant obstructive coronary artery disease by sequential anatomical (coronary computed tomography angiography) and functional (dobutamine stress echocardiography) testing.^a

CAD, coronary artery disease; CCTA, coronary computed tomography angiography; DSE; dobutamine stress echocardiography; ECG, electrocardiogram; FFR, fractional flow reserve. The curves display the post-test likelihood of obstructive CAD for a positive (+) and a negative (−) test result for CCTA and DSE, as the pre-test likelihood of obstructive CAD increases. The post-test likelihoods were calculated using the likelihood ratios taken from recent meta-analyses.^148,388

^aBased on invasive FFR measurement or diameter stenosis of ≥70%.

• A 70-year-old woman with four coronary risk factors and exertional dyspnoea has a pre-test likelihood of 16% (A). A normal CCTA almost completely rules out obstructive CAD with a very low negative post-test likelihood (2%).

• A 55-year-old man with two coronary risk factors and all three anginal symptom characteristics has a pre-test likelihood of 27% (B). An abnormal CCTA brings the post-test likelihood to 40%, insufficient to rule in obstructive CAD. Sequential testing with DSE performed after CCTA brings the post-test likelihood to 82%. A normal CCTA effectively rules out obstructive CAD.

• A 69-year-old man with four coronary risk factors and all three anginal symptom characteristics has an adjusted pre-test likelihood of 60% (C) (adjustment based on abnormalities on the resting ECG and on symptoms during exercise). A positive DSE alone has a high post-test likelihood (± 90%). A negative DSE is associated with a 32% post-test likelihood. Sequential testing by CCTA would allow ruling out obstructive CAD (<5% post-test likelihood).

Recommendation Table 13

Recommendations for selection of initial diagnostic tests in individuals with suspected chronic coronary syndrome (see also Evidence Table 13)

After confirmation of diagnosis with the first line of testing, all patients should receive lifestyle and risk-factor modification recommendations, and disease-modifying and antianginal therapy should be prescribed. The ISCHEMIA trial (Initial Invasive or Conservative Strategy for Stable Coronary Disease)⁴⁷ showed that an early revascularization strategy did not yield a short-term survival benefit in patients without left main disease nor reduced LVEF and with moderate-severe ischaemia at non-invasive testing, suggesting that most such patients should initially be treated conservatively with optimized GDMT. Patients can be referred for ICA if CCTA detects a ≥50% stenosis of the left main stem, three-vessel or two-vessel disease including the proximal LAD artery with ≥70% stenosis, or if functional imaging shows moderate or severe ischaemia encompassing an extensive perfusion territory.

For patients with obstructive CAD and refractory symptoms despite optimized GDMT, a referral for ICA may be considered to improve symptoms through revascularization. Optimization of medical therapy by combining two or more antianginal drugs can safely be obtained over 6 weeks in almost all patients and should be awaited before referral to ICA.^402,403 It is worth noting that in the Objective Randomised Blinded Investigation with optimal medical Therapy of Angioplasty in stable angina (ORBITA) trial, PCI did not provide short-term advantages compared with GDMT in terms of reducing anginal frequency or physical limitations.⁴⁰² In the CLARIFY registry, anginal symptoms resolved in many CCS patients over time without requiring revascularization or changes in antianginal therapy.⁴⁰⁴

Combined anatomical and functional imaging before ICA facilitates its planning by orientating the invasive cardiologist to perform, in the same session, haemodynamic assessment of coronary stenoses and ICFT to detect microvascular disease or vasospasm in individuals suspected of ANOCA/INOCA, performing these tests in a single session rather than in staged procedures.

3.3.5. Adverse-event risk assessment

Chronic coronary syndromes can be complicated by cardiovascular death, ischaemic and haemorrhagic events, HF, arrhythmic events, the development of valvular heart disease, and other comorbidities, which are further discussed in the Supplementary data, available at European Heart Journal online. It is recommended that all patients with newly diagnosed obstructive CAD or myocardial ischaemia undergo an adverse-risk event assessment to identify those at high risk of adverse outcomes who could benefit from revascularization beyond symptom relief. Based on large registries and historical RCTs, a high event risk has been defined as a cardiac mortality rate of >3% per year, intermediate event risk as between ≥1% and ≤3% per year, and low event risk as <1% per year.⁴⁰⁵

Adverse-event risk stratification is usually based on the same clinical, non-invasive and invasive investigations used to diagnose obstructive CAD (see Table 14).

Clinical history, physical examination, 12-lead ECG and laboratory tests can provide important prognostic information. Assessment of risk factors such as advanced age, diabetes mellitus (DM), or renal failure allows the identification of patients at high risk of events.^406–408 Left ventricular function is the strongest predictor of long-term survival; a patient with an LVEF of <50% is already at high risk for all-cause and cardiovascular death.^409,410

Although the diagnostic value of an exercise ECG is limited, the occurrence of ST-segment depression at a low workload combined with exertional symptoms (angina or dyspnoea), low exercise capacity, complex ventricular ectopy, or other arrhythmias and abnormal BP response are markers of a high risk of cardiac mortality.^411–414

High plaque burden and coronary stenoses are well-known prognostic markers. The ISCHEMIA trial using a cut-off of 70% stenosis on CCTA³¹⁷ confirms the very old observations of the Coronary Artery Surgery Study¹⁸² that the prognosis of obstructive CAD-related CCS is mainly determined by the number of >70% obstructed coronary arteries or by the presence of a left main stenosis (using for the latter a cut-off of >50% diameter stenosis on coronary angiography).³¹⁷ More recently, the classical paradigm that the severity of stenoses and the number of diseased vessels are the main determinants of prognosis has been challenged by post hoc analyses of the SCOT-HEART trial and other CCTA-based registries showing that plaque burden and presence of adverse plaque characteristics, especially low-attenuation plaque, are the strongest predictors of fatal and non-fatal MI above the classical risk factors, including stenosis severity.^{210,415–417} These findings emphasize a major advantage of anatomical imaging by CCTA as an initial test in selected patients, allowing the assessment of severity and extent of obstructive CAD as well as coronary plaque characteristics.

Regarding the prognostic impact of inducible myocardial ischaemia by functional stress imaging, the evidence remains conflicting. While there are extensive data from large observational studies^{315,418–425} consistently demonstrating a robust prognostic value conferred by the extent of inducible ischaemia as detected by functional imaging (e.g. ≥3/16 abnormal segments at stress echocardiography, ≥10% LV ischaemia at nuclear or magnetic resonance perfusion imaging, or decreased hyperaemic flow or flow reserve at quantitative PET imaging), post hoc analyses of the randomized COURAGE^426,427 and ISCHEMIA³¹⁷ trials showed that only CAD severity, but not ischaemia severity, was independently predictive of long-term mortality and MI risk. These discrepancies may be explained by selection and entry biases between registries and RCTs.⁴²⁸ Registries typically report on all-comer populations with suspected CCS referred for diagnostic testing and/or revascularization, representing the real-life scenario. RCTs usually include only a very selected group of patients, and the external applicability of their findings is always open for debate. As COURAGE and ISCHEMIA selectively included only patients with functionally moderate or severe myocardial ischaemia but without any information on CAD anatomical severity, it becomes harder to demonstrate a prognostic effect of myocardial ischaemia, and the anatomical burden becomes the prominent prognostic factor. The PROMISE (Prospective Multicenter Imaging Study for Evaluation of Chest Pain) trial, which included patients more representative of an all-comer population, demonstrated that CCTA, mainly by detecting non-obstructive CAD, outperformed functional testing in predicting outcomes, emphasizing the prognostic significance of imaging coronary atherosclerosis beyond myocardial ischaemia.²⁰⁸ However, adding the Framingham Risk Score to the functional test result improved its prognostic value, making the difference with anatomical testing insignificant. Both modalities are thus equivalent for detecting CCS symptoms and predicting outcomes when considering risk factors.

Besides imaging coronary atherosclerosis, the additional benefit of ICA is the ability to perform intracoronary pressure measurements. While FFR of ≤0.8 and iFR of ≤0.89 have been associated with a higher risk of vessel-related cardiovascular events, it is important to remember that a lower FFR/iFR reflects more profound ischaemia in the vessel territory and is associated with a progressive and proportional increase in risk.^318,319 A similar observation has been made with FFR-CT.⁴⁰¹ It has also been shown that for any given FFR value, a more proximal lesion is associated with more extensive ischaemia and an increased risk of a clinical event.⁴²⁹ In addition, global FFR, summing the coronary pressure collected in each of the three main coronary vessel territories as a single patient-related index (normal value of global FFR = 1 + 1 + 1 = 3), can appreciate overall cardiovascular risk; patients with a borderline FFR but with a global FFR of <2.72 showed a significantly increased risk compared with higher global-FFR patients.^430,431 One of the main limitations of such a global integrative approach based on invasive coronary pressure is that it requires advancing a pressure wire in each of the three coronary arteries, which is not often performed³⁴¹ and is not recommended as a routine, based on the RIPCORD2³⁴⁷ and FUTURE results.³⁴⁶ Recent methods using 3-dimensional image reconstruction and computational fluid dynamics enable FFR estimation with CCTA⁴³² or with 'wire-less' invasive coronary angiography.^433,434 This allows a less invasive, easier and more accurate global FFR calculation, provided imaging is of sufficiently good quality.^369–371

In summary, when assessing event risk, clinicians should choose an integrative approach, considering risk factors, comorbidities, LV dysfunction, the severity of myocardial ischaemia, the number of functionally significantly stenotic coronary arteries, and the coronary plaque burden and characteristics, as all of these are likely interrelated factors that affect overall prognosis.

Recommendation Table 14

Recommendations for definition of high risk of adverse events (see also Evidence Table 14)

3.4. STEP 4: Initial therapy

Initial therapy frequently starts during the diagnostic process. In individuals with a high suspicion of CCS, sublingual nitroglycerine is frequently prescribed to treat anginal pain symptoms. Rapid relief within 1 or 2 min of chest discomfort after sublingual nitroglycerine increases the likelihood of CCS. Patients may be advised to refrain from strenuous physical activities before the diagnostic process is completed and should be instructed what to do if prolonged anginal chest pain indicative of acute MI arises.

Guideline-directed management and therapy are started during or after the diagnostic process is concluded. The main goals of treating CCS are to improve both QoL and life expectancy. This involves various interventions to reduce the risk of (i) cardiac mortality, (ii) non-fatal ischaemic events, (iii) progression of epicardial and/or microvascular chronic coronary disease, and (iv) symptoms and limitations caused by CCS. When deciding on treatment options, it is important to consider patient preferences, possible complications of procedures or medications, and healthcare costs. In shared decision-making with patients, clinicians should clearly explain that certain treatments can alleviate symptoms, while others can reduce the likelihood of ischaemic events.

4. Guideline-directed therapy

4.1. Patient education, lifestyle optimization for risk-factor control, and exercise therapy

4.1.1. Patient education

In CCS patients, education on risk factors and symptom management is associated with improvements in knowledge, self-care, and patient empowerment, and may improve health-related QoL.⁴³⁶ In addition, education can facilitate long-term adherence to lifestyle interventions.^437,438 Educational programmes—either alone or as a core component of multidisciplinary care management programmes—promote patients’ awareness of their condition and the rationale for lifestyle interventions. However, awareness of CVD risk factors through education alone might be insufficient for adoption of healthy behaviour.⁴³⁹ Therefore, self-care programmes are needed to enable patients to have a major role in coping with their condition and accepting their prescribed treatment.^440,441 Elements in patient education include (modifiable) risk factors in relation to individual cardiovascular risk, since risk perception is an integral part of many major health behaviour theories, ultimately leading to modification of human habits.^441,442

Information on benefits of risk-factor control on recurrence risk, disease progression, complications, and overall survival should be discussed. The format, time horizon, and outcome used for risk estimation influence patient perceptions and should be considered when designing risk communication tools.^443–445

Lifelong education for patient-centred information and problem-based learning is superior to home-sent information in improving risk-factor control in the long term.^438,444 Refer to Section 6.2.1 for further guidance on patient education.

4.1.2. Key lifestyle interventions for risk-factor control

Reducing CVD risk at the individual level begins with effective information on risk and anticipated risk reduction by treatment. Risk algorithms are available for use in clinical practice by means of interactive tools online. The use of the Smart risk score (U-prevent.com) is suggested by the European Association of Preventive Cardiology for risk estimation in patients with previous CVD.⁴⁴⁶ Ideally, patients are made aware of their individual risks and the potential benefit of prevention treatments and then actively engaged in managing their disease. Treatment goals are communicated using a patient-centred approach (Table 7).

Table 7

Practical advice on lifestyle counselling and interventions

Topic	Recommendation and treatment goals in patients with established CCS
Lifestyle counselling
Immunization	Vaccination against influenza, pneumococcal disease and other widespread infections, e.g. COVID-19
Sleep quality	Treat sleep-related breathing disorders
Sexual activity	Males and females: low risk for stable patients who are not symptomatic at low-to-moderate activity levels Males: PDE-5 inhibitors are generally safe, not to be taken in combination with nitrate medications because of risk of severe hypotension
Psychosocial aspects	Avoid psychosocial stress Treat depression and anxiety by psychological or pharmacological interventions
Environment/pollution	Avoid passive smoking Reduce environmental noise Avoid exposure to air pollution
Lifestyle interventions for risk-factor control
Smoking and substance abuse	Use pharmacological and behavioural strategies to assist in smoking cessation Avoid e-cigarettes Abstain from substance abuse
Obesity and being overweight	Obtain and maintain a healthy weight (BMI 18.5–25 kg/m²) Reduce weight through recommended energy intake and increased physical activity and through pharmacological/surgical interventions in selected patients
Hyperlipidaemia	Ultimate LDL-C goal of <1.4 mmol/L (55 mg/dL) and a ≥50% reduction in LDL-C vs. baseline is recommended
Diabetes	HbA1c < 7.0% (53 mmol/mol)
Arterial hypertension	SBP 120–129 mmHg, provided the antihypertensive treatment is well tolerated
Diet and alcohol consumption	Limit alcohol consumption to <100 g/week Diet high in vegetables, fruit, and wholegrains (Mediterranean diet) Limit saturated fat to <10% of total calorie intake
Physical activity and exercise	30–60 min moderate activity, >5 days/week Reduce sedentary time and engage in at least light activity throughout the day

Topic	Recommendation and treatment goals in patients with established CCS
Lifestyle counselling
Immunization	Vaccination against influenza, pneumococcal disease and other widespread infections, e.g. COVID-19
Sleep quality	Treat sleep-related breathing disorders
Sexual activity	Males and females: low risk for stable patients who are not symptomatic at low-to-moderate activity levels Males: PDE-5 inhibitors are generally safe, not to be taken in combination with nitrate medications because of risk of severe hypotension
Psychosocial aspects	Avoid psychosocial stress Treat depression and anxiety by psychological or pharmacological interventions
Environment/pollution	Avoid passive smoking Reduce environmental noise Avoid exposure to air pollution
Lifestyle interventions for risk-factor control
Smoking and substance abuse	Use pharmacological and behavioural strategies to assist in smoking cessation Avoid e-cigarettes Abstain from substance abuse
Obesity and being overweight	Obtain and maintain a healthy weight (BMI 18.5–25 kg/m²) Reduce weight through recommended energy intake and increased physical activity and through pharmacological/surgical interventions in selected patients
Hyperlipidaemia	Ultimate LDL-C goal of <1.4 mmol/L (55 mg/dL) and a ≥50% reduction in LDL-C vs. baseline is recommended
Diabetes	HbA1c < 7.0% (53 mmol/mol)
Arterial hypertension	SBP 120–129 mmHg, provided the antihypertensive treatment is well tolerated
Diet and alcohol consumption	Limit alcohol consumption to <100 g/week Diet high in vegetables, fruit, and wholegrains (Mediterranean diet) Limit saturated fat to <10% of total calorie intake
Physical activity and exercise	30–60 min moderate activity, >5 days/week Reduce sedentary time and engage in at least light activity throughout the day

BMI, body mass index; CCS, chronic coronary syndrome; COVID-19, coronavirus disease 2019; HbA1c, glycated haemoglobin; LDL-C, low-density lipoprotein cholesterol; PDE-5, phosphodiesterase-5; SBP, systolic blood pressure.

Table 7

Practical advice on lifestyle counselling and interventions

Topic	Recommendation and treatment goals in patients with established CCS
Lifestyle counselling
Immunization	Vaccination against influenza, pneumococcal disease and other widespread infections, e.g. COVID-19
Sleep quality	Treat sleep-related breathing disorders
Sexual activity	Males and females: low risk for stable patients who are not symptomatic at low-to-moderate activity levels Males: PDE-5 inhibitors are generally safe, not to be taken in combination with nitrate medications because of risk of severe hypotension
Psychosocial aspects	Avoid psychosocial stress Treat depression and anxiety by psychological or pharmacological interventions
Environment/pollution	Avoid passive smoking Reduce environmental noise Avoid exposure to air pollution
Lifestyle interventions for risk-factor control
Smoking and substance abuse	Use pharmacological and behavioural strategies to assist in smoking cessation Avoid e-cigarettes Abstain from substance abuse
Obesity and being overweight	Obtain and maintain a healthy weight (BMI 18.5–25 kg/m²) Reduce weight through recommended energy intake and increased physical activity and through pharmacological/surgical interventions in selected patients
Hyperlipidaemia	Ultimate LDL-C goal of <1.4 mmol/L (55 mg/dL) and a ≥50% reduction in LDL-C vs. baseline is recommended
Diabetes	HbA1c < 7.0% (53 mmol/mol)
Arterial hypertension	SBP 120–129 mmHg, provided the antihypertensive treatment is well tolerated
Diet and alcohol consumption	Limit alcohol consumption to <100 g/week Diet high in vegetables, fruit, and wholegrains (Mediterranean diet) Limit saturated fat to <10% of total calorie intake
Physical activity and exercise	30–60 min moderate activity, >5 days/week Reduce sedentary time and engage in at least light activity throughout the day

Topic	Recommendation and treatment goals in patients with established CCS
Lifestyle counselling
Immunization	Vaccination against influenza, pneumococcal disease and other widespread infections, e.g. COVID-19
Sleep quality	Treat sleep-related breathing disorders
Sexual activity	Males and females: low risk for stable patients who are not symptomatic at low-to-moderate activity levels Males: PDE-5 inhibitors are generally safe, not to be taken in combination with nitrate medications because of risk of severe hypotension
Psychosocial aspects	Avoid psychosocial stress Treat depression and anxiety by psychological or pharmacological interventions
Environment/pollution	Avoid passive smoking Reduce environmental noise Avoid exposure to air pollution
Lifestyle interventions for risk-factor control
Smoking and substance abuse	Use pharmacological and behavioural strategies to assist in smoking cessation Avoid e-cigarettes Abstain from substance abuse
Obesity and being overweight	Obtain and maintain a healthy weight (BMI 18.5–25 kg/m²) Reduce weight through recommended energy intake and increased physical activity and through pharmacological/surgical interventions in selected patients
Hyperlipidaemia	Ultimate LDL-C goal of <1.4 mmol/L (55 mg/dL) and a ≥50% reduction in LDL-C vs. baseline is recommended
Diabetes	HbA1c < 7.0% (53 mmol/mol)
Arterial hypertension	SBP 120–129 mmHg, provided the antihypertensive treatment is well tolerated
Diet and alcohol consumption	Limit alcohol consumption to <100 g/week Diet high in vegetables, fruit, and wholegrains (Mediterranean diet) Limit saturated fat to <10% of total calorie intake
Physical activity and exercise	30–60 min moderate activity, >5 days/week Reduce sedentary time and engage in at least light activity throughout the day

BMI, body mass index; CCS, chronic coronary syndrome; COVID-19, coronavirus disease 2019; HbA1c, glycated haemoglobin; LDL-C, low-density lipoprotein cholesterol; PDE-5, phosphodiesterase-5; SBP, systolic blood pressure.

4.1.2.1. Smoking and substance abuse

Smoking cessation in CCS patients improves prognosis, with a reported 36% risk reduction of premature death in those who quit compared with those who continue to smoke.⁴⁴⁷ Measures to promote smoking cessation include brief advice, counselling and behavioural interventions, and pharmacological therapy.^448,449 Patients should also avoid passive smoking.

Drug support to assist in smoking cessation should be considered in all smokers who are ready to undertake this action. Nicotine-replacement therapy, bupropion, or varenicline are effective,^450,451 and are not linked to an increase in MACE.⁴⁵²

The use of electronic cigarettes (e-cigarettes), as an alternative to conventional cigarettes, should be discouraged because they are not harm-free.⁴⁵³ Newer devices deliver higher nicotine contents, and e-cigarettes emit other constituents, such as carbonyls, and fine and ultrafine particulates.⁴⁵⁴ Evidence from several studies indicates that acute inhalation of e-cigarettes leads to negative changes in vascular endothelial function.^453,454 E-cigarettes should only be considered to aid tobacco cessation alongside a formal tobacco cessation programme.^453,455,456

Various substances, including cocaine, opioids, and marihuana can have adverse effects on the cardiovascular system and have a potential for drug–drug interactions with cardiovascular medication.^457–459 Single-question screening for unhealthy drug use has been validated in primary care and can identify individuals requiring counselling on adverse cardiovascular effects.⁴⁶⁰

4.1.2.2. Weight management

In a population-based study, lifetime risk of incident CVD, and cardiovascular morbidity and mortality, were higher in those who were overweight or obese compared with those with a normal BMI (18.5–24.9 kg/m²).⁴⁶¹

Compared with normal BMI, among middle-aged men and women, competing hazard ratios (HR) for incident CVD were 1.21 [95% confidence interval (CI), 1.14–1.28] and 1.32 (95% CI, 1.24–1.40), respectively, for overweight (BMI of 25.0–29.9 kg/m²), 1.67 (95% CI, 1.55–1.79) and 1.85 (95% CI, 1.72–1.99) for obesity (BMI of 30.0–39.9 kg/m²), and 3.14 (95% CI, 2.48–3.97) and 2.53 (95% CI, 2.20–2.91) for morbid obesity (BMI of ≥40.0 kg/m²). Obesity was associated with a shorter overall lifespan, and being overweight was associated with developing CVD at an earlier age.⁴⁶¹ In subjects with CAD, intentional weight loss is associated with a significantly lower risk of adverse clinical outcomes,⁴⁶² and has beneficial effects on risk-factor control and QoL.⁴⁶³ Healthy diets with energy intake limited to the amount needed to obtain and maintain a healthy weight (BMI of 18.5–25 kg/m²), and combined with increasing physical activity, are recommended for weight management.¹⁶ If weight targets are not reached, pharmacological treatment with glucagon-like peptide-1 (GLP-1) receptor agonists may be considered for further weight reduction (Section 4.3.4). In patients without diabetes, the STEP8 trial showed a significant reduction in weight after 68 weeks with either semaglutide (mean weight change of −15.8%; 95% CI, −17.6% to −13.9%) or liraglutide (mean weight change of −6.4%; 95% CI, −8.2% to −4.6%) compared with placebo (−1.9%; 95% CI, −4.0% to 0.2%).⁴⁶⁴ The double-blind, placebo-controlled Semaglutide Effects on Cardiovascular Outcomes in People with Overweight or Obesity (SELECT) trial showed a significant reduction in the incidence of cardiovascular death, MI, or stroke (HR 0.80; 95% CI, 0.72–0.90) in patients with pre-existing CVD who were overweight or obese, but without diabetes, treated with weekly subcutaneous semaglutide.⁴⁶⁵

The SURMOUNT-1 (Efficacy and Safety of Tirzepatide Once Weekly in Participants Without Type 2 Diabetes Who Have Obesity or Are Overweight With Weight- Related Comorbidities: A Randomized, Double-Blind, Placebo-Controlled Trial) trial showed a dose-dependent weight-loss benefit (mean weight change of up to −20.9%; 95% CI, −21.8% to −19.9%) with tirzepatide, a combined glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 receptor agonist, compared with placebo in obese adults without diabetes over 72 weeks,⁴⁶⁶ a dose effect that was confirmed in the SURMOUNT-2 trial.⁴⁶⁷ Bariatric surgery in severe obesity appears to be a safe and effective intervention for further weight loss in CCS patients.⁴⁶⁸

Cardiac rehabilitation programmes should include weight-loss interventions to reach a healthy weight as a specific component. The incremental value of telehealth interventions and pharmacological interventions need full consideration in secondary prevention.⁴⁶⁹

4.1.2.3. Diet and alcohol

Dietary habits influence cardiovascular risk, mainly through risk factors such as lipids, BP, body weight, and DM. It is recommended to adopt a Mediterranean or similar diet to lower the risk of CVD, as described in the 2021 ESC Guidelines on cardiovascular disease prevention in clinical practice.¹⁶ If alcohol is consumed, it should be limited to <100 g/week or 15 g/day, since alcohol intake of >100 g/week is associated with higher all-cause and other CVD mortality in large individual-data meta-analyses.⁴⁷⁰ A recent genetic analysis showed that the causal association between light-to-moderate levels of alcohol intake and lower cardiovascular risk is possibly mediated by confounding lifestyle factors, therefore questioning the previously observed cardioprotective role of light alcohol use.⁴⁷¹

4.1.2.4. Mental health

Psychosocial stress, depression, and anxiety are associated with worse cardiovascular outcomes, and make it difficult for patients to make positive changes to their lifestyles or adhere to a therapeutic regimen. Therefore, assessment for psychosocial risk factors is recommended in secondary prevention.¹⁶ Clinical trials have shown that psychological (e.g. counselling and/or cognitive behavioural therapy) and pharmacological interventions have a beneficial effect on depression, anxiety, and stress, with some evidence of a reduction in cardiac mortality and events compared with placebo (see Section 6.1.2).⁴⁷²

4.1.2.5. Physical activity and sedentary behaviour

Physical activity reduces the risk of many adverse health outcomes and risk factors in all ages and both sexes. There is an inverse relationship between moderate-to-vigorous physical activity and all-cause mortality, cardiovascular mortality, and atherosclerotic cardiovascular disease (ASCVD).⁴⁷³ The reduction in risk continues across the full range of physical activity volumes, and the slope of risk decline is steepest for the least active individuals.⁴⁷⁴ Adults are recommended to perform at least 150–300 min per week of moderate-intensity physical activity, or 75–150 min of vigorous-intensity physical activity, or an equivalent combination of both, spread throughout the week.⁴⁷³ Additional benefits are gained with even more physical activity.⁴⁷⁵ Practising physical activity should still be encouraged in individuals unable to meet the minimum. In sedentary individuals, a gradual increase in activity level is recommended.⁴⁷⁶ Physical activity can be incorporated flexibly, either daily or limited to specific days. Activity patterns limited to 1–2 sessions per week but meeting recommended levels of physical activity have been shown to reduce all-cause mortality (HR 0.66; 95% CI, 0.62–0.72), CVD mortality (HR 0.60; 95% CI, 0.52–0.69), and cancer mortality (HR 0.83; 95% CI, 0.73–0.94) when compared with inactive participants.⁴⁷⁷ Physical activity accumulated in bouts of even <10 min is associated with favourable outcomes, including mortality.⁴⁷⁸

High levels of time spent sedentary is associated with an increased risk for several major chronic diseases and mortality.⁴⁷⁹ For physically inactive adults, light-intensity physical activity, even as little as 15 min a day, is likely to produce benefits.⁴⁷⁹

4.1.3. Exercise therapy

Exercise training, either alone or in the context of multidisciplinary, exercise-based cardiac rehabilitation, leads to reduction in hospitalizations, adverse cardiovascular events, mortality rates, and improved CVD risk profile in patients with ASCVD.^480–483 Therefore, exercise is a therapy that should be offered to every CCS patient in the setting of secondary disease prevention.¹⁶

Exercise training should be individually prescribed according to the FITT (frequency, intensity, time, type) model for aerobic and resistance training.⁴⁸⁴

For aerobic training (walking, jogging, cycling, swimming, etc.), an exercise frequency of at least 3 days/week, preferably 6–7 days/week, at moderate or moderate-to-high intensity is recommended. Relative intensity is determined based on an individual’s maximum (peak) effort, e.g. percentage of cardiorespiratory fitness (%VO₂ max), percentage of maximum (peak) heart rate (%HRmax) or ventilatory thresholds (VT1 and VT2).⁴⁸⁵ To date, there is insufficient evidence to promote high-intensity interval training over moderate-intensity continuous training; nevertheless, optimizing total energy expenditure (either by increasing intensity or total exercise volume) is related to greater favourable changes in cardiovascular risk and physical fitness.⁴⁸⁶ Moderate-intensity continuous training is the most feasible and cost-effective aerobic training modality for patients with CCS. High-intensity interval training can be prescribed in selected patients for specific targets of intervention (e.g. to increase VO₂ peak).⁴⁸⁵

Resistance exercise in addition to aerobic training is associated with lower risks of total cardiovascular events and all-cause mortality.¹⁶ The suggested prescription is one to three sets of 8–12 repetitions, at the intensity of 6%–80% of the individual’s one-repetition maximum, at a frequency of at least 2 days per week, using a variety of 8–10 different exercises involving each major muscle group.^16,484

Exercise is contraindicated in patients with refractory/unstable angina and other high-risk cardiovascular conditions (e.g. high-grade arrhythmias, decompensated HF, severe aortic dilatation, active thrombo-embolic disease). In non-cardiac unstable conditions (e.g. active infection, uncontrolled diabetes, end-stage cancer, chronic obstructive pulmonary disease exacerbation), exercise is contraindicated. Maintenance of the prescribed exercise regimen is crucial. According to a meta-regression analysis, no single exercise component predicts mortality outcomes, whereas the largest reductions in total and cardiovascular mortality were seen in post-cardiac rehabilitation patients with the highest adherence rate.⁴⁸⁷ In addition, continuation of the exercise therapy (Phase III cardiac rehabilitation) is recommended as it will result in increased/maintained functional capacity, QoL, and physical activity levels.⁴⁸⁸

Sharing decision-making and offering a personalized prescription, based on the patient’s preferences (self-selected training) and abilities (age, concomitant diseases, leisure and working habits, logistical restraints), is recommended to increase long-term adherence.⁴⁸⁹ In addition, smartphone applications⁴⁹⁰ and wearable activity trackers⁴⁹¹ may assist in long-term adherence to physical activity goals and exercise therapy (see Section 6.2.1.3).⁴⁹²

Home-based cardiac rehabilitation with or without telemonitoring may increase participation and be as effective as centre-based cardiac rehabilitation.⁴⁹³ Telehealth interventions are more effective than no intervention and may also complement conventional cardiac rehabilitation.^494,495 Also, mobile device-based healthcare (mHealth) delivery through smartphones may be as effective as traditional centre-based cardiac rehabilitation, showing significant improvements in health-related QoL.⁴⁹⁶

Small, single-centre studies on exercise training in patients with INOCA show that it is feasible and improves cardiorespiratory function and QoL.⁴⁹⁷ Larger trials are needed to determine the optimal rehabilitation protocols and define its long-term benefits.

Recommendation Table 15

Recommendations for cardiovascular risk reduction, lifestyle changes, and exercise interventions in patients with established chronic coronary syndrome (see also Evidence Table 15)

4.2. Antianginal/anti-ischaemic medication

4.2.1. General strategy

In patients with CCS, antianginal medical therapy aims to control symptoms while ensuring acceptable tolerability and patient adherence. Several factors should be considered for the selection of antianginal medical therapy. First, there is no robust evidence from direct comparisons that some antianginal drugs are more effective than others for improving symptoms.^504,505 There have been no large randomized trials comparing head-to-head the historically first approved antianginal medications [i.e. beta-blockers or calcium channel blockers (CCBs)] vs. newer anti-ischaemic drugs (ivabradine, nicorandil, ranolazine, trimetazidine);^504,506 the latter have been tested in smaller trials assessing non-inferiority compared with beta-blockers⁵⁰⁷ or CCBs,⁵⁰⁸ or in a larger trial as add-on therapy with a background of beta-blockers and/or CCBs.^508,509 Moreover, there is no evidence that any antianginal medication may improve long-term cardiovascular outcomes, except beta-blockers if administered within 1 year after an acute MI.⁵¹⁰ Second, many patients require a combination of anti-ischaemic drugs to adequately control symptoms.⁵¹¹ It remains unclear whether upfront combination therapy with two antianginal drugs is preferable to monotherapy, or which combinations of antianginal classes may be better than others for improving angina symptoms. Third, in any given patient, myocardial ischaemia and angina symptoms may be caused by various underlying pathophysiological mechanisms, alone or in combination;^6,512 these may include obstruction of epicardial coronary arteries, vasospasm, and endothelial/microvascular dysfunction. Based on their mechanisms of action, different classes of antianginal drugs may be preferable (as initial therapy or as part of combination therapy) for patients with myocardial ischaemia of predominantly obstructive, vasospastic, or microvascular origin.⁵¹³

The current empirical paradigm for the selection of antianginal medical therapy has consisted of a hierarchical, stepwise approach including first-line (beta-blockers, CCBs) and second-line drugs (long-acting nitrates, nicorandil, ranolazine, ivabradine, trimetazidine).^1,514 This task force reinforces the concept that medical therapy for symptom control in CCS should be tailored to each patient’s haemodynamic profile (BP, heart rate), comorbidities (particularly presence of HF), concomitant medications with potential drug interactions, and preferences, also taking into account the pathophysiological basis of myocardial ischaemia in each patient, as well as local availability of different drugs.^515,516 For many patients with CCS, initial drug therapy should include a beta-blocker and/or a CCB. Other antianginal drugs (long-acting nitrates, ivabradine, nicorandil, ranolazine, trimetazidine) can be added on top of a beta-blocker and/or a CCB, or as a part of initial combination therapy in appropriately selected patients (Figure 9).

Figure 9

Possible combinations of antianginal drugs.

CAD, coronary artery disease; CCB, calcium channel blocker; COPD, chronic obstructive pulmonary disease; HCM, hypertrophic cardiomyopathy; HFrEF, heart failure with reduced ejection fraction. The schematic shows useful combinations (green lines), combinations that are not recommended (red lines), possible combinations (solid blue lines), and drugs with similar effects (blue dashed lines), which can be combined in selected indications: HFrEF (ivabradine and beta-blocker), atrial fibrillation (diltiazem/verapamil and beta-blocker), vasospastic angina (dihydropyridine CCB and nitrates). Modified from Davies et al.⁵⁵⁵.

Regardless of the initial strategy, response to initial antianginal therapy should be reassessed, and treatment should be adapted if adequate angina control is not achieved or if the initial treatment is poorly tolerated.

A review of the antianginal agents that can be used in the medical treatment of CCS can be found in the Supplementary data.

4.2.2. Beta blockers

Beta-blockers can be used for symptomatic relief of angina, or to improve prognosis in some patients with CCS. If used for antianginal purposes, the aim should be to lower resting heart rate to 55–60 beats per minute (b.p.m.).^517,518

Beyond improving symptoms, the clinical benefit of beta-blockers in patients with CAD without prior MI and with normal LVEF is largely unknown in the absence of evidence from RCTs. The main findings of some observational studies addressing this issue are summarized in the Supplementary data.

The clinical benefit of beta-blockers in post-ACS patients with reduced LVEF is supported by solid evidence.^519–521 However, there are no large RCTs supporting the prescription of beta-blockers after uncomplicated ACS in patients with LVEF >40%.⁵²² The evidence provided by observational studies and meta-analyses is conflicting (some suggest an association between beta-blockers and better clinical outcomes, whereas others show a lack of association).^{521,523–526} There have been only two open-label trials testing the efficacy of beta blockers in post-MI patients (NCT03278509 and NCT01155635), though both trials were underpowered to yield solid conclusions.⁵²⁷ To further elucidate the benefit of beta-blockers in this clinical scenario, three European pragmatic, prospective, large-scale RCTs recruiting post-ACS patients with preserved LVEF to receive beta-blockers or control treatment are currently underway.^{522,528–530}

The duration of beta-blocker therapy, in the long run, is a matter of debate, particularly in patients with prior MI and preserved LVEF.⁵³¹ Evidence from RCTs assessing beta-blockers rarely goes beyond a few years of follow-up, but patients are often given continuous treatment up to old age.⁵³¹ Observational data are also conflicting in this regard. One study has suggested that the clinical benefit of beta-blockers might be restricted to the first year after the index event, showing that their discontinuation at 1 year was not associated with higher 5-year mortality.⁵³² In contrast, a Swedish study starting the follow-up 1 year after the ACS episode has shown a lack of association between the use of beta-blockers and a composite of all-cause mortality, MI, unscheduled revascularization, or hospitalization for HF.⁵³³ Another study has shown that the discontinuation of beta-blockers beyond 1 year after acute MI was associated with an increased risk of a composite of death or readmission for ACS, but not of all-cause mortality.⁵³⁴ The impact of beta-blocker withdrawal 6–12 months after uncomplicated ACS in patients with LVEF ≥40% is being tested in two large-scale RCTs (NCT03498066, NCT04769362.⁵³⁵

Recommendation Table 16

Recommendations for antianginal drugs in patients with chronic coronary syndrome (see also Evidence Table 16)

4.2.3. Combination therapy

The aim of antianginal medications is to ensure adequate relief of angina symptoms in patients with CCS, in part independently of their effect or lack of effect on MACE. Initiation of monotherapy, with subsequent escalation to a combination of antianginal drugs in the case of inadequate relief of symptoms, is a reasonable approach. In this context, the empirical approach of starting with a beta-blocker can be recommended in many patients with CCS, unless there are contraindications or other drugs are more suitable instead of beta-blockers (e.g. patients with low heart rate and/or BP). If a combination of antianginal drugs is required, the selection of the most appropriate drugs should be individualized and determined by the haemodynamic profile, comorbidities, and tolerability. The combination of a beta-blocker with a dihydropyridine CCB is appropriate for most patients, whereas the addition of other antianginal drugs (long-acting nitrates, ranolazine, nicorandil, trimetazidine, or ivabradine in patients with LV systolic dysfunction) can be considered when treatment with a beta-blocker and/or CCB is contraindicated or poorly tolerated, or when angina symptoms are inadequately controlled.

The following points should additionally be kept in mind: (i) beta-blockers are not indicated in the presence of sick sinus syndrome or atrioventricular conduction disorders,⁵⁵⁴ and should be used with caution in patients with PAD and chronic obstructive pulmonary disease; (ii) CCBs require caution in patients with heart failure with reduced ejection fraction (HFrEF);⁵²⁶ (iii) ivabradine should not be combined with non-dihydropyridine CCBs (verapamil or diltiazem); and (iv) ranolazine and trimetazidine are reasonable options as part of antianginal combination therapy in patients with low heart rate and/or BP.

4.3. Medical therapy for event prevention

Prevention of coronary ischaemic events is based on lowering the risk of coronary artery occlusion and consequent ACS. Medical event-preventing therapies include antithrombotic, lipid-lowering, anti-RAAS (renin–angiotensin–aldosterone system), anti-inflammatory, and metabolic-acting agents.

4.3.1. Antithrombotic drugs

The standard antithrombotic treatment of patients with epicardial atherosclerotic CAD is single antiplatelet therapy (SAPT), typically with aspirin. In patients with ACS or post-PCI, standard treatment is dual antiplatelet therapy (DAPT) with aspirin and an oral P2Y₁₂ inhibitor, for a duration of 12 months after ACS (with or without PCI)⁶⁵ or 6 months after CCS-PCI.^1,556 Thus, in ACS or CCS-PCI patients, DAPT is usually replaced by SAPT at some point. Several recent trials have investigated shortened DAPT durations and P2Y₁₂ inhibitor monotherapy post-PCI to reduce the risk of bleeding. On the other hand, in CCS patients with persistently high ischaemic risk and low bleeding risk, extended intensified antithrombotic therapy should be considered. Ultimately, the choice and duration of antithrombotic regimens largely depend on the delicate balance between each individual’s ischaemic and bleeding risks.

The mechanisms of action of the most commonly used antithrombotic drugs in CCS patients are depicted in Figure 10.

Figure 10

Antithrombotic drugs for chronic coronary syndromes: pharmacological targets.

ADP, adenosine diphosphate; FVIIa, activated factor VII; FXa, activated factor X; GP, glycoprotein; PAR, protease-activated receptor; TF, tissue factor; TxA₂, thromboxane A2; UFH, unfractionated heparin; VKA, vitamin K antagonist. Orally administered drugs are shown on a blue background, parenterally administered ones on red. Aspirin prevents TxA2 formation by acetylating platelet cyclooxygenase-1.

4.3.1.1. Antiplatelet drugs

For details on antiplatelet drugs, please see Supplementary data, Table S1.

Aspirin monotherapy

Low-dose aspirin (75–100 mg once daily) is the traditional drug of choice in patients with CCS, with or without prior MI.^557,558 In an individual-patient data meta-analysis of secondary prevention trials (43 000 patient-years), aspirin vs. no aspirin significantly reduced the combined risk of non-fatal MI, non-fatal ischaemic stroke, or death from vascular causes [from 8.2% to 6.7% per year (P < .0001), with relative risk (RR) reductions of 31%, 22%, and 9%, respectively], translating into 15 fewer fatal and non-fatal serious vascular events for every 1000 patients treated for 1 year.⁵⁵⁸ Aspirin allocation increased major gastrointestinal (GI) and extracranial bleeds, from 0.07% to 0.10% per year (P < .0001), with a non-significant increase in haemorrhagic stroke but reductions of about a fifth in total stroke (from 2.54% to 2.08% per year, P = .002) and in coronary events (from 5.3% to 4.3% per year, P < .0001).

Thus, for secondary prevention, the reduction of ischaemic events with aspirin outweighs serious bleeding events.^557,558 There is no evidence of different aspirin effects in women and men.^558,559 Daily aspirin doses of 75–100 mg seem to be as effective as higher doses for long-term treatments.^558–561

Oral P2Y₁₂ inhibitor monotherapy

Clopidogrel monotherapy

In addition to the cyclooxygenase-I pathway inhibited by aspirin, the platelet P2Y₁₂ receptor also plays a pivotal role in arterial thrombus formation and is the target for three oral platelet inhibitors: clopidogrel, prasugrel, and ticagrelor. The relative efficacy and safety of clopidogrel compared with aspirin for secondary prevention in CCS patients has been tested in multiple randomized trials that, taken together, have involved over 29 000 patient-years.^562,563

In an overall population of 19 185 patients with either previous MI (within 35 days), stroke (within 6 months), or PAD, followed for a mean of 1.9 years, the CAPRIE trial (Clopidogrel versus Aspirin in Patients at Risk of Ischaemic Events) demonstrated a small benefit in ischaemic events (RR reduction of 8.7%) with clopidogrel 75 mg/day vs. aspirin 325 mg/day.⁵⁶⁴

In the recent, open-label, South Korean, non-inferiority HOST-EXAM (Harmonizing Optimal Strategy for Treatment of Coronary Artery Stenosis-EXtended Antiplatelet Monotherapy) trial, clopidogrel was compared with low-dose aspirin in 5530 patients after 6–18 months of uneventful DAPT post-PCI (72% initial ACS, 28% initial CCS).⁵⁶⁵ Relative to aspirin, clopidogrel reduced the composite of all-cause death, non-fatal MI, readmission attributable to ACS, stroke, and BARC (Bleeding Academic Research Consortium) ≥3 bleeding from 7.7% to 5.7% at the end of the 2-year follow-up; the results were maintained at 5.8 years, in a post hoc, per-protocol, post-trial analysis.⁵⁶⁶

A very recent individual patient-level meta-analysis examined seven trials involving 24 325 patients (including recent ACS, post-CABG, or initial CCS patients) randomized to either aspirin monotherapy (12 147 patients) or P2Y₁₂ inhibitor monotherapy [clopidogrel in 7545 (62.0%), ticagrelor in 4633 (38.0%)] and followed for 6–36 months.⁵⁶² P2Y₁₂ inhibitors reduced the combined ischaemic outcome of cardiovascular death, MI, and stroke compared with aspirin (in doses of 100 or 325 mg daily), mainly through reduction of infarction. The risk of major bleeding was similar, whereas GI bleeding and haemorrhagic stroke occurred less frequently with a P2Y₁₂ inhibitor. The treatment effect was consistent across pre-specified subgroups (ACS or CCS) and type of P2Y₁₂ inhibitor.⁵⁶²

The above overall evidence supports clopidogrel monotherapy as an effective and safe alternative to aspirin monotherapy for long-term secondary prevention in patients with CCS.

Ticagrelor monotherapy

Since ticagrelor compared with clopidogrel is more effective and displays less variable platelet inhibition,^567,568 although with greater bleeding potential,⁵⁶⁹ ticagrelor monotherapy has been compared with aspirin monotherapy for secondary prevention in CCS patients treated with PCI.

The RCT GLOBAL LEADERS trial [Ticagrelor plus aspirin for 1 month, followed by ticagrelor monotherapy for 23 months vs. aspirin plus clopidogrel or ticagrelor for 12 months, followed by aspirin monotherapy for 12 months after implantation of a drug-eluting stent (DES): a multicentre, open-label, randomized superiority trial]⁵⁷⁰ of 15 968 patients (53% with initial CCS) did not show superiority of ticagrelor monotherapy vs. standard of care in terms of survival or new Q-wave MI.⁵⁷⁰ A pre-specified GLOBAL LEADERS ancillary analysis of independently adjudicated outcomes in 7585 patients reported non-inferiority for ischaemic events and no difference in BARC major bleeding between the two strategies.⁵⁷¹ A post hoc landmark analysis of the GLOBAL LEADERS trial, conducted in 11 121 uneventful patients at 1 year (53% CCS from trial onset, 47% transitioning to CCS from ACS), showed reduced ischaemic events, but increased BARC 3 and 5 major bleeding, during ticagrelor monotherapy compared with aspirin monotherapy from 1 to 2 years after PCI.⁵⁷²

The double-blind, non-inferiority TWILIGHT trial, conducted in 7119 patients [35% CCS, 65% NSTE (non-ST-segment elevation)-ACS] undergoing high-risk PCI (defined as multivessel, stenting of >30 mm, thrombotic, two-stent bifurcation, left main, proximal LAD, or atherectomy-treated calcified lesions) and uneventfully receiving 3 months of ticagrelor-based DAPT after PCI, showed that ticagrelor monotherapy 90 mg b.i.d. (twice daily) compared with ticagrelor-based DAPT for an additional 12 months significantly reduced the primary endpoint of clinically relevant bleeds (BARC 2, 3, and 5, or BARC 3 and 5), with no significant increase in the composite of any death, MI, or stroke (3.9% in both groups).⁵⁷³

The above trial data^570–573 and meta-analytical data^562,563,574 suggest that ticagrelor monotherapy may be an option for selected CCS or stabilized post-ACS patients treated with PCI. However, the overall evidence is weaker than for other recommended antithrombotic strategies. Moreover, the optimal timing and duration (longest tested duration 23 months) are unclear. Only the 90 mg b.i.d. regimen has been tested as monotherapy.^573,575 Data on prasugrel monotherapy for CCS patients are limited to a single-armed, open-label study with 3 months of follow-up.⁵⁷⁶

In summary, for long-term secondary prevention in CCS patients without an indication for oral anticoagulant (OAC), aspirin or, as an alternative, clopidogrel monotherapy are generally recommended. In selected patients at high ischaemic risk without high bleeding risk (HBR), ticagrelor monotherapy may be considered [at the time of writing not contemplated by the European Medicines Agency (EMA) (https://www.ema.europa.eu/en/medicines/human/EPAR/brilique)] with a lower level of evidence than for aspirin or clopidogrel (Figure 11). Details on the pharmacology of antiplatelet drugs^{567,577–582} and on the randomized evidence (including trial limitations) can be found in the Supplementary data, Table S1 and in the evidence tables.

Dual antiplatelet therapy post-percutaneous coronary intervention

After PCI for CCS, DAPT consisting of aspirin and clopidogrel is recommended to reduce the risk of stent thrombosis and MI compared with aspirin alone.⁵⁵⁶ With few exceptions, there is no reason to replace clopidogrel with ticagrelor, based on the ALPHEUS (Assessment of Loading with the P2Y₁₂ Inhibitor Ticagrelor or Clopidogrel to Halt Ischemic Events in Patients Undergoing Elective Coronary Stenting) trial results demonstrating, in 1883 patients followed for 30 days, that ticagrelor did not significantly reduce PCI-related MI or major myocardial injury, while minor bleeding was significantly increased compared with clopidogrel.⁵⁸³

In the THEMIS trial (The Effect of Ticagrelor on Health Outcomes in diabEtes Mellitus patients Intervention Study) of 19 220 CCS patients aged ≥50 years, with type 2 DM and no previous MI or stroke (58% with prior PCI), ticagrelor plus low-dose aspirin marginally reduced ischaemic events compared with placebo plus aspirin at a median follow-up of 40 months, but increased major bleeding, including intracranial haemorrhage.⁵⁸⁴

A default DAPT duration of 6 months is recommended for CCS patients undergoing PCI.⁵⁵⁶ However, multiple RCTs have investigated shorter DAPT durations (1 or 3 months) to decrease the risk of bleeding.^{570,573,585–588} The combined evidence indeed shows a decrease in—mostly minor—bleeding, without an increase in ischaemic events, indicating that a shorter duration of DAPT of 1–3 months post-PCI may benefit CCS patients who are not at high ischaemic risk or who are at HBR.

This concept was tested in the MASTER-DAPT trial (Management of High Bleeding Risk Patients Post Bioresorbable Polymer Coated Stent Implantation with an Abbreviated versus Standard DAPT Regimen), randomizing 4579 PCI patients (∼50% CCS) with HBR, after 1-month uneventful DAPT, to immediate DAPT discontinuation or to DAPT continuation for at least 2 additional months.⁵⁸⁷ After 335 days, the trial demonstrated that discontinuation was non-inferior for ischaemic events compared with standard duration of DAPT, but major and clinically relevant non-major bleeding was reduced.⁵⁸⁷

A meta-analysis, including 11 RCTs and 9006 patients (42% CCS) at HBR [defined by a PREdicting bleeding Complications In patients undergoing Stent implantation and subsEquent Dual AntiPlatelet Therapy (PRECISE-DAPT) score of >25 or by Academic Research Consortium for High Bleeding Risk (ARC-HBR) criteria, listed in Supplementary data, Table S2]^589–591 showed at 12 months of follow-up that an abbreviated DAPT of 1–3 months reduced both major bleeding and ischaemic events, as well as cardiovascular mortality, compared with standard DAPT, irrespective of CCS or ACS presentation.⁵⁹¹

The overall data indicate that, in CCS patients with HBR, DAPT discontinuation 1–3 months after PCI is recommended, while in patients without HBR, DAPT duration may be reduced only in the absence of high ischaemic risk (Figure 11). For patients at high ischaemic risk without HBR, see below.

Figure 11

Antithrombotic treatment in chronic coronary syndrome patients undergoing percutaneous coronary intervention.

ARC-HBR, Academic Research Consortium for High Bleeding Risk; b.i.d., bis in die (twice daily); CCS, chronic coronary syndrome; CYP2C19, cytochrome P450 2C19; DAPT, dual antiplatelet therapy; mo., months; OAC, oral anticoagulant; o.d., once daily; PCI, percutaneous coronary intervention; PRECISE-DAPT, PREdicting bleeding Complications In patients undergoing Stent implantation and subsEquent Dual Anti Platelet Therapy. ^aIn CCS patients undergoing high-thrombotic risk stenting (e.g. complex left main stem, 2-stent bifurcation, suboptimal stenting result, prior stent thrombosis, previously known CYP2C19*2/*3 polymorphisms), prasugrel or ticagrelor (in addition to aspirin) may be considered instead of clopidogrel for the first month, and up to 3-6 months. ^bPrasugrel 5 mg o.d. for patients aged ≥75 years or with a body weight <60 kg. Bleeding risk criteria according to PRECISE-DAPT or ARC-HBR.

Extended intensified antithrombotic therapy

In patients at high ischaemic risk without HBR, there are three options for intensifying antithrombotic therapy to prevent ischaemic events, albeit at the cost of increased bleeding: (i) continue DAPT, consisting of aspirin and clopidogrel or of aspirin and prasugrel after PCI, based on the results of the DAPT Study;⁵⁹² (ii) add ticagrelor to aspirin in post-MI patients, based on the PEGASUS-TIMI (Prevention of Cardiovascular Events in Patients with Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin - Thrombolysis In Myocardial Infarction) 54 trial;⁵⁹³ or (iii) add very low-dose rivaroxaban to aspirin in CCS patients, based on the COMPASS trial (Cardiovascular Outcomes for People Using Anticoagulant Strategies).⁵⁹⁴

The randomized DAPT Study demonstrated, in patients at 1-year post-PCI, that an additional 18 months of DAPT reduced ischaemic events compared with aspirin alone, but moderate and severe GUSTO (Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Arteries) or BARC bleeding rates were higher, and all-cause death tended to be increased.⁵⁹² Of note, in the DAPT Study, first-generation DES were used with an increased risk of stent thrombosis.

The PEGASUS-TIMI 54 trial showed that in aspirin-treated patients with a history of MI 1–3 years previously and at least one high-risk characteristic (i.e. aged >65 years, DM, second MI, multivessel CAD, or CKD), ticagrelor (90 or 60 mg b.i.d.) vs. placebo reduced ischaemic events at 3 years, while it increased TIMI (Thrombolysis In Myocardial Infarction) major, but not fatal, bleeding.⁵⁹³ The 60 mg dose was safer and better tolerated than the 90 mg dose^584,593 and therefore approved. The subgroups of patients with (compared with those without) DM, multivessel CAD, and PAD benefited more from ticagrelor.^595–597

The COMPASS trial demonstrated that the combination of aspirin plus rivaroxaban 2.5 mg b.i.d., but not rivaroxaban 5.0 mg b.i.d. monotherapy, reduced ischaemic events, but increased modified-ISTH (International Society on Thrombosis and Haemostasis) major bleeding, compared with aspirin alone in patients with stable atherosclerotic disease (mostly CAD, with additional risk conditions if younger than 65 years).⁵⁹⁴ There was no significant difference in intracranial or fatal bleeding between the two treatment arms, and death rates were lower in the aspirin plus rivaroxaban 2.5 mg b.i.d. group. Subgroups of patients with (compared with those without) DM, PAD, mild CKD, and active smoking habit benefited more from aspirin plus rivaroxaban.^594,598

Patient eligibility for extended intensified antithrombotic therapy must be defined taking into account individual patient characteristics (see Supplementary data, Table S2), as well as study inclusion and exclusion criteria. The different options are described in Table 8.

Table 8

Options for extended intensified antithrombotic therapy

Drug	Dose	Clinical setting	NNT (ischaemic outcomes)	NNH (bleeding outcomes)
Co-administered with aspirin 100 mg o.d.
Rivaroxaban (COMPASS trial; vs. placebo)	2.5 mg b.i.d.	Patients with CAD or symptomatic PAD at high risk of ischaemic events	77	84 (modified-ISTH major bleeding)
Co-administered with low-dose aspirin 75–162 mg o.d.
Clopidogrel, (6505/9961 of DAPT trial; vs. placebo)	75 mg/day	Post MI in patients who have tolerated DAPT for 1 year (25% ACS, 22% previous MI)	63	105 (moderate and severe GUSTO bleeds, or BARC 2, 3, and 5 bleeds)
Prasugrel, (3456/9961 of DAPT trial; vs. placebo)	10 mg/day (5 mg/day if body weight <60 kg or age ≥75 years)	Post PCI for MI in patients who have tolerated DAPT for 1 year	63	105 (as above)
Ticagrelor (PEGASUS-TIMI 54; vs. placebo)	60/90 mg b.i.d.	Post-MI in patients who have tolerated DAPT for 1 year	84	81 (TIMI major bleeds)

Drug	Dose	Clinical setting	NNT (ischaemic outcomes)	NNH (bleeding outcomes)
Co-administered with aspirin 100 mg o.d.
Rivaroxaban (COMPASS trial; vs. placebo)	2.5 mg b.i.d.	Patients with CAD or symptomatic PAD at high risk of ischaemic events	77	84 (modified-ISTH major bleeding)
Co-administered with low-dose aspirin 75–162 mg o.d.
Clopidogrel, (6505/9961 of DAPT trial; vs. placebo)	75 mg/day	Post MI in patients who have tolerated DAPT for 1 year (25% ACS, 22% previous MI)	63	105 (moderate and severe GUSTO bleeds, or BARC 2, 3, and 5 bleeds)
Prasugrel, (3456/9961 of DAPT trial; vs. placebo)	10 mg/day (5 mg/day if body weight <60 kg or age ≥75 years)	Post PCI for MI in patients who have tolerated DAPT for 1 year	63	105 (as above)
Ticagrelor (PEGASUS-TIMI 54; vs. placebo)	60/90 mg b.i.d.	Post-MI in patients who have tolerated DAPT for 1 year	84	81 (TIMI major bleeds)

ACS, acute coronary syndrome; BARC, Bleeding Academic Research Consortium; b.i.d., bis in die (twice daily); CAD, coronary artery disease; DAPT, dual antiplatelet therapy; GUSTO, Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Arteries; ISTH, International Society on Thrombosis and Haemostasis; MI, myocardial infarction; NNH, number needed to cause a harmful event; NNT, number needed to treat to prevent an adverse event; o.d., once daily; PAD, peripheral artery disease; PCI, percutaneous coronary intervention; TIMI, Thrombolysis In Myocardial Infarction. Drugs (in addition to aspirin 75–100 mg/day) for extended DAPT options are listed in alphabetical order. For definitions of highly/moderately increased ischaemic and bleeding risk see Supplementary data, Tables S2 and S3. NNT refers to the primary ischaemic endpoints and NNH refers to the key safety endpoints of the respective trials. NNT and NNH from the DAPT trial are pooled numbers for clopidogrel and prasugrel.

Table 8

Options for extended intensified antithrombotic therapy

Drug	Dose	Clinical setting	NNT (ischaemic outcomes)	NNH (bleeding outcomes)
Co-administered with aspirin 100 mg o.d.
Rivaroxaban (COMPASS trial; vs. placebo)	2.5 mg b.i.d.	Patients with CAD or symptomatic PAD at high risk of ischaemic events	77	84 (modified-ISTH major bleeding)
Co-administered with low-dose aspirin 75–162 mg o.d.
Clopidogrel, (6505/9961 of DAPT trial; vs. placebo)	75 mg/day	Post MI in patients who have tolerated DAPT for 1 year (25% ACS, 22% previous MI)	63	105 (moderate and severe GUSTO bleeds, or BARC 2, 3, and 5 bleeds)
Prasugrel, (3456/9961 of DAPT trial; vs. placebo)	10 mg/day (5 mg/day if body weight <60 kg or age ≥75 years)	Post PCI for MI in patients who have tolerated DAPT for 1 year	63	105 (as above)
Ticagrelor (PEGASUS-TIMI 54; vs. placebo)	60/90 mg b.i.d.	Post-MI in patients who have tolerated DAPT for 1 year	84	81 (TIMI major bleeds)

Drug	Dose	Clinical setting	NNT (ischaemic outcomes)	NNH (bleeding outcomes)
Co-administered with aspirin 100 mg o.d.
Rivaroxaban (COMPASS trial; vs. placebo)	2.5 mg b.i.d.	Patients with CAD or symptomatic PAD at high risk of ischaemic events	77	84 (modified-ISTH major bleeding)
Co-administered with low-dose aspirin 75–162 mg o.d.
Clopidogrel, (6505/9961 of DAPT trial; vs. placebo)	75 mg/day	Post MI in patients who have tolerated DAPT for 1 year (25% ACS, 22% previous MI)	63	105 (moderate and severe GUSTO bleeds, or BARC 2, 3, and 5 bleeds)
Prasugrel, (3456/9961 of DAPT trial; vs. placebo)	10 mg/day (5 mg/day if body weight <60 kg or age ≥75 years)	Post PCI for MI in patients who have tolerated DAPT for 1 year	63	105 (as above)
Ticagrelor (PEGASUS-TIMI 54; vs. placebo)	60/90 mg b.i.d.	Post-MI in patients who have tolerated DAPT for 1 year	84	81 (TIMI major bleeds)

ACS, acute coronary syndrome; BARC, Bleeding Academic Research Consortium; b.i.d., bis in die (twice daily); CAD, coronary artery disease; DAPT, dual antiplatelet therapy; GUSTO, Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Arteries; ISTH, International Society on Thrombosis and Haemostasis; MI, myocardial infarction; NNH, number needed to cause a harmful event; NNT, number needed to treat to prevent an adverse event; o.d., once daily; PAD, peripheral artery disease; PCI, percutaneous coronary intervention; TIMI, Thrombolysis In Myocardial Infarction. Drugs (in addition to aspirin 75–100 mg/day) for extended DAPT options are listed in alphabetical order. For definitions of highly/moderately increased ischaemic and bleeding risk see Supplementary data, Tables S2 and S3. NNT refers to the primary ischaemic endpoints and NNH refers to the key safety endpoints of the respective trials. NNT and NNH from the DAPT trial are pooled numbers for clopidogrel and prasugrel.

In summary, in high ischaemic risk CCS patients without HBR, either aspirin plus ticagrelor 60 mg b.i.d. or aspirin plus rivaroxaban 2.5 mg b.i.d. should be considered, based on patient characteristics (Figure 11). DAPT prolongation with clopidogrel or prasugrel may also be an option, although the evidence for this choice suffers limitations. In patients with extended intensified antithrombotic therapy, re-evaluation of bleeding and ischaemic risk at regular intervals is essential. Randomized evidence beyond study follow-up times is unavailable.

Genotype- and phenotype-guided dual antiplatelet therapy

There is high laboratory interindividual variability in patients treated with clopidogrel, with patients who carry a cytochrome P450 2C19 (CYP2C19) loss-of-function allele having less platelet inhibition and a higher risk of ischaemic events post-PCI compared with non-carriers.^599,600 In ST-segment elevation myocardial infarction (STEMI) patients, early de-escalation from aspirin plus ticagrelor or aspirin plus prasugrel to aspirin plus clopidogrel based on genotyping or platelet function testing was non-inferior for net adverse clinical events (ischaemic endpoints and bleeding combined) compared with routine treatment with ticagrelor or prasugrel.^601,602 In patients with CCS, current evidence does not support the routine use of genotype or platelet function testing.^602–607 However, in patients undergoing high-risk PCI who are known carriers of a CYP2C19 loss-of-function allele, replacing aspirin plus clopidogrel with aspirin plus ticagrelor or prasugrel is a reasonable option.^600,607,608

4.3.1.2. Anticoagulant therapy

Monotherapy with oral anticoagulant

Historical randomized data from patients with recent MI not undergoing PCI, followed for up to 4 years, showed that OAC monotherapy with a vitamin K antagonist (VKA) targeted to an international normalized ratio (INR) of about 3.0–4.0 was at least as effective as low-dose aspirin in preventing MACE, but with a significant increase in major bleeding.^609,610 Moreover, given the obsoletely high INR target and the cumbersome management, VKA has not gained popularity for secondary prevention in patients with CCS. Successful introduction of the direct oral anticoagulants (DOACs) for stroke prevention in AF and for prevention and treatment of venous thrombo-embolism (VTE) has renewed the interest in OAC for patients with CAD. The COMPASS trial in CCS and/or PAD patients at high ischaemic risk, however, reported no significant ischaemic benefit of rivaroxaban monotherapy 5 mg twice daily over aspirin alone, with a significantly higher incidence of modified-ISTH major bleeding, although not of fatal bleeding.⁵⁹⁴

Thus, in CCS patients without a concomitant long-term indication for OAC, OAC monotherapy with either VKA or rivaroxaban (the only DOAC currently tested in this context) is not recommended. OAC may be considered, however, when antiplatelet agents are not tolerated, if the risk of bleeding is not high,^594,611 or in CCS patients with a concomitant long-term indication for OAC (see below).

Combination of anticoagulant and antiplatelet therapy after percutaneous coronary intervention in chronic coronary syndrome patients with AF or other indication for oral anticoagulant

Approximately one in five patients with AF need to undergo PCI, with a theoretical indication for both OAC for stroke prevention (for which DOACs are preferred to VKA) and DAPT for stent thrombosis and MI prevention, leading to triple antithrombotic therapy.^612,613 The combination of an OAC plus DAPT, however, leads to an increased bleeding risk, and major bleeding is associated with earlier mortality and should therefore be avoided when possible.⁶¹⁴ In this setting, the results of five RCTs have shown that double compared with triple antithrombotic therapy reduced major or clinically relevant non-major bleeding, without a significant increase of ischaemic events, leading to the recommended use of double antithrombotic therapy (OAC plus P2Y₁₂ receptor inhibitor, mostly clopidogrel) after a 1–4 week period of triple antithrombotic therapy in CCS patients with AF undergoing PCI.^615–620

The AUGUSTUS trial (Open-Label, 2 × 2 Factorial, Randomized Controlled, Clinical Trial to Evaluate the Safety of Apixaban versus Vitamin K Antagonist and Aspirin versus Aspirin Placebo in Patients with AF and Acute Coronary Syndrome or Percutaneous Coronary Intervention) additionally demonstrated that the DOAC apixaban reduced major or clinically relevant non-major bleeding compared with VKA, independently of a double or triple antithrombotic regimen.⁶¹⁹ The AUGUSTUS trial and several meta-analyses demonstrated that aspirin compared with placebo reduced stent thrombosis events, which occurred mainly during the first 30 days after PCI and not thereafter, while increasing bleeding risk.^620–622

Thus, based on the combined evidence, double antithrombotic therapy with a DOAC and clopidogrel for up to 12 months should be standard care for CCS patients with AF undergoing PCI, with additional aspirin only for a limited initial period (from during PCI up to a maximum of 30 days in patients at high ischaemic risk). In patients with the highest bleeding risk, clopidogrel discontinuation at 6 (or even 3) months post-PCI and continuation of OAC alone may be considered when ischaemic risk is not high [Class IIb/level of evidence (LOE) C]. Ticagrelor or prasugrel should generally not be used as part of triple antithrombotic therapy, while ticagrelor, and possibly prasugrel (although specific data are not available), may be considered as part of double antithrombotic therapy when there is a very high risk of stent thrombosis and a low bleeding risk.^619,623,624

After a 6- to 12-month period of double antithrombotic therapy, in most AF-PCI CCS patients, OAC alone is preferred over continuation of double antithrombotic therapy.^625,626 An open-label randomized trial, conducted in 2236 Japanese AF patients who had undergone PCI (71% of patients) or CABG (11% of patients) >1 year before or had known CAD not requiring revascularization, compared rivaroxaban monotherapy (15 or 10 mg once daily based on creatinine clearance) with rivaroxaban plus SAPT (mostly aspirin).⁶²⁷ At a median follow-up of 23 months, the occurrence of ISTH major bleeding and of all-cause deaths were each significantly lower with rivaroxaban monotherapy, whereas MACE occurrence did not differ significantly in the two treatment arms.⁶²⁷

Whether the above considerations remain valid when the indication for OAC is other than AF, e.g. mechanical heart valves (where DOACs are not indicated) or VTE, is uncertain given limited available evidence. In the absence of data regarding the efficacy for MACE prevention of rivaroxaban 10 mg once daily and apixaban 2.5 mg twice daily, which should be used for extended OAC after the first 6 months of therapeutic anticoagulation in patients with VTE,⁶²⁸ it is recommended to resume full doses of these anticoagulants in case of concomitant CCS.

4.3.1.3. Coronary artery bypass grafting and antithrombotic therapy

Low-dose aspirin is recommended lifelong in patients undergoing CABG.^629,630 Aspirin should be continued until the day of CABG and restarted as soon as there is no concern over bleeding, possibly within 24 h of CABG.^631,632 In general, other antithrombotic drugs should be stopped at intervals related to their duration of action (prasugrel stopped ≥7 days before; clopidogrel ≥5 days before; ticagrelor ≥3 days before; and rivaroxaban, apixaban, edoxaban, and dabigatran 1–2 days before, depending on drug and renal function).^633,634 Although not consistent, there is evidence that DAPT with a P2Y₁₂ receptor inhibitor compared with aspirin monotherapy provides higher graft patency rates after CABG.^635,636,637 A meta-analysis of four RCTs, involving 1316 patients (with 3079 grafts) followed for 3 to 12 months after CABG, reported superior vein graft patency with ticagrelor-based DAPT vs. aspirin alone, but with increased rates of BARC 2–5 (but not BARC 3–5) bleeds, and no significant differences in cardiovascular death, or the composite of cardiovascular death, MI, and stroke, or the composite of all-cause death, MI, stroke, and revascularization.⁶³⁵ Therefore, in patients undergoing CABG for CCS, DAPT is not routinely indicated; however, it may be considered in selected cases at increased risk of graft occlusion who are not at high bleeding risk (defined in Supplementary data, Tables S2 and S3).

Transient new-onset AF is common 2 to 3 days after CABG, occurring in approximately one-third of patients.⁶³⁸ AF after CABG is associated with a higher stroke risk,⁶³⁹ which is, however, lower than that with AF unrelated to surgery.⁶⁴⁰ The impact of early OAC initiation on patient outcomes remains unclear.^641,642 In a Danish cohort study, early OAC initiation was associated with a lower risk of thrombo-embolic events,⁶⁴¹ while in a Swedish cohort study, OAC was associated with no reduction of thrombo-embolic complications but an increased risk of major bleeding.⁶⁴²

Decisions on OAC should consider thrombo-embolic and bleeding risks, timing, and duration of post-operative AF. Longer AF durations and delayed-onset post-CABG have higher risks. We refer to the 2024 ESC Guidelines for the management of AF regarding recommendations for OAC in this context. It is unknown whether, in such patients, the combination of aspirin and OAC may be more effective compared with OAC alone in preventing ischaemic events post-CABG.

4.3.1.4. Proton pump inhibitors

Antithrombotic therapy may provoke GI bleeding, especially in patients at increased risk, such as the elderly, those with a history of GI bleeding or peptic disease, high alcohol consumption, chronic use of steroids or non-steroidal anti-inflammatory drugs (NSAIDs), or receiving a combination of antithrombotic drugs.^643–645 In patients on various types of antithrombotic therapy, proton pump inhibitors may be effective in reducing the risk of GI bleeding, in particular from gastroduodenal lesions.^646–648 In general, gastric protection with proton pump inhibitors is recommended in patients at increased risk of GI bleeding for as long as any antithrombotic therapy is administered.^65,86 Because the proton pump inhibitors omeprazole and esomeprazole inhibit CYP2C19, when administered with clopidogrel, they reduce exposure to clopidogrel’s active metabolite; while their use is discouraged in combination with clopidogrel, univocal effects of these combinations on the risk of ischaemic events or stent thrombosis have not been demonstrated (https://www.ema.europa.eu/en/medicines/human/EPAR/plavix).^643,646 Of note, proton pump inhibitors do not increase MACE vs. placebo in patients with CVD.⁶⁴⁶

Recommendation Table 17

Recommendations for antithrombotic therapy in patients with chronic coronary syndrome (see also Evidence Table 17)

4.3.2. Lipid-lowering drugs

Evidence from genetic, epidemiological, and randomized clinical studies has established the key causal role of LDL-C and other apo-B-containing lipoproteins in the development of atherosclerotic disease.⁶⁶⁹ In patients with established ASCVD, lowering of LDL-C levels reduces the risk of recurrent MACE.^128,670,671 Elevated lipid levels should be managed according to the 2019 ESC/EAS Guidelines for the management of dyslipidaemias⁶⁴ and the 2021 ESC Guidelines on cardiovascular disease prevention in clinical practice.¹⁶

Because patients with CCS are considered at very high cardiovascular risk, the treatment goal is to lower LDL-C levels to <1.4 mmol/L (<55 mg/dL) and achieve a reduction by at least 50% from baseline. For patients who experience a second vascular event within 2 years while taking maximum tolerated statin-based therapy, an even lower LDL-C goal of <1.0 mmol/L (40 mg/dL) may be considered.

In addition to exercise, diet, and weight control, which favourably affect blood lipid levels and are recommended for all patients with CCS (see Section 5.1), pharmacological treatment with a maximally tolerated dose of a potent statin is the first-line therapy recommended for all CCS patients.^128,670,671 In a landmark meta-analysis involving patients with and without ASCVD, statin treatment was shown to reduce the risk of major vascular events by 22%, all-cause mortality by 10%, and mortality due to coronary heart disease by 20% per 1.0 mmol/L of achieved reduction in LDL-C levels.⁶⁷⁰ High-intensity statin treatment (i.e. atorvastatin ≥40 mg or rosuvastatin ≥20 mg daily) reduces LDL-C levels by 45%–50% on average, although interindividual variability exists.⁶⁷² Statins should not be given when pregnancy is planned, during pregnancy, or during the breastfeeding period.⁶⁴

In many patients with CCS, statin therapy alone will not suffice to achieve the recommended LDL-C goals;⁶⁷³ hence, a combination of lipid-lowering drug therapy is required. In a trial of patients with recent ACS, the combination of statin with ezetimibe resulted in additional reduction of LDL-C levels by 20%–25% compared with simvastatin monotherapy. This LDL-C reduction translated into a modest reduction of a composite endpoint involving fatal and non-fatal events (6.4% RR reduction, 2.0% absolute risk reduction).⁶⁷⁴ Ezetimibe should be used as second-line therapy when the treatment goal is not achieved with maximally tolerated statin therapy, or as first-line therapy in the case of intolerance to any statin regimen. Proprotein convertase subtilisin/kexin type 9 inhibitors (alirocumab or evolocumab), administered subcutaneously every 2 or 4 weeks, lower LDL-C levels by 60% when added to statin therapy.⁶⁷⁵ In cardiovascular outcomes trials, these monoclonal antibodies resulted in significant reduction of non-fatal cardiovascular events, with no impact on cardiovascular mortality.^675,676 Their favourable safety profile was recently confirmed for longer follow-up (median 5 years) in open-label extension studies of the outcomes trials.⁶⁷⁷ The high cost of PCSK9 inhibitors is still a limitation for broader implementation.

Bempedoic acid is an oral cholesterol synthesis inhibitor that lowers LDL-C by approximately 18% in monotherapy and 38% when combined with ezetimibe.^678,679 In a recent cardiovascular outcomes trial including statin-intolerant patients, bempedoic acid significantly reduced MACE.⁶⁸⁰ Inclisiran, a small interfering ribonucleic acid molecule, is administered subcutaneously every 3–6 months and reduces LDL-C by approximately 50% either in combination with statin or without statin therapy.⁶⁸¹ A cardiovascular outcomes trials for inclisiran is currently underway (ClinicalTrials.gov identifier: NCT03705234).

In patients scheduled to undergo elective PCI, pre-treatment with a high-dose statin in statin-naïve patients or loading with high-dose statin in statin-treated patients has been shown to reduce the risk of periprocedural events.⁶⁸² Routine pre-treatment or loading (in the context of pre-existing statin treatment) with a high-dose statin can be considered in patients with CCS undergoing PCI.

Recommendation Table 18

Recommendations for lipid-lowering drugs in patients with chronic coronary syndrome (see also Evidence Table 18)

4.3.3. Renin–angiotensin–aldosterone blockers/angiotensin receptor neprilysin inhibitor

Modulation of the RAAS and the neprilysin inhibitor sacubitril in combination with a RAS blocker has proved beneficial in patients with HF post-MI and in patients with hypertension. In these clinical syndromes, RAAS inhibition has greatly improved morbidity and mortality. Angiotensin-converting enzyme inhibitors (ACE-Is) can reduce mortality, MI, stroke, and HF among patients with LV dysfunction,^683–685 previous vascular disease,^686–688 and high-risk DM.⁶⁸⁹ These data bring strong evidence to recommend ACE-Is [or angiotensin receptor blockers (ARBs) in cases of intolerance] for the treatment of patients with CCS with co-existing hypertension, LVEF ≤40%, DM, or CKD, unless contraindicated (e.g. severe renal impairment, hyperkalaemia, etc.). In trials that include patients with mildly reduced and preserved LV function >40%, the effect of ACE-Is to reduce all-cause death, cardiovascular death, non-fatal MI, stroke, or HF in patients with atherosclerosis is not uniform.^686,687,690 A meta-analysis, including 24 trials and 61 961 patients, documented that, in CCS patients without HF, RAAS inhibitors reduced cardiovascular events and death only when compared with placebo, but not when compared with active control treatment.⁶⁹¹ For this reason ACE-I therapy in CCS patients without HF or high cardiovascular risk is not generally recommended, unless required to meet BP targets. However, a new observational study showed that ACE-I/ARB therapy was associated with significant long-term survival benefit in patients post-PCI for STEMI/non-ST-segment elevation myocardial infarction (NSTEMI). This survival benefit is apparent in patients with both preserved and reduced LV function. These findings provide contemporary evidence to support the use of these agents in coronary patients who underwent PCI for STEMI/NSTEMI, irrespective of their baseline LV function.⁶⁹²

Sacubitril/valsartan contains an ARB and a prodrug of neprilysin inhibitor, which inhibits the degradation of endogenous natriuretic peptides. In patients with LVEF ≤35% (of ischaemic aetiology in 60%), sacubitril/valsartan proved to reduce HF hospitalization and cardiovascular death compared with ACE-I.⁶⁹³ Moreover, sacubitril/valsartan may decrease myocardial ischaemia because of its effect in reducing LV wall stress and improving coronary circulation. The risk of coronary events using sacubitril/valsartan compared with ACE-I was also significantly reduced on post-hoc analyses.⁶⁹⁴

4.3.4. Sodium–glucose cotransporter 2 inhibitors and glucagon-like peptide-1 receptor agonists

Sodium–glucose cotransporter 2 (SGLT2) inhibitors and GLP-1 receptor agonists were initially intended as glucose-lowering medications for patients with type 2 DM; however, a growing body of evidence has established that these drugs lower ASCVD risk and confer cardiovascular benefits beyond their glucose-lowering potential.^{688,695–697} Among patients with DM, SGLT2 inhibitor use was associated with a reduced risk of MACE, especially in patients with established ASCVD.⁶⁹⁸ The exact mechanism(s) by which SGLT2 inhibitors improve CVD outcomes remain largely unknown, but several hypotheses have been proposed.^{695,696,699–702} The benefits of SGLT2 inhibitors may relate more to cardiorenal haemodynamic effects than to atherosclerosis¹⁶ The cardiovascular benefits of GLP-1 receptor agonists is driven by reduced risk of ASCVD-related events.⁷⁰³ Overall, the results of cardiovascular outcome trials of SGLT2 inhibitors and GLP-1 receptor agonists support their recommendation as first-line treatment for all patients with type 2 DM and ASCVD including CCS, independently of decisions about glycaemic management (Recommendation Table 19).

In patients with HF with reduced (HFrEF) or preserved EF (HFpEF), dapagliflozin and empagliflozin lowered the risk of worsening HF or cardiovascular death in the presence or absence of type 2 DM.^704–707 Recent results indicate benefits of SGLT2 inhibitors on hospitalization for HF and cardiovascular death in patients at high cardiovascular risk, irrespective of HF history.⁷⁰⁸ Recommendations for the use of SGLT2 inhibitors in patients with diabetes and patients with HF are detailed in the 2023 ESC Guidelines for the management of cardiovascular disease in patients with diabetes⁸⁶ and the 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure⁵²⁶ and its 2023 Focused Update. ⁷⁰⁹ Recommendations on the use of these medications in patients with HF are given in Section 4.3.4 and Recommendation Table 24.

In patients with pre-existing CVD, the SELECT trial assessed the effect of weekly subcutaneous administration of the GLP-1 receptor agonist semaglutide at a dose of 2.4 mg on MACE reduction in overweight or obese adults without type 2 DM. The trial involved 17 604 patients with established CVD and a BMI ≥27 kg/m². Patients lost a mean of 9.4% of body weight over the first 2 years with semaglutide vs. 0.88% with placebo. The primary cardiovascular endpoint—a composite of death from cardiovascular causes, non-fatal MI, or non-fatal stroke—was reduced significantly, with an HR of 0.80 (95% CI, 0.72–0.90; P < .001).⁴⁶⁵

Recommendation Table 19

Recommendations for sodium–glucose cotransporter 2 inhibitors and/or glucagon-like peptide-1 receptor agonists in patients with chronic coronary syndrome (see also Evidence Table 19)

4.3.5. Anti-inflammatory agents for event prevention

Four large double-blind trials have compared the effects of anti-inflammatory agents vs. placebo in patients with atherothrombotic CAD. The Canakinumab Antiinflammatory Thrombosis Outcome Study (CANTOS) tested three doses of the anti-interleukin-1-beta monoclonal antibody canakinumab against placebo in over 10 000 patients with previous MI and plasma C-reactive protein ≥2 mg/L.⁷¹² The highest dose (300 mg every 3 months) reduced plasma interleukin-6 and C-reactive protein and the combined endpoint of cardiovascular death, non-fatal MI, and non-fatal stroke over a mean of 3.7 years: 3.90 vs. 4.50 events per 100 person-years (HR 0.86; 95% CI, 0.75–0.99; P = .031). The other doses did not provide favourable results. Despite efficacy, the drug was not developed further for this indication because of the risk of fatal infections and high costs.

Low-dose methotrexate (target dose 15–20 mg once weekly) did not reduce the composite of cardiovascular death, non-fatal MI, non-fatal stroke, or unstable angina-driven revascularization in 4786 patients with previous MI or multivessel coronary atherosclerosis and additional DM or metabolic syndrome.⁷¹³ The trial was stopped early (median 2.3 year follow-up) for futility.

The COLCOT (Colchicine Cardiovascular Outcomes Trial) tested low-dose colchicine (0.5 mg daily) vs. placebo in 4745 patients with recent MI (<30 days) regardless of C-reactive protein values.⁷¹⁴ During a median of 2.3 years, the composite of cardiovascular death, resuscitated cardiac arrest, non-fatal MI, non-fatal stroke, or unstable angina-driven revascularization occurred in 5.5% on colchicine vs. 7.1% on placebo (HR 0.77; 95% CI, 0.61–0.96; P = .02). Colchicine had favourable effects on each outcome component. All-cause mortality did not differ (43 vs. 44 events). Diarrhoea was reported in 9.7% vs. 8.9% (statistically non-significant); pneumonia, although not frequent, was recorded more often with colchicine than placebo (0.9% vs. 0.4%; P = .03).

The LODOCO2 trial (Low-Dose Colchicine 2) randomized 5500 patients with atherosclerotic CAD who had been stable for at least 6 months to low-dose colchicine (0.5 mg daily) or placebo for a median of 2.4 years.⁷¹⁵ The primary endpoint (cardiovascular death, spontaneous MI, ischaemic stroke, or ischaemia-driven revascularization) occurred in 6.8% on colchicine vs. 9.6% on placebo (HR 0.69; 95% CI, 0.57–0.83; P < .001). The main secondary endpoint (cardiovascular death, non-fatal MI, or non-fatal stroke) was reduced by 28% (4.2% on colchicine vs. 5.7% on placebo; HR 0.72; 95% CI, 0.57–0.92; P = .007). There were no significant differences in rates of pneumonia or GI disorders. The incidence of non-cardiovascular death was nominally higher, but not statistically significant (0.7 vs. 0.5 events per 100 person-years; HR 1.51; 95% CI, 0.99–2.31).

A recent meta-analysis including over 12 000 patients with atherothrombotic CAD⁷¹⁶ has estimated the treatment effects of colchicine vs. placebo for individual outcome components. Significantly lower risks were found for MI (RR, 0.76; 95% CI, 0.61–0.96), stroke (RR, 0.48; 95% CI, 0.30–0.77) and unstable angina-driven revascularization (RR, 0.61; 95% CI, 0.42–0.89), with no significant difference for cardiovascular death (RR, 0.73; 95% CI, 0.45–1.21), all-cause death (RR, 1.01; 95% CI, 0.71–1.43), or GI events (provided colchicine daily dose did not exceed 0.5 mg; RR, 1.02; 95% CI, 0.92–1.14).

Recommendation Table 20

Recommendations for anti-inflammatory drugs in patients with chronic coronary syndrome (see also Evidence Table 20)

Recommendation Table 21

Recommendations for angiotensin-converting enzyme inhibitors in patients with chronic coronary syndrome (see also Evidence Table 21)

4.4. Revascularization for chronic coronary syndromes

Invasive treatment of CAD with either CABG or PCI is historically described under the term revascularization. Although both procedures increase CFC^365,366 and prevent myocardial ischaemia during exercise or emotional stress, they do not heal coronary atherosclerosis. Revascularization by both modalities improves angina-related health status.^50,52,717 Randomized and meta-analytical evidence supports a survival benefit above medical therapy for CABG in patients with left main disease,^718–721 as well as three-vessel disease,⁷²² particularly in patients with LV dysfunction.^719,723,724 Most of this evidence was obtained prior to the introduction of disease-modifying therapies such as ACE-Is/ARBs and statins. Meta-analytical evidence suggests a potential benefit of PCI on cardiovascular survival,^55,725,726 which, similarly to CABG, appears to be related to the prevention of MI.^55,727 In general, among surgically eligible patients with multivessel disease, CABG is superior to PCI and to medical therapy, particularly in those with diabetes and higher coronary complexity.^727,728 Recent evidence has generated controversy on (i) the value of routine early revascularization compared with optimal medical therapy alone,^{47,56,314,729} (ii) the value of PCI vs. CABG for complex CAD,^326,730 and (iii) the value of ischaemia testing for decision-making in revascularization.^315,317,726 At the same time, advances in interventional technologies and medications have expanded the application of PCI to more complex forms of CAD.⁷³¹

4.4.1. Appropriate indication for myocardial revascularization

In CAD patients with moderate or severe inducible ischaemia but no left main disease nor LVEF of <35%, the largest-to-date ISCHEMIA trial, up to 5 years, did not show significant benefit of an initial invasive strategy over an initial conservative strategy for the primary endpoint of ischaemic cardiovascular events or death from any cause,⁴⁷ triggering discussion about the role of initial angiography followed by revascularization when feasible, in this type of CCS patients, once optimal medical therapy has been established. The CLARIFY registry found that many CCS patients with angina experience a resolution of symptoms over time, often without changes in treatment or revascularization, and experience good outcomes.⁴⁰⁴ While these findings suggest that this type of CCS patients should initially receive conservative medical management, it is worth noting that patients who were randomly assigned to the invasive strategy in the ISCHEMIA trial experienced significantly lower rates of spontaneous MI and greater improvement in angina-related health status compared with those assigned to the conservative strategy.^47,50 Furthermore, the ORBITA 2 trial demonstrated that patients with stable angina, who were receiving minimal or no antianginal medication and had objective evidence of ischaemia, experienced a lower angina symptom score following PCI treatment compared with a placebo procedure, indicating a better health status with respect to angina.⁵² Although initial conservative medical management of CCS patients is generally preferred, symptom improvement by revascularization should therefore not be neglected if patients remain symptomatic despite antianginal treatment.

After publication of the ISCHEMIA trial results, several meta-analyses have reported similar overall survival and inevitably higher rates of procedural MI with routine revascularization, while confirming consistently greater freedom from spontaneous MI, unstable angina, and anginal symptoms after revascularization compared with GDMT alone.^732–734 Of note, these meta-analyses showed some differences in methodology, in selected trials, and follow-up duration. Furthermore, the importance of ‘any myocardial infarction’ as an endpoint is complicated by a debate over the prognostic importance of procedural infarctions as well as how various MI definitions affect the prediction of long-term outcomes^735,736 A more recent meta-analysis of RCTs that included the longest available follow-up showed that adding revascularization to GDMT reduced cardiac mortality compared with GDMT alone. The cardiac survival benefit improved with the duration of follow-up and was linearly related to a lower rate of spontaneous MI.⁵⁵

In ISCHEMIA, patients randomized to initial medical therapy alone had significantly more spontaneous MIs during the 5-year follow-up, which were associated with subsequent cardiovascular death.⁷³⁷ An early invasive strategy was associated with lower long-term risks of cardiovascular events, mainly spontaneous MIs, compared with a conservative strategy, at the cost of a higher risk of procedural MIs.⁷³⁸

Extended follow-up of the ISCHEMIA trial population up to 7 years (ISCHEMIA-EXTEND) revealed a significant 2.2% absolute decrease in cardiovascular mortality (adjusted HR 0.78; 95% CI, 0.63–0.96) favouring the initial invasive strategy.⁵⁶ The benefit was most marked in patients with multivessel CAD (≥70% diameter stenosis on CCTA; adjusted HR 0.68; 95% CI, 0.48–0.97) but was offset by a significant 1.2% absolute increase in non-cardiac mortality, without a significant difference (absolute decrease of −0.7%) in all-cause mortality.⁵⁶ In a recent meta-analysis of 18 trials, on the other hand, non-cardiac mortality did not differ significantly by initial invasive or conservative strategy in CCS patients with preserved or slightly impaired LVEF.⁷³⁹ In a post hoc analysis of the ISCHEMIA trial, CAD severity was associated with a higher risk of all-cause death, MI, and the primary endpoint of the trial.³¹⁷ This effect appeared to be most noticeable in patients with multivessel disease and/or proximal LAD stenosis (≥70% diameter stenosis on CCTA).

4.4.2. Additional considerations on reduced systolic left ventricular function: myocardial viability, revascularization, and its modality

Ischaemic cardiomyopathy is the leading cause of HFrEF, and new ischaemic events are the main drivers of worsening LV function, strongly impacting long-term survival.⁷⁴⁰ Ischaemic HFrEF is characterized by irreversibly damaged and scarred myocardium alternating with ‘viable’ myocardium that may be dysfunctional owing to repetitive ischaemic episodes (stunning) or chronic hypoperfusion (hibernation).⁷⁴¹ According to classical concepts, revascularization combined with GDMT synergistically improves systolic LV function and overall prognosis in patients with ischaemic HFrEF by restoring sufficient perfusion to dysfunctional yet viable myocardial segments and preventing new ischaemic events.⁷⁴² However, it carries increased periprocedural risk, especially in patients with severe LV dysfunction (LVEF ≤ 35%). A meta-analysis of 26 observational studies, including 4119 patients, showed that CABG can be performed with acceptable operative mortality (5.4%; 95% CI, 4.5%–6.4%) and 5-year actuarial survival (75%) in patients with severe LV dysfunction (mean pre-operative EF of 24.7%).⁷⁴³

In the 1990s, observational studies reported improved survival after revascularization in patients with severe CAD, significant LV dysfunction, and evidence of myocardial viability on imaging tests.⁷⁴⁴ The PARR-2 trial (PET and Recovery Following Revascularization) randomized 430 patients with suspected ischaemic cardiomyopathy to an F-18-fluorodeoxyglucose PET-assisted strategy or standard care. While there was a non-significant trend towards lower risk of cardiac events at 1 year with PET assistance,⁷⁴⁵ the 5-year follow-up showed no overall reduction in cardiac events.⁷⁴⁶ However, significant benefits were observed when adhering to PET recommendations (after excluding 25% protocol violations).⁷⁴⁶ Post hoc analyses and substudies confirmed the positive outcomes of a PET-guided strategy.^747,748

The Surgical Treatment for Ischemic Heart Failure (STICH) trial randomized 1212 patients with CAD without left main diseases eligible for CABG and LVEF ≤35% to receive either CABG and GDMT, or GDMT alone. The trial failed to achieve its primary endpoint of all-cause mortality at a median follow-up of 4 years (HR with CABG, 0.86; 95% CI, 0.72–1.04; P = .12).⁵³ However, at a median follow-up of 9.8 years, both all-cause and cardiovascular mortality were significantly reduced with CABG compared with GDMT alone (from 66.1% to 58.9%; HR 0.84; 95% CI, 0.73–0.97; P = .02; and from 49.3% to 40.5%; HR 0.79; 95% CI, 0.66–0.93; P = .006, respectively).⁵⁴ The reduction of cardiovascular mortality by CABG was greater in patients with three-vessel disease⁵⁴ and the reduction of all-cause mortality was greater in younger patients, in whom cardiovascular deaths accounted for a larger proportion of deaths vs. older patients (P = .004 for interaction).⁷⁴⁹ Viability was assessed by SPECT, dobutamine echocardiography, or both in 50% of STICH patients (298 randomized to CABG and 303 randomized to GDMT alone).⁷⁵⁰ There were no significant interactions between presence or absence of myocardial viability and improved LV function or long-term survival benefit for CABG above GDMT.^747,748,750

There have been no RCTs directly comparing CABG and PCI in patients with ischaemic HF. A meta-analysis of 21 studies, mostly observational except three including STICH, published between 1983 and 2016, supported CABG and PCI on a background of GDMT in appropriate patients with multivessel disease and LV systolic dysfunction; revascularization with either CABG or PCI improved long-term survival compared with GDMT, but compared with PCI, CABG provided a survival benefit and a lower risk of MI or repeat revascularization, with a slightly higher incidence of stroke.⁷⁵¹

PCI is increasingly used over CABG for treating patients with ischaemic HF and multivessel disease, as shown by two large registries.^752,753 While these registries suggest that CABG is associated with a lower risk of long-term all-cause and cardiovascular mortality and lower MACE compared with PCI in patients with CAD and LVEF ≤35%,^752,753 it is important to interpret these observational studies with great caution, given significant differences in baseline characteristics, including age, history of previous MI, severity of CAD, and completeness of revascularization.⁷⁵⁴ For the comparison of CABG with PCI in managing ischaemic HF with severely impaired LV dysfunction and multivessel CAD, the results of ongoing trials (NCT05427370 and NCT05329285) are awaited.

The Percutaneous Revascularization for Ischemic Left Ventricular Dysfunction (REVIVED-BCIS2) trial randomized 700 patients with impaired LV function (EF ≤ 35%), extensive CAD amenable to PCI, and evidence of myocardial viability in at least four dysfunctional myocardial segments to a strategy of PCI plus GDMT or GDMT alone.⁷²⁹ After a 3.4-year follow-up, PCI showed no significant reduction in the composite primary endpoint of all-cause death or HF rehospitalization (HR 0.99; 95% CI, 0.78–1.27; P = .96). Patients treated by PCI showed slight and temporary improvements in their symptoms and no incremental improvement of overall LV function compared with GDMT.

A pre-specified secondary analysis of REVIVED-BCIS2, conducted in 87% of patients, failed to establish significant correlations between viability extent (assessed by CMR or dobutamine stress echocardiography) and outcomes, thereby challenging the traditional concept of myocardial hibernation, which can be reversed by revascularization.⁷⁵⁵ However, the analysis did find that larger amounts of non-viable myocardium were linked to an increased risk of the primary outcome, regardless of whether PCI was performed, suggesting that viability assessment may be useful for risk stratification.

The two main RCTs, STICH and REVIVED-BCIS2, differ in various aspects. The REVIVED-BCIS2 trial patients were, on average, 10 years older than those in the STICH trial, had a less frequent history of MI (50% vs. 78%) and were more likely to be angina-free at baseline (67% vs. 36%). REVIVED-BCIS2 included fewer patients with three-vessel disease (38% vs. 60%). Additionally, patients in REVIVED-BCIS2 received more modern HF therapy and were more commonly treated with an ICD/CRT (cardiac resynchronization therapy) (21%/53% vs. 2%/19%). Finally, the duration of follow-up was shorter compared with the STICH trials. All these factors may have contributed to the absence of any PCI effect on survival.

In conclusion, the heterogeneous designs of the above studies, the statistical underpower of subgroup analyses, the heterogeneous methods of viability assessments (e.g. based on metabolism, contractile reserve, or scar extent) and variable quantification (dichotomous vs. continuous) leave many open questions on how viability should be defined,⁷⁵⁶ and when and why it should be assessed in ischaemic HFrEF patients. For instance, the classical binary definition of myocardial viability may benefit from more contemporary paradigms and from greater focus on anatomic alignment between viable myocardial regions and feasible revascularization of corresponding perfusing arteries.⁷⁴¹ Moreover, therapeutic aims should go beyond enhancing local and overall LV function to include safeguarding against new ischaemic events⁷²⁷ and their ensuing possibly lethal arrhythmias. Therefore, an integrative approach, including highly specialized imaging, HF, arrhythmia, and revascularization specialists, is needed for optimal patient management and improved outcomes.

4.4.3. Additional considerations—complete vs. partial revascularization

Complete revascularization treating all vessels and lesions causing ischaemia is preferable to incomplete revascularization.⁷⁵⁷ However, various factors may influence the implementation of complete revascularization, including clinical setting, comorbidities, anatomical and procedural features, advanced age, or frailty.^758,759 Furthermore, whether the focus of complete revascularization should be anatomical or functional is still unclear. In the PCI group of the SYNTAX (SYNergy Between PCI with TAXUS and Cardiac Surgery) trial, a higher residual SYNTAX score, indicating incomplete anatomical revascularization, was associated with a higher mortality rate.⁷⁶⁰ However, the outcomes of anatomically incomplete but functionally complete revascularization by PCI were superior to those of anatomically complete revascularization.^49,308,761 Of note, recent studies suggest that significant levels of residual ischaemia can persist despite good angiographic results after complex coronary stenting.

Individual reports suggest that incomplete revascularization is associated with increased mortality compared with complete revascularization.⁷⁶² In addition, unintended incomplete revascularization appears to be a surrogate marker of anatomic complexity and comorbidities, predisposing to more rapid native CAD progression.^760,763 An important predictor of anatomical incomplete revascularization by PCI is the presence of chronic total occlusion. Randomized trials have shown improvements of angina and QoL with PCI for chronic total occlusion lesions,^764,765 but failed to show any reduction of mortality risk and MI rates.^764–767

Among patients with high-risk multivessel CAD, incomplete anatomical revascularization is reported more frequently among those treated with PCI compared with those treated with CABG. The rate ranges from 32% to 56% for PCI and 30% to 37% for CABG.^759,762,768 However, interpreting these data is challenging due to several factors. Firstly, there is no uniform definition of complete revascularization.^769,770 Secondly, although completeness of revascularization with PCI can be evaluated immediately after the procedure, many patients require staged procedures to achieve complete revascularization. Thirdly, within the first year after CABG, 20% to 40% of patients may experience asymptomatic graft failure as determined by CCTA.^771–773 Therefore, selecting a revascularization modality cannot be based solely on completeness of revascularization but rather should be determined through shared decision-making and a risk–benefit assessment.

4.4.4. Assessment of clinical risk and anatomical complexity

While both CABG and PCI have shown continuous technical improvements and better clinical outcomes over time,^774,775 the potential benefit of revascularization must be carefully evaluated against the procedural risk. The Society of Thoracic Surgeons Predicted Risk of Mortality (STS-PROM) risk model has proved to be more effective than the EuroSCORE II risk model in predicting peri-operative mortality and complications in CABG patients due to its continuous calibration.⁷⁷⁶ It has also shown satisfactory discrimination for all-cause death at 30 days in patients undergoing CABG, allowing differentiation of high (>8%) and intermediate (4% to 8%) from low (<4%) surgical mortality risk. Although primarily designed for surgical risk assessment, the STS-PROM score can also be used to evaluate the risk of revascularization through PCI in patients with multivessel disease, as recent studies³²⁶ have shown similar mortality rates between PCI and CABG. However, in patients with left main coronary artery disease (LMCAD) participating in the EXCEL trial (Evaluation of XIENCE versus Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization), the STS risk models were effective in predicting outcomes for CABG but not for PCI regarding peri-operative mortality and renal failure.⁷⁷⁷ Interestingly, the STS stroke risk model was more successful in predicting outcomes for PCI compared with CABG. More accurate risk prediction tools are needed to precisely estimate adverse events following LMCAD revascularization through both CABG and PCI. Other clinical factors, such as frailty or liver cirrhosis,^778,779 have been found to increase post-operative mortality and should be taken into consideration during the decision-making process.⁷⁸⁰

The SYNTAX score was prospectively developed as an angiographic stratification tool to quantify the complexity of coronary lesions in patients with left main coronary artery (LMCA) or multivessel CAD and aid clinicians in deciding the most appropriate revascularization procedure during Heart Team discussions.⁷⁸¹ However, there are limitations to the SYNTAX score. Firstly, it is a time-consuming score requiring a detailed angiographic evaluation of each lesion. Secondly, there is considerable inter-observer variability in its calculation, with a poor correlation between core lab and operator-calculated SYNTAX score being reported.⁷⁷⁹ Thirdly, it is an anatomical score that quantifies obstruction but not plaque burden. Fourthly, it does not take physiological and clinical variables into account.⁷⁸² Machine learning may streamline this process, generating prognostic information that is superior to clinical risk scores⁷⁸³ and relevant to clinical decision-making.

The SYNTAX II score was developed by combining clinical and anatomic features to better guide decision-making between CABG and PCI than the anatomical SYNTAX score.^784,785 Although the usefulness of the SYNTAX II score was demonstrated in several studies,^785–787 it overestimated 4-year all-cause mortality in the EXCEL trial.⁷⁸⁸ The updated version, SYNTAX score II 2020, using the SYNTAX Extended Survival (SYNTAXES) data and external validation in the population of the FREEDOM, BEST, and PRECOMBAT trials,⁷⁸⁹ showed modest discrimination for predicting 5-year MACE (c-index for PCI and CABG of 0.62 and 0.67, respectively) and acceptable discrimination for predicting 10-year mortality. Another validation study indicated that the score displayed acceptable discrimination for all-cause mortality at 5 years in a Japanese cohort with LMCAD and/or multivessel CAD,⁷⁸⁷ but external validation in a prospective setting is lacking.⁷⁸³

The British Cardiovascular Intervention Society myocardial jeopardy score (BCIS-JS) is an alternative to the SYNTAX score, enabling the assessment of the severity and extent of CAD. It has been proven effective in predicting mortality after PCI and assessing the completeness of revascularization,⁷⁹⁰ but it is not as commonly used as the SYNTAX score.

4.4.5. Choice of myocardial revascularization modality

Both myocardial revascularization modalities—PCI and CABG—can achieve excellent outcomes, although through different mechanisms, in appropriately selected patients when GDMT alone fails.

4.4.5.1. Patients with single- or two-vessel coronary artery disease

Randomized evidence and subgroup analyses of trials enrolling a broader spectrum of CAD patients showed similar performance of PCI and CABG in patients with one- or two-vessel CAD, with or without the involvement of the proximal LAD in terms of death, stroke, or MI.^791–797 In patients with complex LAD lesions, the need for late repeat revascularization is higher after PCI than CABG,⁷⁹⁷ but CABG is a more invasive procedure with inherent risks, longer hospital stay and healing.⁷⁵⁸

4.4.5.2. Patients with unprotected left main coronary artery disease

Over the past two decades, several trials have compared PCI and CABG in patients with multivessel CAD, with or without unprotected LMCAD^{326,728,730,798–801} (Table 9). The patients who were included in these trials had to meet the eligibility criteria for both CABG or PCI at an acceptable risk level, and their coronary anatomy had to allow complete revascularization through both procedures. However, due to the strict inclusion criteria, only a small percentage of eligible patients (ranging from 6% to 40%) were enrolled in these trials.^798,801 The strict inclusion criteria resulted in enrolling a relatively young population with a lower burden of comorbidities (mean age <66 years).^{728,730,798,801}

Table 9

Summary of trial-based evidence for the comparison of percutaneous coronary intervention and coronary artery bypass grafting in patients with left main coronary artery disease

Study	Study population	Primary endpoint	Follow-up	Findings
PRECOMBAT (non-inferiority)⁸¹⁴	600 patients with newly diagnosed LMCAD who had stable angina, unstable angina, silent ischaemia, or non-ST-segment elevation MI	All-cause death, MI, stroke, or ischaemia-driven target vessel revascularization	2 years	1-year follow-up: 8.7% and 6.7% primary endpoints for PCI and CABG, respectively, absolute risk difference 2% (95% CI, –1.6% to 5.6%), P = .01 for non-inferiority 2-year follow-up: 12.2% and 8.1% primary endpoints for PCI and CABG, respectively, HR 1.50 (95% CI, 0.90–2.52), P = .12
PRECOMBAT (extended follow-up)⁸¹⁵			5 years	17.5% and 14.3% primary endpoints for PCI and CABG, respectively, HR 1.27 (95% CI, 0.84–1.90), P = .26
PRECOMBAT (extended follow-up)⁸¹⁶			11.3 years (median)	29.8% and 24.7% primary endpoints for PCI and CABG, respectively, HR 1.25 (95% CI, 0.93–1.69)
SYNTAX⁸¹⁷	1800 patients with de novo three-vessel (n = 1095) and LMCAD (n = 795)	All-cause death, stroke, MI, and repeat revascularization	1 year	For the LMCAD group: 15.8% and 13.7% primary endpoints for PCI and CABG, respectively; P = .44
SYNTAX⁸¹⁸			3 years	For the LMCAD group: 26.8% and 22.3%, primary endpoints for PCI and CABG, respectively; P = .20
SYNTAX⁸¹³			5 years	For the LMCAD group: 36.9% and 31.0% primary endpoints for PCI and CABG, respectively, HR 1.25 (95% CI, 0.93–1.69), P = .12
SYNTAX (extended follow-up)⁷⁹⁵		All-cause death	10 years	For the LMCAD group: 27% and 28% primary endpoints for PCI and CABG, respectively, HR 0.92 (95% CI, 0.69–1.22)
NOBLE (non-inferiority hypothesis)⁸¹⁹	1201 patients with LMCAD who had stable angina pectoris, unstable angina pectoris, or non-ST-segment elevation myocardial infarction	All-cause death, non-procedural MI, any repeat coronary revascularization, or stroke	3.1 years (mean)	28% and 18% primary endpoints for PCI and CABG, HR 1.51 (95% CI, 1.13–2.00), P = .004 for superiority
NOBLE (extended follow-up)⁸²⁰			4.9 years (median)	28% and 19% primary endpoints for PCI and CABG, HR 1.58 (95% CI, 1.24–2.01), P < .001 for superiority
EXCEL (non-inferiority hypothesis)⁸²¹	1905 patients with LMCAD of low or intermediate anatomical complexity (SYNTAX score ≤ 32)	All-cause death, stroke, or MI	3 years (median)	15.4% and 14.7% primary endpoints for PCI and CABG, absolute risk difference 0.7% (upper 97.5% confidence limit: 4%), P = .02 for non-inferiority; HR 1.00 (95% CI, 0.79–1.26), P = .98 for superiority
EXCEL (extended follow-up)⁸²²			5 years	22.0% and 19.2% primary endpoints for PCI and CABG, absolute risk difference 2.8% (95% CI, −0.9 to 6.5), P = .13; OR 1.19 (95% CI, 0.95–1.50)

Study	Study population	Primary endpoint	Follow-up	Findings
PRECOMBAT (non-inferiority)⁸¹⁴	600 patients with newly diagnosed LMCAD who had stable angina, unstable angina, silent ischaemia, or non-ST-segment elevation MI	All-cause death, MI, stroke, or ischaemia-driven target vessel revascularization	2 years	1-year follow-up: 8.7% and 6.7% primary endpoints for PCI and CABG, respectively, absolute risk difference 2% (95% CI, –1.6% to 5.6%), P = .01 for non-inferiority 2-year follow-up: 12.2% and 8.1% primary endpoints for PCI and CABG, respectively, HR 1.50 (95% CI, 0.90–2.52), P = .12
PRECOMBAT (extended follow-up)⁸¹⁵			5 years	17.5% and 14.3% primary endpoints for PCI and CABG, respectively, HR 1.27 (95% CI, 0.84–1.90), P = .26
PRECOMBAT (extended follow-up)⁸¹⁶			11.3 years (median)	29.8% and 24.7% primary endpoints for PCI and CABG, respectively, HR 1.25 (95% CI, 0.93–1.69)
SYNTAX⁸¹⁷	1800 patients with de novo three-vessel (n = 1095) and LMCAD (n = 795)	All-cause death, stroke, MI, and repeat revascularization	1 year	For the LMCAD group: 15.8% and 13.7% primary endpoints for PCI and CABG, respectively; P = .44
SYNTAX⁸¹⁸			3 years	For the LMCAD group: 26.8% and 22.3%, primary endpoints for PCI and CABG, respectively; P = .20
SYNTAX⁸¹³			5 years	For the LMCAD group: 36.9% and 31.0% primary endpoints for PCI and CABG, respectively, HR 1.25 (95% CI, 0.93–1.69), P = .12
SYNTAX (extended follow-up)⁷⁹⁵		All-cause death	10 years	For the LMCAD group: 27% and 28% primary endpoints for PCI and CABG, respectively, HR 0.92 (95% CI, 0.69–1.22)
NOBLE (non-inferiority hypothesis)⁸¹⁹	1201 patients with LMCAD who had stable angina pectoris, unstable angina pectoris, or non-ST-segment elevation myocardial infarction	All-cause death, non-procedural MI, any repeat coronary revascularization, or stroke	3.1 years (mean)	28% and 18% primary endpoints for PCI and CABG, HR 1.51 (95% CI, 1.13–2.00), P = .004 for superiority
NOBLE (extended follow-up)⁸²⁰			4.9 years (median)	28% and 19% primary endpoints for PCI and CABG, HR 1.58 (95% CI, 1.24–2.01), P < .001 for superiority
EXCEL (non-inferiority hypothesis)⁸²¹	1905 patients with LMCAD of low or intermediate anatomical complexity (SYNTAX score ≤ 32)	All-cause death, stroke, or MI	3 years (median)	15.4% and 14.7% primary endpoints for PCI and CABG, absolute risk difference 0.7% (upper 97.5% confidence limit: 4%), P = .02 for non-inferiority; HR 1.00 (95% CI, 0.79–1.26), P = .98 for superiority
EXCEL (extended follow-up)⁸²²			5 years	22.0% and 19.2% primary endpoints for PCI and CABG, absolute risk difference 2.8% (95% CI, −0.9 to 6.5), P = .13; OR 1.19 (95% CI, 0.95–1.50)

CABG, coronary artery bypass grafting; CI, confidence interval; HR, hazard ratio; LMCAD, left main coronary artery disease; MI, myocardial infarction; OR, odds ratio; PCI, percutaneous coronary intervention.

Table 9

Summary of trial-based evidence for the comparison of percutaneous coronary intervention and coronary artery bypass grafting in patients with left main coronary artery disease

Study	Study population	Primary endpoint	Follow-up	Findings
PRECOMBAT (non-inferiority)⁸¹⁴	600 patients with newly diagnosed LMCAD who had stable angina, unstable angina, silent ischaemia, or non-ST-segment elevation MI	All-cause death, MI, stroke, or ischaemia-driven target vessel revascularization	2 years	1-year follow-up: 8.7% and 6.7% primary endpoints for PCI and CABG, respectively, absolute risk difference 2% (95% CI, –1.6% to 5.6%), P = .01 for non-inferiority 2-year follow-up: 12.2% and 8.1% primary endpoints for PCI and CABG, respectively, HR 1.50 (95% CI, 0.90–2.52), P = .12
PRECOMBAT (extended follow-up)⁸¹⁵			5 years	17.5% and 14.3% primary endpoints for PCI and CABG, respectively, HR 1.27 (95% CI, 0.84–1.90), P = .26
PRECOMBAT (extended follow-up)⁸¹⁶			11.3 years (median)	29.8% and 24.7% primary endpoints for PCI and CABG, respectively, HR 1.25 (95% CI, 0.93–1.69)
SYNTAX⁸¹⁷	1800 patients with de novo three-vessel (n = 1095) and LMCAD (n = 795)	All-cause death, stroke, MI, and repeat revascularization	1 year	For the LMCAD group: 15.8% and 13.7% primary endpoints for PCI and CABG, respectively; P = .44
SYNTAX⁸¹⁸			3 years	For the LMCAD group: 26.8% and 22.3%, primary endpoints for PCI and CABG, respectively; P = .20
SYNTAX⁸¹³			5 years	For the LMCAD group: 36.9% and 31.0% primary endpoints for PCI and CABG, respectively, HR 1.25 (95% CI, 0.93–1.69), P = .12
SYNTAX (extended follow-up)⁷⁹⁵		All-cause death	10 years	For the LMCAD group: 27% and 28% primary endpoints for PCI and CABG, respectively, HR 0.92 (95% CI, 0.69–1.22)
NOBLE (non-inferiority hypothesis)⁸¹⁹	1201 patients with LMCAD who had stable angina pectoris, unstable angina pectoris, or non-ST-segment elevation myocardial infarction	All-cause death, non-procedural MI, any repeat coronary revascularization, or stroke	3.1 years (mean)	28% and 18% primary endpoints for PCI and CABG, HR 1.51 (95% CI, 1.13–2.00), P = .004 for superiority
NOBLE (extended follow-up)⁸²⁰			4.9 years (median)	28% and 19% primary endpoints for PCI and CABG, HR 1.58 (95% CI, 1.24–2.01), P < .001 for superiority
EXCEL (non-inferiority hypothesis)⁸²¹	1905 patients with LMCAD of low or intermediate anatomical complexity (SYNTAX score ≤ 32)	All-cause death, stroke, or MI	3 years (median)	15.4% and 14.7% primary endpoints for PCI and CABG, absolute risk difference 0.7% (upper 97.5% confidence limit: 4%), P = .02 for non-inferiority; HR 1.00 (95% CI, 0.79–1.26), P = .98 for superiority
EXCEL (extended follow-up)⁸²²			5 years	22.0% and 19.2% primary endpoints for PCI and CABG, absolute risk difference 2.8% (95% CI, −0.9 to 6.5), P = .13; OR 1.19 (95% CI, 0.95–1.50)

Study	Study population	Primary endpoint	Follow-up	Findings
PRECOMBAT (non-inferiority)⁸¹⁴	600 patients with newly diagnosed LMCAD who had stable angina, unstable angina, silent ischaemia, or non-ST-segment elevation MI	All-cause death, MI, stroke, or ischaemia-driven target vessel revascularization	2 years	1-year follow-up: 8.7% and 6.7% primary endpoints for PCI and CABG, respectively, absolute risk difference 2% (95% CI, –1.6% to 5.6%), P = .01 for non-inferiority 2-year follow-up: 12.2% and 8.1% primary endpoints for PCI and CABG, respectively, HR 1.50 (95% CI, 0.90–2.52), P = .12
PRECOMBAT (extended follow-up)⁸¹⁵			5 years	17.5% and 14.3% primary endpoints for PCI and CABG, respectively, HR 1.27 (95% CI, 0.84–1.90), P = .26
PRECOMBAT (extended follow-up)⁸¹⁶			11.3 years (median)	29.8% and 24.7% primary endpoints for PCI and CABG, respectively, HR 1.25 (95% CI, 0.93–1.69)
SYNTAX⁸¹⁷	1800 patients with de novo three-vessel (n = 1095) and LMCAD (n = 795)	All-cause death, stroke, MI, and repeat revascularization	1 year	For the LMCAD group: 15.8% and 13.7% primary endpoints for PCI and CABG, respectively; P = .44
SYNTAX⁸¹⁸			3 years	For the LMCAD group: 26.8% and 22.3%, primary endpoints for PCI and CABG, respectively; P = .20
SYNTAX⁸¹³			5 years	For the LMCAD group: 36.9% and 31.0% primary endpoints for PCI and CABG, respectively, HR 1.25 (95% CI, 0.93–1.69), P = .12
SYNTAX (extended follow-up)⁷⁹⁵		All-cause death	10 years	For the LMCAD group: 27% and 28% primary endpoints for PCI and CABG, respectively, HR 0.92 (95% CI, 0.69–1.22)
NOBLE (non-inferiority hypothesis)⁸¹⁹	1201 patients with LMCAD who had stable angina pectoris, unstable angina pectoris, or non-ST-segment elevation myocardial infarction	All-cause death, non-procedural MI, any repeat coronary revascularization, or stroke	3.1 years (mean)	28% and 18% primary endpoints for PCI and CABG, HR 1.51 (95% CI, 1.13–2.00), P = .004 for superiority
NOBLE (extended follow-up)⁸²⁰			4.9 years (median)	28% and 19% primary endpoints for PCI and CABG, HR 1.58 (95% CI, 1.24–2.01), P < .001 for superiority
EXCEL (non-inferiority hypothesis)⁸²¹	1905 patients with LMCAD of low or intermediate anatomical complexity (SYNTAX score ≤ 32)	All-cause death, stroke, or MI	3 years (median)	15.4% and 14.7% primary endpoints for PCI and CABG, absolute risk difference 0.7% (upper 97.5% confidence limit: 4%), P = .02 for non-inferiority; HR 1.00 (95% CI, 0.79–1.26), P = .98 for superiority
EXCEL (extended follow-up)⁸²²			5 years	22.0% and 19.2% primary endpoints for PCI and CABG, absolute risk difference 2.8% (95% CI, −0.9 to 6.5), P = .13; OR 1.19 (95% CI, 0.95–1.50)

CABG, coronary artery bypass grafting; CI, confidence interval; HR, hazard ratio; LMCAD, left main coronary artery disease; MI, myocardial infarction; OR, odds ratio; PCI, percutaneous coronary intervention.

Meta-analyses of RCTs have shown that the risk of death is similar for both CABG and PCI for LMCAD, even for patients with a high SYNTAX score, up to 5–10 years after the intervention. However, the risk of stroke is higher with CABG, while the risk of spontaneous MI is higher with PCI.^{728,730,800,802–804} In the individual-patient data meta-analysis of four randomized trials,⁷³⁰ mortality over 5 years was not statistically different between patients treated with PCI or with CABG [11.2% vs. 10.2%; HR 1.10 (95% CI, 0.91–1.32); P = .33; absolute risk difference of 0.9%]. A similar treatment effect was observed for 10-year mortality [22.4% vs. 20.4%; HR 1.10 (95% CI, 0.93–1.29); P = .25; absolute risk difference 2.0%]. Spontaneous MI was lower in the CABG arm [6.2% vs. 2.6%; HR 2.35 (95% CI, 1.71–3.23); P < .0001; absolute risk difference 3.5%], while the results of periprocedural MI differed according to whether the analysis used the protocol definition or the universal definition of MI (available for only two studies). Stroke was not statistically different overall [2.7% vs. 3.1%; HR 0.84 (95% CI, 0.59–1.21); P = .36; absolute risk difference of −0.4%]. However, in a pre-specified analysis of the first 12 months of follow-up, stroke was lower after PCI than after CABG [0.6% vs. 1.6%; HR 0.37 (95% CI, 0.19–0.69); P = .002; absolute risk difference of −1.0%].⁷⁸² Subgroup analysis based on the SYNTAX score and the number of additionally involved coronary vessels revealed no difference in all-cause mortality between CABG and PCI for SYNTAX score ≤32 or LMCA stenosis with 0/1 vessel disease. However, a trend for higher all-cause mortality was noted with PCI for SYNTAX score >32 (HR 1.30; 95% CI, 0.92–1.84) and/or LMCA stenosis with 2/3 vessel disease (HR 1.25; 95% CI, 0.97–1.60).⁷⁸² Of note, the LMCA stenosis involved distal bifurcation in 75% of the patients, and the absence of a bifurcation lesion had no impact on mortality.⁷³⁰ True bifurcation left main lesions (defined as Medina type 1,1,1 or 0,1,1 both main vessel and side vessel >50% narrowed with reference diameters ≥2.75 mm),⁸⁰⁵ which frequently require 2-stent techniques, have worse clinical outcomes than non-bifurcation lesions.^806–808 Despite excellent results after LMCA bifurcation stenting on angiography, 13% of patients still experience residual ischaemia in turn associated with higher long-term cardiovascular mortality.⁸⁰⁹ Using intracoronary imaging guidance to optimize stent expansion and prevent side-branch jailing may improve outcomes after PCI of bifurcation LMCA lesions.⁸¹⁰

Operator experience may significantly affect the outcomes after interventional procedures. A single-centre study from China found that operators with a higher volume of procedures performed (>15 per year) had better outcomes for unprotected LMCA PCI.⁸¹¹ An analysis of the outcome data from the British Cardiovascular Intervention Society’s national PCI database on 6724 patients who underwent PCI for unprotected LMCA between 2012 and 2014 revealed that the volume of procedures performed by the operator plays a significant role in determining the outcome after PCI of unprotected LMCA.⁸¹² Although high-volume operators undertook PCIs on patients with greater comorbid burden and CAD complexity compared with low-volume operators, 12-month survival was lower in high-volume operators [odds ratio (OR) 0.54; 95% CI, 0.39–0.73]. A close association between operator volume and superior 12-month survival was observed (P < .001).

A 2022 Joint ESC/EACTS (European Association for Cardio-Thoracic Surgery) task force recently reviewed the 2018 guideline recommendations on the revascularization of LMCAD in low-risk surgical patients with suitable anatomy for PCI or CABG.⁷⁸² The review was mainly based on the recent individual-patient data meta-analysis⁷³⁰ of the long-term outcomes after CABG or PCI for LMCAD from four randomized clinical trials that included 4394 patients between March 2005 and January 2015. The review confirmed that for stable CCS patients with left main stem disease requiring revascularization, both treatment options are clinically reasonable based on patient preference, expertise availability, and local operator volumes. It was proposed that revascularization with CABG be the recommended option, with suggested class I and LOE A, while PCI be overall recommended with a suggested class IIa and LOE A. The present guidelines confirm that, among patients suitable for both revascularization modalities, CABG is recommended as the overall preferred revascularization mode over PCI, given the lower risk of spontaneous MI and repeat revascularization.^730,782 The present guidelines also acknowledge that in patients with significant LMCA stenosis of low complexity (SYNTAX score ≤22), in whom PCI can provide equivalent completeness of revascularization to that of CABG, PCI is recommended as an alternative to CABG, given its lower invasiveness and non-inferior survival.^{718,728,730,802,813}

4.4.5.3. Patients with multivessel coronary artery disease

The SYNTAX and SYNTAXES randomized trials, comparing PCI and CABG for multivessel CAD with or without unprotected LMCAD, reported differences in terms of survival and freedom from cardiovascular events dependent on SYNTAX score.^795,798,823 The recently published 10-year follow-up results of the SYNTAX trial (SYNTAXES trial) reported similar all-cause death rates with both revascularization modalities,⁷⁹⁵ while there was significantly higher mortality in patients with SYNTAX scores ≥33 who were randomized for PCI (HR 1.41; 95% CI, 1.05–1.89).⁷⁹⁵ A significant 5-year mortality gap between PCI and CABG has been reported among patients with complex multivessel CAD in the presence of DM (15.7% after PCI vs. 10.7% after CABG; HR 1.44; 95% CI, 1.20–1.77; P = .0001).⁷²⁸

In the FREEDOM trial (Strategies for Multivessel Revascularization in Patients with Diabetes), 1900 patients with diabetes and multivessel disease without LMCAD were randomized to CABG vs. PCI (using first-generation DES). Long-term results at a median follow-up duration of 3.8 years [interquartile range (IQR) 2.5–4.9 years] showed higher all-cause mortality in the PCI group vs. CABG group (24.3% vs. 18.3%; P = .01).⁸⁰¹ Out of all the centres that participated in the study, only 25 agreed to participate in the FREEDOM extended follow-up, and therefore, only 49.6% of patients in the study were followed up for up to 8 years thus limiting statistical power. The all-cause mortality rate among the FREEDOM follow-up patients was not significantly different between those who underwent PCI and CABG procedures (23.7% vs. 18.7%; HR 1.32; 95% CI, 0.97–1.79; P = .076). In multivariable analysis, a significant interaction emerged between patient age and long-term survival benefit of CABG surgery. Patients younger than the median age at study entry (63.3 years) preferentially derived benefit from CABG; mortality among patients ≤63.3 years old was 20.7% (PCI) vs. 10.2% (CABG); mortality among patients >63.3 years old was 26.3% vs. 27.6% (P = .01 for interaction).⁸²⁴

4.4.5.4. Impact of coronary pressure guidance on multivessel coronary artery disease patients undergoing percutaneous coronary intervention

Consistently higher rates of repeat revascularizations following PCI compared with CABG have been shown in clinical trials involving multivessel CAD patients, with significant impacts on outcomes.⁸²⁵ With the use of modern DESs, the rate of repeat revascularization after PCI has declined.^{725,795,802,820} FFR guidance during PCI leads to lower revascularization rates compared with angiography-guided PCI, with fewer stents placed in the FFR group.⁸²⁶

In the FAME 3 trial, 1500 patients with three-vessel CAD not involving the LMCA were randomly assigned to PCI with second-generation DESs (durable polymer zotarolimus-eluting stents) guided by FFR, or to CABG.³²⁶ At 1-year follow-up, the incidence of the composite primary endpoint, MACCE [major adverse cardiac (death from any cause, MI, stroke, or repeat revascularization) or cerebrovascular events], was 10.6% among patients assigned to FFR-guided PCI and 6.9% among patients assigned to CABG surgery (HR 1.5; 95% CI, 1.1–2.2), findings that were not consistent with non-inferiority (P = .35 for non-inferiority).³²⁶ At 3-year follow-up, there still was a significantly higher rate of MACCE for PCI than for CABG (18.6% vs. 12.5%; HR 1.5; 95% CI, 1.2–2.0; P = .002), consistent with the 1-year follow-up results. However, there was no difference in the incidence of the composite of death, MI, or stroke after FFR-guided PCI compared with CABG (12.0% vs. 9.2%; HR 1.3; 95% CI, 0.98–1.83; P = .07). The rates of death (4.1% vs. 3.9%; HR 1.0; 95% CI, 0.6–1.7; P = .88) and stroke (1.6% vs. 2.0%; HR 0.8; 95% CI, 0.4–1.7; P = .56) were not different, while MI again occurred more frequently after PCI (7.0% vs. 4.2%; HR 1.7; 95% CI, 1.1–2.7; P = .02).⁸²⁷ Repeat revascularization was also more frequent after PCI (11.1% vs. 5.9%; HR 1.9; 95% CI, 1.3–2.7; P = .001). Of note, after both PCI and CABG, event rates were lower (about half for mortality) than in the SYNTAX cohort of patients with three-vessel CAD. There was a narrower difference for MI rates between the two modalities, probably owing to procedural advances with PCI and CABG and improvements in GDMT. In patients with less complex CAD (SYNTAX score ≤22), outcomes were as favourable as after CABG.

4.4.5.5. Virtual percutaneous coronary intervention: combination of coronary pressure mapping with coronary anatomy for percutaneous coronary intervention planning

There is increasing evidence on the impact of post-PCI FFR/iFR/QFR on outcomes after PCI.^828–833 A quarter of these patients have residual ischaemia (FFR < 0.80 or iFR ≤ 0.89) after angiographically successful PCI, with circa 80% of cases attributable to focal lesions not identified by angiography alone.⁸³⁰ One randomized trial reported that post-PCI iFR/FFR can be improved by additional intracoronary intervention, including post-dilatation or additional stent implantation, but remains ≤0.80 in 18% of cases.⁸²⁹ Preliminary results demonstrate that the combination of invasive coronary pressure mapping by iFR pullback or QFR mapping superimposed on the anatomical information of ICA accurately predict the post-PCI coronary pressure for any combination of stent location and stent length, as part of a ‘virtual PCI’ approach,^348,834 and allows modification of the procedural planning in about 30% of cases.⁸³⁵ The AQVA (Angio-based Quantitative Flow Ratio Virtual PCI Versus Conventional Angio-guided PCI in the Achievement of an Optimal Post-PCI QFR) trial (n = 300) demonstrated that a strategy of QFR/ICA-based virtual PCI was associated with a higher rate of post-PCI QFR ≥0.90 compared with angiography-based PCI (93.4% vs. 84.9%, P = .009).⁸³⁶ The DEFINE GPS trial (NCT04451044) is currently investigating the clinical benefit of pre-procedural coronary pressure mapping with iFR pullback and ‘virtual PCI’ to clarify this issue further and improve post-PCI clinical outcomes.

Virtual PCI can be conducted by combining anatomical information from CCTA with that of FFR-CT. FFR-CT/CCTA-based virtual PCI has two theoretical advantages over ICA-based virtual PCI: (i) it does not require invasive investigation, and (ii) it provides information on vessel wall/plaque composition.⁸³⁷ FFR-CT/CCTA-based virtual PCI has been shown to accurately predict post-PCI FFR⁸³⁸ and to modify PCI procedural planning in 31% of lesions and 45% of patients.⁸³⁹ The Precise Procedural and PCI Plan (P4) trial (NCT05253677) is currently investigating the clinical benefit of iFR-based virtual PCI to clarify this issue further and improve post-PCI clinical outcomes.

4.4.5.6. Impact of intracoronary imaging guidance on multivessel coronary artery disease patients undergoing percutaneous coronary intervention

Three large randomized trials have recently investigated the clinical benefit of intracoronary imaging during ‘complex’ PCI. One trial, RENOVATE-COMPLEX PCI,⁸⁴⁰ mainly investigated the benefit of IVUS (74% IVUS, 26% OCT), while the two others, OCTOBER⁸¹⁰ and ILUMIEN IV,⁸⁴¹ investigated the benefit of OCT. Importantly, while OCTOBER (true bifurcation lesions) and RENOVATE-COMPLEX PCI (including true bifurcation lesions, long lesions, chronic total occlusion lesions) focused on ‘anatomically’ complex lesions, ILUMIEN IV made the choice to define ‘complexity’ by the clinical context (DM and STEMI/NSTEMI) and/or by the anatomical characteristics of the lesions.

In RENOVATE-COMPLEX PCI, intravascular imaging-guided PCI led to a lower risk of a composite of death from a cardiac cause, target vessel-related MI, or clinically driven target-vessel revascularization than angiography-guided PCI by 2 years (7.7% vs. 12.3%; HR 0.64; 95% CI, 0.45–0.89; P = .008).⁸⁴⁰

In OCTOBER, OCT-guided PCI led to a lower risk of a composite of death from a cardiac cause, target-lesion MI, or ischaemia-driven target-lesion revascularization than angiography-guided PCI by 2 years (10.1% vs. 14.1%; HR 0.70; 95% CI, 0.50–0.98; P = .035).⁸¹⁰ In ILUMIEN IV, OCT-guided PCI failed to decrease the rate of the primary efficacy endpoint of target-vessel failure, defined as death from cardiac causes, target-vessel MI, or ischaemia-driven target-vessel revascularization (7.4% vs. 8.2%; HR 0.90; 95% CI, 0.67–1.19; P = .45), while the incidence of definite/probable stent thrombosis was significantly reduced by OCT guidance vs. angiography guidance (0.5% vs. 1.4%; HR 0.36; 95% CI, 0.14–0.91; P = .02).⁸⁴¹

4.4.5.7. Hybrid revascularization in multivessel coronary artery disease patients

Arterial grafting with left internal mammary artery (LIMA) to the LAD system and multiple arterial grafting reduces the risk of graft occlusion, thus increasing the longevity of revascularization efficacy after CABG.^842,843 Hybrid revascularization of multivessel CAD with minimally invasive direct coronary artery bypass (MIDCAB)-LAD plus PCI of the remaining arteries may represent an alternative option. Hybrid off-pump revascularization seems a suitable option for patients at moderate-to-high risk for surgery by avoiding the use of cardiopulmonary bypass. Despite this attractive concept, the frequency of hybrid revascularizations remains extremely modest, with about 0.1% of surgical revascularizations.⁸⁴⁴ Few data are available comparing hybrid revascularization vs. conventional CABG or PCI. Large registry data report higher rates of bleeding, renal failure, MI, and HF with hybrid revascularization compared with PCI alone,⁸⁴⁴ while a very small randomized trial reported similar clinical outcomes at long-term follow-up.⁸⁴⁵ It seems challenging to perform larger RCTs to investigate this question. The recent National Heart, Lung, and Blood Institute-funded Hybrid Trial (Hybrid Coronary Revascularization Trial; NCT03089398) was prematurely discontinued due to slow enrolment, with only 200 patients in 5 years.

4.4.6. Patient–physician shared decision-making to perform and select revascularization modality

Shared decision-making between patients and healthcare professionals, based on patient-centred care, is considered a paramount process in defining the appropriate therapeutic pathway. Essential aspects of shared decision-making are: a complete and accurate explanation of the disease; presentation and description of therapeutic options; discussion of potential risks, benefits, and impact on QoL for each procedure; considering patient preferences and goals; and carefully explaining each step of the post-procedural course and follow-up. Poor shared decision-making is associated with worse physical and mental outcomes, lower adherence to therapy, and an increased number of emergency department visits.^846–848 Shared decision-making and family meetings involving relatives increase patient trust in the physicians, with greater adherence to therapeutic decisions. Shared decision-making and patient medical education, considering the patient’s characteristics, mental status, cultural beliefs, and educational level, are therefore associated with increased patient knowledge and better QoL and with lower levels of anxiety and depression.^849–851

Using lay language and discussion with patients and relatives of short-term procedure-related and long-term risks and benefits—such as survival, relief of angina, QoL, the potential need for late reintervention, the need for prevention measures, and uncertainties associated with different treatment strategies—are of great importance. Although current recommendations are primarily based on the ability of treatments to reduce adverse events, including improved survival, there is growing interest in PROMs.⁸⁵² Patients are not only interested in knowing how recommended treatment impacts prognosis but also their QoL in the way they perceive it.⁸⁵³ The patient’s right to decline the treatment option recommended by the Heart Team must be respected. Patient refusal of a recommended treatment should be acknowledged in a written document after the patient has received the necessary information. In this case, the Heart Team may offer the patient an alternative treatment option.

The multidisciplinary Heart Team, on site or with partner institutions (Hub-Spoke institutions)—comprising clinical or non-invasive cardiologists, cardiac surgeons and interventional cardiologists, as well as anaesthetists or other specialists and healthcare professionals, if deemed necessary—should provide a balanced multidisciplinary decision-making process.

Transparency in informed consent is critical, particularly when treatment options are debated. Complex cases, such as patients with CAD of high anatomic complexity and significant non-cardiac comorbidities, should be discussed in the Heart Team, taking into consideration other characteristics not always included in traditional databases, such as frailty. Heart Team/guideline discordance is common in complex CAD patients undergoing revascularization, especially in elderly patients, those with complex coronary disease, and those treated at centres without cardiac surgery service. These patients have a higher risk of mid-term mortality.⁸⁵⁴

In all cases, it is necessary to allow sufficient time to assess all available information and clearly explain and discuss the findings with each patient. The rationale for a decision and consensus on the optimal revascularization treatment should be documented on the patient’s chart. While the Heart Team decision is mainly driven by long-term survival benefits with a certain modality of revascularization, patient’s preferences must be respected.^853,855,856

4.4.7. Institutional protocols, clinical pathways, and quality of care

Institutional protocols, developed by the Heart Team and aligned with the current guidelines, should delineate specific anatomical and functional criteria of disease complexity and specific clinical subsets of patient’ risk for cardiac surgery or intervention that may or may not be treated ad hoc. These protocols should be incorporated into clinical pathways, with regular meetings to assess the applied indications for myocardial revascularization and monitor the safety and effectiveness of the procedures, ensuring the quality of delivered patient care. Collaborative protocols are necessary when cardiac surgery isn’t available on site, and remote Heart Team meetings should be established.

Recommendation Table 22

Recommendations for revascularization in patients with chronic coronary syndrome (see also Evidence Table 22)

Recommendation Table 23

Recommendations for mode of revascularization in patients with chronic coronary syndrome (see also Evidence Table 23)

5. Optimal assessment and treatment of specific groups

5.1. Coronary artery disease and heart failure

About half of acute and chronic HF patients have an ischaemic aetiology.^880,881 Over the last decades, the proportion of ischaemic HFrEF has decreased while that of HFpEF, defined according to the 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure,⁵²⁶ has increased.⁸⁸² The evaluation of inducible ischaemia is important in patients with HF, given the high prevalence of CAD.^883–885 Moreover, patients with HFpEF may present MVA due to CMD.⁸⁸⁶ Indeed, CMD was observed in up to 75% of patients with HFpEF and was associated with worse diastolic relaxation velocities, as well as higher filling pressures, and an increased risk of adverse events.^{883–885,887–890} Clinical assessment alone may under-estimate the proportion of patients with obstructive or non-obstructive CAD, which can be found in up to 81% of HFpEF patients.⁸⁸⁷ Under-estimation of obstructive CAD leads to failure in identifying those patients who may benefit from revascularization. Conversely, in ANOCA patients with preserved LV function, a CFR of <2 was independently associated with diastolic dysfunction and future MACE, especially HFpEF events.⁸⁹¹ This suggests that CMD and myocardial stiffness may contribute to HFpEF pathophysiology.⁸⁹² In HFpEF patients, functional imaging should, therefore, be considered to detect CMD and epicardial CAD.

Exercise or pharmacological stress echocardiography can be used for the assessment of inducible ischaemia and can also help in the differential diagnosis of HFpEF.^893,894 Stress SPECT or PET can also be used for the detection of inducible ischaemia. Non-invasive stress testing can be difficult in patients with HF because of possible exercise intolerance. CCTA is recommended in patients with HF with a low-to-intermediate pre-test likelihood of obstructive CAD and those with equivocal non-invasive stress tests, provided there is no contraindication to contrast administration.^894–898 In HFpEF patients, perfusion PET should be considered for the detection of CMD.⁸⁹¹ In patients with HFrEF and moderate-to-severe inducible myocardial ischaemia, surgical revascularization improved long-term survival.^54,315 The results of the REVIVED-BCIS2 trial seem to contradict these findings, as PCI did not reduce mortality or HF hospitalization in patients with severe LV systolic dysfunction (LVEF ≤ 35%) receiving optimal medical therapy.⁷²⁹ The same trial also revealed that viability testing did not offer any prognostic benefit.⁷⁵⁵ The role of myocardial revascularization and viability testing is further addressed in Section 4.4.2.

In HF patients with anginal (or equivalent) symptoms, despite optimized GDMT, CCTA or ICA is recommended to confirm the diagnosis of obstructive CAD and its severity.

Over the past three decades, several landmark clinical trials have provided robust evidence on the prognostic benefit of pharmacological therapies in patients with HFrEF. In these patients, four drug classes [ACE-Is or angiotensin receptor neprilysin inhibitors (ARNIs),⁸⁹¹ beta-blockers, mineralocorticoid receptor antagonists (MRAs), and SGLT2 inhibitors] are recommended for outcome improvement regardless of HF aetiology and comorbidities, including CAD.⁵²⁶

In patients with HFrEF, an ARB is recommended in patients who do not tolerate ACE-Is or ARNIs. Also, ivabradine should be considered in addition to the four pillars. It can be used as an alternative to beta-blockers, when contraindicated or not tolerated, or as additional antianginal therapy in patients with sinus rhythm and heart rate of >70 b.p.m.⁸⁹⁹ Other antianginal drugs (e.g. amlodipine, felodipine, nicorandil, trimetazidine, ranolazine, and nitrates) are effective for improving symptoms in patients with HFrEF.^{546,900–902} Diltiazem and verapamil increase HF-related events in patients with HFrEF and are contraindicated.⁵²⁶ In patients with LVEF ≤35% of ischaemic aetiology, an ICD is strongly recommended for primary prevention; in those with LVEF ≤35% and QRS >130 ms, CRT needs to be considered.⁵²⁶ Further details regarding the management of patients with HFrEF are reported in the 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure.⁵²⁶

In patients with HFpEF, in addition to diuretics for treating congestion, SGLT2 inhibitors are now recommended for outcome improvement.⁷⁰⁹ Additionally, beta-blockers, long-acting nitrates, CCBs, ivabradine, ranolazine, trimetazidine, nicorandil, and their combinations should be considered in patients with HFpEF and CAD for angina relief, but without foreseen benefits on HF and coronary endpoints. Low-dose rivaroxaban may be considered in patients with CAD and HF, LVEF of >40%, and sinus rhythm when at high risk of stroke and with low haemorrhagic risk.^526,903,904

Evidence and recommendations for myocardial revascularization in patients with HF are reported in Section 4.4.2. Notably, patients with advanced HF may be candidates for LV assistance devices and/or heart transplantation.⁵²⁶

During of high-risk PCI for complex CAD⁹⁰⁵ in patients with HFrEF, mechanical cardiac support, such as the microaxial flow pump, may minimize the risk of severe complications and provide haemodynamic stability, facilitating the achievement of complete revascularization.^906,907

Recommendation Table 24

Recommendations for management of chronic coronary syndrome patients with chronic heart failure (see also Evidence Table 24)

5.2. Angina/ischaemia with non-obstructive coronary arteries

5.2.1. Definition

A large proportion of patients undergoing coronary angiography because of angina do not have obstructive epicardial coronary arteries (ANOCA). In these patients, the prevalence of demonstrable ischaemia (INOCA) varies, depending on the stress test performed, between 10% and 30% (Figure 12).^926–928 Angina/ischaemia with non-obstructive coronary arteries is more frequent among women (approximately 50% to 70%) than in men (30% to 50%) referred for ICA.^7,929 The mismatch between blood supply and myocardial oxygen demands leading to angina and ischaemia in ANOCA/INOCA may be caused by CMD and/or epicardial coronary artery spasm.³⁶ However, these conditions are rarely correctly diagnosed, and, therefore, no tailored therapy is prescribed for these patients. As a consequence, these patients continue to experience recurrent angina with poor QoL, leading to repeated hospitalizations, unnecessary repeat coronary angiography, and adverse cardiovascular outcomes in the short and long term.³⁶

Figure 12

Prevalence of disease characteristics in patients with ANOCA/INOCA referred for invasive coronary functional testing.

Ach, acetylcholine; ANOCA, angina with non-obstructive coronary arteries; CFR, coronary flow reserve; i.c., intracoronary; INOCA, ischaemia with non-obstructive coronary arteries. In the ILIAS (Inclusive Invasive Physiological Assessment in Angina Syndromes) registry,⁹²⁷ ANOCA is present in up to 70% of patients referred for invasive coronary angiography and functional testing. Endothelial dysfunction is present in 80% and an acetylcholine test is positive in 60% of these patients. An impaired CFR (≤2.5), measured by i.c. Doppler guidewires, is present in 50%, while ischaemia (INOCA) is documented by non-invasive functional testing in only 25% of ANOCA patients. The prevalence of coronary vasospasm can vary in different studies depending on dose of acetylcholine and test protocol.

^aPrevalence of ischaemia by non-invasive functional testing increases from non-obstructive to obstructive CAD.

5.2.2. Angina/ischaemia with non-obstructive coronary arteries endotypes

Invasive functional coronary testing using Ach and adenosine in individuals suspected of CCS and with non-obstructive coronary arteries enables the differentiation of the following endotypes: (i) endothelial dysfunction; (ii) impaired vasodilation (low coronary flow reserve and/or high microvascular resistance); (iii) epicardial vasospastic angina; (iv) microvascular vasospastic angina; (v) endotype combinations; (vi) equivocal response, i.e. angina without fulfilling any endotype criteria.^37,38 The prevalence of ANOCA and INOCA in relation to the presence of the endotypes is shown in Figure 12. Angina with non-obstructive coronary arteries occurs in up to 70% of the patients undergoing ICA, of whom 25% have documented ischaemia (INOCA). Among the patients who are tested with Ach, 80% show endothelial dysfunction, 60% have MVA/VSA, and 50% have an impaired CFR and/or high microvascular resistance.^{38,927,930,931} This emphasizes the importance of testing not only patients with INOCA but also all patients with ANOCA to determine the final endotype so that appropriate treatment can be initiated.

5.2.2.1. Microvascular angina

Microvascular angina is the clinical manifestation of myocardial ischaemia caused by structural or functional changes in the coronary microvasculature (leading to impaired CFR and/or reduced microcirculatory conductance) and/or abnormal vasoconstriction of coronary arterioles (causing dynamic arteriolar obstruction).^932,933 Both vascular dysfunction mechanisms may co-exist and contribute to MVA.

The prevalence of MVA was 26% in a study of patients with non-obstructive CAD who had a CFVR below 2 when assessed by transthoracic Doppler echocardiography.⁹³⁴ Studies assessing CMD invasively or by PET with different cut-offs have found that 39% to 54% had CMD.^935,936 The threshold for CMD varies between studies and depending on the techniques used (PET, CMR, thermodilution, or Doppler); the threshold is a CFR of <2.0–2.5.^36,39 A thermodilution CFR of <2.0 has low sensitivity for identifying CMD, but using the same threshold as for Doppler (<2.5) results in reasonable diagnostic accuracy.⁹³⁷

Smoking, age, diabetes, hypertension, and dyslipidaemia are associated with CMD.^934,935,938 Other studies have shown that diabetes was uncommon among patients with angina and non-obstructive CAD, while hypertension and dyslipidaemia were relatively more prevalent.^939,940 Inflammatory conditions such as systemic lupus erythematosus (SLE) and rheumatoid arthritis appear to be associated with MVA and are not infrequently encountered in patients with angina.⁹⁴¹ Inflammatory diseases occur more often in women after menopause than in men, which may contribute to the sex differences in MVA.^942–944 Last, but not least, there is increasing evidence that psychosocial stress is involved in coronary vasomotor disorders.^945,946

5.2.2.2. Epicardial vasospastic angina

Vasospastic angina is the clinical manifestation of myocardial ischaemia caused by abnormal vasoconstriction of one or more epicardial coronary arteries leading to a dynamic coronary obstruction. Standardized diagnostic criteria for VSA have been defined.⁷³ Microvascular angina and epicardial VSA can co-exist, which is associated with a worse prognosis.⁹⁴⁷ Concomitant endothelial dysfunction is prevalent in most patients with INOCA with inducible coronary artery spasm and/or impaired adenosine-mediated vasodilation.^38,948

The Japanese population has a higher prevalence of coronary vasospasm than Western populations. In addition, the frequencies of multiple coronary spasms (≥2 spastic arteries) by provocative testing in Japanese (24.3%) and Taiwanese populations (19.3%) are markedly higher than those in Caucasians (7.5%).^949–951

5.2.3. Clinical presentations

Angina/ischaemia with non-obstructive coronary arteries is associated with a wide variation in its clinical presentation, and symptom burden may vary over time. Failure to diagnose epicardial obstructive CAD in a patient with documented ischaemia should stimulate a subsequent search pathway to elucidate ANOCA/INOCA endotypes.

5.2.4. Short- and long-term prognosis

Symptoms of angina/ischaemia with non-obstructive coronary arteries are associated with adverse physical, mental, and social health.⁹⁵² Angina/ischaemia with non-obstructive coronary arteries is associated with poor QoL, higher risk of disability, and a higher incidence of adverse events, including mortality, morbidity, healthcare costs, recurrent hospital readmissions and repeat coronary angiograms.^{300,953–958} The incidence of all-cause death and non-fatal MI in patients with non-obstructive atherosclerosis was higher than in those with angiographically normal epicardial vessels.^{298,959–961} Proven myocardial ischaemia by stress echocardiography or nuclear imaging was associated with a higher incidence of events compared with ischaemia detected by exercise electrocardiographic stress testing.⁹⁵⁸ There is a two- to four-fold higher risk of adverse cardiovascular outcomes in patients with MVA diagnosed by PET or transthoracic echocardiography and a two-fold higher risk in patients with epicardial endothelial-dependent dysfunction.^300,962 Microvascular angina due to impaired CFR was associated with increased major adverse cardiac events and target-vessel failure rates over a 5-year follow-up period.⁹³¹ Vasospastic angina is associated with major adverse events, including sudden cardiac death, acute MI, and syncope.⁹⁶³ In a group of ANOCA/INOCA patients, abnormal non-invasive testing did not allow the identification of patients with a higher risk of long-term cardiovascular events. However, adding intracoronary physiological assessment to non-invasive information allowed the identification of patient subgroups with up to a four-fold difference in long-term cardiovascular events.³⁵⁷

5.2.5. Diagnosis

The presence of myocardial ischaemia on functional imaging without obstructive CAD on CCTA or ICA should always raise the clinical suspicion of ANOCA/INOCA. The diagnosis of ANOCA/INOCA is exclusively based on invasive functional evaluation of the coronary microcirculation, given that no technique allows direct visualization of the coronary microcirculation in vivo in humans. Several non-invasive and invasive tests have been established to assess the coronary microvascular function (Figure 13).^6,41,964,965

Figure 13

Diagnostic algorithm for patients with angina/ischaemia with non-obstructive coronary arteries.

Ach, acetylcholine; ANOCA, angina with non-obstructive coronary arteries; CAD, coronary artery disease; CCS, chronic coronary syndrome; CCTA, coronary computed tomography angiography; CFR, coronary flow reserve; ECG, electrocardiogram; echo, echocardiography; FFR, fractional flow reserve; GDMT, guideline-directed medical therapy; HMR, hyperaemic myocardial velocity resistance; i.c., intracoronary; ICA, invasive coronary angiography; iFR, instantaneous-wave free ratio; IMR, index of microcirculatory resistance; INOCA, ischaemia with non-obstructive coronary arteries; MRI, magnetic resonance imaging; PET, positron emission tomography; SPECT, single-photon emission computed tomography.

5.2.5.1. Non-invasive diagnosis

Non-invasive tests (stress echocardiography, PET, perfusion CCTA, and CMR) allow diagnosing ANOCA/INOCA by measuring the CFR.⁴¹ These techniques have an excellent negative predictive value, but the positive predictive value is an issue for most, as obstructive CAD needs to be ruled out before the diagnosis of CMD can be made. Only hybrid techniques such as CCTA with perfusion and PET-CT offer combined imaging of the epicardial coronary arteries and functional testing of the coronary microcirculation in a single test.^6,964

5.2.5.2. Invasive coronary functional testing

Invasive coronary functional testing consists of a comprehensive evaluation of the coronary circulation in a single procedure by combining angiography, direct invasive assessment of the coronary haemodynamics by intracoronary pressure and flow measurement either by thermodilution (bolus/continuous) or Doppler techniques, and pharmacological vasomotor testing. Recently, a standardized protocol has been proposed.³⁶

Basic coronary functional testing

Intracoronary pressure and flow measurements allow assessment of the haemodynamic significance of focal or diffuse coronary lesions by measuring FFR or iFR (see Section 3.3.3.2) and of microcirculatory function by measuring CFR and IMR, HMR, or MRR^361,961 (see Section 3.3.3.3). Coronary microvascular dysfunction is characterized by decreased CFR and increased microvascular vascular resistance (IMR, HMR, MRR). Decreased CFR can be due to structural or functional microvascular dysfunction.^926,966 Functional CMD is characterized by increased resting flow linked to enhanced nitric oxide synthase (NOS) activity, whereas patients with structural CMD have endothelial dysfunction, leading to a reduced increase of coronary blood flow during exercise.^926,966

A Doppler-derived CFR of <2.5 in non-obstructive CAD indicates an abnormal microcirculatory response corresponding to a thermodilution-derived CFR of <2.5.^{361,926,937,961} Of note, in assessing coronary microvascular function, continuous thermodilution showed significantly less variability than bolus thermodilution on repeated measurements.³⁸² An increased IMR (≥25) indicates microvascular dysfunction.^380,381 For the Doppler-derived HMR, a value of >2.5 mmHg/cm/s indicates augmented microvascular resistance.⁴² Recently, MRR has been considered abnormal for values <2.7.^364,967 Doppler flow analysis allows assessment of the flow-recovery time after Ach administration as a sign of myocardial ischaemia, which is helpful in the diagnosis of patients with equivocal test results.⁹⁶⁸

Coronary vasomotor testing

Epicardial and microvascular endothelium-dependent vasodilation and vasospasm are tested by intracoronary bolus administration or graded infusion of Ach, first at a low dose/grade to assess endothelial dysfunction at the microvascular or epicardial level, and after that at a higher dose/grade to eventually induce microvascular or/and epicardial coronary vasospasm. The LAD artery is usually preferred as the pre-specified target vessel reflecting its subtended myocardial mass and coronary dominance. The left circumflex coronary artery is also tested if Ach is administered in the LMCA. Additional studies in the right coronary artery may be appropriate if the initial tests are negative and clinical suspicion is high. As Ach exerts a cholinergic effect on the atrioventricular node, significant bradycardia may ensue if infused especially in the right coronary artery or a dominant left circumflex coronary artery. Bradycardia can be prevented by selective infusion in the LAD, prophylactic ventricular pacing, or reduction of the concentration infused or of the injected dose. If necessary, the bradycardia effect of Ach can be antagonized by atropine. The effect of Ach is short in contrast to the prolonged effect of ergonovine, which was previously used for the provocation of coronary vasospasm.⁹⁶⁹ The diagnosis of MVA and VSA due to microvascular or macrovascular vasospasm is made according to established criteria.^41,73,932 The test is considered positive for macrovascular spasm if symptoms occur, accompanied by ischaemic ECG changes and an angiographic ≥90% reduction of the coronary lumen. If the lumen reduction is <90%, the diagnosis of microvascular spasm is made. The vasospastic effect of Ach is rapidly transient and can, if needed, be reversed by intracoronary administration of nitroglycerine, which also allows assessment of endothelium-independent epicardial coronary vasodilation. The safety of coronary vasospasm provocation testing with increasing intracoronary Ach boluses of up to a maximum of 200 μg has been repeatedly reported.^37,970,971 In a small study, testing coronary vasospasm using this algorithm was also safe in patients with a recent ACS.⁹⁷²

At the end of the procedure, microcirculatory vasomotor response to i.v. administration of the endothelium-independent vasodilator adenosine⁹⁷³ is assessed and CFR, IMR, HMR, or MRR are measured. In patients with contraindications to the use of adenosine, papaverine can be used⁹⁷⁴ but precautionary measures need to be taken given the risk of inducing polymorphic ventricular tachycardia.^975,976

Different protocols have been applied in clinical practice. Figure 14 shows an example of a standardized and stepwise algorithm for ICFT that may be adopted in the cardiac catheterization laboratory for diagnosing vasospasm. Informed consent should be obtained, mentioning unlicensed, parenteral use of Ach, and administration performed by an experienced interventional cardiologist.

Figure 14

Spasm provocation and functional testing protocol.

Ach, acetylcholine; CCB, calcium channel blocker; CFR, coronary flow reserve; ECG, electrocardiogram; i.c., intracoronary; i.v., intravenous; MR, microvascular resistance; NTG, nitroglycerine. i.c. bolus injections of Ach over 60s to assess: (i) endothelial-dependent vasodilation using low-dose Ach (2–20 µg), and (ii) endothelial dysfunction and vasoconstriction using high-dose Ach (100–200 µg). This is followed by i.c. administration of nitroglycerine (200 µg) to revert vasospasm. Endothelial-independent vasodilation is assessed by i.c. adenosine (200 µg) or i.v. infusion to determine CFR and IMR. Coronary flow can be continuously monitored if i.c. Doppler guidewires are used.

^aThe incremental administration of Ach is stopped whenever a coronary vasospasm is induced.

^bi.v. adenosine can also be used.

5.2.6. Management of angina/ischaemia with non-obstructive coronary arteries

Management should be patient-centred with a patient-oriented multidisciplinary care approach.⁹⁷⁷ Figure 15 provides an algorithm for the therapeutic management of ANOCA/INOCA. In all patients with established ANOCA/INOCA due to the frequent presence of coronary atherosclerosis and endothelial dysfunction, tailored counselling on lifestyle factors is warranted to address risk factors, reduce symptoms, and improve QoL and prognosis. Management of traditional CVD risk factors, hypertension, dyslipidaemia, smoking, and diabetes should be as per clinical practice guidelines recommendations.

Figure 15

Treatment of angina/ischaemia with non-obstructive coronary arteries.

ACE-I, angiotensin-converting enzyme inhibitor; ANOCA, angina with non-obstructive coronary arteries; ARB, angiotensin receptor blocker; CCB, calcium channel blocker; INOCA, ischaemia with non-obstructive coronary arteries. Treatment of ANOCA/INOCA patients includes lifestyle modification, management of cardiovascular risk factors, and antianginal treatment according to underlying endotypes. Note: endotypes frequently overlap, requiring combined medical therapy.

Treatment of anginal symptoms in patients with ANOCA/INOCA is challenging as the patients represent a heterogeneous group and randomized trials are lacking. A small study showed that a stratified antianginal therapy algorithm based on coronary functional testing resulted in improved angina symptoms and QoL compared with a control group treated with standard therapy.⁹⁷⁸ In patients with MVA and reduced CFR and/or increased IMR (which may reflect arteriolar remodelling), beta-blockers, CCBs, ranolazine, and ACE-Is are used.⁹⁷⁹ In these patients, anti-ischaemic therapy with amlodipine or ranolazine resulted in a significant improvement in exercise time.⁹⁸⁰ In patients with either epicardial or microvascular spasm following Ach testing, calcium antagonists should be considered as first-line therapy. In patients with severe VSA, it may be necessary to administer unusually high dosages of calcium antagonist (2 × 200 mg diltiazem daily or higher up to 960 mg daily) or even a combination of non-dihydropyridine (such as diltiazem) with dihydropyridine calcium blockers (such as amlodipine). Of note, a small study using either oral diltiazem or placebo up to 360 mg/day in CMD for 6 weeks did not substantially improve symptoms or QoL, but diltiazem therapy did reduce the prevalence of epicardial spasm.⁹⁸¹ Nicorandil, a combinatorial vasodilator agent acting via nitrate- and potassium-channel activation, may be an effective alternative, although side effects are frequent.⁹⁸² First-line therapy can also be combined with ranolazine, an antianginal agent that improves myocyte relaxation and ventricular compliance by decreasing sodium and calcium overload.⁹⁸³ Spinal cord stimulation is an option for patients who remain refractory after medical therapy.⁹⁸⁴

There are currently several studies evaluating therapies specific to ANOCA/INOCA. The Women’s IschemiA Trial to Reduce Events in Non-ObstRuctIve CORonary Artery Disease (WARRIOR, NCT03417388) is currently enrolling subjects in a multicentre, prospective, randomized, blinded outcome evaluation to assess intensive statin and ACE-I/ARB therapy (ischaemia-intensive medical therapy) vs. usual care on MACE in symptomatic women with ANOCA. The Precision Medicine with Zibotentan in Microvascular Angina (PRIZE) trial holds future promise (NCT04097314). Zibotentan is an oral, endothelin A receptor antagonist that may provide benefit by opposing the reported vasoconstrictor response of coronary microvessels to endothelin.

Recommendation Table 25

Recommendations for diagnosis and management of patients with angina/ischaemia with non-obstructive coronary arteries (see also Evidence Table 25)

5.3. Other specific patient groups

5.3.1. Older adults

Between 2015 and 2050, the proportion of the world’s population aged >60 years is set to nearly double to 22%. Ageing predisposes patients to a high incidence and prevalence of CAD, in both men and women. Typically, in the context of CVD, older patients are defined as those ≥75 years of age;¹ it should be noted, however, that such age cut-offs are relatively arbitrary, and biological age influences this threshold in clinical practice. Clinical characteristics of the older adult population are heterogeneous, with frailty, comorbidity, cognitive function, and health-related QoL playing important roles in guiding clinical care and as predictors of adverse outcomes.^1001–1005 Older patients often present with symptoms other than angina, which may delay the diagnosis of CCS.¹⁰⁰⁴

Ageing is often accompanied by both comorbidities and frailty, and consequently leads to potentially excessive polypharmacy.⁵³¹ In making treatment decisions, clinicians should take into account the limited external validity of RCTs for older adults.³⁶ Older people are often underrepresented in RCTs as a consequence of exclusion criteria and under-recruitment,^{531,1006,1007} though they have been shown to have a higher underlying risk for cardiovascular outcomes.¹⁰⁰⁸ The treatment of CCS in older adults is complicated by a higher vulnerability to complications for both conservative and invasive strategies, such as bleeding, renal failure, and neurological impairments, all of which require special attention. The use of DES, compared with bare-metal stents, in combination with a short duration of DAPT, is associated with significant safety and efficacy benefits in older adults.¹⁰⁰⁹ Frailty is of utmost importance in the clinical decision-making.¹⁰¹⁰

5.3.2. Sex differences in chronic coronary syndromes

Ischaemic heart disease is the leading cause of mortality for women, yet they have been historically underrepresented in RCTs.^1011–1013 Differences in symptom presentation, in the accuracy of diagnostic tests for obstructive CAD, and other factors that lead to differential triage, evaluation, or early treatment of women with myocardial ischaemia compared with men could contribute to unfavourable outcomes. There are also risk factors that are unique to women.^1014,1015 Not only premature menopause,¹⁰¹⁶ but also hypertensive disorders of pregnancy, pre-term delivery, gestational diabetes, small-for-gestational-age delivery, placental abruption, and pregnancy loss are predictors of subsequent CVD.¹⁰¹⁷ Also, the association between low socioeconomic status and increased cardiovascular risk seems stronger in women.¹⁰¹⁸ In addition, higher levels of residential segregation are associated with incident CVD and obesity among black women.¹⁰¹⁹

Women are less likely to be referred for diagnostic testing and are under-treated for essential secondary prevention therapies.¹⁰²⁰ Compared with men, women have a shorter survival after PCI¹⁰²¹ and CABG.¹⁰²² In a large-scale, individual-patient data pooled analysis of contemporary PCI trials with early and new-generation DES, women had a higher risk of MACE and ischaemia-driven target-lesion revascularization compared with men at 5 years following PCI.¹⁰²¹ However, the excess risk after PCI among women can be primarily explained by a greater burden of cardiovascular risk factors and comorbid conditions.¹⁰²³ Nevertheless, in a population undergoing contemporary PCI, women and men had similar risks of death or new Q-wave MI at 2 years, but women faced a higher risk of bleeding and haemorrhagic stroke compared with men.¹⁰²⁴

Women with signs and symptoms suggestive of cardiac ischaemia should be investigated carefully. The same guideline-recommended cardiovascular preventive therapy should be provided to women and men.¹⁰²⁵ Hormone replacement therapy in post-menopausal women does not reduce the risk of ischaemic myocardial disease¹⁰¹⁵ and it may come at the cost of other health risks,¹⁰²⁶ which should be discussed with the patient.

5.3.3. High bleeding-risk patients

An HBR is increasingly present in many CCS patients referred for coronary revascularization. The ARC-HBR consortium provided a consistent definition of HBR for patients undergoing PCI. Patients are considered at HBR if at least one major or two minor criteria are met.⁵⁹⁰ In the context of PCI in HBR patients, short duration of DAPT (1–3 months) and PCI with a DES was beneficial in many recent studies.^{1009,1027–1032}

5.3.4. Inflammatory rheumatic diseases

Patients with inflammatory rheumatic diseases have an increased risk of CVD compared with the general population.^1033,1034 Accumulating evidence has shown elevated cardiovascular morbidity and mortality in other rheumatic and musculoskeletal diseases, including gout, vasculitis, systemic sclerosis, myositis, mixed connective tissue disease, Sjögren syndrome, SLE, and the antiphospholipid syndrome.^1035–1044

Some of these patient categories have two- to three-fold higher prevalences of asymptomatic ASCVD compared with the general population,^1045–1051 which is linked to ASCVD outcomes.^{1049,1052–1054} Thus, identification of ASCVD such as carotid artery plaque(s) may be considered in ASCVD and CAD risk evaluation.^{1050,1055–1057}

In patients with inflammatory rheumatic diseases and CCS, CVD preventive medications such as lipid-lowering medications and antihypertensive treatment should be used as in the general population.^1058–1062

5.3.5. Hypertension

Blood pressure lowering has been associated with favourable cardiovascular outcomes in patients regardless of the presence of CAD.¹⁰⁶³ Due to concerns of a possible J-curve relationship between achieved BP and cardiovascular outcomes in patients with CAD, previous guidelines did not recommend a target BP of <120/70 mmHg. In line with the 2024 ESC Hypertension Guidelines¹⁰⁶⁴, the present guidelines recommend that treated systolic BP values in most CCS patients be targeted to 120–129 mmHg, provided the treatment is well tolerated. In cases where on-treatment systolic BP is at or below target (120–129 mmHg) but diastolic BP is not at target (≥80 mmHg), intensifying BP-lowering treatment to achieve an on-treatment diastolic BP of 70–79 mmHg may be considered to reduce CVD risk.¹⁰⁶⁵ More lenient targets (e.g. 140/90 mmHg) can be considered in older patients (≥85 years of age) or patients with pre-treatment symptomatic orthostatic hypotension. In hypertensive patients with a history of MI, beta-blockers and RAS blockers are first-line treatments. In patients with symptomatic angina, beta-blockers and/or CCBs can be useful.¹⁰⁶⁵

5.3.6. Atrial fibrillation

Diagnostic assessment of CAD (CCTA and non-invasive tests) may be difficult in AF with a high ventricular rate. In patients with CAD and AF, rhythm or rate control strategies may help improve symptoms of myocardial ischaemia. Amiodarone or dronedarone are drugs of choice for rhythm control, as an alternative to catheter ablation, in patients with CAD and AF. Sotalol may also be considered. Beta-blockers, diltiazem, verapamil, or digoxin can be used for rate control depending on the LVEF.⁶¹³ After PCI, combined anticoagulant and antiplatelet therapies are needed. Recommendations on post-PCI antithrombotic therapy in patients with AF and indication for OAC are detailed in Section 4.3.1.2.2 and Recommendation Table 17.^613,621,659 Surgical ablation of AF during isolated CABG seems to be safe and effective in improving long-term outcomes.¹⁰⁶⁶ Concomitant surgical closure of the left atrial appendage is recommended as an adjunct to oral anticoagulation in patients with AF undergoing cardiac surgery (e.g. CABG) to prevent ischaemic stroke and thrombo-embolism (see the ESC 2024 Guidelines for the management of Atrial Fibrillation).¹⁰⁶⁷

5.3.7. Valvular heart disease

In patients with valvular heart disease with a risk for associated CAD who require surgery or in whom a decision of a percutaneous or surgical approach is still pending, ICA or CCTA is recommended to determine the need for coronary revascularization.¹⁰⁶⁸ Evidence of CAD in patients with valvular heart disease can drive to a surgical instead of a percutaneous treatment of valvular heart disease. Invasive coronary angiography is recommended in patients with secondary mitral regurgitation as this condition is frequently due to ischaemic LV dysfunction.¹⁰⁶⁸ Routine stress testing to detect CAD associated with severe symptomatic valvular heart disease is not recommended because of low diagnostic value and potential risk. The usefulness of FFR or iFR in patients with valvular heart disease is not well established, and caution is warranted in interpreting these measurements, especially in the presence of aortic stenosis.¹⁰⁶⁸ Beta-blockers need to be used with caution in patients with aortic valve disease. Coronary artery bypass grafting is recommended in patients with a primary indication for aortic/mitral/tricuspid valve surgery and significant coronary stenosis. Percutaneous coronary intervention should be considered in patients with a primary indication of transcatheter aortic valve implantation or transcatheter mitral valve intervention and coronary artery diameter stenosis of >70% in proximal segments.¹⁰⁶⁸

5.3.8. Chronic kidney disease

Chronic kidney disease increases the risk of CAD progression and is associated with high mortality rates due to cardiovascular causes.^1069,1070 Patients with CKD have a higher burden of atherosclerosis and more advanced plaque features.¹⁰⁷⁰ Despite the higher prevalence of disease, non-invasive diagnostic testing is often less accurate, and guidance related to the use of pharmacological and interventional therapy is limited due to inconsistent definitions of CKD and underrepresentation of CKD patients in clinical trials.^1070–1072

Careful assessment of the risk-to-benefit ratio is needed in patients with CKD before considering ICA, CCTA, or non-invasive tests requiring nephrotoxic agents.¹⁰⁷³ Pre-existing CKD is the primary patient-related risk factor for the development of acute kidney injury (AKI), whereas DM increases the susceptibility to develop AKI. The most important measures to prevent AKI are using the lowest necessary total dose of low-osmolality or iso-osmolality contrast medium and sufficient pre- and post-hydration.¹⁰⁷³

CKD raises the risks associated with both CABG and PCI.³¹⁶ The ISCHEMIA-CKD trial included patients with advanced CKD [estimated glomerular filtration rate (eGFR) of <30 mL/min/1.73 m² or dialysis] and CCS with moderate or severe myocardial ischaemia detected by stress test. An invasive strategy of ICA and PCI was not superior to conservative management in reducing the primary endpoint of death or non-fatal MI.¹⁰⁷⁴

In a propensity score-matched analysis involving 5920 CKD patients (2960 pairs), PCI utilizing second-generation DES displayed a reduced risk of death, stroke, and repeat revascularization at 30 days when compared with CABG.¹⁰⁷⁵ However, PCI was associated with a higher risk of repeat revascularization over the long term. Conversely, among patients on dialysis, the findings favoured CABG over PCI. Additionally, a meta-analysis of 11 registries revealed lower rates of death, MI, and repeat revascularization with CABG in contrast to PCI among patients with eGFR of <60 mL/min/1.73 m².¹⁰⁷⁶ Nevertheless, there is a notable absence of large RCTs comparing revascularization modalities among CKD patients.

5.3.9. Cancer

Several cancer treatments are associated with an increased risk of CCS. Spontaneous bleeding in ACS and CCS patients has been associated with subsequent cancer diagnosis.¹⁰⁷⁷ A prompt evaluation of bleeding may be useful to enable an early detection of cancer. The management of CCS is similar in patients with and without cancer. However, decisions regarding coronary revascularization should be undertaken by a multidisciplinary team. The approach should be individualized and based on life expectancy, additional comorbidities such as thrombocytopaenia, increased thrombosis, or bleeding risk, and potential interactions between drugs used in CCS management and anticancer therapy.^1078,1079

5.3.10. Optimal treatment of patients with human immunodeficiency virus

Patients with human immunodeficiency virus (HIV) have longer life expectancy than before due to effective antiretroviral therapy (ART), but are twice as likely to develop CVD compared with the general population.¹⁰⁸⁰ The long-term CVD outcomes in patients with HIV may change, given the relatively recent epidemiological transition of HIV to a chronic disease. Dyslipidaemia is a common condition in patients with HIV, whether treated or untreated with ART.¹⁰⁸¹ The treatment of dyslipidaemia in patients with HIV includes both non-pharmacological and pharmacological options. Special attention to the impact of polypharmacy, drug interactions between ART and lipid-lowering medications, and close monitoring for adverse events is critical to successfully managing dyslipidaemia and risk of CVD in patients with HIV. Hepatic cytochrome P450 3A4 (CYP3A4) metabolizes many statins; many ARTs are also metabolized by CYP3A4 and, thus, may have interactions with statins. Simvastatin and lovastatin are contraindicated with protease inhibitors; atorvastatin has less of a CYP3A4 interaction; pravastatin, fluvastatin, pitavastatin and rosuvastatin are not or minimally metabolized through CYP3A4.^1082,1083 Ezetimibe has no interactions with CYP3A4 or ART.¹⁰⁸¹

A clinical trial investigating the impact of PCSK9 inhibitor therapy on lipids, inflammatory markers, and subclinical ASCVD (including non-calcified plaque and arterial inflammation) in HIV is currently being conducted [EPIC-HIV study (Effect of PCSK9 Inhibition on Cardiovascular Risk in Treated HIV Infection), NCT03207945]. Future studies are needed to evaluate the impact of PCSK9 inhibition on clinical events in HIV.

5.3.11. Socially and geographically diverse groups

A lower socioeconomic status has implications of increased CVD mortality¹⁰⁸⁴ and poorer CVD risk factor profiles.¹⁰⁸⁵ A multicohort study of 1.7 million adults followed up for any cause of death for an average of 13 years found that low socioeconomic status was associated with a 2.1-year reduction in life expectancy between the ages 40 and 85 years.¹⁰⁸⁶ Education level, occupation, household income, health, disability, and living conditions also contribute to socioeconomic status. There were different rates of decline in mortality from CVD in Europe between the most and the least deprived.¹⁰⁸⁷ It has been proposed that on this basis, CVD could become a disease prevalently of the lower socioeconomic groups by the mid-2020s.¹⁰⁸⁸

Black patients with diabetes have a higher hospitalization burden with a concomitant disparity in comorbid presentation and outcome compared with other patients with diabetes.¹⁰⁸⁹ South Asian ethnicity, even after adjustment for traditional risk factors, is associated with an increased risk of coronary heart disease outcomes. This risk was greater than other studied racial/ethnic groups and second only to diabetes in coronary heart disease risk prediction.¹⁰⁹⁰

Within a large prospective study, South Asian individuals had a substantially higher risk of ASCVD than individuals of European ancestry.¹⁰⁹¹ South Asians have a more diffuse pattern with multivessel involvement. However, less is known about other morphological characteristics, such as atherosclerotic plaque composition and coronary diameter in South Asian populations. Despite a similar coronary calcification burden, higher non-calcified plaque contribution, elevated thrombosis, and inflammatory markers likely contribute to the disease pattern. Although the current evidence on the role of coronary vessel size remains inconsistent, smaller diameters in South Asians could play a potential role in the higher disease prevalence.¹⁰⁹² Individuals of South Asian descent have a high prevalence of CYP2C19 loss-of-function alleles (poor metabolizers: 13% vs. 2.4% in European populations),¹⁰⁹³ which are associated with reduced efficacy of clopidogrel.

Recommendation Table 26

Recommendations for older, female, high bleeding risk, comorbid, and socially/geographically diverse patients (see also Evidence Table 26)

5.4. Screening for coronary artery disease in asymptomatic individuals

Presence of asymptomatic atherosclerotic CAD is common in the general population.^1097–1100 In the Swedish Cardiopulmonary Bioimage Study, CCTA was performed in randomly selected individuals from the general population.¹⁰⁹⁷ In the 25 182 individuals without known CAD, atherosclerotic plaque was present in 42% of participants. Plaque was more common in older individuals and in males (males 50–54 vs. 60–64 years old: 41% vs. 69%, and females 50–54 vs. 60–64 years old: 19% vs. 40%). Obstructive coronary stenosis was present in 5% of participants. In the PESA study (Progression of Early Subclinical Atherosclerosis), 63% of asymptomatic middle-aged participants had subclinical atherosclerosis,¹⁵⁷ although most of them were categorized as low-risk individuals by several risk scores.¹⁴²

The risk of adverse events in asymptomatic subjects can be estimated using the European risk-estimation system [Systematic Coronary Risk Estimation 2 (SCORE2)], described in the 2021 ESC Guidelines on cardiovascular disease prevention in clinical practice.^16,1101 Systematic screening of risk factors cannot be strongly recommended in the general population as it did not affect CVD outcomes.¹¹⁰² However, when patients are seen for other reasons, opportunistic screening is effective at increasing detection rates of CVD risk factors, such as high BP or lipids. Hence, opportunistic screening is recommended, although its beneficial effect on clinical outcomes remains uncertain.¹¹⁰³

Information on CAC can be used to guide risk-factor management, and initiate lipid-lowering and antithrombotic treatment in patients with estimated future risk around treatment decision thresholds.¹¹⁰⁴ To date, two randomized screening studies have indicated that statin therapy impacts outcomes when guided by CACS in younger patients with high CACS.^1105,1106 Coronary artery calcium score could potentially guide not only risk-factor management but also primary prophylaxis with aspirin, but randomized studies are lacking.¹¹⁰⁷ Importantly, opportunistic screening of the burden of calcified atherosclerotic CAD can be accurately accessed with non-ECG-gated chest CT performed for other reasons.^17,1108 Reporting the visual interpretation of the coronary plaque burden according to a simple score with four categories (none, mild, moderate, severe) is recommended.^1108–1110 However, there is no current evidence to support further diagnostic imaging in asymptomatic individuals on the basis of presence of calcified plaque alone.

Carotid ultrasound,¹¹¹¹ aortic pulse wave velocity, arterial augmentation index, and ankle–brachial index are other modalities to improve the prediction of future CVD events. However, evidence is less extensive for these modalities compared with CACS.

Recommendation Table 27

Recommendations for screening for coronary artery disease in asymptomatic individuals (see also Evidence Table 27)

6. Long-term follow-up and care

6.1. Voice of the patient

A diagnosis of CCS can have an impact on self-identity, lifestyle, employment, and cause anxiety, depression, and burdensome treatment. Patients are experts in their own conditions, and their voices and preferences are integral to decisions about treatment. Health outcomes improve with better patient involvement, and shared decision-making is central to future patient care.¹¹¹³

6.1.1. Communication

Communication is essential to support patients' understanding, adherence, and engagement in decision-making.¹¹¹⁴ Good communication requires providing information at an appropriate level, active listening, assessing patient understanding, and determining patient perspectives and priorities. A meta-analysis summarizing a total of 127 studies of communication training concluded that patients were 19% more likely to be non-adherent when physicians had poor communication, and 12% more likely to be non-adherent when their physicians had not received communication training.¹¹¹⁵ Communication and shared decision-making can be particularly challenging when patients have comorbidities, low health literacy, language differences, cognitive impairment, depression, or anxiety, and when evidence for treatment is less robust.

Patient reported outcome measures can be useful to improve assessment and communication of symptoms, function, and QoL, and can highlight problems that may not have been previously discussed. Under- and overestimation of symptoms can lead to a lack of or inappropriate treatment.^1116,1117 The routine use of PROMs in clinical practice is hampered by the challenge of interpretation of scores and their integration into routine clinical processes.¹¹¹⁶

Although quality of communication can be improved through training, meta-analyses have not found evidence of significant impact on outcomes such as physical or mental health, satisfaction, QoL, or specific risk factors in patients with cancer, diabetes, and hypertension.^{1115,1118,1119} Structured tools and a flexible range of resources (including videos, workbooks, and health-literacy materials) that provide individualized information and decision aids can be adjuncts to better communication and shared decision-making.⁴⁴³ A systematic review of 17 RCTs of tools to support decision-making in severe illness concluded that they improved patient knowledge and readiness to make decisions.¹¹²⁰

Communicating the risk of future CVD events and how risk can be lowered through lifestyle and medications is best presented using visual or imaging approaches, natural frequencies rather than percentages, and positive framing (focusing on risk-reduction benefits).^1121–1125 Relative risk reduction is more persuasive than either absolute risk reduction or the number needed to treat.¹¹²² The use of risk prediction estimates may have an impact on individuals’ health when their information (i.e. predicted risk stratification) changes individuals’ behaviour, self-management decisions, and even treatment decisions.⁴⁴⁶ This enables patients to gain insights into their cardiovascular prognosis and to empower them to take part in the decision-making process.¹¹²⁶ This approach may increase self-motivation for therapy adherence and lifestyle changes, including changes in nutrition, physical activity, relaxation training, weight management, and participation in smoking cessation programmes for resistant smokers.⁴⁴⁶ Previous unsuccessful attempts to change to a healthy lifestyle or take guideline-recommended treatment can be addressed to set realistic goals.⁴⁴⁶

Communication should be clear regarding symptoms, even if not cardiac. Patients with CCS experiencing non-cardiac chest pain experience uncertainty about the cause and actions to take. A multidisciplinary approach and evaluation of non-cardiac aetiology with an appropriate referral are advocated to ensure that appropriate treatment is initiated.^1127,1128

6.1.2. Depression and anxiety

Depression is common (15%–20% prevalence) in CVD, and associated with poor adherence and worse outcomes, including MACE and premature death.¹¹²⁹ Coronary microvascular dysfunction (prevalent in INOCA) is linked with psychological stress and depression.⁹⁴⁶ Unfortunately, depression and psychological stress are often unrecognized due to a lack of systematic screening using validated tools.¹¹²⁹ For anxiety, a recent meta-analysis involving 16 studies reported a prevalence in post-MI between 5.5% and 58%, and a 27% greater risk of poor clinical outcomes in anxious patients compared with those without anxiety.¹¹³⁰ In contrast, in a 15-year follow-up of 1109 patients with CCS moderate anxiety did not increase the risk of cardiovascular events compared with low anxiety levels. Patients on a high but decreasing anxiety trajectory had an HR of 1.72 (95% CI, 1.11–2.68) for cardiovascular events.¹¹³¹ Treatment of psychosocial factors, depression, and anxiety with pharmacotherapy, psychotherapy, and/or exercise can improve symptoms and QoL in some patients, and there is some evidence for improvement in cardiac outcomes.^{472,1132–1134} Stepped care (initial therapy based on patient preferences) and a combination of therapies may be more efficacious.^1129,1135 First-line treatment with selective serotonin reuptake inhibitors (recommended in CCS) or non-pharmacological interventions and a multidisciplinary collaborative approach are recommended.¹¹²⁹

6.2. Adherence and persistence

Earlier analyses reported that adherence to long-term therapies in chronic conditions in Western countries averaged 50% and was lower in developing countries.¹¹³⁶ Pooled prevalence of non-adherence from a recent meta-analysis of eight studies (n = 3904 patients with multimorbidity) was 42.63% (95% CI, 34%–51%).¹¹³⁷ Data from the ESC-EORP EUROASPIRE V registry indicate that many CCS patients still have unhealthy lifestyles in terms of smoking, diet, and sedentary behaviour.¹¹³⁸ Poor adherence and persistence (duration of time in which medications and healthy behaviours are continued) have a profound effect on effective management, patient safety, and outcomes. The World Health Organization (WHO) advocates training in adherence for healthcare professionals, a multidisciplinary approach, support rather than blame, tailored interventions based on illness-related demands for each patient, and viewing adherence as a dynamic process.¹¹³⁶

The five dimensions of adherence are patient, disease, provider, therapy, and healthcare system (Figure 16).¹¹³⁹ Therefore, identifying patients at risk of non-adherence, addressing all five dimensions, developing a multidisciplinary pathway to support sustained adherence, and a follow-up strategy are essential steps.¹¹³⁹

Figure 16

Actions on the five dimensions of adherence to therapy.

e-Health, healthcare services provided electronically; mHealth, mobile device-based healthcare; PROMs, patient-reported outcome measures. Adapted from Pedretti et al.¹¹³⁹.

6.2.1. Adherence to healthy lifestyle behaviours

Different strategies may help improve long-term adherence to a healthy lifestyle (Figure 17).

Figure 17

Strategies for long-term adherence to a healthy lifestyle.

mHealth, mobile device-based healthcare; PROMs, patient-reported outcome measures.

6.2.1.1. Why behavioural changes are difficult

Making changes to unhealthy lifestyles and controlling risk factors can be a daunting task as these are usually longstanding habits and patterns of behaviour. Habits and environmental cues primarily govern behaviours, so education and information alone are seldom enough.¹¹⁴⁰ Factors such as psychological state and low health literacy (associated with depression and worse behavioural risk factors) also impact the ability to make changes.^1141,1142

6.2.1.2. How to change behaviour and support healthy lifestyles

A multidisciplinary approach and behavioural counselling can improve adherence. A systematic review and meta-analysis of 12 RCTs of nurse-led patient-centred interventions for secondary prevention found greater adherence to smoking cessation and physical activity, and better control of total cholesterol (with medication titration), but no improvements in dietary habits, BP, blood glucose, or survival.¹¹⁴³ A systematic review of behavioural counselling found that medium- to high-contact counselling resulted in 20% lower risk of CVD events, lower BP, and decreased LDL-C and adiposity in adults with CVD risk factors.¹¹⁴⁴ Incorporating cardiovascular visual images into risk-factor discussions is effective in reducing subsequent 10-year risk assessment and individual risk factors.⁴⁴⁵

Lifestyle changes also impact relatives, partners, and friends, so they should be involved in patient support.¹¹³⁹ Physical activity can be incorporated flexibly, either daily, or limited to specific days. Activity patterns limited to 1–2 sessions per week but meeting recommended levels of physical activity have been shown to reduce or postpone all-cause, CVD, and cancer mortality risk.⁴⁷⁷ Importantly, maintaining changed behaviour over time is a challenge. Some trials have shown an impact of lifestyle intervention on cardiovascular health and behavioural metrics, which became attenuated in the long term as the intensity of the intervention declined.¹¹⁴⁵

6.2.1.3. Digital and mHealth

Behavioural change and habit formation can be facilitated through technology such as wearable devices, the internet, and smartphones. In 27 studies including 5165 patients with CAD or cerebrovascular disease, text messaging and smartphone apps resulted in a greater ability to reach BP targets and exercise goals, less anxiety, and increased awareness of diet and exercise compared with control.¹¹⁴⁶ Nevertheless, there was no significant difference in smoking cessation, LDL-C, and hospital readmissions.¹¹⁴⁶ Digital interventions mainly stimulate healthy behavioural factors but are less effective in reducing unhealthy behavioural factors (smoking, alcohol intake, sedentary behaviour, and unhealthy diet) and clinical outcomes.^1146,1147

The use of wearable devices has significantly increased physical activity and decreased waist circumference, systolic BP, and LDL-C among individuals with chronic conditions including CVD.⁴⁹¹ Younger age has been associated with a higher increase in physical activity, and CVD has been associated with a lower increase. Wearable activity trackers have shown effectiveness, but the effect was greater when combined with other behaviour-change strategies.⁴⁹¹ A systematic review of CCS patients that used activity trackers combined with feedback by healthcare professionals (most also giving lifestyle education) showed a significant increase in peak VO₂ in studies using an accelerometer (but not a pedometer) compared with non-users. The overall effect across studies reduced MACE and improved QoL.¹¹⁴⁸ Similarly, smartphone and tablet computer apps have been shown to increase physical activity (minutes per week or steps per day) among people with CVD (1543 participants, most of them with CCS). This effect was largest in small studies focused on physical activity only, participants ≥60 years old, and duration of up to 3 months.¹¹⁴⁹ Adherence to the apps was 20% to 85% and tended to wane over time. Of note, the implementation of digital and mHealth should not be at odds with a less digital-oriented care for those unfamiliar with new technologies (e.g. elderly people).

6.2.1.4. How to assess adherence

Addressing lifestyle behaviour and medication adherence in a non-judgemental way at clinical encounters is important to identify barriers and offer tailored solutions to promote healthier actions. The encounter can be useful to review patient self-monitoring records (digital or written), accelerometer data, and diaries, or validated questionnaires on physical activity.

6.2.2. Adherence to medical therapy

Guideline-directed medications are key to the effective management of CCS and prevention of subsequent cardiovascular events, but dependent on patient adherence and persistence with treatment. Despite robust evidence of benefits in terms of mortality and morbidity,¹¹⁵⁰ adherence remains suboptimal.¹¹⁵¹ Although adherence is usually higher in RCTs, approximately 28% of CCS patients in the ISCHEMIA trial were non-adherent to prescribed medications at baseline.¹¹⁵² Non-adherence was associated with significantly worse health status regardless of randomization to the conservative or invasive strategy.¹¹⁵² Medication adherence can be intentional or unintentional, and can be adversely affected by polypharmacy, complex drug regimens, high cost, and side effects.

6.2.2.1. Strategies to improve medication adherence

Improving adherence to medications has proved challenging.¹¹⁵³ One systematic review and meta-analysis (771 studies to 2015) found that interventions that were behaviourally focused, e.g. linking medication-taking to existing habits, were more effective than those that were cognitively focused.¹¹⁵⁴ A systematic review of 17 trials of adherence for secondary CVD prevention found that a short message service, a fixed-dose combination pill, and a community health worker-based intervention (one trial each) increased adherence compared with usual care.¹¹⁵⁵ Behavioural and mixed behavioural/educational interventions improved adherence in older adults with multiple medications (low-quality evidence), with little evidence for educational-only interventions.¹¹⁵⁶ Drug reminder packaging—i.e. incorporating the date and time for the medication to be taken in a package (pre-filled containers)—can act as a prompt, with some evidence that it increases pills taken and improves diastolic BP and HbA1c levels.¹¹⁵⁷ Treating depression is important, as depression was associated with reduced adequate and optimal adherence to recommended medications 12 months post-PCI in an analysis of 124 443 patients.¹¹⁵⁸ Simplifying medication regimens using fixed-dose polypills has been shown to increase adherence.^1159–1162 The SECURE trial demonstrated that patients 6 months post-MI randomized to a polypill containing aspirin, ramipril, and atorvastatin had significantly lower MACE and were more likely to have high adherence at 6 and 24 months compared with the usual care group.¹¹⁶³

6.2.2.2. mHealth strategies for medication adherence

A review of mobile phone text messaging found promising, if limited, evidence that such messaging could improve medication adherence up to 12 months after acute coronary events.¹¹⁶⁴ Similarly, another review of 24 studies of text messages and/or apps found robust evidence for adherence to pharmacological therapy.¹¹⁴⁶ A pilot trial of 135 non-adherent patients with hypertension and/or diabetes randomized patients to a highly tailored digital intervention (text messages and interactive voice response) or usual care for 12 weeks. Medication adherence was significantly improved in the intervention group, along with improvements in systolic BP and HbA1c, compared with the control group.¹¹⁶⁵

Recommendation Table 28

Recommendations for adherence to medical therapy and lifestyle changes (see also Evidence Table 28)

6.3. Diagnosis of disease progression

Long-term follow-up of patients with CCS who have either established CAD (prior acute MI, revascularization, known CAD) or non-obstructive CAD includes surveillance for disease progression. However, current literature is sparse regarding mode, frequency, and duration. Follow-up of patients is based on their clinical condition, which includes cardiovascular risk factors, residual symptoms, cardiac complications [such as post-infarction LV remodelling and dysfunction, associated mitral regurgitation (mostly functional), known HF, significant arrhythmias], and non-cardiac comorbidities like PAD, stroke, and renal dysfunction.

The main goal of follow-up is to determine the patient’s risk of developing new cardiac events through risk stratification and to identify symptoms suggestive of CAD progression. A second goal is to promptly diagnose and manage extracoronary complications, such as the onset of HF, arrhythmias, and valvular dysfunction. Additionally, during long-term follow-up, antianginal and disease-modifying medication should be optimized and adjusted based on the development of comorbidities. The potential benefits vs. bleeding risks of antithrombotic drugs should be considered and evaluated over time.

Although assessing the anginal status is traditionally considered the cornerstone of clinical follow-up, it is worth noting that angina resolves in 40% of CCS patients at 1 year with further annual decreases, most often without revascularization or adaptation of antianginal therapy.⁴⁰⁴ In contrast to patients with resolving symptoms, those with persistent or recurrent angina are at higher risk of cardiovascular death or MI.⁴⁰⁴ The worse prognosis of persisting angina, however, was only observed in patients with a previous MI.⁴⁰⁸

6.3.1. Risk factors for recurrent coronary artery disease events

Patients with established ASCVD are at high risk of recurrent events and different risk factors have been identified. The REACH registry demonstrated that, in addition to the traditional risk factors, the burden of disease, lack of treatment, and geographical location are all related to an increased risk of cardiovascular morbidity and mortality in CCS patients and validated a risk score that allows estimation of the risk for MACE.¹¹⁶⁷ Using data from stabilized CCS patients from 27 European countries included in the EUROASPIRE IV and V surveys, a new risk model with an online risk calculator to predict recurrent CVD events in patients under the age of 75 years was developed and externally validated in the SWEDEHEART registry.^1168,1169 This model indicated that the risk of recurrent MACE is mainly driven by comorbidities including diabetes, renal insufficiency, and dyslipidaemia, but also symptoms of depression and anxiety. A study of patients with established CAD from the UK Biobank confirmed the value of classical risk factors, lifestyle, and sociodemographic factors in predicting recurrent MACE.¹¹⁷⁰ In addition, it was found that high genetic predisposition to CAD, low HDL-C, and younger age at first ACS event most strongly predicted the recurrence risk. A polygenic risk score, when added to the Framingham score, improved predictions of events in a large population in the USA.¹¹⁷¹ Although the prediction of recurrent MACE has been refined, it must be emphasized that the predictive power of the different risk factors is weak and that a significant part of recurrent MACE in CCS patients remains unexplained. Furthermore, the models do not incorporate information on LV function, HF, concomitant valvular disease, atherosclerotic disease burden in other vascular beds, or the severity of existing CAD.¹¹⁷² While risk factors for recurrent cardiac events have been established, no clinical studies have tested predefined clinical pathways for long-term follow-up of various types of CCS patients. As a result, the long-term clinical follow-up of CCS patients is primarily empirical, based on good clinical judgement, and on the same criteria used in the initial diagnostic process to define high risk of adverse events (Section 3.3.5 and Figure 18).

Figure 18

Approach for the follow-up of patients with established chronic coronary syndrome.

ACS, acute coronary syndrome; AF, atrial fibrillation; CABG, coronary aortic bypass grafting; CAD, coronary artery disease; CCS, chronic coronary syndrome; CKD, chronic kidney disease; ECG, electrocardiogram; LV, left ventricle; PAD, peripheral artery disease; PCI, percutaneous coronary intervention; RV, right ventricle.

6.3.2. Organization of long-term follow-up

When scheduling long-term follow-up for CCS patients with recurring or worsening angina, it is important to consider factors such as patient type, the presence of risk factors, availability of diagnostic techniques, and cost-effectiveness following regional or national healthcare policies. Different CCS phenotypes may develop or recur during long-term follow-up, altering the follow-up needed over time. The intervals and examination methods during long-term follow-up may vary based on the CCS phenotype, coronary atherosclerotic burden, presence of CMD, and severity of ischaemic LV dysfunction.

A stepwise approach based on risk assessment can be followed, like that applied for diagnosing and treating individuals with suspected CCS.

Step 1: This involves an annual clinical evaluation, by a general practitioner or a cardiologist, encompassing symptom evaluation, medication review, physical examination, a resting 12-lead ECG, and blood tests for lipid profile, renal function, glycaemic status, and full blood count. The ECG should be scrutinized for heart rate, rhythm, evidence of silent ischaemia/infarction, and evaluation of PR, QRS, and QT intervals. Any new symptoms suggestive of ACS, especially with ECG changes, warrant adherence to the 2023 ESC Guidelines for the management of patients with acute coronary syndromes. ⁶⁵ Current medical therapy and lifestyle measures for risk-factor control can be maintained or optimized for asymptomatic patients.

Step 2: If CCS patients develop new or worsening angina or HF symptoms, arrhythmias or ECG changes, further cardiac evaluation is crucial, especially if symptoms persist despite optimized GDMT. Recurrent CAD event risk should be assessed based on symptoms, progression of risk factors, and resting ECG changes. Echocardiography may be performed to assess LV function, cardiac dimensions, and valvular abnormalities. Exercise ECG testing may be considered to confirm symptoms and evaluate functional capacity if it alters patient management. However, routine functional testing is not recommended for asymptomatic post-PCI patients, as it has not been shown to improve outcomes compared with standard care after 2 years.¹¹⁷³

Step 3: CCS patients with persistent symptoms at low exercise levels despite optimized GDMT or unexpectedly reduced LV function, especially with regional contraction abnormalities, need further cardiac testing to detect the progression of CAD and assess the event risk.

For patients with known non-obstructive CAD, CCTA can help detect new obstructive stenoses, evaluate atherosclerotic disease progression, and identify high-risk plaque features, while functional imaging is reasonable for detecting myocardial ischaemia and guiding further management. In patients with ANOCA/INOCA and stratified medical therapy, CCTA can be useful to detect new or progressing CAD.

For patients with obstructive CAD or previous cardiac events, non-invasive functional imaging is the preferred method to detect and quantify myocardial ischaemia and/or scar. However, in patients with severely limiting angina and known severe ischaemia on functional testing or high-risk CAD on CCTA, direct referral to ICA for revascularization is preferred due to the very high risk of recurrent CAD events. Although CCTA can detect CABG graft patency and exclude in-stent restenosis (ISR) in broad lumen arteries, functional imaging is preferred for assessing patients with prior revascularization because of the high frequency of extensive CAD in these patients.^1174–1176

Step 4: In all patients with recurrent or worsening anginal symptoms, lifestyle modifications, risk-factor management, and GDMT should be intensified before considering further interventions. For patients with significant inducible myocardial ischaemia or high-risk CAD, and persistent anginal symptoms despite lifestyle modifications and intensified GDMT, repeat coronary revascularization may be necessary to alleviate symptoms and improve prognosis. For patients with prior CABG experiencing stable symptoms, it’s important to optimize GDMT whenever possible. If frequent angina persists despite GDMT optimization, ICA or CCTA can assist in guiding treatment decisions.^1177–1179 When symptoms are uncertain, functional testing may help clarify the presence and extent of myocardial ischaemia.

6.3.3. Non-invasive diagnostic testing

All non-invasive diagnostic testing, including CCTA, stress SPECT, or PET myocardial perfusion imaging, stress echocardiography, and stress CMR have been shown to provide prognostic information in patients with established CAD.^{296,1180,1181} Anatomical imaging with CCTA has the advantage of providing information on left main disease and graft patency. Stress imaging provides information on the degree of ischaemia, which helps guide an appropriate management plan. For example, symptomatic patients with moderate-to-severe myocardial ischaemia despite GDMT will usually undergo additional revascularization. In patients with known ANOCA/INOCA, non-invasive imaging with stress SPECT or PET myocardial perfusion imaging, stress CMR, or stress echocardiography remain first-line investigations, although the diagnostic yield may be low;⁹²⁷ however, the current standard remains invasive coronary functional testing.

Recommendation Table 29

Recommendations for diagnosis of disease progression in patients with established chronic coronary syndrome (see also Evidence Table 29)

6.4. Treatment of myocardial revascularization failure

One in five revascularized patients needs a repeat revascularization within the first 5 years after myocardial revascularization, with higher risk after PCI compared with CABG.¹¹⁸² Revascularization failure can manifest either shortly after the initial procedure (within 30 days) or later on, and recurring symptoms may result from either restenosis of the treated coronary segment or the failure of bypass grafts,⁷⁷² alongside the progression of underlying native CAD.^1183,1184 Published evidence regarding diagnosis and management of myocardial revascularization failure has been summarized in the 2020 EAPCI (European Association of Percutaneous Cardiovascular Interventions) Expert Consensus Paper.¹¹⁸²

6.4.1. Percutaneous coronary intervention failure

Stent thrombosis and ISR are the most frequent reasons for PCI failure. Stent thrombosis occurs infrequently and is multifactorial. Anatomical and mechanical factors, as well as lack of adherence or hyporesponsiveness to antiplatelet treatment, are frequently the reasons behind this.^1182,1185 The majority of patients with stent thrombosis present with ACS and should be treated according to the 2023 ESC Guidelines for the management of patients with acute coronary syndromes.⁶⁵ Urgent ICA to confirm diagnosis and treatment is indicated. After restoration of coronary flow, intracoronary imaging to identify mechanical failure should be performed. Repeated DES implantation is indicated in case of stent fracture or collapse and residual edge dissections, while high-pressure non-compliant balloon dilation is indicated in case of stent under-expansion or malapposition.

In-stent restenosis results as a response to vessel wall injury (neointimal hyperplasia) or neoatherosclerosis in the stented segment of the coronary artery. Although significantly less frequent than after bare-metal stent implantation, the incidence of clinical in-DES restenosis is up to 10% within the first 10 years after DES implantation¹¹⁸² and remains the most frequent cause of PCI failure. The clinical presentation of ISR is mostly CCS, with 20% ACS, and the remaining asymptomatic. The indication to treat ISR is like that for native CAD. Radiological stent enhancement and intracoronary imaging are encouraged to determine the ISR mechanism. PCI treatment of ISR should be focused on the stenotic segment. Lesion preparation (ultra-high pressure balloon dilation, intravascular lithotripsy, rotation atherectomy) and correction of mechanical issues are required.¹¹⁸² Thereafter, drug-coated balloon angioplasty or DES implantation is necessary.^1186,1187 Drug-eluting balloon angioplasty and repeat stenting with DES were equally effective and safe in treating bare-metal ISR, but drug-coated balloon angioplasty was less effective than repeat paclitaxel DES implantation in treating DES ISR.¹¹⁸⁶ However, at 10-year follow-up there was no difference in clinical endpoints between drug-coated balloon angioplasty and DES implantation, whereas both were more effective than balloon angioplasty in preventing target-lesion revascularization.¹¹⁸⁷ Everolimus DES was associated with better long-term outcomes than drug-coated balloons.¹¹⁸⁸

6.4.2. Managing graft failure after coronary artery bypass grafting

A variety of reasons have the potential to adversely affect bypass graft patency.¹¹⁸⁹ These include technical (quality of graft material, surgical precision) and pathophysiological aspects (competitive flow, activity of the coagulation system, disease progression, etc.). Technical aspects and competitive flow are thought to influence early graft failure, while disease progression and graft degeneration affect long-term patency.^1182,1189

The majority of graft occlusions are clinically silent.¹¹⁸⁹ If symptoms occur, prompt diagnostic workup (including ECG, assessment of biomarkers, and possibly repeat coronary angiography) is warranted to limit or prevent potential damage from graft occlusion.³¹⁶ Acute CABG graft failure (<1 month after surgery) is observed in approximately 12% of grafts mostly due to technical problems.¹¹⁹⁰ Late failure of saphenous vein grafts occurs in up to 50% at 10 years, with vein graft occlusion rates in up to 27% within 1 year after surgery. ^771,1191

The decision for optimal treatment (conservative, CABG revision/redo CABG or PCI of the native vessel or of the failed graft) should be made individually considering haemodynamic stability, technical reasons for graft failure, and ability to treat native CAD. PCI is the first choice over redo CABG for late graft failure, with PCI of the native vessel rather than PCI of the graft. ^{772,1182,1192,1193}

If re-operation is required, the surgical risk is generally increased.^1182,1192 If acute re-operation is required, acute ischaemia is generally present, and adhesions and the presence of patent grafts increase the complexity of the procedure. It is, therefore, important to weigh this risk against the expected benefit. Since a patent left internal thoracic artery (LITA) to the LAD confers the largest part of CABG prognostic potential,^1189,1194 redo CABG is primarily recommended in patients with indications for CABG and occluded LITA or if the LITA was not used during the first operation.⁷⁷²

Recommendation Table 30

Recommendations for treatment of revascularization failure (see also Evidence Table 30)

6.5. Recurrent or refractory angina/ischaemia

An ageing population and an increased survival rate in patients with CAD due to improvements in anti-ischaemic medical therapy and coronary revascularization have led to a growing number of patients with severe and diffuse CAD not amenable to further revascularization procedures. Despite the use of antianginal drugs and/or PCI or CABG, the proportion of patients with CAD who have daily or weekly angina ranges from 2% to 24%.⁵⁵⁵

Refractory angina is defined as long-lasting symptoms (for >3 months) due to established reversible ischaemia: (i) in the presence of obstructive CAD, which cannot be controlled by escalating medical therapy with additional antianginal drugs, bypass grafting, or PCI including recanalization of chronic total coronary occlusion; or (ii) due to ANOCA/INOCA. In the case of ANOCA/INOCA, further investigations are required to define the different endotypes (Section 4.4.2) and appropriate treatment (Section 6.3) before diagnosing refractory angina.³⁶

The QoL of patients with refractory angina is poor, with frequent hospitalization and a high level of resource utilization.⁵⁵⁵ Once conventional anti-ischaemic targets have been exhausted, novel therapies can be ranked by mechanism of action, promotion of collateral growth, transmural redistribution of blood flow, and neuromodulation of the cardiac pain syndrome.

Considering the chronic nature of the disease and according to risk–benefit assessments, among the currently available options, the most promising and easily implementable in everyday clinical practice are enhanced external counterpulsation and the coronary sinus reducer device,⁵⁵⁵ after all medical therapy and mechanical revascularization options have been exhausted (see Sections 4.2 and 4.4). Enhanced external counterpulsation has been shown to ameliorate refractory angina in several trials.¹¹⁹⁸

The coronary sinus reducer consists of controlled coronary sinus narrowing with the implantation of a large stainless-steel device to increase coronary sinus pressure and improve perfusion in the LAD territory.¹¹⁹⁹ In a recent meta-analysis including eight registries and one RCT, in a total of 846 patients with refractory angina, use of a coronary sinus reducer led to improvement of ≥1 CCS class in 76% (95% CI, 73%–80%) of patients and an improvement of ≥2 CCS class in 40% (95% CI, 35%–46%) of patients.¹²⁰⁰ The Coronary Sinus Reducer Objective Impact on Symptoms, MRI Ischaemia and Microvascular Resistance (ORBITA-COSMIC) trial, a small proof-of-concept RCT, found no evidence that implantation of a coronary sinus reducer improved transmural myocardial perfusion, but it was associated with improved angina symptoms compared with placebo. ¹²⁰¹

There are several ongoing RCTs evaluating the use of coronary sinus reducer in ANOCA/INOCA, such as COronary SInus Reducer for the Treatment of Refractory Microvascular Angina (COSIMA; NCT04606459), and the Efficacy of the COronary SInus Reducer in Patients with Refractory Angina II (COSIRA-II; NCT05102019).

A variety of new pharmacological approaches is becoming available and includes angiogenetic therapies with vascular endothelial growth factors and fibroblast growth factors, as well as stem cell therapy with intramyocardial delivery of CD34⁺ cells.^1202,1203 However, further RCTs are needed to validate the feasibility of such therapeutic strategies.

To date, the main limitations of reported experiences with all novel therapeutic options regard the small number of treated patients and the duration of follow-up. Larger sham-controlled RCTs are required to define the role of each treatment modality for specific subgroups, and ultimately to aim at the best possible personalized treatment algorithm, based on aetiology stratification, and escalation of available therapeutic modalities.

Recommendation Table 31

Recommendations for recurrent or refractory angina/ischaemia (see also Evidence Table 31)

$Recommendations for recurrent or refractory angina/ischaemia (see also Evidence Table 31)$

6.6. Treatment of disease complications

Patients with CCS who develop LV dysfunction may experience advanced HF, malignant arrhythmias and secondary valvular heart disease (i.e. mitral and tricuspid regurgitation).

Prior MI and ischaemic aetiology are negative prognostic markers in patients with advanced HF,¹²⁰⁵ as well as in those with secondary mitral regurgitation.¹²⁰⁶ Specific treatments need to be considered in these patients regardless of HF aetiology (i.e. ischaemic).⁵²⁶ Advanced HF treatments include: high diuretic doses; a combination of diuretics and renal replacement therapy to treat congestion; inotropic and vasopressor agents to reduce hypoperfusion; and mechanical circulatory support in selected patients with severe symptoms or exercise intolerance, despite optimal medical therapies, and without right ventricular dysfunction. Heart transplantation is recommended for patients with advanced HF, refractory to medical/device therapy, and who do not have absolute contraindications. Early evaluation for mechanical circulatory supports or heart transplantation is currently suggested also in patients with mild symptoms [i.e. New York Heart Association (NYHA) class II] and high-risk profile (i.e. LVEF of <20%, recurrent HF events, hypotension, intolerance to medical therapy, worsening organ failure, ventricular arrhythmias/ICD shock).⁵²⁶

An ICD is recommended in patients with ischaemic cardiomyopathy and LVEF of <35% or who have recovered from ventricular arrhythmias.⁵²⁶ Frequent, symptomatic ventricular arrhythmias in ICD recipients should be treated medically with either beta-blockers or amiodarone. In patients with CCS who develop ventricular fibrillation or polymorphic ventricular tachycardia, assessment for myocardial ischaemia should be performed without delay. In patients with CAD in whom sustained monomorphic ventricular tachycardia recurs while on amiodarone treatment, catheter ablation is recommended over the escalation of antiarrhythmic drugs.¹²⁰⁷ Percutaneous treatment of secondary mitral regurgitation in patients with advanced HF may be considered to improve symptoms.⁵²⁶ Treatment of secondary tricuspid regurgitation in advanced stages of disease was, until recently, supported by limited evidence.¹²⁰⁸ Percutaneous tricuspid transcatheter edge-to-edge repair was found to reduce significantly severe tricuspid regurgitation and was associated with improvements in QoL at 1 year.¹²⁰⁹

7. Key messages

Symptoms of myocardial ischaemia due to obstructive atherosclerotic CAD overlap with those of CMD or vasospasm.
Similar guideline-directed cardiovascular preventive therapy is recommended in women and men in spite of the sex differences in the clinical presentation.
Inclusion of risk factors to classic pre-test likelihood models of obstructive atherosclerotic CAD improves the identification of patients with very low (≤5%) pre-test likelihood of obstructive CAD in whom deferral of diagnostic testing should be considered.
CACS is a reliable ‘simple’ test to modify the pre-test likelihood of atherosclerotic obstructive CAD.
First-line diagnostic testing of suspected CCS should be done by non-invasive anatomic or functional imaging.
Selection of the initial non-invasive diagnostic test should be based on the pre-test likelihood of obstructive CAD, other patient characteristics that influence the performance of non-invasive tests, and local expertise and availability.
CCTA is preferred to rule out obstructive CAD and detect non-obstructive CAD.
Functional imaging is preferred to correlate symptoms to myocardial ischaemia, estimate myocardial viability, and guide decisions on coronary revascularization.
PET is preferred for absolute MBF measurements, but CMR perfusion studies may offer an alternative.
Selective second-line cardiac imaging with functional testing in patients with abnormal CCTA and CCTA after abnormal functional testing may improve patient selection for ICA.
ICA is recommended to diagnose obstructive CAD in individuals with a very high pre- or post-test likelihood of disease, severe symptoms refractory to GDMT, angina at a low level of exercise, and/or high event risk.
When ICA is indicated, it is recommended to evaluate the functional severity of ‘intermediate’ stenoses by invasive functional testing (FFR, iFR) before revascularization.
Computed FFR based on the 3D reconstruction of ICA is emerging as a valuable alternative to wire-based coronary pressure to evaluate the functional severity of ‘intermediate’ stenoses.
The use of imaging guidance is now recommended when performing complex PCI.
A single antiplatelet agent, aspirin or clopidogrel, is generally recommended long term in CCS patients with obstructive atherosclerotic CAD.
For high thrombotic-risk CCS patients, long-term therapy with two antithrombotic agents is reasonable, as long as bleeding risk is not high.
For CCS patients with sinus rhythm, DAPT is recommended at the time of PCI and for 1 to 6 month(s), according to high or low bleeding risk, respectively.
For CCS patients requiring OAC and undergoing PCI, OAC and DAPT (aspirin and clopidogrel) for 1 to 4 weeks, followed by OAC and clopidogrel for up to 6 months in patients not at high ischaemic risk and up to 12 months in patients at high ischaemic risk, followed by OAC alone should be considered.
In CCS patients with functionally significant multivessel CAD, current evidence indicates benefit of myocardial revascularization over GDMT alone for symptom improvement, prevention of spontaneous MI, and reduction of cardiovascular mortality at long follow-up.
Among CCS patients with normal LV function and no significant left main or proximal LAD lesions, current evidence indicates that myocardial revascularization over GDMT alone does not prolong overall survival.
Among CCS patients with reduced LV function and ischaemic cardiomyopathy, current evidence indicates that surgical revascularization compared with GDMT alone prolongs overall survival at very long follow-up.
Among patients with complex multivessel CAD without LMCAD, particularly in the presence of diabetes, who are clinically and anatomically suitable for both revascularization modalities, current evidence indicates longer overall survival after CABG than PCI.
Among patients who are clinically and anatomically suitable for both revascularization modalities, a greater need for repeat revascularization after PCI than surgery, independently of multivessel CAD anatomical severity, has been consistently reported with current surgical and stent technology.
Lifestyle and risk-factor modification combined with disease-modifying and antianginal medications are cornerstones in the management of CCS.
Shared decision-making between patients and healthcare professionals, based on patient-centred care, is paramount in defining the appropriate therapeutic pathway for CCS patients. Patient education is key to improve risk-factor control in the long term.
The relatively high prevalence of ANOCA/INOCA and its associated MACE rate warrants improvement in the diagnosis and treatment of affected patients.
Persistently symptomatic patients with suspected ANOCA/INOCA who do not respond to GDMT should undergo invasive coronary functional testing to determine underlying endotypes.
Characterization of endotypes is important to guide appropriate medical therapy for ANOCA/INOCA patients.
Research on effective methods to support specific healthy lifestyle behaviours, and sustain medication and healthy lifestyle adherence over time, is needed.
More research is needed on improving the implementation of health-promoting policies and practices in the workplace setting.

8. Gaps in evidence

It remains unclear if screening for subclinical obstructive CAD in the general population is useful.^1106,1210 Further large-scale studies are needed to investigate the prognostic benefit of screening and treating asymptomatic CCS in the general population, preferably involving different geographical regions. Optimal screening options remain to be determined for specific groups at high risk (e.g. asymptomatic individuals with diagnosed diabetes for longer than 10 years).
Most studies assessing diagnostic strategies in individuals with symptoms suspected of CCS were performed in populations with a moderate (>15%–50%) pre-test clinical likelihood of obstructive CAD. Further studies are needed to determine the optimal and most cost-effective diagnostic strategy in individuals with a low (>5%–15%) pre-test clinical likelihood of obstructive CAD.
The current diagnosis of ANOCA/INOCA and its different endotypes is mainly determined by invasive coronary functional testing.³⁶ Further research is needed to refine and assess non-invasive diagnostic imaging modalities for CMD. Currently available and new non-invasive imaging modalities should be calibrated against invasive testing, allowing the use of their measurements interchangeably.
The role of antithrombotic therapy in CCS patients with ANOCA/INOCA remains to be established.
Because of how evidence has accrued over time, there is no clear evidence about the existence of first- and second-line antianginal therapy. It is unclear whether long-acting nitrates, ranolazine, nicorandil, ivabradine, trimetazidine, or any of their combinations improve anginal symptoms more than beta-blockers or CCBs.
The optimal type and duration of DAPT is still uncertain in some subsets of patients (e.g. patients with prior revascularization who might benefit from shorter or longer DAPT strategies).
The long-term benefit of beta-blocker therapy in post-MI patients without reduced EF remains to be elucidated.
In view of the reported positive impact of low-dose colchicine in patients with CCS in reducing MI, stroke, and revascularization, future studies should identify whether certain patient subgroups (e.g. those with elevated biomarker levels) might derive even greater clinical benefit from this treatment.
A post hoc analysis of ISCHEMIA detected a graded association between the severity of obstructive CAD assessed by CCTA and all-cause mortality and acute MI during follow-up.³¹⁷ There is a need for randomized data comparing contemporary medical treatment against early revascularization plus medical therapy in subsets of patients with an increased risk for death or MI as determined by the post hoc analysis. Moreover, because the benefit of an invasive strategy with respect to cardiac mortality was shown in a meta-analysis of chronologically heterogeneous trials, including several conducted more than two decades ago, the impact of early revascularization plus GDMT vs. contemporary GDMT on all-cause and cardiac mortality in patients with CCS should ideally be tested in a well-designed, adequately powered randomized trial.
Some meta-analyses have reported a reduction in cardiac mortality without a reduction in all-cause mortality. There is a need to clarify the impact of revascularization in CCS patients on cardiovascular and non-cardiovascular mortality.
Complete revascularization of multivessel CAD by PCI can be achieved as a single procedure (index PCI) or as staged PCI. In the setting of CCS, the value of staged PCI and the optimal interval between interventions needs to be evaluated.
Whether CABG surgery and PCI are comparable among patients with ischaemic cardiomyopathy and HFrEF in the modern era of HF treatment needs to be evaluated.
Various imaging techniques, such as low-dose DSE, CMR, and PET/CT, can identify hibernating myocardium with the potential for functional recovery after revascularization.¹²¹¹ Further randomized trials with contemporary, well-defined modalities and strict adherence to protocol are needed to clarify the clinical benefits (if any) of viability testing.
Residual ischaemia post-PCI, as determined by FFR/iFR, reflects remaining atherosclerotic lesions and/or suboptimal PCI results, but also persistent or worsening microvascular dysfunction. Whether post-PCI FFR/iFR is a ‘modifiable’ risk factor remains to be proved.
Among patients suitable for off-pump CABG with complex multivessel CAD but no LMCAD, the impact of hybrid revascularization on outcomes, including peri-operative complications other than MACE, needs more extensive investigation. Data on the optimal time interval between MIDCAB-LIMA and PCI are lacking.
Whether the decision process based on a multidisciplinary Heart Team leads to better outcomes than standard institutional practice remains to be investigated.
The medical therapy of ANOCA/INOCA is largely empirical. Therefore, prospective randomized clinical trials are needed to determine the efficacy of antianginal treatments in improving symptoms and outcomes for the different endotypes.
Research on effective methods to support healthy lifestyle behaviours, and sustain medication and healthy lifestyle adherence over time, is needed. In addition, more research is needed on improving the implementation of health-promoting policies and practices in the workplace setting.
There is a need for further evidence on the effectiveness of neuromodulation, spinal cord stimulation, therapeutic angiogenesis, and coronary sinus occlusion in patients who suffer from refractory angina, despite guideline-directed medical treatment and revascularization.

9. ‘What to do’ and ‘What not to do’ messages from the guidelines

Table 10 lists all Class I and Class III recommendations from the text alongside their level of evidence.

Table 10

10.1016/j.jacc.2019.07.072

‘What to do’ and ‘What not to do’

10. Evidence tables

Evidence tables are available at European Heart Journal online.

11. Data availability statement

No new data were generated or analysed in support of this research.

12. Author information

Author/task force Member Affiliations: Konstantinos C. Koskinas, Department of Cardiology, Bern University Hospital—INSELSPITAL, University of Bern, Bern, Switzerland; Xavier Rossello, Cardiology Department Hospital Universitari Son Espases, Palma de Mallorca, Spain, Health Research Institute of the Balearic Islands (IdISBa), Universitat de les Illes Balears (UIB), Palma de Mallorca, Spain, and Clinical Research Department, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain; Marianna Adamo, Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, Institute of Cardiology, ASST Spedali Civili di Brescia and University of Brescia, Brescia, Italy; James Ainslie, ESC Patient Forum, Sophia Antipolis, France; Adrian Paul Banning, Oxford Heart Centre, Oxford University Hospitals, Oxford, United Kingdom; Andrzej Budaj, Department of Cardiology, Centre of Postgraduate Medical Education, Warsaw, Poland; Ronny R. Buechel, Department of Nuclear Medicine, Cardiac Imaging, University and University Hospital Zurich, Zurich, Switzerland; Giovanni Alfonso Chiariello, Department of Cardiovascular Sciences, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy, and Università Cattolica del Sacro Cuore, Rome, Italy; Alaide Chieffo, Vita Salute San Raffaele University, Milan, Italy, and Interventional Cardiology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy; Ruxandra Maria Christodorescu, Department V Internal Medicine, University of Medicine and Pharmacy V Babes, Timisoara, Romania, and Research Center, Institute of Cardiovascular Diseases, Timisoara, Romania; Christi Deaton, Public Health and Primary Care, Cambridge University School of Clinical Medicine, Cambridge, United Kingdom; Torsten Doenst, Department of cardiothoracic surgery, Friedrich-Schiller-University Jena, university hospital, Jena, Germany; Hywel W. Jones, ESC Patient Forum, Sophia Antipolis, France; Vijay Kunadian, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University and Cardiothoracic Centre, Freeman Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom; Julinda Mehilli, Medizinische Klinik I, Landshut-Achdorf Hospital, Landshut, Germany, and Klinikum der Universität München Ludwig-Maximilians University, Munich, Germany; Milan Milojevic, Department of Cardiac Surgery and Cardiovascular Research, Dedinje Cardiovascular Institute, Belgrade, Serbia; Jan J. Piek, Heart Center, Department of Clinical and Experimental Cardiology, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands; Francesca Pugliese, Centre for Advanced Cardiovascular Imaging, The William Harvey Research Institute, Queen Mary University of London, London, United Kingdom, Barts Health NHS Trust, London, United Kingdom, and Heart Vascular and Thoracic Institute, Cleveland Clinic London, London, United Kingdom; Andrea Rubboli, Department of Emergency, Internal Medicine, and Cardiology, Division of Cardiology, S. Maria delle Croci Hospital, Ravenna, Italy; Anne Grete Semb, Preventive cardio-rheuma clinic, Diakonhjemmet Hospital, Oslo, Norway, and REMEDY Centre Diakonhjemmet Hospital, Oslo, Norway; Roxy Senior, Cardiology Royal Brompton Hospital and Imperial College London, London, United Kingdom, and Cardiology, Northwick Park Hospital, Harrow, United Kingdom; Jurrien M. ten Berg, Cardiology, St Antonius Hospital, Nieuwegein, Netherlands, and Cardiology, Maastricht University Medical Centre, Maastricht, Netherlands; Eric van Belle, Cardiology, Institut Cour Poumon—CHU de Lille, Lille, France, and Equipe 2, INSERM U 1011, Lille, France; Emeline M. Van Craenenbroeck, Cardiology department, Antwerp University Hospital, Edegem, Belgium, and GENCOR, University of Antwerp, Antwerp, Belgium; Rafael Vidal-Perez, Cardiology, Cardiac Imaging Unit, Complexo Hospitalario Universitario de A Coruña (CHUAC), A Coruña, Spain, and Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain; and Simon Winther, Department of cardiology, Gødstrup hospital, Herning, Denmark, and Institute of clinical medicine, Aarhus university, Aarhus, Denmark.

13. Appendix

ESC Scientific Document Group

Includes Document Reviewers and ESC National Cardiac Societies.

Document Reviewers: Michael Borger (CPG Review Co-ordinator) (Germany); Ingibjörg J. Gudmundsdóttir (CPG Review Co-ordinator) (Iceland); Juhani Knuuti (CPG Review Co-ordinator) (Finland); Ingo Ahrens (Germany); Michael Böhm (Germany); Davide Capodanno (Italy); Evald Høj Christiansen (Denmark); Jean-Philippe Collet^¶ (France); Kenneth Dickstein (Norway); Christian Eek (Norway); Volkmar Falk (Germany); Peter A. Henriksen (United Kingdom); Borja Ibanez (Spain); Stefan James (Sweden); Sasko Kedev (Macedonia); Lars Køber (Denmark); Martha Kyriakou (Cyprus); Emma F. Magavern (United Kingdom); Angela McInerney (Ireland); John William McEvoy (United Kingdom); Caius Ovidiu Mersha (Romania); Borislava Mihaylova (United Kingdom); Richard Mindham (United Kingdom); Lis Neubeck (United Kingdom); Franz-Josef Neumann (Germany); Jens Cosedis Nielsen (Denmark); Pasquale Paolisso (Italy); Valeria Paradies (Netherlands); Agnes A. Pasquet (Belgium); Massimo Piepoli (Italy); Eva Prescott (Denmark); Amina Rakisheva (Kazakhstan); Bianca Rocca (Italy); Marc Ruel (Canada); Sigrid Sandner (Austria); Antti Saraste (Finland); Karolina Szummer (Sweden); Ilonca Vaartjes (Netherlands); William Wijns (Ireland); Stephan Windecker (Switzerland); Adam Witkowsky (Poland); Marija Zdrakovic (Serbia); and Katja Zeppenfeld (Netherlands).

^¶Professor Jean-Philippe Collet sadly passed away during the development of these guidelines. Professor Collet’s contribution to these guidelines was, as always, highly valued.

ESC National Cardiac Societies actively involved in the review process of the 2024 ESC Guidelines on the management of chronic coronary syndromes:

Albania: Albanian Society of Cardiology, Naltin Shuka; Algeria: Algerian Society of Cardiology, Mohamed Abed Bouraghda; Armenia: Armenian Cardiologists Association, Hamlet G. Hayrapetyan; Austria: Austrian Society of Cardiology, Sebastian J. Reinstadler; Azerbaijan: Azerbaijan Society of Cardiology, Ogtay Musayev; Belgium: Belgian Society of Cardiology, Michel De Pauw; Bosnia and Herzegovina: Association of Cardiologists of Bosnia and Herzegovina, Zumreta Kušljugić; Bulgaria: Bulgarian Society of Cardiology, Valeri Gelev; Croatia: Croatian Cardiac Society, Bosko Skoric; Cyprus: Cyprus Society of Cardiology, Maria Karakyriou; Czechia: Czech Society of Cardiology, Tomas Kovarnik; Denmark: Danish Society of Cardiology, Lene H. Nielsen; Egypt: Egyptian Society of Cardiology, Islam Sh. Abdel-Aziz; Estonia: Estonian Society of Cardiology, Tiia Ainla; Finland: Finnish Cardiac Society, Pekka Porela; France: French Society of Cardiology, Hakim Benamer; Georgia: Georgian Society of Cardiology, Kakha Nadaraia; Germany: German Cardiac Society, Gert Richardt; Greece: Hellenic Society of Cardiology, Michail I. Papafaklis; Hungary: Hungarian Society of Cardiology, Dávid Becker; Iceland: Icelandic Society of Cardiology, Ingibjörg J. Gudmundsdóttir; Israel: Israel Heart Society, Arik Wolak; Italy: Italian Federation of Cardiology, Carmine Riccio; Kazakhstan: Association of Cardiologists of Kazakhstan, Bekbolat Kulzhanovich Zholdin; Kosovo (Republic of): Kosovo Society of Cardiology, Shpend Elezi; Kyrgyzstan: Kyrgyz Society of Cardiology, Saamay Abilova; Latvia: Latvian Society of Cardiology, Iveta Mintale; Lebanon: Lebanese Society of Cardiology, Bachir Allam; Lithuania: Lithuanian Society of Cardiology, Jolita Badarienė; Luxembourg: Luxembourg Society of Cardiology, Bruno Pereira; Malta: Maltese Cardiac Society, Philip Dingli; Moldova (Republic of): Moldavian Society of Cardiology, Valeriu Revenco; Montenegro: Montenegro Society of Cardiology, Nebojsa Bulatovic; Morocco: Moroccan Society of Cardiology, El Ghali Mohamed Benouna; Netherlands: Netherlands Society of Cardiology, Admir Dedic; North Macedonia: National Society of Cardiology of North Macedonia, Irena Mitevska; Norway: Norwegian Society of Cardiology, Kristin Angel; Poland: Polish Cardiac Society, Krzysztof Bryniarski; Portugal: Portuguese Society of Cardiology, André Miguel Coimbra Luz; Romania: Romanian Society of Cardiology, Bogdan Alexandru Popescu; San Marino: San Marino Society of Cardiology, Luca Bertelli; Serbia: Cardiology Society of Serbia, Branko Dušan Beleslin; Slovakia: Slovak Society of Cardiology, Martin Hudec; Slovenia: Slovenian Society of Cardiology, Zlatko Fras; Spain: Spanish Society of Cardiology, Román Freixa-Pamias; Sweden: Swedish Society of Cardiology, Anna Holm; Switzerland: Swiss Society of Cardiology, Raban Jeger; Syrian Arab Republic: Syrian Cardiovascular Association, Mhd Yassin Bani Marjeh; Tunisia: Tunisian Society of Cardiology and Cardiovascular Surgery, Rania Hammami; Türkiye: Turkish Society of Cardiology, Vedat Aytekin; Ukraine: Ukrainian Association of Cardiology, Elena G. Nesukay; United Kingdom: British Cardiovascular Society, Neil Swanson; and Uzbekistan: Association of Cardiologists of Uzbekistan, Aleksandr Borisovich Shek.

ESC Clinical Practice Guidelines (CPG) Committee: Eva Prescott (Chairperson) (Denmark), Stefan James (Co-Chairperson) (Sweden), Elena Arbelo (Spain), Colin Baigent (United Kingdom), Michael A. Borger (Germany), Sergio Buccheri (Sweden), Borja Ibanez (Spain), Lars Køber (Denmark), Konstantinos C. Koskinas (Switzerland), John William McEvoy (Ireland), Borislava Mihaylova (United Kingdom), Richard Mindham (United Kingdom), Lis Neubeck (United Kingdom), Jens Cosedis Nielsen (Denmark), Agnes A. Pasquet (Belgium), Amina Rakisheva (Kazakhstan), Bianca Rocca (Italy), Xavier Rossello (Spain), Ilonca Vaartjes (Netherlands), Christiaan Vrints (Belgium), Adam Witkowski (Poland), Katja Zeppenfeld (Netherlands), and Alexia Rossi^§ (Italy).

^§Contributor either stepped down or was engaged in only a part of the review process.

14. References

1

Knuuti

J

,

Wijns

W

,

Saraste

A

,

Capodanno

D

,

Barbato

E

,

Funck-Brentano

C

, et al.

2019 ESC Guidelines for the diagnosis and management of chronic coronary syndromes

.

Eur Heart J

2020

;

41

:

407

–

77

.

10.1093/eurheartj/ehz425

2

Collet

C

,

Sonck

J

,

Vandeloo

B

,

Mizukami

T

,

Roosens

B

,

Lochy

S

, et al.

Measurement of hyperemic pullback pressure gradients to characterize patterns of coronary atherosclerosis

.

J Am Coll Cardiol

2019

;

74

:

1772

–

84

.

3

Scarsini

R

,

Fezzi

S

,

Leone

AM

,

De Maria

GL

,

Pighi

M

,

Marcoli

M

, et al.

Functional patterns of coronary disease: diffuse, focal, and serial lesions

.

JACC Cardiovasc Interv

2022

;

15

:

2174

–

91

.

10.1016/j.jcin.2022.07.015

4

Sternheim

D

,

Power

DA

,

Samtani

R

,

Kini

A

,

Fuster

V

,

Sharma

S

.

Myocardial bridging: diagnosis, functional assessment, and management: JACC state-of-the-art review

.

J Am Coll Cardiol

2021

;

78

:

2196

–

212

.

10.1016/j.jacc.2021.09.859

5

Gentile

F

,

Castiglione

V

,

De Caterina

R

.

Coronary artery anomalies

.

Circulation

2021

;

144

:

983

–

96

.

10.1161/CIRCULATIONAHA.121.055347

6

Del Buono

MG

,

Montone

RA

,

Camilli

M

,

Carbone

S

,

Narula

J

,

Lavie

CJ

, et al.

Coronary microvascular dysfunction across the spectrum of cardiovascular diseases: JACC state-of-the-art review

.

J Am Coll Cardiol

2021

;

78

:

1352

–

71

.

10.1016/j.jacc.2021.07.042

7

Marzilli

M

,

Crea

F

,

Morrone

D

,

Bonow

RO

,

Brown

DL

,

Camici

PG

, et al.

Myocardial ischemia: from disease to syndrome

.

Int J Cardiol

2020

;

314

:

32

–

5

.

10.1016/j.ijcard.2020.04.074

8

Gutierrez

E

,

Flammer

AJ

,

Lerman

LO

,

Elizaga

J

,

Lerman

A

,

Fernandez-Aviles

F

.

Endothelial dysfunction over the course of coronary artery disease

.

Eur Heart J

2013

;

34

:

3175

–

81

.

10.1093/eurheartj/eht351

9

Allaqaband

H

,

Gutterman

DD

,

Kadlec

AO

.

Physiological consequences of coronary arteriolar dysfunction and its influence on cardiovascular disease

.

Physiology (Bethesda)

2018

;

33

:

338

–

47

.

10.1152/physiol.00019.2018

10

Alexander

Y

,

Osto

E

,

Schmidt-Trucksäss

A

,

Shechter

M

,

Trifunovic

D

,

Duncker

DJ

, et al.

Endothelial function in cardiovascular medicine: a consensus paper of the European Society of Cardiology Working Groups on Atherosclerosis and Vascular Biology, Aorta and Peripheral Vascular Diseases, Coronary Pathophysiology and Microcirculation, and Thrombosis

.

Cardiovasc Res

2021

;

117

:

29

–

42

.

11

Trask

AJ

,

Katz

PS

,

Kelly

AP

,

Galantowicz

ML

,

Cismowski

MJ

,

West

TA

, et al.

Dynamic micro- and macrovascular remodeling in coronary circulation of obese Ossabaw pigs with metabolic syndrome

.

J Appl Physiol

2012

;

113

:

1128

–

40

.

10.1152/japplphysiol.00604.2012

12

Campbell

DJ

,

Somaratne

JB

,

Prior

DL

,

Yii

M

,

Kenny

JF

,

Newcomb

AE

, et al.

Obesity is associated with lower coronary microvascular density

.

PLoS One

2013

;

8

:

e81798

.

10.1371/journal.pone.0081798

13

Hinkel

R

,

Howe

A

,

Renner

S

,

Ng

J

,

Lee

S

,

Klett

K

, et al.

Diabetes mellitus-induced microvascular destabilization in the myocardium

.

J Am Coll Cardiol

2017

;

69

:

131

–

43

.

10.1016/j.jacc.2016.10.058

14

Bajaj Navkaranbir

S

,

Osborne

MT

,

Gupta

A

,

Tavakkoli

A

,

Bravo

PE

,

Vita

T

, et al.

Coronary microvascular dysfunction and cardiovascular risk in obese patients

.

J Am Coll Cardiol

2018

;

72

:

707

–

17

.

10.1016/j.jacc.2018.05.049

15

Seitz

A

,

Martínez Pereyra

V

,

Sechtem

U

,

Ong

P

.

Update on coronary artery spasm 2022—a narrative review

.

Int J Cardiol

2022

;

359

:

1

–

6

.

10.1016/j.ijcard.2022.04.011

16

Visseren

FLJ

,

Mach

F

,

Smulders

YM

,

Carballo

D

,

Koskinas

KC

,

Bäck

M

, et al.

2021 ESC Guidelines on cardiovascular disease prevention in clinical practice

.

Eur Heart J

2021

;

42

:

3227

–

337

.

10.1093/eurheartj/ehab484

17

Sandhu

AT

,

Rodriguez

F

,

Ngo

S

,

Patel

BN

,

Mastrodicasa

D

,

Eng

D

, et al.

Incidental coronary artery calcium: opportunistic screening of previous nongated chest computed tomography scans to improve statin rates (NOTIFY-1 project)

.

Circulation

2023

;

147

:

703

–

14

.

10.1161/CIRCULATIONAHA.122.062746

18

Bairey Merz

CN

,

Shaw

LJ

,

Reis

SE

,

Bittner

V

,

Kelsey

SF

,

Olson

M

, et al.

Insights from the NHLBI-Sponsored Women’s Ischemia Syndrome Evaluation (WISE) Study: Part II: gender differences in presentation, diagnosis, and outcome with regard to gender-based pathophysiology of atherosclerosis and macrovascular and microvascular coronary disease

.

J Am Coll Cardiol

2006

;

47

:

S21

–

9

.

10.1016/j.jacc.2004.12.084

19

Andreotti

F

,

Marchese

N

.

Women and coronary disease

.

Heart

2008

;

94

:

108

–

16

.

10.1136/hrt.2005.072769

20

Ferrari

R

,

Abergel

H

,

Ford

I

,

Fox

KM

,

Greenlaw

N

,

Steg

PG

, et al.

Gender- and age-related differences in clinical presentation and management of outpatients with stable coronary artery disease

.

Int J Cardiol

2013

;

167

:

2938

–

43

.

10.1016/j.ijcard.2012.08.013

21

Mehta

PK

,

Bess

C

,

Elias-Smale

S

,

Vaccarino

V

,

Quyyumi

A

,

Pepine

CJ

, et al.

Gender in cardiovascular medicine: chest pain and coronary artery disease

.

Eur Heart J

2019

;

40

:

3819

–

26

.

10.1093/eurheartj/ehz784

22

Ford

ES

,

Capewell

S

.

Proportion of the decline in cardiovascular mortality disease due to prevention versus treatment: public health versus clinical care

.

Annu Rev Public Health

2011

;

32

:

5

–

22

.

10.1146/annurev-publhealth-031210-101211

23

Safiri

S

,

Karamzad

N

,

Singh

K

,

Carson-Chahhoud

K

,

Adams

C

,

Nejadghaderi

SA

, et al.

Burden of ischemic heart disease and its attributable risk factors in 204 countries and territories, 1990–2019

.

Eur J Prev Cardiol

2022

;

29

:

420

–

31

.

10.1093/eurjpc/zwab213

24

Andreotti

F

,

Crea

F

,

Sechtem

U

.

Diagnoses and outcomes in patients with suspected angina: what are they trying to tell us?

Eur Heart J

2019

;

40

:

1436

–

9

.

10.1093/eurheartj/ehz032

25

Diamond

GA

,

Forrester

JS

.

Analysis of probability as an aid in the clinical diagnosis of coronary-artery disease

.

N Engl J Med

1979

;

300

:

1350

–

8

.

10.1056/NEJM197906143002402

26

Genders

TS

,

Steyerberg

EW

,

Alkadhi

H

,

Leschka

S

,

Desbiolles

L

,

Nieman

K

, et al.

A clinical prediction rule for the diagnosis of coronary artery disease: validation, updating, and extension

.

Eur Heart J

2011

;

32

:

1316

–

30

.

10.1093/eurheartj/ehr014

27

Reeh

J

,

Therming

CB

,

Heitmann

M

,

Højberg

S

,

Sørum

C

,

Bech

J

, et al.

Prediction of obstructive coronary artery disease and prognosis in patients with suspected stable angina

.

Eur Heart J

2019

;

40

:

1426

–

35

.

10.1093/eurheartj/ehy806

28

Gerber

Y

,

Gibbons

RJ

,

Weston

SA

,

Fabbri

M

,

Herrmann

J

,

Manemann

SM

, et al.

Coronary disease surveillance in the community: angiography and revascularization

.

J Am Heart Assoc

2020

;

9

:

e015231

.

10.1161/jaha.119.015231

29

Juarez-Orozco

LE

,

Saraste

A

,

Capodanno

D

,

Prescott

E

,

Ballo

H

,

Bax

JJ

, et al.

Impact of a decreasing pre-test probability on the performance of diagnostic tests for coronary artery disease

.

Eur Heart J Cardiovasc Imaging

2019

;

20

:

1198

–

207

.

30

Winther

S

,

Schmidt

SE

,

Rasmussen

LD

,

Juárez Orozco

LE

,

Steffensen

FH

,

Bøtker

HE

, et al.

Validation of the European Society of Cardiology pre-test probability model for obstructive coronary artery disease

.

Eur Heart J

2021

;

42

:

1401

–

11

.

10.1093/eurheartj/ehaa755

31

Serruys

PW

,

Hara

H

,

Garg

S

,

Kawashima

H

,

Nørgaard

BL

,

Dweck

MR

, et al.

Coronary computed tomographic angiography for complete assessment of coronary artery disease: JACC state-of-the-art review

.

J Am Coll Cardiol

2021

;

78

:

713

–

36

.

10.1016/j.jacc.2021.06.019

32

Serruys

WP

,

Kotoku

N

,

Nørgaard

LB

,

Garg

S

,

Nieman

K

,

Dweck

MR

, et al.

Computed tomographic angiography in coronary artery disease

.

EuroIntervention

2023

;

18

:

e1307

–

27

.

10.4244/EIJ-D-22-00776

33

Douglas

PS

,

Hoffmann

U

,

Patel

MR

,

Mark

DB

,

Al-Khalidi

HR

,

Cavanaugh

B

, et al.

Outcomes of anatomical versus functional testing for coronary artery disease

.

N Engl J Med

2015

;

372

:

1291

–

300

.

10.1056/NEJMoa1415516

34

SCOT-HEART Investigators

;

Newby

DE

,

Adamson

PD

,

Berry

C

,

Boon

NA

,

Dweck

MR

, et al.

Coronary CT angiography and 5-year risk of myocardial infarction

.

N Engl J Med

2018

;

379

:

924

–

33

.

10.1056/NEJMoa1805971

35

Mezquita

AJV

,

Biavati

F

,

Falk

V

,

Alkadhi

H

,

Hajhosseiny

R

,

Maurovich-Horvat

P

, et al.

Clinical quantitative coronary artery stenosis and coronary atherosclerosis imaging: a consensus statement from the Quantitative Cardiovascular Imaging Study Group

.

Nat Rev Cardiol

2023

;

20

:

696

–

714

.

10.1038/s41569-023-00880-4

36

Kunadian

V

,

Chieffo

A

,

Camici

PG

,

Berry

C

,

Escaned

J

,

Maas

AHEM

, et al.

An EAPCI expert consensus document on ischaemia with non-obstructive coronary arteries in collaboration with European Society of Cardiology Working Group on Coronary Pathophysiology & Microcirculation Endorsed by Coronary Vasomotor Disorders International Study Group

.

Eur Heart J

2020

;

41

:

3504

–

20

.

10.1093/eurheartj/ehaa503

37

Ong

P

,

Athanasiadis

A

,

Borgulya

G

,

Vokshi

I

,

Bastiaenen

R

,

Kubik

S

, et al.

Clinical usefulness, angiographic characteristics, and safety evaluation of intracoronary acetylcholine provocation testing among 921 consecutive white patients with unobstructed coronary arteries

.

Circulation

2014

;

129

:

1723

–

30

.

10.1161/CIRCULATIONAHA.113.004096

38

Feenstra

RGT

,

Boerhout

CKM

,

Woudstra

J

,

Vink

CEM

,

Wittekoek

ME

,

de Waard

GA

, et al.

Presence of coronary endothelial dysfunction, coronary vasospasm, and adenosine-mediated vasodilatory disorders in patients with ischemia and nonobstructive coronary arteries

.

Circ Cardiovasc Interv

2022

;

15

:

e012017

.

10.1161/circinterventions.122.012017

39

Samuels

BA

,

Shah

SM

,

Widmer

RJ

,

Kobayashi

Y

,

Miner

SES

,

Taqueti

VR

, et al.

Comprehensive management of ANOCA, Part 1—definition, patient population, and diagnosis: JACC state-of-the-art review

.

J Am Coll Cardiol

2023

;

82

:

1245

–

63

.

10.1016/j.jacc.2023.06.043

40

Smilowitz

NR

,

Prasad

M

,

Widmer

RJ

,

Toleva

O

,

Quesada

O

,

Sutton

NR

, et al.

Comprehensive management of ANOCA, Part 2—program development, treatment, and research initiatives: JACC state-of-the-art review

.

J Am Coll Cardiol

2023

;

82

:

1264

–

79

.

10.1016/j.jacc.2023.06.044

41

Ong

P

,

Safdar

B

,

Seitz

A

,

Hubert

A

,

Beltrame

JF

,

Prescott

E

.

Diagnosis of coronary microvascular dysfunction in the clinic

.

Cardiovasc Res

2020

;

116

:

841

–

55

.

42

Feenstra

RGT

,

Seitz

A

,

Boerhout

CKM

,

de Winter

RJ

,

Ong

P

,

Beijk

MAM

, et al.

Reference values for intracoronary Doppler flow velocity-derived hyperaemic microvascular resistance index

.

Int J Cardiol

2023

;

371

:

16

–

20

.

10.1016/j.ijcard.2022.09.054

43

Jansen

TPJ

,

Konst

RE

,

Elias-Smale

SE

,

van den Oord

SC

,

Ong

P

,

de Vos

AMJ

, et al.

Assessing microvascular dysfunction in angina with unobstructed coronary arteries: JACC review topic of the week

.

J Am Coll Cardiol

2021

;

78

:

1471

–

9

.

10.1016/j.jacc.2021.08.028

44

Taqueti

VR

,

Hachamovitch

R

,

Murthy

VL

,

Naya

M

,

Foster

CR

,

Hainer

J

, et al.

Global coronary flow reserve is associated with adverse cardiovascular events independently of luminal angiographic severity and modifies the effect of early revascularization

.

Circulation

2015

;

131

:

19

–

27

.

10.1161/CIRCULATIONAHA.114.011939

45

Schindler

TH

,

Fearon

WF

,

Pelletier-Galarneau

M

,

Ambrosio

G

,

Sechtem

U

,

Ruddy

TD

, et al.

PET for detection and reporting coronary microvascular dysfunction

.

JACC Cardiovasc Imaging

2023

;

16

:

536

–

48

.

10.1016/j.jcmg.2022.12.015

46

Ong

P

,

Seitz

A

.

Advances in risk stratification of patients with coronary microvascular dysfunction: usefulness of stress perfusion CMR

.

JACC Cardiovasc Imaging

2021

;

14

:

612

–

4

.

10.1016/j.jcmg.2020.09.036

47

Maron

DJ

,

Hochman

JS

,

Reynolds

HR

,

Bangalore

S

,

O’Brien

SM

,

Boden

WE

, et al.

Initial invasive or conservative strategy for stable coronary disease

.

New Engl J Med

2020

;

382

:

1395

–

407

.

10.1056/NEJMoa1915922

48

Boden

WE

,

O’Rourke

RA

,

Teo

KK

,

Hartigan

PM

,

Maron

DJ

,

Kostuk

WJ

, et al.

Optimal medical therapy with or without PCI for stable coronary disease

.

N Engl J Med

2007

;

356

:

1503

–

16

.

49

De Bruyne

B

,

Pijls

NH

,

Kalesan

B

,

Barbato

E

,

Tonino

PAL

,

Piroth

Z

, et al.

Fractional flow reserve-guided PCI versus medical therapy in stable coronary disease

.

N Engl J Med

2012

;

367

:

991

–

1001

.

10.1056/NEJMoa1205361

50

Spertus

JA

,

Jones

PG

,

Maron

DJ

,

O’Brien

SM

,

Reynolds

HR

,

Rosenberg

Y

, et al.

Health-status outcomes with invasive or conservative care in coronary disease

.

N Engl J Med

2020

;

382

:

1408

–

19

.

10.1056/NEJMoa1916370

51

Creber

RM

,

Dimagli

A

,

Spadaccio

C

,

Myers

A

,

Moscarelli

M

,

Demetres

M

, et al.

Effect of coronary artery bypass grafting on quality of life: a meta-analysis of randomized trials

.

Eur Heart J Qual Care Clin Outcomes

2022

;

8

:

259

–

68

.

10.1093/ehjqcco/qcab075

52

Rajkumar

CA

,

Foley

MJ

,

Ahmed-Jushuf

F

,

Nowbar

AN

,

Simader

FA

,

Davies

JR

, et al.

A placebo-controlled trial of percutaneous coronary intervention for stable angina

.

New Engl J Med

2023

;

389

:

2319

–

30

.

10.1056/NEJMoa2310610

53

Velazquez

EJ

,

Lee

KL

,

Deja

MA

,

Jain

A

,

Sopko

G

,

Marchenko

A

, et al.

Coronary-artery bypass surgery in patients with left ventricular dysfunction

.

N Engl J Med

2011

;

364

:

1607

–

16

.

10.1056/NEJMoa1100356

54

Velazquez

EJ

,

Lee

KL

,

Jones

RH

,

Al-Khalidi

HR

,

Hill

JA

,

Panza

JA

, et al.

Coronary-artery bypass surgery in patients with ischemic cardiomyopathy

.

N Engl J Med

2016

;

374

:

1511

–

20

.

10.1056/NEJMoa1602001

55

Navarese

EP

,

Lansky

AJ

,

Kereiakes

DJ

,

Kubica

J

,

Gurbel

PA

,

Gorog

DA

, et al.

Cardiac mortality in patients randomised to elective coronary revascularisation plus medical therapy or medical therapy alone: a systematic review and meta-analysis

.

Eur Heart J

2021

;

42

:

4638

–

51

.

10.1093/eurheartj/ehab246

56

Hochman

JS

,

Anthopolos

R

,

Reynolds

HR

,

Bangalore

S

,

Xu

Y

,

O’Brien

SM

, et al.

Survival after invasive or conservative management of stable coronary disease

.

Circulation

2023

;

147

:

8

–

19

.

10.1161/CIRCULATIONAHA.122.062714

57

Douglas

PS

,

Nanna

MG

,

Kelsey

MD

,

Yow

E

,

Mark

DB

,

Patel

MR

, et al.

Comparison of an initial risk-based testing strategy vs usual testing in stable symptomatic patients with suspected coronary artery disease: the PRECISE randomized clinical trial

.

JAMA Cardiology

2023

;

8

:

904

–

14

.

10.1001/jamacardio.2023.2595

58

Douglas

PS

,

Ginsburg

GS

.

The evaluation of chest pain in women

.

New Engl J Med

1996

;

334

:

1311

–

5

.

10.1056/nejm199605163342007

59

Hemal

K

,

Pagidipati

NJ

,

Coles

A

,

Dolor

RJ

,

Mark

DB

,

Pellikka

PA

, et al.

Sex differences in demographics, risk factors, presentation, and noninvasive testing in stable outpatients with suspected coronary artery disease: insights from the PROMISE trial

.

JACC Cardiovasc Imaging

2016

;

9

:

337

–

46

.

10.1016/j.jcmg.2016.02.001

60

Garcia

M

,

Mulvagh

SL

,

Bairey Merz

CN

,

Buring

JE

,

Manson

JE

.

Cardiovascular disease in women: clinical perspectives

.

Circ Res

2016

;

118

:

1273

–

93

.

10.1161/CIRCRESAHA.116.307547

61

Stepinska

J

,

Lettino

M

,

Ahrens

I

,

Bueno

H

,

Garcia-Castrillo

L

,

Khoury

A

, et al.

Diagnosis and risk stratification of chest pain patients in the emergency department: focus on acute coronary syndromes. A position paper of the Acute Cardiovascular Care Association

.

Eur Heart J Acute Cardiovasc Care

2020

;

9

:

76

–

89

.

10.1177/2048872619885346

62

Hoorweg

BB

,

Willemsen

RT

,

Cleef

LE

,

Boogaerts

T

,

Buntinx

F

,

Glatz

JFC

, et al.

Frequency of chest pain in primary care, diagnostic tests performed and final diagnoses

.

Heart

2017

;

103

:

1727

–

32

.

10.1136/heartjnl-2016-310905

63

Reynolds

HR

,

Shaw

LJ

,

Min

JK

,

Spertus

JA

,

Chaitman

BR

,

Berman

DS

, et al.

Association of sex with severity of coronary artery disease, ischemia, and symptom burden in patients with moderate or severe ischemia: secondary analysis of the ISCHEMIA randomized clinical trial

.

JAMA Cardiol

2020

;

5

:

773

–

86

.

10.1001/jamacardio.2020.0822

64

Mach

F

,

Baigent

C

,

Catapano

AL

,

Koskinas

KC

,

Casula

M

,

Badimon

L

, et al.

2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk

.

Eur Heart J

2020

;

41

:

111

–

88

.

10.1093/eurheartj/ehz455

65

Byrne

RA

,

Rossello

X

,

Coughlan

JJ

,

Barbato

E

,

Berry

C

,

Chieffo

A

, et al.

2023 ESC Guidelines for the management of patients with acute coronary syndromes

.

Eur Heart J

2023

;

44

:

3720

–

826

.

10.1093/eurheartj/ehad191

66

Campeau

L

.

Letter: grading of angina pectoris

.

Circulation

1976

;

54

:

522

–

3

.

10.1161/circ.54.3.947585

67

Fiol-Sala

M

,

Birnbaum

J

,

Nikus

K

,

Bayés de Luna

A

.

Electrocardiography in Ischemic Heart Disease

.

Hoboken, NJ

:

Wiley Blackwell

,

2019

.

68

Kannel

WB

,

Abbott

RD

,

Savage

DD

,

McNamara

PM

.

Coronary heart disease and atrial fibrillation: the Framingham study

.

Am Heart J

1983

;

106

:

389

–

96

.

10.1016/0002-8703(83)90208-9

69

Cohn

PF

,

Fox

KM

,

Daly

C

.

Silent myocardial ischemia

.

Circulation

2003

;

108

:

1263

–

77

.

10.1161/01.CIR.0000088001.59265.EE

70

Androulakis

A

,

Aznaouridis

KA

,

Aggeli

CJ

,

Roussakis

GN

,

Michaelides

AP

,

Kartalis

AN

, et al.

Transient ST-segment depression during paroxysms of atrial fibrillation in otherwise normal individuals: relation with underlying coronary artery disease

.

J Am Coll Cardiol

2007

;

50

:

1909

–

11

.

10.1016/j.jacc.2007.08.005

71

Guo

Y

,

Zhang

L

,

Wang

C

,

Zhao

Y

,

Chen

W

,

Gao

M

, et al.

Medical treatment and long-term outcome of chronic atrial fibrillation in the aged with chest distress: a retrospective analysis versus sinus rhythm

.

Clin Interv Aging

2011

;

6

:

193

–

8

.

72

Nucifora

G

,

Schuijf

JD

,

van Werkhoven

JM

,

Trines

SA

,

Kajander

S

,

Tops

LF

, et al.

Relationship between obstructive coronary artery disease and abnormal stress testing in patients with paroxysmal or persistent atrial fibrillation

.

Int J Cardiovasc Imaging

2011

;

27

:

777

–

85

.

10.1007/s10554-010-9725-x

73

Beltrame

JF

,

Crea

F

,

Kaski

JC

,

Ogawa

H

,

Ong

P

,

Sechtem

U

, et al.

International standardization of diagnostic criteria for vasospastic angina

.

Eur Heart J

2017

;

38

:

2565

–

8

.

10.1093/eurheartj/ehv351

74

Forslund

L

,

Hjemdahl

P

,

Held

C

,

Björkander

I

,

Eriksson

SV

,

Rehnqvist

N

.

Ischaemia during exercise and ambulatory monitoring in patients with stable angina pectoris and healthy controls. Gender differences and relationships to catecholamines

.

Eur Heart J

1998

;

19

:

578

–

87

.

10.1053/euhj.1997.0819

75

Davies

RF

,

Goldberg

AD

,

Forman

S

,

Pepine

CJ

,

Knatterud

GL

,

Geller

N

, et al.

Asymptomatic Cardiac Ischemia Pilot (ACIP) study two-year follow-up: outcomes of patients randomized to initial strategies of medical therapy versus revascularization

.

Circulation

1997

;

95

:

2037

–

43

.

10.1161/01.cir.95.8.2037

76

Stone

PH

,

Chaitman

BR

,

Forman

S

,

Andrews

TC

,

Bittner

V

,

Bourassa

MG

, et al.

Prognostic significance of myocardial ischemia detected by ambulatory electrocardiography, exercise treadmill testing, and electrocardiogram at rest to predict cardiac events by one year (the Asymptomatic Cardiac Ischemia Pilot [ACIP] study)

.

Am J Cardiol

1997

;

80

:

1395

–

401

.

10.1016/s0002-9149(97)00706-6

77

Shaw

LJ

,

Bairey Merz

CN

,

Pepine

CJ

,

Reis

SE

,

Bittner

V

,

Kelsey

SF

, et al.

Insights from the NHLBI-Sponsored Women’s Ischemia Syndrome Evaluation (WISE) Study: Part I: gender differences in traditional and novel risk factors, symptom evaluation, and gender-optimized diagnostic strategies

.

J Am Coll Cardiol

2006

;

47

:

S4

–

20

.

10.1016/j.jacc.2005.01.072

78

Reichlin

T

,

Hochholzer

W

,

Bassetti

S

,

Steuer

S

,

Stelzig

C

,

Hartwiger

S

, et al.

Early diagnosis of myocardial infarction with sensitive cardiac troponin assays

.

N Engl J Med

2009

;

361

:

858

–

67

.

10.1056/NEJMoa0900428

79

Keller

T

,

Zeller

T

,

Peetz

D

,

Tzikas

S

,

Roth

A

,

Czyz

E

, et al.

Sensitive troponin I assay in early diagnosis of acute myocardial infarction

.

N Engl J Med

2009

;

361

:

868

–

77

.

10.1056/NEJMoa0903515

80

Nelson

SD

,

Kou

WH

,

Annesley

T

,

de Buitleir

M

,

Morady

F

.

Significance of ST segment depression during paroxysmal supraventricular tachycardia

.

J Am Coll Cardiol

1988

;

12

:

383

–

7

.

10.1016/0735-1097(88)90410-x

81

Imrie

JR

,

Yee

R

,

Klein

GJ

,

Sharma

AD

.

Incidence and clinical significance of ST segment depression in supraventricular tachycardia

.

Can J Cardiol

1990

;

6

:

323

–

6

.

10.1016/j.amjmed.2017.01.002

82

Riva

SI

,

Della Bella

P

,

Fassini

G

,

Carbucicchio

C

,

Tondo

C

.

Value of analysis of ST segment changes during tachycardia in determining type of narrow QRS complex tachycardia

.

J Am Coll Cardiol

1996

;

27

:

1480

–

5

.

10.1016/0735-1097(96)00013-7

83

Rivera

S

,

De La Paz Ricapito

M

,

Conde

D

,

Verdu

M

,

Roux

J

,

Paredes

F

.

The retrograde P-wave theory: explaining ST segment depression in supraventricular tachycardia by retrograde AV node conduction

.

Pacing Clin Electrophysiol

2014

;

37

:

1100

–

5

.

84

Mercik

J

,

Radziejewska

J

,

Pach

K

,

Zawadzki

G

,

Zyśko

D

,

Gajek

J

, et al.

ST-segment depression in atrioventricular nodal reentrant tachycardia: important finding or just an artifact?

Medicine (Baltimore)

2022

;

101

:

e31806

.

10.1097/md.0000000000031806

85

Cosentino

F

,

Grant

PJ

,

Aboyans

V

,

Bailey

CJ

,

Ceriello

A

,

Delgado

V

, et al.

2019 ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD: the Task Force for diabetes, pre-diabetes, and cardiovascular diseases of the European Society of Cardiology (ESC) and the European Association for the Study of Diabetes (EASD)

.

Eur Heart J

2019

;

41

:

255

–

323

.

10.1093/eurheartj/ehz486

10.1093/eurheartj/ehad192

86

Marx

N

,

Federici

M

,

Schütt

K

,

Müller-Wieland

D

,

Ajjan

RA

,

Antunes

MJ

, et al.

2023 ESC Guidelines for the management of cardiovascular disease in patients with diabetes: developed by the task force on the management of cardiovascular disease in patients with diabetes of the European Society of Cardiology (ESC)

.

Eur Heart J

2023

;

44

:

4043

–

140

.

87

Nordestgaard

BG

,

Langsted

A

,

Mora

S

,

Kolovou

G

,

Baum

H

,

Bruckert

E

, et al.

Fasting is not routinely required for determination of a lipid profile: clinical and laboratory implications including flagging at desirable concentration cut-points—a joint consensus statement from the European Atherosclerosis Society and European Federation of Clinical Chemistry and Laboratory Medicine

.

Eur Heart J

2016

;

37

:

1944

–

58

.

10.1093/eurheartj/ehw152

88

Kamstrup

PR

,

Tybjærg-Hansen

A

,

Nordestgaard

BG

.

Extreme lipoprotein(a) levels and improved cardiovascular risk prediction

.

J Am Coll Cardiol

2013

;

61

:

1146

–

56

.

10.1016/j.jacc.2012.12.023

89

Rossello

X

.

Lifetime risk estimation in atherosclerotic cardiovascular disease: where inflammation meets lipoprotein(a)

.

J Am Coll Cardiol

2021

;

78

:

1095

–

6

.

10.1016/j.jacc.2021.07.035

90

Boffa

MB

,

Stranges

S

,

Klar

N

,

Moriarty

PM

,

Watts

GF

,

Koschinsky

ML

.

Lipoprotein(a) and secondary prevention of atherothrombotic events: a critical appraisal

.

J Clin Lipidol

2018

;

12

:

1358

–

66

.

10.1016/j.jacl.2018.08.012

91

Malick

WA

,

Goonewardena

SN

,

Koenig

W

,

Rosenson

RS

.

Clinical trial design for lipoprotein(a)-lowering therapies: JACC focus seminar 2/3

.

J Am Coll Cardiol

2023

;

81

:

1633

–

45

.

10.1016/j.jacc.2023.02.033

92

Kronenberg

F

,

Mora

S

,

Stroes

ESG

,

Ference

BA

,

Arsenault

BJ

,

Berglund

L

, et al.

Lipoprotein(a) in atherosclerotic cardiovascular disease and aortic stenosis: a European Atherosclerosis Society consensus statement

.

Eur Heart J

2022

;

43

:

3925

–

46

.

10.1093/eurheartj/ehac361

93

Lopes

NH

,

da Silva Paulitsch

F

,

Pereira

A

,

Garzillo

CL

,

Ferreira

JF

,

Stolf

N

, et al.

Mild chronic kidney dysfunction and treatment strategies for stable coronary artery disease

.

J Thorac Cardiovasc Surg

2009

;

137

:

1443

–

9

.

10.1016/j.jtcvs.2008.11.028

94

Di Angelantonio

E

,

Chowdhury

R

,

Sarwar

N

,

Aspelund

T

,

Danesh

J

,

Gudnason

V

.

Chronic kidney disease and risk of major cardiovascular disease and non-vascular mortality: prospective population based cohort study

.

BMJ

2010

;

341

:

c4986

.

95

Nitsch

D

,

Grams

M

,

Sang

Y

,

Black

C

,

Cirillo

M

,

Djurdjev

O

, et al.

Associations of estimated glomerular filtration rate and albuminuria with mortality and renal failure by sex: a meta-analysis

.

BMJ

2013

;

346

:

f324

.

96

Omland

T

,

de Lemos

JA

,

Sabatine

MS

,

Christophi

CA

,

Rice

MM

,

Jablonski

KA

, et al.

A sensitive cardiac troponin T assay in stable coronary artery disease

.

N Engl J Med

2009

;

361

:

2538

–

47

.

10.1056/NEJMoa0805299

97

de Lemos

JA

,

Drazner

MH

,

Omland

T

,

Ayers

CR

,

Khera

A

,

Rohatgi

A

, et al.

Association of troponin T detected with a highly sensitive assay and cardiac structure and mortality risk in the general population

.

JAMA

2010

;

304

:

2503

–

12

.

10.1001/jama.2010.1768

98

Omland

T

,

Pfeffer

MA

,

Solomon

SD

,

de Lemos

JA

,

Røsjø

H

,

Šaltytė Benth

J

, et al.

Prognostic value of cardiac troponin I measured with a highly sensitive assay in patients with stable coronary artery disease

.

J Am Coll Cardiol

2013

;

61

:

1240

–

9

.

10.1016/j.jacc.2012.12.026

99

van Holten

TC

,

Waanders

LF

,

de Groot

PG

,

Vissers

J

,

Hoefer

IE

,

Pasterkamp

G

, et al.

Circulating biomarkers for predicting cardiovascular disease risk; a systematic review and comprehensive overview of meta-analyses

.

PLoS One

2013

;

8

:

e62080

.

10.1371/journal.pone.0062080

100

Everett

BM

,

Brooks

MM

,

Vlachos

HE

,

Chaitman

BR

,

Frye

RL

,

Bhatt

DL

, et al.

Troponin and cardiac events in stable ischemic heart disease and diabetes

.

N Engl J Med

2015

;

373

:

610

–

20

.

10.1056/NEJMoa1415921

101

Laufer

EM

,

Mingels

AM

,

Winkens

MH

,

Joosen

IAPG

,

Schellings

MWM

,

Leiner

T

, et al.

The extent of coronary atherosclerosis is associated with increasing circulating levels of high sensitive cardiac troponin T

.

Arterioscler Thromb Vasc Biol

2010

;

30

:

1269

–

75

.

10.1161/ATVBAHA.109.200394

102

Madsen

DM

,

Diederichsen

ACP

,

Hosbond

SE

,

Gerke

O

,

Mickley

H

.

Diagnostic and prognostic value of a careful symptom evaluation and high sensitive troponin in patients with suspected stable angina pectoris without prior cardiovascular disease

.

Atherosclerosis

2017

;

258

:

131

–

7

.

10.1016/j.atherosclerosis.2016.11.030

103

Adamson

PD

,

Hunter

A

,

Madsen

DM

,

Shah

ASV

,

McAllister

DA

,

Pawade

TA

, et al.

High-sensitivity cardiac troponin I and the diagnosis of coronary artery disease in patients with suspected angina pectoris

.

Circ Cardiovasc Qual Outcomes

2018

;

11

:

e004227

.

10.1161/circoutcomes.117.004227

104

Januzzi

JL

Jr,

Suchindran

S

,

Coles

A

,

Ferencik

M

,

Patel

MR

,

Hoffmann

U

, et al.

High-sensitivity troponin I and coronary computed tomography in symptomatic outpatients with suspected cad: insights from the PROMISE trial

.

JACC Cardiovasc Imaging

2019

;

12

:

1047

–

55

.

10.1016/j.jcmg.2018.01.021

105

Vavassori

C

,

Cipriani

E

,

Colombo

GI

.

Circulating microRNAs as novel biomarkers in risk assessment and prognosis of coronary artery disease

.

Eur Cardiol

2022

;

17

:

e06

.

106

Hoogeveen

RM

,

Pereira

JPB

,

Nurmohamed

NS

,

Zampoleri

V

,

Bom

MJ

,

Baragetti

A

, et al.

Improved cardiovascular risk prediction using targeted plasma proteomics in primary prevention

.

Eur Heart J

2020

;

41

:

3998

–

4007

.

10.1093/eurheartj/ehaa648

107

Ibrahim

NE

,

Januzzi

JL

Jr,

Magaret

CA

,

Gaggin

HK

,

Rhyne

RF

,

Gandhi

PU

, et al.

A clinical and biomarker scoring system to predict the presence of obstructive coronary artery disease

.

J Am Coll Cardiol

2017

;

69

:

1147

–

56

.

10.1016/j.jacc.2016.12.021

108

Hilvo

M

,

Meikle

PJ

,

Pedersen

ER

,

Tell

GS

,

Dhar

I

,

Brenner

H

, et al.

Development and validation of a ceramide- and phospholipid-based cardiovascular risk estimation score for coronary artery disease patients

.

Eur Heart J

2020

;

41

:

371

–

80

.

10.1093/eurheartj/ehz387

109

Ridker

PM

,

Hennekens

CH

,

Buring

JE

,

Rifai

N

.

C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women

.

N Engl J Med

2000

;

342

:

836

–

43

.

10.1056/nejm200003233421202

110

Danesh

J

,

Wheeler

JG

,

Hirschfield

GM

,

Eda

S

,

Eiriksdottir

G

,

Rumley

A

, et al.

C-reactive protein and other circulating markers of inflammation in the prediction of coronary heart disease

.

N Engl J Med

2004

;

350

:

1387

–

97

.

111

Sinning

JM

,

Bickel

C

,

Messow

CM

,

Schnabel

R

,

Lubos

E

,

Rupprecht

HJ

, et al.

Impact of C-reactive protein and fibrinogen on cardiovascular prognosis in patients with stable angina pectoris: the AtheroGene study

.

Eur Heart J

2006

;

27

:

2962

–

8

.

10.1093/eurheartj/ehl362

112

Jia

RF

,

Li

L

,

Li

H

,

Cao

X-J

,

Ruan

Y

,

Meng

S

, et al.

Meta-analysis of C-reactive protein and risk of angina pectoris

.

Am J Cardiol

2020

;

125

:

1039

–

45

.

10.1016/j.amjcard.2020.01.005

113

Ridker

PM

,

Cushman

M

,

Stampfer

MJ

,

Tracy

RP

,

Hennekens

CH

.

Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men

.

N Engl J Med

1997

;

336

:

973

–

9

.

10.1056/nejm199704033361401

114

Thompson

SG

,

Kienast

J

,

Pyke

SD

,

Haverkate

F

,

van de Loo

JC

.

Hemostatic factors and the risk of myocardial infarction or sudden death in patients with angina pectoris. European Concerted Action on Thrombosis and Disabilities Angina Pectoris Study Group

.

N Engl J Med

1995

;

332

:

635

–

41

.

10.1056/nejm199503093321003

115

De Luca

G

,

Verdoia

M

,

Cassetti

E

,

Schaffer

A

,

Cavallino

C

,

Bolzani

V

, et al.

High fibrinogen level is an independent predictor of presence and extent of coronary artery disease among Italian population

.

J Thromb Thrombolysis

2011

;

31

:

458

–

63

.

10.1007/s11239-010-0531-z

116

Ndrepepa

G

,

Braun

S

,

King

L

,

Fusaro

M

,

Keta

D

,

Cassese

S

, et al.

Relation of fibrinogen level with cardiovascular events in patients with coronary artery disease

.

Am J Cardiol

2013

;

111

:

804

–

10

.

10.1016/j.amjcard.2012.11.060

117

Kannel

WB

,

Wolf

PA

,

Castelli

WP

,

D’Agostino

RB

.

Fibrinogen and risk of cardiovascular disease: the Framingham study

.

JAMA

1987

;

258

:

1183

–

6

.

10.1001/jama.1987.03400090067035

118

Appiah

D

,

Schreiner

PJ

,

MacLehose

RF

,

Folsom

AR

.

Association of plasma γ′ fibrinogen with incident cardiovascular disease: the Atherosclerosis Risk in Communities (ARIC) study

.

Arterioscler Thromb Vasc Biol

2015

;

35

:

2700

–

6

.

10.1161/atvbaha.115.306284

119

Ridker

PM

,

Bhatt

DL

,

Pradhan

AD

,

Glynn

RJ

,

MacFadyen

JG

,

Nissen

SE

, et al.

Inflammation and cholesterol as predictors of cardiovascular events among patients receiving statin therapy: a collaborative analysis of three randomised trials

.

Lancet

2023

;

401

:

1293

–

301

.

10.1016/S0140-6736(23)00215-5

120

Ridker

PM

,

Lei

L

,

Louie

MJ

,

Haddad

T

,

Nicholls

SJ

,

Lincoff

AM

, et al.

Inflammation and cholesterol as predictors of cardiovascular events among 13 970 contemporary high-risk patients with statin intolerance

.

Circulation

2024

;

149

:

28

–

35

.

10.1161/CIRCULATIONAHA.123.066213

121

Bohula

EA

,

Giugliano

RP

,

Leiter

LA

,

Verma

S

,

Park

J-G

,

Sever

PS

, et al.

Inflammatory and cholesterol risk in the FOURIER trial

.

Circulation

2018

;

138

:

131

–

40

.

10.1161/circulationaha.118.034032

122

Tokgözoğlu

L

,

Libby

P

.

The dawn of a new era of targeted lipid-lowering therapies

.

Eur Heart J

2022

;

43

:

3198

–

208

.

10.1093/eurheartj/ehab841

123

Byrne

P

,

Demasi

M

,

Jones

M

,

Smith

SM

,

O’Brien

KK

,

DuBroff

R

.

Evaluating the association between low-density lipoprotein cholesterol reduction and relative and absolute effects of statin treatment: a systematic review and meta-analysis

.

JAMA Intern Med

2022

;

182

:

474

–

81

.

10.1001/jamainternmed.2022.0134

124

Nurmohamed

NS

,

Navar

AM

,

Kastelein

JJP

.

New and emerging therapies for reduction of LDL-cholesterol and apolipoprotein B: JACC focus seminar 1/4

.

J Am Coll Cardiol

2021

;

77

:

1564

–

75

.

10.1016/j.jacc.2020.11.079

125

Pradhan

AD

,

Aday

AW

,

Rose

LM

,

Ridker

PM

.

Residual inflammatory risk on treatment with PCSK9 inhibition and statin therapy

.

Circulation

2018

;

138

:

141

–

9

.

10.1161/CIRCULATIONAHA.118.034645

126

Waksman

R

,

Merdler

I

,

Case

BC

,

Waksman

O

,

Porto

I

.

Targeting inflammation in atherosclerosis: overview, strategy and directions

.

EuroIntervention

2024

;

20

:

32

–

44

.

10.4244/EIJ-D-23-00606

127

Ridker

PM

,

Devalaraja

M

,

Baeres

FMM

,

Engelmann

MDM

,

Hovingh

GK

,

Ivkovic

M

, et al.

IL-6 inhibition with ziltivekimab in patients at high atherosclerotic risk (RESCUE): a double-blind, randomised, placebo-controlled, phase 2 trial

.

Lancet

2021

;

397

:

2060

–

9

.

10.1016/S0140-6736(21)00520-1

128

Silverman

MG

,

Ference

BA

,

Im

K

,

Wiviott

SD

,

Giugliano

RP

,

Grundy

SM

, et al.

Association between lowering LDL-C and cardiovascular risk reduction among different therapeutic interventions: a systematic review and meta-analysis

.

JAMA

2016

;

316

:

1289

–

97

.

10.1001/jama.2016.13985

129

Arant

CB

,

Wessel

TR

,

Olson

MB

,

Bairey Merz

CN

,

Sopko

G

,

Rogers

WJ

, et al.

Hemoglobin level is an independent predictor for adverse cardiovascular outcomes in women undergoing evaluation for chest pain: results from the National Heart, Lung, and Blood Institute Women’s Ischemia Syndrome Evaluation Study

.

J Am Coll Cardiol

2004

;

43

:

2009

–

14

.

10.1016/j.jacc.2004.01.038

130

da Silveira

AD

,

Ribeiro

RA

,

Rossini

AP

,

Stella

SF

,

Ritta

HAR

,

Stein

R

, et al.

Association of anemia with clinical outcomes in stable coronary artery disease

.

Coron Artery Dis

2008

;

19

:

21

–

6

.

10.1097/MCA.0b013e3282f27c0a

131

Muzzarelli

S

,

Pfisterer

M

;

Time Investigators

.

Anemia as independent predictor of major events in elderly patients with chronic angina

.

Am Heart J

2006

;

152

:

991

–

6

.

10.1016/j.ahj.2006.06.014

132

Kalra

PR

,

Greenlaw

N

,

Ferrari

R

,

Ford

I

,

Tardif

J-C

,

Tendera

M

, et al.

Hemoglobin and change in hemoglobin status predict mortality, cardiovascular events, and bleeding in stable coronary artery disease

.

Am J Med

2017

;

130

:

720

–

30

.

10.1016/j.amjmed.2017.01.002

133

Asif

A

,

Wei

J

,

Lauzon

M

,

Sopko

G

,

Reis

SE

,

Handberg

E

, et al.

Anemia and long-term cardiovascular outcomes in women with suspected ischemia—the Women’s Ischemia Syndrome Evaluation (WISE)

.

Am Heart J Plus Cardiol Res Pract

2021

;

10

:

100059

.

10.1016/j.ahjo.2021.100059

10.1371/journal.pmed.0040270

134

Di Angelantonio

E

,

Danesh

J

,

Eiriksdottir

G

,

Gudnason

V

.

Renal function and risk of coronary heart disease in general populations: new prospective study and systematic review

.

PLoS Med

2007

;

4

:

e270

.

135

Bartnik

M

,

Ryden

L

,

Malmberg

K

,

Ohrvik

J

,

Pyorala

K

,

Standl

E

, et al.

Oral glucose tolerance test is needed for appropriate classification of glucose regulation in patients with coronary artery disease: a report from the Euro Heart Survey on Diabetes and the Heart

.

Heart

2007

;

93

:

72

–

7

.

10.1136/hrt.2005.086975

136

Gyberg

V

,

De Bacquer

D

,

Kotseva

K

,

De Backer

G

,

Schnell

O

,

Sundvall

J

, et al.

Screening for dysglycaemia in patients with coronary artery disease as reflected by fasting glucose, oral glucose tolerance test, and HbA1c: a report from EUROASPIRE IV—a survey from the European Society of Cardiology

.

Eur Heart J

2015

;

36

:

1171

–

7

.

10.1093/eurheartj/ehv008

137

Corona

G

,

Croce

L

,

Sparano

C

,

Petrone

L

,

Sforza

A

,

Maggi

M

, et al.

Thyroid and heart, a clinically relevant relationship

.

J Endocrinol Invest

2021

;

44

:

2535

–

44

.

10.1007/s40618-021-01590-9

138

Sohn

SY

,

Lee

E

,

Lee

MK

,

Lee

JH

.

The association of overt and subclinical hyperthyroidism with the risk of cardiovascular events and cardiovascular mortality: meta-analysis and systematic review of cohort studies

.

Endocrinol Metab (Seoul)

2020

;

35

:

786

–

800

.

139

Winther

S

,

Schmidt

SE

,

Mayrhofer

T

,

Bøtker

HE

,

Hoffmann

U

,

Douglas

PS

, et al.

Incorporating coronary calcification into pre-test assessment of the likelihood of coronary artery disease

.

J Am Coll Cardiol

2020

;

76

:

2421

–

32

.

10.1016/j.jacc.2020.09.585

140

Genders

TS

,

Steyerberg

EW

,

Hunink

MG

,

Nieman

K

,

Galema

TW

,

Mollet

NR

, et al.

Prediction model to estimate presence of coronary artery disease: retrospective pooled analysis of existing cohorts

.

BMJ

2012

;

344

:

e3485

.

141

Zhou

J

,

Zhao

J

,

Li

Z

,

Cong

H

,

Wang

C

,

Zhang

H

, et al.

Coronary calcification improves the estimation for clinical likelihood of obstructive coronary artery disease and avoids unnecessary testing in patients with borderline pretest probability

.

Eur J Prev Cardiol

2022

;

29

:

e105

–

7

.

10.1093/eurjpc/zwab036

142

Winther

S

,

Murphy

T

,

Schmidt

SE

,

Bax

JJ

,

Wijns

W

,

Knuuti

J

, et al.

Performance of the American Heart Association/American College of Cardiology guideline-recommended pretest probability model for the diagnosis of obstructive coronary artery disease

.

J Am Heart Assoc

2022

:

e027260

.

10.1161/JAHA.122.027260

10.1016/j.jacc.2022.08.805

143

Winther

S

,

Schmidt

SE

,

Foldyna

B

,

Mayrhofer

T

,

Rasmussen

LD

,

Dahl

JN

, et al.

Coronary calcium scoring improves risk prediction in patients with suspected obstructive coronary artery disease

.

J Am Coll Cardiol

2022

;

80

:

1965

–

77

.

144

Rasmussen

LD

,

Schmidt

SE

,

Knuuti

J

,

Newby

DE

,

Singh

T

,

Nieman

K

, et al.

Exercise electrocardiography for pre-test assessment of the likelihood of coronary artery disease

.

Heart

2023

;

110

:

263

–

70

.

10.1136/heartjnl-2023-322970

10.1111/j.1742-1241.2012.02900.x

145

McKavanagh

P

,

Lusk

L

,

Ball

PA

,

Verghis

RM

,

Agus

AM

,

Trinick

TR

, et al.

A comparison of cardiac computerized tomography and exercise stress electrocardiogram test for the investigation of stable chest pain: the clinical results of the CAPP randomized prospective trial

.

Eur Heart J Cardiovasc Imaging

2015

;

16

:

441

–

8

.

146

Lubbers

M

,

Dedic

A

,

Coenen

A

,

Galema

T

,

Akkerhuis

J

,

Bruning

T

, et al.

Calcium imaging and selective computed tomography angiography in comparison to functional testing for suspected coronary artery disease: the multicentre, randomized CRESCENT trial

.

Eur Heart J

2016

;

37

:

1232

–

43

.

10.1093/eurheartj/ehv700

147

Banerjee

A

,

Newman

DR

,

Van den Bruel

A

,

Heneghan

C

.

Diagnostic accuracy of exercise stress testing for coronary artery disease: a systematic review and meta-analysis of prospective studies

.

Int J Clin Pract

2012

;

66

:

477

–

92

.

148

Knuuti

J

,

Ballo

H

,

Juarez-Orozco

LE

,

Saraste

A

,

Kolh

P

,

Rutjes

AWS

, et al.

The performance of non-invasive tests to rule-in and rule-out significant coronary artery stenosis in patients with stable angina: a meta-analysis focused on post-test disease probability

.

Eur Heart J

2018

;

39

:

3322

–

30

.

10.1093/eurheartj/ehy267

149

Cole

JP

,

Ellestad

MH

.

Significance of chest pain during treadmill exercise: correlation with coronary events

.

Am J Cardiol

1978

;

41

:

227

–

32

.

10.1016/0002-9149(78)90161-3

150

Lindow

T

,

Ekström

M

,

Brudin

L

,

Carlén

A

,

Elmberg

V

,

Hedman

K

.

Typical angina during exercise stress testing improves the prediction of future acute coronary syndrome

.

Clin Physiol Funct Imaging

2021

;

41

:

281

–

91

.

151

Agha

AM

,

Pacor

J

,

Grandhi

GR

,

Mszar

R

,

Khan

SU

,

Parikh

R

, et al.

The prognostic value of CAC zero among individuals presenting with chest pain

.

JACC Cardiovasc Imaging

2022

;

15

:

1745

–

57

.

10.1016/j.jcmg.2022.03.031

152

Mortensen

MB

,

Gaur

S

,

Frimmer

A

,

Bøtker

HE

,

Sørensen

HT

,

Kragholm

KH

, et al.

Association of age with the diagnostic value of coronary artery calcium score for ruling out coronary stenosis in symptomatic patients

.

JAMA Cardiol

2022

;

7

:

36

–

44

.

10.1001/jamacardio.2021.4406

153

Lubbers

M

,

Coenen

A

,

Kofflard

M

,

Bruning

T

,

Kietselaer

B

,

Galema

T

, et al.

Comprehensive cardiac CT with myocardial perfusion imaging versus functional testing in suspected coronary artery disease: the multicenter, randomized CRESCENT-II trial

.

JACC Cardiovasc Imaging

2018

;

11

:

1625

–

36

.

10.1016/j.jcmg.2017.10.010

154

Zhou

J

,

Li

C

,

Cong

H

,

Duan

L

,

Wang

H

,

Wang

C

, et al.

Comparison of different investigation strategies to defer cardiac testing in patients with stable chest pain

.

JACC Cardiovasc Imaging

2022

;

15

:

91

–

104

.

10.1016/j.jcmg.2021.08.022

155

Heald

CL

,

Fowkes

FG

,

Murray

GD

,

Price

JF

.

Risk of mortality and cardiovascular disease associated with the ankle-brachial index: systematic review

.

Atherosclerosis

2006

;

189

:

61

–

9

.

10.1016/j.atherosclerosis.2006.03.011

156

Molnár

S

,

Kerényi

L

,

Ritter

MA

,

Magyar

MT

,

Ida

Y

,

Szöllősi

Z

, et al.

Correlations between the atherosclerotic changes of femoral, carotid and coronary arteries: a post mortem study

.

J Neurol Sci

2009

;

287

:

241

–

5

.

10.1016/j.jns.2009.06.001

157

Fernandez-Friera

L

,

Penalvo

JL

,

Fernandez-Ortiz

A

,

Ibañez

B

,

López-Melgar

B

,

Laclaustra

M

, et al.

Prevalence, vascular distribution, and multiterritorial extent of subclinical atherosclerosis in a middle-aged cohort: the PESA (Progression of Early Subclinical Atherosclerosis) study

.

Circulation

2015

;

131

:

2104

–

13

.

10.1161/CIRCULATIONAHA.114.014310

158

Laclaustra

M

,

Casasnovas

JA

,

Fernández-Ortiz

A

,

Fuster

V

,

León-Latre

M

,

Jiménez-Borreguero

LJ

, et al.

Femoral and carotid subclinical atherosclerosis association with risk factors and coronary calcium: the AWHS study

.

J Am Coll Cardiol

2016

;

67

:

1263

–

74

.

10.1016/j.jacc.2015.12.056

159

Gepner

AD

,

Young

R

,

Delaney

JA

,

Budoff

MJ

,

Polak

JF

,

Blaha

MJ

, et al.

Comparison of carotid plaque score and coronary artery calcium score for predicting cardiovascular disease events: the multi-ethnic study of atherosclerosis

.

J Am Heart Assoc

2017

;

6

:

e005179

.

10.1161/jaha.116.005179

160

Colledanchise

KN

,

Mantella

LE

,

Hétu

MF

,

Liblik

K

,

Abunassar

JG

,

Johri

AM

.

Femoral plaque burden by ultrasound is a better indicator of significant coronary artery disease over ankle brachial index

.

Int J Cardiovasc Imaging

2021

;

37

:

2965

–

73

.

10.1007/s10554-021-02334-9

161

Bjerking

LH

,

Winther

S

,

Hansen

KW

,

Galatius

S

,

Böttcher

M

,

Prescott

E

.

Prediction models as gatekeepers for diagnostic testing in angina patients with suspected chronic coronary syndrome

.

Eur Heart J Qual Care Clin Outcomes

2022

;

8

:

630

–

9

.

10.1093/ehjqcco/qcac025

162

Rasmussen

LD

,

Karim

SR

,

Westra

J

, et al.

Clinical likelihood prediction of hemodynamically obstructive coronary artery disease in patients with stable chest pain

.

JACC Cardiovasc Imaging

2024

; In press.

10.1016/j.jcmg.2024.04.015

10.1016/j.jcmg.2021.11.019

163

Winther

S

,

Nissen

L

,

Westra

J

,

Schmidt

SE

,

Bouteldja

N

,

Knudsen

LL

, et al.

Pre-test probability prediction in patients with a low to intermediate probability of coronary artery disease: a prospective study with a fractional flow reserve endpoint

.

Eur Heart J Cardiovasc Imaging

2019

;

20

:

1208

–

18

.

164

Winther

S

,

Schmidt Samuel

E

,

Knuuti

J

,

Bøttcher

M

.

Comparison of pretest probability models of obstructive coronary artery disease

.

JACC Cardiovasc Imaging

2022

;

15

:

173

–

5

.

165

Brix

GS

,

Rasmussen

LD

,

Rohde

PD

,

Schmidt

SE

,

Nyegaard

M

,

Douglas

PS

, et al.

Calcium scoring improves clinical management in patients with low clinical likelihood of coronary artery disease

.

JACC Cardiovasc Imaging

2024;

17

:

625

–

39

.

10.1016/j.jcmg.2023.11.008

166

Christman

MP

,

Bittencourt

MS

,

Hulten

E

,

Saksena

E

,

Hainer

J

,

Skali

H

, et al.

Yield of downstream tests after exercise treadmill testing: a prospective cohort study

.

J Am Coll Cardiol

2014

;

63

:

1264

–

74

.

10.1016/j.jacc.2013.11.052

167

Daly

CA

,

De Stavola

B

,

Sendon

JL

,

Tavazzi

L

,

Boersma

E

,

Clemens

F

, et al.

Predicting prognosis in stable angina—results from the Euro heart survey of stable angina: prospective observational study

.

BMJ

2006

;

332

:

262

–

7

.

10.1136/bmj.38695.605440.AE

168

Cerqueira

MD

,

Weissman

NJ

,

Dilsizian

V

,

Jacobs

AK

,

Kaul

S

,

Laskey

WK

, et al.

Standardized myocardial segmentation and nomenclature for tomographic imaging of the heart. A statement for healthcare professionals from the Cardiac Imaging Committee of the Council on Clinical Cardiology of the American Heart Association

.

Circulation

2002

;

105

:

539

–

42

.

10.1161/hc0402.102975

169

Eek

C

,

Grenne

B

,

Brunvand

H

,

Aakhus

S

,

Endresen

K

,

Hol

PK

, et al.

Strain echocardiography and wall motion score index predicts final infarct size in patients with non-ST-segment-elevation myocardial infarction

.

Circ Cardiovasc Imaging

2010

;

3

:

187

–

94

.

10.1161/CIRCIMAGING.109.910521

170

Smedsrud

MK

,

Sarvari

S

,

Haugaa

KH

,

Gjesdal

O

,

Ørn

S

,

Aaberge

L

, et al.

Duration of myocardial early systolic lengthening predicts the presence of significant coronary artery disease

.

J Am Coll Cardiol

2012

;

60

:

1086

–

93

.

10.1016/j.jacc.2012.06.022

171

Biering-Sorensen

T

,

Hoffmann

S

,

Mogelvang

R

,

Zeeberg Iversen

A

,

Galatius

S

,

Fritz-Hansen

T

, et al.

Myocardial strain analysis by 2-dimensional speckle tracking echocardiography improves diagnostics of coronary artery stenosis in stable angina pectoris

.

Circ Cardiovasc Imaging

2014

;

7

:

58

–

65

.

10.1161/CIRCIMAGING.113.000989

172

Smedsrud

MK

,

Gravning

J

,

Omland

T

,

Eek

C

,

Mørkrid

L

,

Skulstad

H

, et al.

Sensitive cardiac troponins and N-terminal pro-B-type natriuretic peptide in stable coronary artery disease: correlation with left ventricular function as assessed by myocardial strain

.

Int J Cardiovasc Imaging

2015

;

31

:

967

–

73

.

10.1007/s10554-015-0646-6

173

Edwards

NFA

,

Scalia

GM

,

Shiino

K

,

Sabapathy

S

,

Anderson

B

,

Chamberlain

R

, et al.

Global myocardial work is superior to global longitudinal strain to predict significant coronary artery disease in patients with normal left ventricular function and wall motion

.

J Am Soc Echocardiogr

2019

;

32

:

947

–

57

.

10.1016/j.echo.2019.02.014

174

Shaw

LJ

,

Bugiardini

R

,

Merz

CN

.

Women and ischemic heart disease: evolving knowledge

.

J Am Coll Cardiol

2009

;

54

:

1561

–

75

.

10.1016/j.jacc.2009.04.098

175

Galderisi

M

,

Cosyns

B

,

Edvardsen

T

,

Cardim

N

,

Delgado

V

,

Di Salvo

G

, et al.

Standardization of adult transthoracic echocardiography reporting in agreement with recent chamber quantification, diastolic function, and heart valve disease recommendations: an expert consensus document of the European Association of Cardiovascular Imaging

.

Eur Heart J Cardiovasc Imaging

2017

;

18

:

1301

–

10

.

176

Steeds

RP

,

Garbi

M

,

Cardim

N

,

Kasprzak

JD

,

Sade

E

,

Nihoyannopoulos

P

, et al.

EACVI appropriateness criteria for the use of transthoracic echocardiography in adults: a report of literature and current practice review

.

Eur Heart J Cardiovasc Imaging

2017

;

18

:

1191

–

204

.

177

Senior

R

,

Becher

H

,

Monaghan

M

,

Agati

L

,

Zamorano

J

,

Vanoverschelde

JL

, et al.

Clinical practice of contrast echocardiography: recommendation by the European Association of Cardiovascular Imaging (EACVI) 2017

.

Eur Heart J Cardiovasc Imaging

2017

;

18

:

1205

–

1205af

.

178

Greenwood

JP

,

Ripley

DP

,

Berry

C

,

McCann

GP

,

Plein

S

,

Bucciarelli-Ducci

C

, et al.

Effect of care guided by cardiovascular magnetic resonance, myocardial perfusion scintigraphy, or NICE guidelines on subsequent unnecessary angiography rates: the CE-MARC 2 randomized clinical trial

.

JAMA

2016

;

316

:

1051

–

60

.

10.1001/jama.2016.12680

179

Motwani

M

,

Swoboda

PP

,

Plein

S

,

Greenwood

JP

.

Role of cardiovascular magnetic resonance in the management of patients with stable coronary artery disease

.

Heart

2018

;

104

:

888

–

94

.

10.1136/heartjnl-2017-311658

180

Kim

RJ

,

Wu

E

,

Rafael

A

,

Chen

E-L

,

Parker

MA

,

Simonetti

O

, et al.

The use of contrast-enhanced magnetic resonance imaging to identify reversible myocardial dysfunction

.

N Engl J Med

2000

;

343

:

1445

–

53

.

10.1056/NEJM200011163432003

181

Gómez-Revelles

S

,

Rossello

X

,

Díaz-Villanueva

J

,

López-Lima

I

,

Sciarresi

E

,

Estofán

M

, et al.

Prognostic value of a new semiquantitative score system for adenosine stress myocardial perfusion by CMR

.

Eur Radiol

2019

;

29

:

2263

–

71

.

10.1007/s00330-018-5774-7

182

Emond

M

,

Mock

MB

,

Davis

KB

,

Fisher

LD

,

Holmes

DR

,

Chaitman

BR

, et al.

Long-term survival of medically treated patients in the Coronary Artery Surgery Study (CASS) registry

.

Circulation

1994

;

90

:

2645

–

57

.

10.1161/01.cir.90.6.2645

183

Daly

C

,

Norrie

J

,

Murdoch

DL

,

Ford

I

,

Dargie

HJ

,

Fox

K

, et al.

The value of routine non-invasive tests to predict clinical outcome in stable angina

.

Eur Heart J

2003

;

24

:

532

–

40

.

10.1016/s0195-668x(02)00820-5

184

Vitarelli

A

,

Tiukinhoy

S

,

Di Luzio

S

,

Zampino

M

,

Gheorghiade

M

.

The role of echocardiography in the diagnosis and management of heart failure

.

Heart Fail Rev

2003

;

8

:

181

–

9

.

10.1023/a:1023001104207

185

Petersen

SE

,

Khanji

MY

,

Plein

S

,

Lancellotti

P

,

Bucciarelli-Ducci

C

.

European Association of Cardiovascular Imaging expert consensus paper: a comprehensive review of cardiovascular magnetic resonance normal values of cardiac chamber size and aortic root in adults and recommendations for grading severity

.

Eur Heart J Cardiovasc Imaging

2019

;

20

:

1321

–

31

.

186

Hoffmann

R

,

von Bardeleben

S

,

Kasprzak

JD

,

Borges

AC

,

ten Cate

F

,

Firschke

C

, et al.

Analysis of regional left ventricular function by cineventriculography, cardiac magnetic resonance imaging, and unenhanced and contrast-enhanced echocardiography: a multicenter comparison of methods

.

J Am Coll Cardiol

2006

;

47

:

121

–

8

.

10.1016/j.jacc.2005.10.012

187

Williams

MC

,

Hunter

A

,

Shah

ASV

,

Assi

V

,

Lewis

S

,

Smith

J

, et al.

Use of coronary computed tomographic angiography to guide management of patients with coronary disease

.

J Am Coll Cardiol

2016

;

67

:

1759

–

68

.

10.1016/j.jacc.2016.02.026

188

Singh

T

,

Bing

R

,

Dweck

MR

,

van Beek

EJR

,

Mills

NL

,

Williams

MC

, et al.

Exercise electrocardiography and computed tomography coronary angiography for patients with suspected stable angina pectoris: a post hoc analysis of the randomized SCOT-HEART trial

.

JAMA Cardiol

2020

;

5

:

920

–

8

.

10.1001/jamacardio.2020.1567

189

Zacharias

K

,

Ahmed

A

,

Shah

BN

,

Gurunathan

S

,

Young

G

,

Acosta

D

, et al.

Relative clinical and economic impact of exercise echocardiography vs. exercise electrocardiography, as first line investigation in patients without known coronary artery disease and new stable angina: a randomized prospective study

.

Eur Heart J Cardiovasc Imaging

2017

;

18

:

195

–

202

.

190

Shaw

LJ

,

Mieres

JH

,

Hendel

RH

,

Boden

WE

,

Gulati

M

,

Veledar

E

, et al.

Comparative effectiveness of exercise electrocardiography with or without myocardial perfusion single photon emission computed tomography in women with suspected coronary artery disease: results from the What Is the Optimal Method for Ischemia Evaluation in Women (WOMEN) trial

.

Circulation

2011

;

124

:

1239

–

49

.

10.1161/CIRCULATIONAHA.111.029660

191

Mark

DB

,

Shaw

L

,

Harrell

FE

Jr,

Hlatky

MA

,

Lee

KL

,

Bengtson

JR

, et al.

Prognostic value of a treadmill exercise score in outpatients with suspected coronary artery disease

.

N Engl J Med

1991

;

325

:

849

–

53

.

10.1056/NEJM199109193251204

192

Araki

H

,

Koiwaya

Y

,

Nakagaki

O

,

Nakamura

M

.

Diurnal distribution of ST-segment elevation and related arrhythmias in patients with variant angina: a study by ambulatory ECG monitoring

.

Circulation

1983

;

67

:

995

–

1000

.

10.1161/01.cir.67.5.995

193

Onaka

H

,

Hirota

Y

,

Shimada

S

,

Kita

Y

,

Sakai

Y

,

Kawakami

Y

, et al.

Clinical observation of spontaneous anginal attacks and multivessel spasm in variant angina pectoris with normal coronary arteries: evaluation by 24-hour 12-lead electrocardiography with computer analysis

.

J Am Coll Cardiol

1996

;

27

:

38

–

44

.

10.1016/0735-1097(95)00423-8

194

Beijk

MA

,

Vlastra

WV

,

Delewi

R

,

van de Hoef

TP

,

Boekholdt

SM

,

Sjauw

KD

, et al.

Myocardial infarction with non-obstructive coronary arteries: a focus on vasospastic angina

.

Neth Heart J

2019

;

27

:

237

–

45

.

10.1007/s12471-019-1232-7

195

Tonino

PA

,

Fearon

WF

,

De Bruyne

B

,

Oldroyd

KG

,

Leesar

MA

,

Ver Lee

PN

, et al.

Angiographic versus functional severity of coronary artery stenoses in the FAME study fractional flow reserve versus angiography in multivessel evaluation

.

J Am Coll Cardiol

2010

;

55

:

2816

–

21

.

10.1016/j.jacc.2009.11.096

196

Schuijf

JD

,

Wijns

W

,

Jukema

JW

,

Atsma

DE

,

de Roos

A

,

Lamb

HJ

, et al.

Relationship between noninvasive coronary angiography with multi-slice computed tomography and myocardial perfusion imaging

.

J Am Coll Cardiol

2006

;

48

:

2508

–

14

.

10.1016/j.jacc.2006.05.080

197

Siontis

GC

,

Mavridis

D

,

Greenwood

JP

,

Coles

B

,

Nikolakopoulou

A

,

Jüni

P

, et al.

Outcomes of non-invasive diagnostic modalities for the detection of coronary artery disease: network meta-analysis of diagnostic randomised controlled trials

.

BMJ

2018

;

360

:

k504

.

198

Neglia

D

,

Liga

R

,

Gimelli

A

,

Podlesnikar

T

,

Cvijić

M

,

Pontone

G

, et al.

Use of cardiac imaging in chronic coronary syndromes: the EURECA Imaging registry

.

Eur Heart J

2023

;

44

:

142

–

58

.

10.1093/eurheartj/ehac640

199

Celeng

C

,

Leiner

T

,

Maurovich-Horvat

P

,

Merkely

B

,

de Jong

P

,

Dankbaar

JW

, et al.

Anatomical and functional computed tomography for diagnosing hemodynamically significant coronary artery disease: a meta-analysis

.

JACC Cardiovasc Imaging

2019

;

12

:

1316

–

25

.

10.1016/j.jcmg.2018.07.022

200

Curzen

N

,

Nicholas

Z

,

Stuart

B

,

Wilding

S

,

Hill

K

,

Shambrook

J

, et al.

Fractional flow reserve derived from computed tomography coronary angiography in the assessment and management of stable chest pain: the FORECAST randomized trial

.

Eur Heart J

2021

;

42

:

3844

–

52

.

10.1093/eurheartj/ehab444

201

Mickley

H

,

Veien

KT

,

Gerke

O

,

Lambrechtsen

J

,

Rohold

A

,

Steffensen

FH

, et al.

Diagnostic and clinical value of FFR(CT) in stable chest pain patients with extensive coronary calcification: the FACC study

.

JACC Cardiovasc Imaging

2022

;

15

:

1046

–

58

.

10.1016/j.jcmg.2021.12.010

202

Nørgaard

BL

,

Terkelsen

CJ

,

Mathiassen

ON

,

Grove

EL

,

Bøtker

HE

,

Parner

E

, et al.

Coronary CT angiographic and flow reserve-guided management of patients with stable ischemic heart disease

.

J Am Coll Cardiol

2018

;

72

:

2123

–

34

.

10.1016/j.jacc.2018.07.043

203

Pontone

G

,

Weir-McCall

JR

,

Baggiano

A

,

Del Torto

A

,

Fusini

L

,

Guglielmo

M

, et al.

Determinants of rejection rate for coronary CT angiography fractional flow reserve analysis

.

Radiology

2019

;

292

:

597

–

605

.

10.1148/radiol.2019182673

204

Andreini

D

,

Belmonte

M

,

Penicka

M

,

Van Hoe

L

,

Mileva

N

,

Paolisso

P

, et al.

Impact of coronary CT image quality on the accuracy of the FFR(CT) planner

.

Eur Radiol

2023

;

34

:

2677

–

88

.

10.1007/s00330-023-10228-8

205

Rochitte

CE

,

George

RT

,

Chen

MY

,

Arbab-Zadeh

A

,

Dewey

M

,

Miller

JM

, et al.

Computed tomography angiography and perfusion to assess coronary artery stenosis causing perfusion defects by single photon emission computed tomography: the CORE320 study

.

Eur Heart J

2014

;

35

:

1120

–

30

.

10.1093/eurheartj/eht488

206

Nous

FMA

,

Geisler

T

,

Kruk

MBP

,

Alkadhi

H

,

Kitagawa

K

,

Vliegenthart

R

, et al.

Dynamic myocardial perfusion CT for the detection of hemodynamically significant coronary artery disease

.

JACC Cardiovasc Imaging

2022

;

15

:

75

–

87

.

10.1016/j.jcmg.2021.07.021

207

Rossi

A

,

Merkus

D

,

Klotz

E

,

Mollet

N

,

de Feyter

PJ

,

Krestin

GP

.

Stress myocardial perfusion: imaging with multidetector CT

.

Radiology

2014

;

270

:

25

–

46

.

10.1148/radiol.13112739

208

Hoffmann

U

,

Ferencik

M

,

Udelson

JE

,

Picard

MH

,

Truong

QA

,

Patel

MR

, et al.

Prognostic value of noninvasive cardiovascular testing in patients with stable chest pain: insights from the PROMISE trial (Prospective Multicenter Imaging Study for Evaluation of Chest Pain)

.

Circulation

2017

;

135

:

2320

–

32

.

10.1161/CIRCULATIONAHA.116.024360

209

Adamson

PD

,

Williams

MC

,

Dweck

MR

,

Mills

NL

,

Boon

NA

,

Daghem

M

, et al.

Guiding therapy by coronary CT angiography improves outcomes in patients with stable chest pain

.

J Am Coll Cardiol

2019

;

74

:

2058

–

70

.

10.1016/j.jacc.2019.07.085

210

Williams

MC

,

Moss

AJ

,

Dweck

M

,

Adamson

PD

,

Alam

S

,

Hunter

A

, et al.

Coronary artery plaque characteristics associated with adverse outcomes in the SCOT-HEART study

.

J Am Coll Cardiol

2019

;

73

:

291

–

301

.

10.1016/j.jacc.2018.10.066

211

Foy

AJ

,

Dhruva

SS

,

Peterson

B

,

Mandrola

JM

,

Morgan

DJ

,

Redberg

RF

.

Coronary computed tomography angiography vs functional stress testing for patients with suspected coronary artery disease: a systematic review and meta-analysis

.

JAMA Intern Med

2017

;

177

:

1623

–

31

.

10.1001/jamainternmed.2017.4772

212

SCOT-HEART Investigators

.

CT coronary angiography in patients with suspected angina due to coronary heart disease (SCOT-HEART): an open-label, parallel-group, multicentre trial

.

Lancet

2015

;

385

:

2383

–

91

.

10.1016/S0140-6736(15)60291-4

10.1016/j.jcct.2022.07.002

213

Cury

RC

,

Leipsic

J

,

Abbara

S

,

Achenbach

S

,

Berman

D

,

Bittencourt

M

, et al.

CAD-RADS 2.0—2022 Coronary Artery Disease—Reporting and Data System an expert consensus document of the Society of Cardiovascular Computed Tomography (SCCT), the American College of Cardiology (ACC), the American College of Radiology (ACR) and the North America Society of Cardiovascular Imaging (NASCI)

.

J Cardiovasc Comput Tomogr

2022

;

16

:

536

–

57

.

214

Meijboom

WB

,

Meijs

MF

,

Schuijf

JD

,

Cramer

MJ

,

Mollet

NR

,

van Mieghem

CAG

, et al.

Diagnostic accuracy of 64-slice computed tomography coronary angiography: a prospective, multicenter, multivendor study

.

J Am Coll Cardiol

2008

;

52

:

2135

–

44

.

10.1016/j.jacc.2008.08.058

215

Miller

JM

,

Rochitte

CE

,

Dewey

M

,

Arbab-Zadeh

A

,

Niinuma

H

,

Gottlieb

I

, et al.

Diagnostic performance of coronary angiography by 64-row CT

.

N Engl J Med

2008

;

359

:

2324

–

36

.

10.1056/NEJMoa0806576

216

Budoff

MJ

,

Dowe

D

,

Jollis

JG

,

Gitter

M

,

Sutherland

J

,

Halamert

E

, et al.

Diagnostic performance of 64-multidetector row coronary computed tomographic angiography for evaluation of coronary artery stenosis in individuals without known coronary artery disease: results from the prospective multicenter ACCURACY (Assessment by Coronary Computed Tomographic Angiography of Individuals Undergoing Invasive Coronary Angiography) trial

.

J Am Coll Cardiol

2008

;

52

:

1724

–

32

.

10.1016/j.jacc.2008.07.031

217

Min

JK

,

Koduru

S

,

Dunning

AM

,

Cole

JH

,

Hines

JL

,

Greenwell

D

, et al.

Coronary CT angiography versus myocardial perfusion imaging for near-term quality of life, cost and radiation exposure: a prospective multicenter randomized pilot trial

.

J Cardiovasc Comput Tomogr

2012

;

6

:

274

–

83

.

10.1016/j.jcct.2012.06.002

218

Douglas

PS

,

Pontone

G

,

Hlatky

MA

,

Patel

MR

,

Norgaard

BL

,

Byrne

RA

, et al.

Clinical outcomes of fractional flow reserve by computed tomographic angiography-guided diagnostic strategies vs. usual care in patients with suspected coronary artery disease: the prospective longitudinal trial of FFRCT: outcome and resource impacts study

.

Eur Heart J

2015

;

36

:

3359

–

67

.

10.1093/eurheartj/ehv444

219

Dewey

M

,

Rief

M

,

Martus

P

,

Kendziora

B

,

Feger

S

,

Dreger

H

, et al.

Evaluation of computed tomography in patients with atypical angina or chest pain clinically referred for invasive coronary angiography: randomised controlled trial

.

BMJ

2016

;

355

:

i5441

.

220

Chang

HJ

,

Lin

FY

,

Gebow

D

,

An

HY

,

Andreini

D

,

Bathina

R

, et al.

Selective referral using CCTA versus direct referral for individuals referred to invasive coronary angiography for suspected CAD: a randomized, controlled, open-label trial

.

JACC Cardiovasc Imaging

2019

;

12

:

1303

–

12

.

10.1016/j.jcmg.2018.09.018

221

Sharma

A

,

Coles

A

,

Sekaran

NK

,

Pagidipati

NJ

,

Lu

MT

,

Mark

DB

, et al.

Stress testing versus CT angiography in patients with diabetes and suspected coronary artery disease

.

J Am Coll Cardiol

2019

;

73

:

893

–

902

.

10.1016/j.jacc.2018.11.056

222

The Discharge Trial Group

;

Maurovich-Horvat

P

,

Bosserdt

M

,

Kofoed

KF

,

Rieckmann

N

,

Benedek

T

, et al.

CT or invasive coronary angiography in stable chest pain

.

N Engl J Med

2022

;

386

:

1591

–

602

.

10.1056/NEJMoa2200963

223

Smulders

MW

,

Jaarsma

C

,

Nelemans

PJ

,

Bekkers

SCAM

,

Bucerius

J

,

Leiner

T

, et al.

Comparison of the prognostic value of negative non-invasive cardiac investigations in patients with suspected or known coronary artery disease-a meta-analysis

.

Eur Heart J Cardiovasc Imaging

2017

;

18

:

980

–

7

.

224

Picano

E

,

Mathias

W

Jr,

Pingitore

A

,

Bigi

R

,

Previtali

M

.

Safety and tolerability of dobutamine-atropine stress echocardiography: a prospective, multicentre study. Echo Dobutamine International Cooperative Study Group

.

Lancet

1994

;

344

:

1190

–

2

.

10.1016/s0140-6736(94)90508-8

225

Varga

A

,

Garcia

MA

,

Picano

E

.

Safety of stress echocardiography (from the International Stress Echo Complication Registry)

.

Am J Cardiol

2006

;

98

:

541

–

3

.

10.1016/j.amjcard.2006.02.064

226

Lorenzoni

V

,

Bellelli

S

,

Caselli

C

,

Knuuti

J

,

Underwood

SR

,

Neglia

D

, et al.

Cost-effectiveness analysis of stand-alone or combined non-invasive imaging tests for the diagnosis of stable coronary artery disease: results from the EVINCI study

.

Eur J Health Econ

2019

;

20

:

1437

–

49

.

10.1007/s10198-019-01096-5

227

Pellikka

PA

,

Arruda-Olson

A

,

Chaudhry

FA

,

Chen

MH

,

Marshall

JE

,

Porter

TR

, et al.

Guidelines for performance, interpretation, and application of stress echocardiography in ischemic heart disease: from the American Society of Echocardiography

.

J Am Soc Echocardiogr

2020

;

33

:

1

–

41.e8

.

10.1016/j.echo.2019.07.001

228

Marwick

TH

.

Stress echocardiography

.

Heart

2003

;

89

:

113

–

8

.

10.1136/heart.89.1.113

229

Plana

JC

,

Mikati

IA

,

Dokainish

H

,

Lakkis

N

,

Abukhalil

J

,

Davis

R

, et al.

A randomized cross-over study for evaluation of the effect of image optimization with contrast on the diagnostic accuracy of dobutamine echocardiography in coronary artery disease The OPTIMIZE Trial

.

JACC Cardiovasc Imaging

2008

;

1

:

145

–

52

.

10.1016/j.jcmg.2007.10.014

230

Qian

L

,

Xie

F

,

Xu

D

,

Porter

TR

.

Long-term prognostic value of stress myocardial perfusion echocardiography in patients with coronary artery disease: a meta-analysis

.

Eur Heart J Cardiovasc Imaging

2021

;

22

:

553

–

62

.

10.1093/ehjci/jeaa026

231

Abdelmoneim

SS

,

Dhoble

A

,

Bernier

M

,

Erwin

PJ

,

Korosoglou

G

,

Senior

R

, et al.

Quantitative myocardial contrast echocardiography during pharmacological stress for diagnosis of coronary artery disease: a systematic review and meta-analysis of diagnostic accuracy studies

.

Eur J Echocardiogr

2009

;

10

:

813

–

25

.

10.1093/ejechocard/jep084

232

Porter

TR

,

Smith

LM

,

Wu

J

,

Thomas

D

,

Haas

JT

,

Mathers

DH

, et al.

Patient outcome following 2 different stress imaging approaches: a prospective randomized comparison

.

J Am Coll Cardiol

2013

;

61

:

2446

–

55

.

10.1016/j.jacc.2013.04.019

233

Rinkevich

D

,

Belcik

T

,

Gupta

NC

,

Cannard

E

,

Alkayed

NJ

,

Kaul

S

.

Coronary autoregulation is abnormal in syndrome X: insights using myocardial contrast echocardiography

.

J Am Soc Echocardiogr

2013

;

26

:

290

–

6

.

10.1016/j.echo.2012.12.008

234

Kutty

S

,

Bisselou Moukagna

KS

,

Craft

M

,

Shostrom

V

,

Xie

F

,

Porter

TR

.

Clinical outcome of patients with inducible capillary blood flow abnormalities during demand stress in the presence or absence of angiographic coronary disease

.

Circ Cardiovasc Imaging

2018

;

11

:

e007483

.

10.1161/CIRCIMAGING.117.007483

235

Taqui

S

,

Ferencik

M

,

Davidson

BP

,

Belcik

JT

,

Moccetti

F

,

Layoun

M

, et al.

Coronary microvascular dysfunction by myocardial contrast echocardiography in nonelderly patients referred for computed tomographic coronary angiography

.

J Am Soc Echocardiogr

2019

;

32

:

817

–

25

.

10.1016/j.echo.2019.03.001

236

Porter

TR

,

Mulvagh

SL

,

Abdelmoneim

SS

,

Becher

H

,

Belcik

JT

,

Bierig

M

, et al.

Clinical applications of ultrasonic enhancing agents in echocardiography: 2018 American Society of Echocardiography Guidelines update

.

J Am Soc Echocardiogr

2018

;

31

:

241

–

74

.

10.1016/j.echo.2017.11.013

237

Hu

C

,

Feng

Y

,

Huang

P

,

Jin

J

.

Adverse reactions after the use of SonoVue contrast agent: characteristics and nursing care experience

.

Medicine

2019

;

98

:

e17745

.

10.1097/md.0000000000017745

238

Ciampi

Q

,

Zagatina

A

,

Cortigiani

L

,

Gaibazzi

N

,

Borguezan Daros

C

,

Zhuravskaya

N

, et al.

Functional, anatomical, and prognostic correlates of coronary flow velocity reserve during stress echocardiography

.

J Am Coll Cardiol

2019

;

74

:

2278

–

91

.

10.1016/j.jacc.2019.08.1046

239

Ahmadvazir

S

,

Shah

BN

,

Zacharias

K

,

Senior

R

.

Incremental prognostic value of stress echocardiography with carotid ultrasound for suspected CAD

.

JACC Cardiovasc Imaging

2018

;

11

:

173

–

80

.

10.1016/j.jcmg.2016.12.020

240

Ahmadvazir

S

,

Pradhan

J

,

Khattar

RS

,

Senior

R

.

Long-term prognostic value of simultaneous assessment of atherosclerosis and ischemia in patients with suspected angina: implications for routine use of carotid ultrasound during stress echocardiography

.

J Am Soc Echocardiogr

2020

;

33

:

559

–

69

.

10.1016/j.echo.2019.11.019

241

Fleischmann

KE

,

Hunink

MG

,

Kuntz

KM

,

Douglas

PS

.

Exercise echocardiography or exercise SPECT imaging? A meta-analysis of diagnostic test performance

.

JAMA

1998

;

280

:

913

–

20

.

10.1001/jama.280.10.913

242

Marwick

TH

,

Case

C

,

Vasey

C

,

Allen

S

,

Short

L

,

Thomas

JD

.

Prediction of mortality by exercise echocardiography: a strategy for combination with the Duke treadmill score

.

Circulation

2001

;

103

:

2566

–

71

.

10.1161/01.cir.103.21.2566

243

Shaw

LJ

,

Vasey

C

,

Sawada

S

,

Rimmerman

C

,

Marwick

TH

.

Impact of gender on risk stratification by exercise and dobutamine stress echocardiography: long-term mortality in 4234 women and 6898 men

.

Eur Heart J

2005

;

26

:

447

–

56

.

10.1093/eurheartj/ehi102

244

Gurunathan

S

,

Zacharias

K

,

Akhtar

M

,

Ahmed

A

,

Mehta

V

,

Karogiannis

N

, et al.

Cost-effectiveness of a management strategy based on exercise echocardiography versus exercise electrocardiography in patients presenting with suspected angina during long term follow up: a randomized study

.

Int J Cardiol

2018

;

259

:

1

–

7

.

10.1016/j.ijcard.2018.01.112

245

Vamvakidou

A

,

Danylenko

O

,

Pradhan

J

,

Kelshiker

M

,

Jones

T

,

Whiteside

D

, et al.

Relative clinical value of coronary computed tomography and stress echocardiography-guided management of stable chest pain patients: a propensity-matched analysis

.

Eur Heart J Cardiovasc Imaging

2020

;

22

:

1473

–

81

.

10.1093/ehjci/jeaa303

10.1111/j.1540-8175.2000.tb01223.x

246

Woodward

W

,

Dockerill

C

,

McCourt

A

,

Upton

R

,

O’Driscoll

J

,

Balkhausen

K

, et al.

Real-world performance and accuracy of stress echocardiography: the EVAREST observational multi-centre study

.

Eur Heart J Cardiovasc Imaging

2022

;

23

:

689

–

98

.

10.1093/ehjci/jeab092

247

Senior

R

,

Andersson

O

,

Caidahl

K

,

Carlens

P

,

Herregods

MC

,

Jenni

R

, et al.

Enhanced left ventricular endocardial border delineation with an intravenous injection of SonoVue, a new echocardiographic contrast agent: a European multicenter study

.

Echocardiography

2000

;

17

:

705

–

11

.

248

Edvardsen

T

,

Asch

FM

,

Davidson

B

,

Delgado

V

,

DeMaria

A

,

Dilsizian

V

, et al.

Non-invasive imaging in coronary syndromes: recommendations of the European Association of Cardiovascular Imaging and the American Society of Echocardiography, in collaboration with the American Society of Nuclear Cardiology, Society of Cardiovascular Computed Tomography, and Society for Cardiovascular Magnetic Resonance

.

Eur Heart J Cardiovasc Imaging

2022

;

23

:

e6

–

33

.

10.1093/ehjci/jeab244

249

Tsutsui

JM

,

Elhendy

A

,

Anderson

JR

,

Xie

F

,

McGrain

AC

,

Porter

TR

.

Prognostic value of dobutamine stress myocardial contrast perfusion echocardiography

.

Circulation

2005

;

112

:

1444

–

50

.

10.1161/circulationaha.105.537134

250

Jeetley

P

,

Hickman

M

,

Kamp

O

,

Lang

RM

,

Thomas

JD

,

Vannan

MA

, et al.

Myocardial contrast echocardiography for the detection of coronary artery stenosis: a prospective multicenter study in comparison with single-photon emission computed tomography

.

J Am Coll Cardiol

2006

;

47

:

141

–

5

.

10.1016/j.jacc.2005.08.054

251

Dolan

MS

,

Gala

SS

,

Dodla

S

,

Abdelmoneim

SS

,

Xie

F

,

Cloutier

D

, et al.

Safety and efficacy of commercially available ultrasound contrast agents for rest and stress echocardiography a multicenter experience

.

J Am Coll Cardiol

2009

;

53

:

32

–

8

.

10.1016/j.jacc.2008.08.066

252

Gaibazzi

N

,

Reverberi

C

,

Lorenzoni

V

,

Molinaro

S

,

Porter

TR

.

Prognostic value of high-dose dipyridamole stress myocardial contrast perfusion echocardiography

.

Circulation

2012

;

126

:

1217

–

24

.

10.1161/circulationaha.112.110031

253

Gaibazzi

N

,

Rigo

F

,

Lorenzoni

V

,

Molinaro

S

,

Bartolomucci

F

,

Reverberi

C

, et al.

Comparative prediction of cardiac events by wall motion, wall motion plus coronary flow reserve, or myocardial perfusion analysis: a multicenter study of contrast stress echocardiography

.

JACC Cardiovasc Imaging

2013

;

6

:

1

–

12

.

10.1016/j.jcmg.2012.08.009

254

Senior

R

,

Moreo

A

,

Gaibazzi

N

,

Agati

L

,

Tiemann

K

,

Shivalkar

B

, et al.

Comparison of sulfur hexafluoride microbubble (SonoVue)-enhanced myocardial contrast echocardiography with gated single-photon emission computed tomography for detection of significant coronary artery disease: a large European multicenter study

.

J Am Coll Cardiol

2013

;

62

:

1353

–

61

.

10.1016/j.jacc.2013.04.082

255

Schroder

J

,

Prescott

E

.

Doppler echocardiography assessment of coronary microvascular function in patients with angina and no obstructive coronary artery disease

.

Front Cardiovasc Med

2021

;

8

:

723542

.

10.3389/fcvm.2021.723542

256

Yang

Z

,

Zheng

H

,

Zhou

T

,

Yang

L-F

,

Hu

X-F

,

Peng

Z-H

, et al.

Diagnostic performance of myocardial perfusion imaging with SPECT, CT and MR compared to fractional flow reserve as reference standard

.

Int J Cardiol

2015

;

190

:

103

–

5

.

10.1016/j.ijcard.2015.04.091

257

Takx

RA

,

Blomberg

BA

,

El Aidi

H

,

Habets

J

,

de Jong

PA

,

Nagel

E

, et al.

Diagnostic accuracy of stress myocardial perfusion imaging compared to invasive coronary angiography with fractional flow reserve meta-analysis

.

Circ Cardiovasc Imaging

2015

;

8

:

e002666

.

10.1161/circimaging.114.002666

258

Dai

N

,

Zhang

X

,

Zhang

Y

,

Hou

L

,

Li

W

,

Fan

B

, et al.

Enhanced diagnostic utility achieved by myocardial blood analysis: a meta-analysis of noninvasive cardiac imaging in the detection of functional coronary artery disease

.

Int J Cardiol

2016

;

221

:

665

–

73

.

10.1016/j.ijcard.2016.07.031

259

Mowatt

G

,

Brazzelli

M

,

Gemmell

H

,

Hillis

GS

,

Metcalfe

M

,

Vale

L

, et al.

Systematic review of the prognostic effectiveness of SPECT myocardial perfusion scintigraphy in patients with suspected or known coronary artery disease and following myocardial infarction

.

Nucl Med Commun

2005

;

26

:

217

–

29

.

10.1097/00006231-200503000-00006

260

Cantoni

V

,

Green

R

,

Acampa

W

,

Zampella

E

,

Assante

R

,

Nappi

C

, et al.

Diagnostic performance of myocardial perfusion imaging with conventional and CZT single-photon emission computed tomography in detecting coronary artery disease: a meta-analysis

.

J Nucl Cardiol

2021

;

28

:

698

–

715

.

10.1007/s12350-019-01747-3

261

Panjer

M

,

Dobrolinska

M

,

Wagenaar

NRL

,

Slart

R

.

Diagnostic accuracy of dynamic CZT-SPECT in coronary artery disease. A systematic review and meta-analysis

.

J Nucl Cardiol

2022

;

29

:

1686

–

97

.

10.1007/s12350-021-02721-8

262

Juárez-Orozco

LE

,

Tio

RA

,

Alexanderson

E

,

Dweck

M

,

Vliegenthart

R

,

El Moumni

M

, et al.

Quantitative myocardial perfusion evaluation with positron emission tomography and the risk of cardiovascular events in patients with coronary artery disease: a systematic review of prognostic studies

.

Eur Heart J Cardiovasc Imaging

2018

;

19

:

1179

–

87

.

263

Green

R

,

Cantoni

V

,

Acampa

W

,

Assante

R

,

Zampella

E

,

Nappi

C

, et al.

Prognostic value of coronary flow reserve in patients with suspected or known coronary artery disease referred to PET myocardial perfusion imaging: a meta-analysis

.

J Nucl Cardiol

2021

;

28

:

904

–

18

.

10.1007/s12350-019-02000-7

264

Groepenhoff

F

,

Klaassen

RGM

,

Valstar

GB

,

Bots

SH

,

Onland-Moret

NC

,

Den Ruijter

HM

, et al.

Evaluation of non-invasive imaging parameters in coronary microvascular disease: a systematic review

.

BMC Med Imaging

2021

;

21

:

5

.

10.1186/s12880-020-00535-7

265

Yang

K

,

Yu

SQ

,

Lu

MJ

,

Zhao

SH

.

Comparison of diagnostic accuracy of stress myocardial perfusion imaging for detecting hemodynamically significant coronary artery disease between cardiac magnetic resonance and nuclear medical imaging: a meta-analysis

.

Int J Cardiol

2019

;

293

:

278

–

85

.

10.1016/j.ijcard.2019.06.054

266

Mc Ardle

BA

,

Dowsley

TF

,

deKemp

RA

,

Wells

GA

,

Beanlands

RS

.

Does rubidium-82 PET have superior accuracy to SPECT perfusion imaging for the diagnosis of obstructive coronary disease?: a systematic review and meta-analysis

.

J Am Coll Cardiol

2012

;

60

:

1828

–

37

.

10.1016/j.jacc.2012.07.038

267

Parker

MW

,

Iskandar

A

,

Limone

B

,

Perugini

A

,

Kim

H

,

Jones

C

, et al.

Diagnostic accuracy of cardiac positron emission tomography versus single photon emission computed tomography for coronary artery disease: a bivariate meta-analysis

.

Circ Cardiovasc Imaging

2012

;

5

:

700

–

7

.

10.1161/circimaging.112.978270

268

Danad

I

,

Raijmakers

PG

,

Driessen

RS

,

Leipsic

J

,

Raju

R

,

Naoum

C

, et al.

Comparison of coronary CT angiography, SPECT, PET, and hybrid imaging for diagnosis of ischemic heart disease determined by fractional flow reserve

.

JAMA Cardiol

2017

;

2

:

1100

–

7

.

10.1001/jamacardio.2017.2471

269

Rasmussen

LD

,

Winther

S

,

Eftekhari

A

,

Karim

SR

,

Westra

J

,

Isaksen

C

, et al.

Second-line myocardial perfusion imaging to detect obstructive stenosis: head-to-head comparison of CMR and PET

.

JACC Cardiovasc Imaging

2023

;

16

:

642

–

55

.

10.1016/j.jcmg.2022.11.015

270

Patel

KK

,

Al Badarin

F

,

Chan

PS

,

Spertus

JA

,

Courter

S

,

Kennedy

KF

, et al.

Randomized comparison of clinical effectiveness of pharmacologic SPECT and PET MPI in symptomatic CAD patients

.

JACC Cardiovasc Imaging

2019

;

12

:

1821

–

31

.

10.1016/j.jcmg.2019.04.020

271

Patel

KK

,

Spertus

JA

,

Chan

PS

,

Sperry

BW

,

Al Badarin

F

,

Kennedy

KF

, et al.

Myocardial blood flow reserve assessed by positron emission tomography myocardial perfusion imaging identifies patients with a survival benefit from early revascularization

.

Eur Heart J

2020

;

41

:

759

–

68

.

10.1093/eurheartj/ehz389

272

van Dijk

R

,

van Assen

M

,

Vliegenthart

R

,

de Bock

GH

,

van der Harst

P

,

Oudkerk

M

.

Diagnostic performance of semi-quantitative and quantitative stress CMR perfusion analysis: a meta-analysis

.

J Cardiovasc Magn Reson

2017

;

19

:

92

.

10.1186/s12968-017-0393-z

273

Gargiulo

P

,

Dellegrottaglie

S

,

Bruzzese

D

,

Savarese

G

,

Scala

O

,

Ruggiero

D

, et al.

The prognostic value of normal stress cardiac magnetic resonance in patients with known or suspected coronary artery disease: a meta-analysis

.

Circ Cardiovasc Imaging

2013

;

6

:

574

–

82

.

10.1161/circimaging.113.000035

274

Iwata

K

,

Nakagawa

S

,

Ogasawara

K

.

The prognostic value of normal stress cardiovascular magnetic resonance imaging

.

J Comput Assist Tomogr

2014

;

38

:

36

–

43

.

10.1097/RCT.0b013e3182a474a0

275

Ricci

F

,

Khanji

MY

,

Bisaccia

G

,

Cipriani

A

,

Di Cesare

A

,

Ceriello

L

, et al.

Diagnostic and prognostic value of stress cardiovascular magnetic resonance imaging in patients with known or suspected coronary artery disease: a systematic review and meta-analysis

.

JAMA Cardiol

2023

;

8

:

662

–

73

.

10.1001/jamacardio.2023.1290

276

Nagel

E

,

Greenwood

JP

,

McCann

GP

,

Bettencourt

N

,

Shah

AM

,

Hussain

ST

, et al.

Magnetic resonance perfusion or fractional flow reserve in coronary disease

.

N Engl J Med

2019

;

380

:

2418

–

28

.

10.1056/NEJMoa1716734

277

Nagel

E

,

Lehmkuhl

HB

,

Bocksch

W

,

Klein

C

,

Vogel

U

,

Frantz

E

, et al.

Noninvasive diagnosis of ischemia-induced wall motion abnormalities with the use of high-dose dobutamine stress MRI: comparison with dobutamine stress echocardiography

.

Circulation

1999

;

99

:

763

–

70

.

10.1161/01.cir.99.6.763

278

Ripley

DP

,

Motwani

M

,

Brown

JM

,

Nixon

J

,

Everett

CC

,

Bijsterveld

P

, et al.

Individual component analysis of the multi-parametric cardiovascular magnetic resonance protocol in the CE-MARC trial

.

J Cardiovasc Magn Reson

2015

;

17

:

59

.

10.1186/s12968-015-0169-2

279

Di Leo

G

,

Fisci

E

,

Secchi

F

,

Alì

M

,

Ambrogi

F

,

Sconfienza

LM

, et al.

Diagnostic accuracy of magnetic resonance angiography for detection of coronary artery disease: a systematic review and meta-analysis

.

Eur Radiol

2016

;

26

:

3706

–

18

.

10.1007/s00330-015-4134-0

280

Feger

S

,

Rief

M

,

Zimmermann

E

,

Richter

F

,

Roehle

R

,

Dewey

M

, et al.

Patient satisfaction with coronary CT angiography, myocardial CT perfusion, myocardial perfusion MRI, SPECT myocardial perfusion imaging and conventional coronary angiography

.

Eur Radiol

2015

;

25

:

2115

–

24

.

10.1007/s00330-015-3604-8

281

Shaw

LJ

,

Weintraub

WS

,

Maron

DJ

,

Hartigan

PM

,

Hachamovitch

R

,

Min

JK

, et al.

Baseline stress myocardial perfusion imaging results and outcomes in patients with stable ischemic heart disease randomized to optimal medical therapy with or without percutaneous coronary intervention

.

Am Heart J

2012

;

164

:

243

–

50

.

10.1016/j.ahj.2012.05.018

282

Dorbala

S

,

Di Carli

MF

,

Beanlands

RS

,

Merhige

ME

,

Williams

BA

,

Veledar

E

, et al.

Prognostic value of stress myocardial perfusion positron emission tomography: results from a multicenter observational registry

.

J Am Coll Cardiol

2013

;

61

:

176

–

84

.

10.1016/j.jacc.2012.09.043

283

Kay

J

,

Dorbala

S

,

Goyal

A

,

Fazel

R

,

Di Carli

MF

,

Einstein

AJ

, et al.

Influence of sex on risk stratification with stress myocardial perfusion Rb-82 positron emission tomography: results from the PET (Positron Emission Tomography) Prognosis Multicenter Registry

.

J Am Coll Cardiol

2013

;

62

:

1866

–

76

.

10.1016/j.jacc.2013.06.017

284

Uretsky

S

,

Rozanski

A

.

Long-term outcomes following a normal stress myocardial perfusion scan

.

J Nucl Cardiol

2013

;

20

:

715

–

8

.

10.1007/s12350-013-9769-0

285

Rozanski

A

,

Gransar

H

,

Min

JK

,

Hayes

SW

,

Friedman

JD

,

Thomson

LEJ

, et al.

Long-term mortality following normal exercise myocardial perfusion SPECT according to coronary disease risk factors

.

J Nucl Cardiol

2014

;

21

:

341

–

50

.

10.1007/s12350-013-9830-z

286

Zellweger

MJ

,

Fahrni

G

,

Ritter

M

,

Jeger

RV

,

Wild

D

,

Buser

P

, et al.

Prognostic value of “routine” cardiac stress imaging 5 years after percutaneous coronary intervention: the prospective long-term observational BASKET (Basel Stent Kosteneffektivitats Trial) LATE IMAGING study

.

JACC Cardiovasc Interv

2014

;

7

:

615

–

21

.

10.1016/j.jcin.2014.01.161

287

Patel

KK

,

Spertus

JA

,

Arnold

SV

,

Chan

PS

,

Kennedy

KF

,

Jones

PG

, et al.

Ischemia on PET MPI may identify patients with improvement in angina and health status post-revascularization

.

J Am Coll Cardiol

2019

;

74

:

1734

–

6

.

10.1016/j.jacc.2019.06.074

288

Bom

MJ

,

van Diemen

PA

,

Driessen

RS

,

Everaars

H

,

Schumacher

SP

,

Wijmenga

J-T

, et al.

Prognostic value of [¹⁵O]H₂O positron emission tomography-derived global and regional myocardial perfusion

.

Eur Heart J Cardiovasc Imaging

2020

;

21

:

777

–

86

.

289

Schepis

T

,

Gaemperli

O

,

Koepfli

P

,

Namdar

M

,

Valenta

I

,

Scheffel

H

, et al.

Added value of coronary artery calcium score as an adjunct to gated SPECT for the evaluation of coronary artery disease in an intermediate-risk population

.

J Nucl Med

2007

;

48

:

1424

–

30

.

10.2967/jnumed.107.040758

290

Schenker

MP

,

Dorbala

S

,

Hong

EC

,

Rybicki

FJ

,

Hachamovitch

R

,

Kwong

RY

, et al.

Interrelation of coronary calcification, myocardial ischemia, and outcomes in patients with intermediate likelihood of coronary artery disease: a combined positron emission tomography/computed tomography study

.

Circulation

2008

;

117

:

1693

–

700

.

10.1161/CIRCULATIONAHA.107.717512

291

Chang

SM

,

Nabi

F

,

Xu

J

,

Peterson

LE

,

Achari

A

,

Pratt

CM

, et al.

The coronary artery calcium score and stress myocardial perfusion imaging provide independent and complementary prediction of cardiac risk

.

J Am Coll Cardiol

2009

;

54

:

1872

–

82

.

10.1016/j.jacc.2009.05.071

292

Ghadri

JR

,

Pazhenkottil

AP

,

Nkoulou

RN

,

Goetti

R

,

Buechel

RR

,

Husmann

L

, et al.

Very high coronary calcium score unmasks obstructive coronary artery disease in patients with normal SPECT MPI

.

Heart

2011

;

97

:

998

–

1003

.

10.1136/hrt.2010.217281

293

Brodov

Y

,

Gransar

H

,

Dey

D

,

Shalev

A

,

Germano

G

,

Friedman

JD

, et al.

Combined quantitative assessment of myocardial perfusion and coronary artery calcium score by hybrid 82Rb PET/CT improves detection of coronary artery disease

.

J Nucl Med

2015

;

56

:

1345

–

50

.

10.2967/jnumed.114.153429

294

Hamon

M

,

Fau

G

,

Nee

G

,

Ehtisham

J

,

Morello

R

,

Hamon

M

.

Meta-analysis of the diagnostic performance of stress perfusion cardiovascular magnetic resonance for detection of coronary artery disease

.

J Cardiovasc Magn Reson

2010

;

12

:

29

.

10.1186/1532-429X-12-29

295

Jiang

B

,

Cai

W

,

Lv

X

,

Liu

H

.

Diagnostic performance and clinical utility of myocardial perfusion MRI for coronary artery disease with fractional flow reserve as the standard reference: a meta-analysis

.

Heart Lung Circ

2016

;

25

:

1031

–

8

.

10.1016/j.hlc.2016.02.018

296

Heitner

JF

,

Kim

RJ

,

Kim

HW

,

Klem

I

,

Shah

DJ

,

Debs

D

, et al.

Prognostic value of vasodilator stress cardiac magnetic resonance imaging: a multicenter study with 48 000 patient-years of follow-up

.

JAMA Cardiol

2019

;

4

:

256

–

64

.

10.1001/jamacardio.2019.0035

297

Arai

AE

,

Schulz-Menger

J

,

Shah

DJ

,

Han

Y

,

Bandettini

WP

,

Abraham

A

, et al.

Stress perfusion cardiac magnetic resonance vs SPECT imaging for detection of coronary artery disease

.

J Am Coll Cardiol

2023

;

82

:

1828

–

38

.

10.1016/j.jacc.2023.08.046

298

Ford

TJ

,

Stanley

B

,

Good

R

,

Rocchiccioli

P

,

McEntegart

M

,

Watkins

S

, et al.

Stratified medical therapy using invasive coronary function testing in angina: the CorMicA trial

.

J Am Coll Cardiol

2018

;

72

:

2841

–

55

.

10.1016/j.jacc.2018.09.006

299

Mileva

N

,

Nagumo

S

,

Mizukami

T

,

Sonck

J

,

Berry

C

,

Gallinoro

E

, et al.

Prevalence of coronary microvascular disease and coronary vasospasm in patients with nonobstructive coronary artery disease: systematic review and meta-analysis

.

J Am Heart Assoc

2022

;

11

:

e023207

.

10.1161/JAHA.121.023207

300

Brainin

P

,

Frestad

D

,

Prescott

E

.

The prognostic value of coronary endothelial and microvascular dysfunction in subjects with normal or non-obstructive coronary artery disease: a systematic review and meta-analysis

.

Int J Cardiol

2018

;

254

:

1

–

9

.

10.1016/j.ijcard.2017.10.052

301

Gdowski

MA

,

Murthy

VL

,

Doering

M

,

Monroy-Gonzalez

AG

,

Slart

R

,

Brown

DL

.

Association of isolated coronary microvascular dysfunction with mortality and major adverse cardiac events: a systematic review and meta-analysis of aggregate data

.

J Am Heart Assoc

2020

;

9

:

e014954

.

10.1161/JAHA.119.014954

302

Hozumi

T

,

Yoshida

K

,

Ogata

Y

,

Akasaka

T

,

Asami

Y

,

Takagi

T

, et al.

Noninvasive assessment of significant left anterior descending coronary artery stenosis by coronary flow velocity reserve with transthoracic color Doppler echocardiography

.

Circulation

1998

;

97

:

1557

–

62

.

10.1161/01.CIR.97.16.1557

303

Sicari

R

,

Rigo

F

,

Cortigiani

L

,

Gherardi

S

,

Galderisi

M

,

Picano

E

.

Additive prognostic value of coronary flow reserve in patients with chest pain syndrome and normal or near-normal coronary arteries

.

Am J Cardiol

2009

;

103

:

626

–

31

.

10.1016/j.amjcard.2008.10.033

304

Taqueti

VR

,

Everett

BM

,

Murthy

VL

,

Gaber

M

,

Foster

CR

,

Hainer

J

, et al.

Interaction of impaired coronary flow reserve and cardiomyocyte injury on adverse cardiovascular outcomes in patients without overt coronary artery disease

.

Circulation

2015

;

131

:

528

–

35

.

10.1161/CIRCULATIONAHA.114.009716

305

Michelsen

MM

,

Mygind

ND

,

Pena

A

,

Olsen

RH

,

Christensen

TE

,

Ghotbi

AA

, et al.

Transthoracic Doppler echocardiography compared with positron emission tomography for assessment of coronary microvascular dysfunction: the iPOWER study

.

Int J Cardiol

2017

;

228

:

435

–

43

.

10.1016/j.ijcard.2016.11.004

306

Cortigiani

L

,

Ciampi

Q

,

Lombardo

A

,

Rigo

F

,

Bovenzi

F

,

Picano

E

, et al.

Age- and gender-specific prognostic cutoff values of coronary flow velocity reserve in vasodilator stress echocardiography

.

J Am Soc Echocardiogr

2019

;

32

:

1307

–

17

.

10.1016/j.echo.2019.05.020

307

Everaars

H

,

de Waard

GA

,

Driessen

RS

,

Danad

I

,

van de Ven

PM

,

Raijmakers

PG

, et al.

Doppler flow velocity and thermodilution to assess coronary flow reserve: a head-to-head comparison with [¹⁵O]H₂O PET

.

JACC Cardiovasc Interv

2018

;

11

:

2044

–

54

.

10.1016/j.jcin.2018.07.011

308

Tonino

PA

,

De Bruyne

B

,

Pijls

NH

,

Siebert

U

,

Ikeno

F

,

van ’t Veer

M

, et al.

Fractional flow reserve versus angiography for guiding percutaneous coronary intervention

.

N Engl J Med

2009

;

360

:

213

–

24

.

10.1056/NEJMoa0807611

309

Curzen

N

,

Rana

O

,

Nicholas

Z

,

Golledge

P

,

Zaman

A

,

Oldroyd

K

, et al.

Does routine pressure wire assessment influence management strategy at coronary angiography for diagnosis of chest pain? The RIPCORD study

.

Circ Cardiovasc Interv

2014

;

7

:

248

–

55

.

10.1161/CIRCINTERVENTIONS.113.000978

310

Davies

JE

,

Sen

S

,

Dehbi

HM

,

Al-Lamee

R

,

Petraco

R

,

Nijjer

SS

, et al.

Use of the instantaneous wave-free ratio or fractional flow reserve in PCI

.

N Engl J Med

2017

;

376

:

1824

–

34

.

10.1056/NEJMoa1700445

311

Gotberg

M

,

Christiansen

EH

,

Gudmundsdottir

IJ

,

Sandhall

L

,

Danielewicz

M

,

Jakobsen

L

, et al.

Instantaneous wave-free ratio versus fractional flow reserve to guide PCI

.

N Engl J Med

2017

;

376

:

1813

–

23

.

10.1056/NEJMoa1616540

312

Faria

D

,

Hennessey

B

,

Shabbir

A

,

Mejía-Rentería

H

,

Wang

L

,

Lee

JM

, et al.

Functional coronary angiography for the assessment of the epicardial vessels and the microcirculation

.

EuroIntervention

2023

;

19

:

203

–

21

.

10.4244/EIJ-D-22-00969

10.1161/CIRCULATIONAHA.113.006646

313

Van Belle

E

,

Rioufol

G

,

Pouillot

C

,

Cuisset

T

,

Bougrini

K

,

Teiger

E

, et al.

Outcome impact of coronary revascularization strategy reclassification with fractional flow reserve at time of diagnostic angiography: insights from a large French multicenter fractional flow reserve registry

.

Circulation

2014

;

129

:

173

–

85

.

314

Lopes

RD

,

Alexander

KP

,

Stevens

SR

,

Reynolds

HR

,

Stone

GW

,

Piña

IL

, et al.

Initial invasive versus conservative management of stable ischemic heart disease in patients with a history of heart failure or left ventricular dysfunction

.

Circulation

2020

;

142

:

1725

–

35

.

10.1161/CIRCULATIONAHA.120.050304

315

Rozanski

A

,

Miller

RJH

,

Gransar

H

,

Han

D

,

Slomka

P

,

Dey

D

, et al.

Benefit of early revascularization based on inducible ischemia and left ventricular ejection fraction

.

J Am Coll Cardiol

2022

;

80

:

202

–

15

.

10.1016/j.jacc.2022.04.052

316

Neumann

FJ

,

Sousa-Uva

M

,

Ahlsson

A

,

Alfonso

F

,

Banning

AP

,

Benedetto

U

, et al.

2018 ESC/EACTS Guidelines on myocardial revascularization

.

Eur Heart J

2019

;

40

:

87

–

165

.

10.1093/eurheartj/ehy394

317

Reynolds

HR

,

Shaw

LJ

,

Min

JK

,

Page

CB

,

Berman

DS

,

Chaitman

BR

, et al.

Outcomes in the ISCHEMIA trial based on coronary artery disease and ischemia severity

.

Circulation

2021

;

144

:

1024

–

38

.

10.1161/CIRCULATIONAHA.120.049755

318

Johnson

NP

,

Toth

GG

,

Lai

D

,

Zhu

H

,

Açar

G

,

Agostoni

P

, et al.

Prognostic value of fractional flow reserve: linking physiologic severity to clinical outcomes

.

J Am Coll Cardiol

2014

;

64

:

1641

–

54

.

10.1016/j.jacc.2014.07.973

319

Barbato

E

,

Toth

GG

,

Johnson

NP

,

Pijls

NHJ

,

Fearon

WF

,

Tonino

PAL

, et al.

A prospective natural history study of coronary atherosclerosis using fractional flow reserve

.

J Am Coll Cardiol

2016

;

68

:

2247

–

55

.

10.1016/j.jacc.2016.08.055

320

Ciccarelli

G

,

Barbato

E

,

Toth

GG

,

Gahl

B

,

Xaplanteris

P

,

Fournier

S

, et al.

Angiography versus hemodynamics to predict the natural history of coronary stenoses

.

Circulation

2018

;

137

:

1475

–

85

.

10.1161/CIRCULATIONAHA.117.028782

321

De Bruyne

B

,

Fearon

WF

,

Pijls

NH

,

Barbato

E

,

Tonino

P

,

Piroth

Z

, et al.

Fractional flow reserve-guided PCI for stable coronary artery disease

.

N Engl J Med

2014

;

371

:

1208

–

17

.

10.1056/NEJMoa1408758

322

Van Belle

E

,

Baptista

SB

,

Raposo

L

,

Henderson

J

,

Rioufol

G

,

Santos

L

, et al.

Impact of routine fractional flow reserve on management decision and 1-year clinical outcome of patients with acute coronary syndromes: PRIME-FFR (Insights from the POST-IT [Portuguese Study on the Evaluation of FFR-Guided Treatment of Coronary Disease] and R3F [French FFR Registry] integrated multicenter registries—implementation of FFR [Fractional Flow Reserve] in routine practice)

.

Circ Cardiovasc Interv

2017

;

10

:

e004296

.

10.1161/circinterventions.116.004296

323

Escaned

J

,

Ryan

N

,

Mejía-Rentería

H

,

Cook

CM

,

Dehbi

H-M

,

Alegria-Barrero

E

, et al.

Safety of the deferral of coronary revascularization on the basis of instantaneous wave-free ratio and fractional flow reserve measurements in stable coronary artery disease and acute coronary syndromes

.

JACC Cardiovasc Interv

2018

;

11

:

1437

–

49

.

10.1016/j.jcin.2018.05.029

324

Elguindy

M

,

Stables

R

,

Nicholas

Z

,

Kemp

I

,

Curzen

N

.

Design and rationale of the RIPCORD 2 Trial (does routine pressure wire assessment influence management strategy at coronary angiography for diagnosis of chest pain?): a randomized controlled trial to compare routine pressure wire assessment with conventional angiography in the management of patients with coronary artery disease

.

Circ Cardiovasc Qual Outcomes

2018

;

11

:

e004191

.

10.1161/circoutcomes.117.004191

325

Xu

B

,

Tu

S

,

Song

L

,

Jin

Z

,

Yu

B

,

Fu

G

, et al.

Angiographic quantitative flow ratio-guided coronary intervention (FAVOR III China): a multicentre, randomised, sham-controlled trial

.

Lancet

2021

;

398

:

2149

–

59

.

10.1016/s0140-6736(21)02248-0

326

Fearon

WF

,

Zimmermann

FM

,

De Bruyne

B

,

Piroth

Z

,

van Straten

AHM

,

Szekely

L

, et al.

Fractional flow reserve-guided PCI as compared with coronary bypass surgery

.

N Engl J Med

2022

;

386

:

128

–

37

.

10.1056/NEJMoa2112299

327

Gargiulo

G

,

Giacoppo

D

,

Jolly

SS

,

Cairns

J

,

Le May

M

,

Bernat

I

, et al.

Effects on mortality and major bleeding of radial versus femoral artery access for coronary angiography or percutaneous coronary intervention: meta-analysis of individual patient data from 7 multicenter randomized clinical trials

.

Circulation

2022

;

146

:

1329

–

43

.

10.1161/CIRCULATIONAHA.122.061527

328

Ferrante

G

,

Rao

SV

,

Juni

P

,

Da Costa

BR

,

Reimers

B

,

Condorelli

G

, et al.

Radial versus femoral access for coronary interventions across the entire spectrum of patients with coronary artery disease: a meta-analysis of randomized trials

.

JACC Cardiovasc Interv

2016

;

9

:

1419

–

34

.

10.1016/j.jcin.2016.04.014

329

Kolkailah

AA

,

Alreshq

RS

,

Muhammed

AM

,

Zahran

ME

,

Anas El-Wegoud

M

,

Nabhan

AF

.

Transradial versus transfemoral approach for diagnostic coronary angiography and percutaneous coronary intervention in people with coronary artery disease

.

Cochrane Database Syst Rev

2018

;

4

:

CD012318

.

10.1002/14651858.CD012318.pub2

330

Chiarito

M

,

Cao

D

,

Nicolas

J

,

Roumeliotis

A

,

Power

D

,

Chandiramani

R

, et al.

Radial versus femoral access for coronary interventions: an updated systematic review and meta-analysis of randomized trials

.

Catheter Cardiovasc Interv

2021

;

97

:

1387

–

96

.

331

Hamilos

M

,

Muller

O

,

Cuisset

T

,

Ntalianis

A

,

Chlouverakis

G

,

Sarno

G

, et al.

Long-term clinical outcome after fractional flow reserve-guided treatment in patients with angiographically equivocal left main coronary artery stenosis

.

Circulation

2009

;

120

:

1505

–

12

.

10.1161/CIRCULATIONAHA.109.850073

332

Zimmermann

FM

,

Ferrara

A

,

Johnson

NP

,

van Nunen

LX

,

Escaned

J

,

Albertsson

P

, et al.

Deferral vs. performance of percutaneous coronary intervention of functionally non-significant coronary stenosis: 15-year follow-up of the DEFER trial

.

Eur Heart J

2015

;

36

:

3182

–

8

.

10.1093/eurheartj/ehv452

333

Warisawa

T

,

Cook

CM

,

Rajkumar

C

,

Howard

JP

,

Seligman

H

,

Ahmad

Y

, et al.

Safety of revascularization deferral of left main stenosis based on instantaneous wave-free ratio evaluation

.

JACC Cardiovasc Interv

2020

;

13

:

1655

–

64

.

10.1016/j.jcin.2020.02.035

334

Mallidi

J

,

Atreya

AR

,

Cook

J

,

Garb

J

,

Jeremias

A

,

Klein

LW

, et al.

Long-term outcomes following fractional flow reserve-guided treatment of angiographically ambiguous left main coronary artery disease: a meta-analysis of prospective cohort studies

.

Catheter Cardiovasc Interv

2015

;

86

:

12

–

8

.

335

Modi

BN

,

van de Hoef

TP

,

Piek

JJ

,

Perera

D

.

Physiological assessment of left main coronary artery disease

.

EuroIntervention

2017

;

13

:

820

–

7

.

10.4244/eij-d-17-00135

336

Cerrato

E

,

Echavarria-Pinto

M

,

D'Ascenzo

F

,

Gonzalo

N

,

Quadri

G

,

Quirós

A

, et al.

Safety of intermediate left main stenosis revascularization deferral based on fractional flow reserve and intravascular ultrasound: a systematic review and meta-regression including 908 deferred left main stenosis from 12 studies

.

Int J Cardiol

2018

;

271

:

42

–

8

.

10.1016/j.ijcard.2018.04.032

337

Stone

GW

,

Christiansen

EH

,

Ali

ZA

,

Andreasen

LN

,

Maehara

A

,

Ahmad

Y

, et al.

Intravascular imaging-guided coronary drug-eluting stent implantation: an updated network meta-analysis

.

Lancet

2024

;

403

:

824

–

37

.

10.1016/S0140-6736(23)02454-6

338

Park

S-J

,

Kang

S-J

,

Ahn

J-M

,

Shim

EB

,

Kim

Y-T

,

Yun

S-C

, et al.

Visual-functional mismatch between coronary angiography and fractional flow reserve

.

JACC Cardiovasc Interv

2012

;

5

:

1029

–

36

.

10.1016/j.jcin.2012.07.007

339

Toth

G

,

Hamilos

M

,

Pyxaras

S

,

Mangiacapra

F

,

Nelis

O

,

De Vroey

F

, et al.

Evolving concepts of angiogram: fractional flow reserve discordances in 4000 coronary stenoses

.

Eur Heart J

2014

;

35

:

2831

–

8

.

10.1093/eurheartj/ehu094

340

Baptista

SB

,

Raposo

L

,

Santos

L

,

Ramos

R

,

Calé

R

,

Jorge

E

, et al.

Impact of routine fractional flow reserve evaluation during coronary angiography on management strategy and clinical outcome: one-year results of the POST-IT

.

Circ Cardiovasc Interv

2016

;

9

:

e003288

.

10.1161/CIRCINTERVENTIONS.115.003288

341

Van Belle

E

,

Gil

R

,

Klauss

V

,

Balghith

M

,

Meuwissen

M

,

Clerc

J

, et al.

Impact of routine invasive physiology at time of angiography in patients with multivessel coronary artery disease on reclassification of revascularization strategy: results from the DEFINE REAL study

.

JACC Cardiovasc Interv

2018

;

11

:

354

–

65

.

10.1016/j.jcin.2017.11.030

342

Van Belle

E

,

Dupouy

P

,

Rioufol

G

.

Routine fractional flow reserve combined to diagnostic coronary angiography as a one-stop procedure: episode 3

.

Circ Cardiovasc Interv

2016

;

9

:

e004137

.

10.1161/CIRCINTERVENTIONS.116.004137

343

Eftekhari

A

,

Holck

EN

,

Westra

J

,

Olsen

NT

,

Bruun

NH

,

Jensen

LO

, et al.

Instantaneous wave free ratio vs. fractional flow reserve and 5-year mortality: iFR SWEDEHEART and DEFINE FLAIR

.

Eur Heart J

2023

;

44

:

4376

–

84

.

10.1093/eurheartj/ehad582

344

Berry

C

,

McClure

JD

,

Oldroyd

KG

.

Coronary revascularization guided by instantaneous wave-free ratio compared to fractional flow reserve: pooled 5-year mortality in the DEFINE-FLAIR and iFR-SWEDEHEART trials

.

Eur Heart J

2023

;

44

:

4388

–

90

.

10.1093/eurheartj/ehad552

345

Berntorp

K

,

Rylance

R

,

Yndigegn

T

,

Koul

S

,

Fröbert

O

,

Christiansen

EH

, et al.

Clinical outcome of revascularization deferral with instantaneous wave-free ratio and fractional flow reserve: a 5-year follow-up substudy from the iFR-SWEDEHEART Trial

.

J Am Heart Assoc

2023

;

12

:

e028423

.

10.1161/jaha.122.028423

346

Rioufol

G

,

Derimay

F

,

Roubille

F

,

Perret

T

,

Motreff

P

,

Angoulvant

D

, et al.

Fractional flow reserve to guide treatment of patients with multivessel coronary artery disease

.

J Am Coll Cardiol

2021

;

78

:

1875

–

85

.

10.1016/j.jacc.2021.08.061

347

Stables

RH

,

Mullen

LJ

,

Elguindy

M

,

Nicholas

Z

,

Aboul-Enien

YH

,

Kemp

I

, et al.

Routine pressure wire assessment versus conventional angiography in the management of patients with coronary artery disease: the RIPCORD 2 trial

.

Circulation

2022

;

146

:

687

–

98

.

10.1161/circulationaha.121.057793

348

Nijjer

SS

,

Sen

S

,

Petraco

R

,

Escaned

J

,

Echavarria-Pinto

M

,

Broyd

C

, et al.

Pre-angioplasty instantaneous wave-free ratio pullback provides virtual intervention and predicts hemodynamic outcome for serial lesions and diffuse coronary artery disease

.

JACC Cardiovasc Interv

2014

;

7

:

1386

–

96

.

10.1016/j.jcin.2014.06.015

349

Kikuta

Y

,

Cook

CM

,

Sharp

ASP

,

Salinas

P

,

Kawase

Y

,

Shiono

Y

, et al.

Pre-angioplasty instantaneous wave-free ratio pullback predicts hemodynamic outcome in humans with coronary artery disease

.

JACC Cardiovasc Interv

2018

;

11

:

757

–

67

.

10.1016/j.jcin.2018.03.005

350

Jeremias

A

,

Davies

JE

,

Maehara

A

,

Matsumura

M

,

Schneider

J

,

Tang

K

, et al.

Blinded physiological assessment of residual ischemia after successful angiographic percutaneous coronary intervention: the DEFINE PCI study

.

JACC Cardiovasc Interv

2019

;

12

:

1991

–

2001

.

10.1016/j.jcin.2019.05.054

351

Lee

SH

,

Shin

D

,

Lee

JM

,

Lefieux

A

,

Molony

D

,

Choi

KH

, et al.

Automated algorithm using pre-intervention fractional flow reserve pullback curve to predict post-intervention physiological results

.

JACC Cardiovasc Interv

2020

;

13

:

2670

–

84

.

10.1016/j.jcin.2020.06.062

352

Omori

H

,

Kawase

Y

,

Mizukami

T

,

Tanigaki

T

,

Hirata

T

,

Kikuchi

J

, et al.

Comparisons of nonhyperemic pressure ratios: predicting functional results of coronary revascularization using longitudinal vessel interrogation

.

JACC Cardiovasc Interv

2020

;

13

:

2688

–

98

.

10.1016/j.jcin.2020.06.060

353

Masdjedi

K

,

Tanaka

N

,

Van Belle

E

,

Porouchani

S

,

Linke

A

,

Woitek

FW

, et al.

Vessel fractional flow reserve (vFFR) for the assessment of stenosis severity: the FAST II study

.

EuroIntervention

2022

;

17

:

1498

–

505

.

10.4244/eij-d-21-00471

354

Scoccia

A

,

Byrne

RA

,

Banning

AP

,

Landmesser

U

,

Van Belle

E

,

Amat-Santos

IJ

, et al.

Fractional flow reserve or 3D-quantitative-coronary-angiography based vessel-FFR guided revascularization. Rationale and study design of the prospective randomized fast III trial

.

Am Heart J

2023

;

260

:

1

–

8

.

10.1016/j.ahj.2023.02.003

355

Song

L

,

Xu

B

,

Tu

S

,

Guan

C

,

Jin

Z

,

Yu

B

, et al.

2-Year outcomes of angiographic quantitative flow ratio-guided coronary interventions

.

J Am Coll Cardiol

2022

;

80

:

2089

–

101

.

10.1016/j.jacc.2022.09.007

356

Johnson

NP

,

Matsuo

H

,

Nakayama

M

,

Eftekhari

A

,

Kakuta

T

,

Tanaka

N

, et al.

Combined pressure and flow measurements to guide treatment of coronary stenoses

.

JACC Cardiovasc Interv

2021

;

14

:

1904

–

13

.

10.1016/j.jcin.2021.07.041

357

van de Hoef

TP

,

Lee

JM

,

Boerhout

CKM

,

de Waard

GA

,

Jung

J-H

,

Lee

SH

, et al.

Combined assessment of FFR and CFR for decision making in coronary revascularization: from the multicenter international ILIAS registry

.

JACC Cardiovasc Interv

2022

;

15

:

1047

–

56

.

10.1016/j.jcin.2022.03.016

358

van de Hoef

TP

,

Stegehuis

VE

,

Madera-Cambero

MI

,

van Royen

N

,

van der Hoeven

NW

,

de Waard

GA

, et al.

Impact of core laboratory assessment on treatment decisions and clinical outcomes using combined fractional flow reserve and coronary flow reserve measurements—DEFINE-FLOW core laboratory sub-study

.

Int J Cardiol

2023

;

377

:

9

–

16

.

10.1016/j.ijcard.2023.01.009

359

Meuwissen

M

,

Siebes

M

,

Chamuleau

SA

,

van Eck-Smit

BLF

,

Koch

KT

,

de Winter

RJ

, et al.

Hyperemic stenosis resistance index for evaluation of functional coronary lesion severity

.

Circulation

2002

;

106

:

441

–

6

.

10.1161/01.cir.0000023041.26199.29

360

Boerhout

CKM

,

Echavarria-Pinto

M

,

de Waard

GA

, et al.

Impact of hyperemic stenosis resistance (HSR) on long-term outcomes of stable angina

.

Eurointervention

2024;20:e699–706.

10.4244/EIJ-D-23-00713

10.1016/j.jacc.2021.08.017

361

De Bruyne

B

,

Pijls

NHJ

,

Gallinoro

E

,

Candreva

A

,

Fournier

S

,

Keulards

DCJ

, et al.

Microvascular resistance reserve for assessment of coronary microvascular function: JACC technology corner

.

J Am Coll Cardiol

2021

;

78

:

1541

–

9

.

362

Candreva

A

,

Gallinoro

E

,

Fernandez Peregrina

E

,

Sonck

J

,

Keulards

DCJ

,

van‘t Veer

M

, et al.

Automation of intracoronary continuous thermodilution for absolute coronary flow and microvascular resistance measurements

.

Catheter Cardiovasc Interv

2022

;

100

:

199

–

206

.

363

De Bruyne

B

,

Belmonte

M

,

Jabbour

JR

,

Curzen

N

.

Invasive functional testing in the cath lab as a routine investigation in INOCA: pros and cons

.

EuroIntervention

2023

;

19

:

23

–

5

.

10.4244/EIJ-E-23-00008

364

de Vos

A

,

Jansen

TPJ

,

van ’t Veer

M

,

Dimitriu-Leen

A

,

Konst

RE

,

Elias-Smale

S

, et al.

Microvascular resistance reserve to assess microvascular dysfunction in ANOCA patients

.

JACC Cardiovasc Interv

2023

;

16

:

470

–

81

.

10.1016/j.jcin.2022.12.012

365

Johnson

NP

,

Gould

KL

.

Integrating noninvasive absolute flow, coronary flow reserve, and ischemic thresholds into a comprehensive map of physiological severity

.

JACC Cardiovasc Imaging

2012

;

5

:

430

–

40

.

10.1016/j.jcmg.2011.12.014

366

van de Hoef

TP

,

Echavarria-Pinto

M

,

van Lavieren

MA

,

Meuwissen

M

,

Serruys

PWJC

,

Tijssen

JGP

, et al.

Diagnostic and prognostic implications of coronary flow capacity: a comprehensive cross-modality physiological concept in ischemic heart disease

.

JACC Cardiovasc Interv

2015

;

8

:

1670

–

80

.

10.1016/j.jcin.2015.05.032

367

Murai

T

,

Stegehuis

VE

,

van de Hoef

TP

,

Wijntjens

GWM

,

Hoshino

M

,

Kanaji

Y

, et al.

Coronary flow capacity to identify stenosis associated with coronary flow improvement after revascularization: a combined analysis from DEFINE FLOW and IDEAL

.

J Am Heart Assoc

2020

;

9

:

e016130

.

10.1161/JAHA.120.016130

368

de Winter

RW

,

Jukema

RA

,

van Diemen

PA

,

Schumacher

SP

,

Driessen

RS

,

Stuijfzand

WJ

, et al.

The impact of coronary revascularization on vessel-specific coronary flow capacity and long-term outcomes: a serial [¹⁵O]H₂O positron emission tomography perfusion imaging study

.

Eur Heart J Cardiovasc Imaging

2022

;

23

:

743

–

52

.

10.1093/ehjci/jeab263

369

Park

SJ

,

Ahn

JM

,

Kang

SJ

,

Yoon

S-H

,

Koo

B-K

,

Lee

J-Y

, et al.

Intravascular ultrasound-derived minimal lumen area criteria for functionally significant left main coronary artery stenosis

.

JACC Cardiovasc Interv

2014

;

7

:

868

–

74

.

10.1016/j.jcin.2014.02.015

370

Ziedses des Plantes

AC

,

Scoccia

A

,

Gijsen

F

,

van Soest

G

,

Daemen

J

.

Intravascular imaging-derived physiology-basic principles and clinical application

.

Interv Cardiol Clin

2023

;

12

:

83

–

94

.

10.1016/j.iccl.2022.09.008

371

Noguchi

M

,

Gkargkoulas

F

,

Matsumura

M

,

Kotinkaduwa

LN

,

Hu

X

,

Usui

E

, et al.

Impact of nonobstructive left main coronary artery atherosclerosis on long-term mortality

.

JACC Cardiovasc Interv

2022

;

15

:

2206

–

17

.

10.1016/j.jcin.2022.08.024

372

Pijls

NH

,

van Schaardenburgh

P

,

Manoharan

G

,

Boersma

E

,

Bech

J-W

,

van’t Veer

M

, et al.

Percutaneous coronary intervention of functionally nonsignificant stenosis: 5-year follow-up of the DEFER Study

.

J Am Coll Cardiol

2007

;

49

:

2105

–

11

.

10.1016/j.jacc.2007.01.087

373

Van Belle

E

,

Cosenza

A

,

Baptista

SB

,

Vincent

F

,

Henderson

J

,

Santos

L

, et al.

Usefulness of routine fractional flow reserve for clinical management of coronary artery disease in patients with diabetes

.

JAMA Cardiol

2020

;

5

:

272

–

81

.

10.1001/jamacardio.2019.5097

374

Xu

B

,

Tu

S

,

Qiao

S

,

Qu

X

,

Chen

Y

,

Yang

J

, et al.

Diagnostic accuracy of angiography-based quantitative flow ratio measurements for online assessment of coronary stenosis

.

J Am Coll Cardiol

2017

;

70

:

3077

–

87

.

10.1016/j.jacc.2017.10.035

375

Westra

J

,

Andersen

BK

,

Campo

G

,

Matsuo

H

,

Koltowski

L

,

Eftekhari

A

, et al.

Diagnostic performance of in-procedure angiography-derived quantitative flow reserve compared to pressure-derived fractional flow reserve: the FAVOR II Europe-Japan study

.

J Am Heart Assoc

2018

;

7

:

e009603

.

10.1161/JAHA.118.009603

376

Johnson

NP

,

Gould

KL

,

De Bruyne

B

.

Autoregulation of coronary blood supply in response to demand: JACC review topic of the week

.

J Am Coll Cardiol

2021

;

77

:

2335

–

45

.

10.1016/j.jacc.2021.03.293

377

Masdjedi

K

,

van Zandvoort

LJC

,

Balbi

MM

,

Gijsen

FJH

,

Ligthart

JMR

,

Rutten

MCM

, et al.

Validation of a three-dimensional quantitative coronary angiography-based software to calculate fractional flow reserve: the FAST study

.

EuroIntervention

2020

;

16

:

591

–

9

.

10.4244/eij-d-19-00466

378

Pijls

NH

,

De Bruyne

B

,

Smith

L

,

Aarnoudse

W

,

Barbato

E

,

Bartunek

J

, et al.

Coronary thermodilution to assess flow reserve: validation in humans

.

Circulation

2002

;

105

:

2482

–

6

.

10.1161/01.cir.0000017199.09457.3d

379

Barbato

E

,

Aarnoudse

W

,

Aengevaeren

WR

,

Werner

G

,

Klauss

V

,

Bojara

W

, et al.

Validation of coronary flow reserve measurements by thermodilution in clinical practice

.

Eur Heart J

2004

;

25

:

219

–

23

.

10.1016/j.ehj.2003.11.009

380

Fearon

WF

,

Balsam

LB

,

Farouque

HM

,

Robbins

RC

,

Fitzgerald

PJ

,

Yock

PG

, et al.

Novel index for invasively assessing the coronary microcirculation

.

Circulation

2003

;

107

:

3129

–

32

.

10.1161/01.Cir.0000080700.98607.D1

381

Fearon

WF

,

Kobayashi

Y

.

Invasive assessment of the coronary microvasculature: the index of microcirculatory resistance

.

Circ Cardiovasc Interv

2017

;

10

:

e005361

.

10.1161/circinterventions.117.005361

382

Gallinoro

E

,

Bertolone

DT

,

Fernandez-Peregrina

E

,

Paolisso

P

,

Bermpeis

K

,

Esposito

G

, et al.

Reproducibility of bolus versus continuous thermodilution for assessment of coronary microvascular function in patients with ANOCA

.

EuroIntervention

2023

;

19

:

e155

–

66

.

10.4244/eij-d-22-00772

383

Mejía-Rentería

H

,

Wang

L

,

Chipayo-Gonzales

D

,

van de Hoef

TP

,

Travieso

A

,

Espejo

C

, et al.

Angiography-derived assessment of coronary microcirculatory resistance in patients with suspected myocardial ischaemia and non-obstructive coronary arteries

.

EuroIntervention

2023

;

18

:

e1348

–

56

.

10.4244/EIJ-D-22-00579

384

Ford

TJ

,

Ong

P

,

Sechtem

U

,

Beltrame

J

,

Camici

PG

,

Crea

F

, et al.

Assessment of vascular dysfunction in patients without obstructive coronary artery disease: why, how, and when

.

JACC Cardiovasc Interv

2020

;

13

:

1847

–

64

.

10.1016/j.jcin.2020.05.052

385

Radico

F

,

Cicchitti

V

,

Zimarino

M

,

De Caterina

R

.

Angina pectoris and myocardial ischemia in the absence of obstructive coronary artery disease: practical considerations for diagnostic tests

.

JACC Cardiovasc Interv

2014

;

7

:

453

–

63

.

10.1016/j.jcin.2014.01.157

386

Boerhout

CKM

,

Feenstra

RGT

,

Somsen

GA

,

Appelman

Y

,

Ong

P

,

Beijk

MAM

, et al.

Coronary computed tomographic angiography as gatekeeper for new-onset stable angina

.

Neth Heart J

2021

;

29

:

551

–

6

.

10.1007/s12471-021-01639-7

387

Jukema

R

,

Maaniitty

T

,

van Diemen

P

,

Berkhof

H

,

Raijmakers

PG

,

Sprengers

R

, et al.

Warranty period of coronary computed tomography angiography and [¹⁵O]H₂O positron emission tomography in symptomatic patients

.

Eur Heart J Cardiovasc Imaging

2022

;

24

:

304

–

11

.

10.1093/ehjci/jeac258

10.1007/s00330-017-5246-5

388

Haberkorn

SM

,

Haberkorn

SI

,

Bonner

F

,

Kelm

M

,

Hopkin

G

,

Petersen

SE

.

Vasodilator myocardial perfusion cardiac magnetic resonance imaging is superior to dobutamine stress echocardiography in the detection of relevant coronary artery stenosis: a systematic review and meta-analysis on their diagnostic accuracy

.

Front Cardiovasc Med

2021

;

8

:

630846

.

10.3389/fcvm.2021.630846

389

van der Molen

AJ

,

Reimer

P

,

Dekkers

IA

,

Bongartz

G

,

Bellin

M-F

,

Bertolotto

M

, et al.

Post-contrast acute kidney injury—Part 1: definition, clinical features, incidence, role of contrast medium and risk factors : recommendations for updated ESUR Contrast Medium Safety Committee guidelines

.

Eur Radiol

2018

;

28

:

2845

–

55

.

390

Bittencourt

MS

,

Hulten

EA

,

Murthy

VL

,

Cheezum

M

,

Rochitte

CE

,

Carli

MFD

, et al.

Clinical outcomes after evaluation of stable chest pain by coronary computed tomographic angiography versus usual care: a meta-analysis

.

Circ Cardiovasc Imaging

2016

;

9

:

e004419

.

10.1161/CIRCIMAGING.115.004419

391

Reis

JF

,

Ramos

RB

,

Marques

H

,

Daniel

PM

,

Aguiar

SR

,

Morais

LA

, et al.

Cardiac computed tomographic angiography after abnormal ischemia test as a gatekeeper to invasive coronary angiography

.

Int J Cardiovasc Imaging

2022

;

38

:

883

–

93

.

10.1007/s10554-021-02426-6

392

Maaniitty

T

,

Stenstrom

I

,

Bax

JJ

,

Uusitalo

V

,

Ukkonen

H

,

Kajander

S

, et al.

Prognostic value of coronary CT angiography with selective PET perfusion imaging in coronary artery disease

.

JACC Cardiovasc Imaging

2017

;

10

:

1361

–

70

.

10.1016/j.jcmg.2016.10.025

393

Pezel

T

,

Hovasse

T

,

Lefevre

T

,

Sanguineti

F

,

Unterseeh

T

,

Champagne

S

, et al.

Prognostic value of stress CMR in symptomatic patients with coronary stenosis on CCTA

.

JACC Cardiovasc Imaging

2022

;

15

:

1408

–

22

.

10.1016/j.jcmg.2022.03.008

394

Winther

S

,

Andersen

IT

,

Gormsen

LC

,

Steffensen

FH

,

Nielsen

LH

,

Grove

EL

, et al.

Prognostic value of myocardial perfusion imaging after first-line coronary computed tomography angiography: a multi-center cohort study

.

J Cardiovasc Comput Tomogr

2022

;

16

:

34

–

40

.

10.1016/j.jcct.2021.08.001

395

Min

JK

,

Leipsic

J

,

Pencina

MJ

,

Berman

DS

,

Koo

B-K

,

van Mieghem

C

, et al.

Diagnostic accuracy of fractional flow reserve from anatomic CT angiography

.

JAMA

2012

;

308

:

1237

–

45

.

10.1001/2012.jama.11274

396

Douglas

PS

,

De Bruyne

B

,

Pontone

G

,

Patel

MR

,

Norgaard

BL

,

Byrne

RA

, et al.

1-Year outcomes of FFRCT-guided care in patients with suspected coronary disease: the PLATFORM study

.

J Am Coll Cardiol

2016

;

68

:

435

–

45

.

10.1016/j.jacc.2016.05.057

397

Fairbairn

TA

,

Nieman

K

,

Akasaka

T

,

Nørgaard

BL

,

Berman

DS

,

Raff

G

, et al.

Real-world clinical utility and impact on clinical decision-making of coronary computed tomography angiography-derived fractional flow reserve: lessons from the ADVANCE registry

.

Eur Heart J

2018

;

39

:

3701

–

11

.

10.1093/eurheartj/ehy530

398

Andreini

D

,

Modolo

R

,

Katagiri

Y

,

Mushtaq

S

,

Sonck

J

,

Collet

C

, et al.

Impact of fractional flow reserve derived from coronary computed tomography angiography on heart team treatment decision-making in patients with multivessel coronary artery disease: insights from the SYNTAX III REVOLUTION trial

.

Circ Cardiovasc Interv

2019

;

12

:

e007607

.

10.1161/CIRCINTERVENTIONS.118.007607

399

Patel

MR

,

Norgaard

BL

,

Fairbairn

TA

,

Nieman

K

,

Akasaka

T

,

Berman

DS

, et al.

1-year impact on medical practice and clinical outcomes of FFR(CT): the ADVANCE registry

.

JACC Cardiovasc Imaging

2020

;

13

:

97

–

105

.

10.1016/j.jcmg.2019.03.003

400

Riedl

KA

,

Jensen

JM

,

Ko

BS

,

Leipsic

J

,

Grove

EL

,

Mathiassen

ON

, et al.

Coronary CT angiography derived FFR in patients with left main disease

.

Int J Cardiovasc Imaging

2021

;

37

:

3299

–

308

.

10.1007/s10554-021-02371-4

401

Nørgaard

BL

,

Gaur

S

,

Fairbairn

TA

,

Douglas

PS

,

Jensen

JM

,

Patel

MR

, et al.

Prognostic value of coronary computed tomography angiographic derived fractional flow reserve: a systematic review and meta-analysis

.

Heart

2022

;

108

:

194

–

202

.

10.1136/heartjnl-2021-319773

402

Al-Lamee

R

,

Thompson

D

,

Dehbi

HM

,

Sen

S

,

Tang

K

,

Davies

J

, et al.

Percutaneous coronary intervention in stable angina (ORBITA): a double-blind, randomised controlled trial

.

Lancet

2018

;

391

:

31

–

40

.

10.1016/S0140-6736(17)32714-9

403

Foley

M

,

Rajkumar

CA

,

Shun-Shin

M

,

Ganesananthan

S

,

Seligman

H

,

Howard

J

, et al.

Achieving optimal medical therapy: insights from the ORBITA trial

.

J Am Heart Assoc

2021

;

10

:

e017381

.

10.1161/JAHA.120.017381

404

Mesnier

J

,

Ducrocq

G

,

Danchin

N

,

Ferrari

R

,

Ford

I

,

Tardif

J-C

, et al.

International observational analysis of evolution and outcomes of chronic stable angina: the multinational CLARIFY study

.

Circulation

2021

;

144

:

512

–

23

.

10.1161/CIRCULATIONAHA.121.054567

405

Task Force Members

;

Montalescot

G

,

Sechtem

U

,

Achenbach

S

,

Andreotti

F

,

Arden

C

, et al.

2013 ESC Guidelines on the management of stable coronary artery disease: the Task Force on the management of stable coronary artery disease of the European Society of Cardiology

.

Eur Heart J

2013

;

34

:

2949

–

3003

.

10.1093/eurheartj/eht296

406

Rapsomaniki

E

,

Shah

A

,

Perel

P

,

Denaxas

S

,

George

J

,

Nicholas

O

, et al.

Prognostic models for stable coronary artery disease based on electronic health record cohort of 102

023 patients

.

Eur Heart J

2014

;

35

:

844

–

52

.

10.1093/eurheartj/eht533

407

Barbero

U

,

D’Ascenzo

F

,

Nijhoff

F

,

Moretti

C

,

Biondi-Zoccai

G

,

Mennuni

M

, et al.

Assessing risk in patients with stable coronary disease: when should we intensify care and follow-up? Results from a meta-analysis of observational studies of the COURAGE and FAME era

.

Scientifica (Cairo)

2016

;

2016

:

3769152

.

408

Sorbets

E

,

Fox

KM

,

Elbez

Y

,

Danchin

N

,

Dorian

P

,

Ferrari

R

, et al.

Long-term outcomes of chronic coronary syndrome worldwide: insights from the international CLARIFY registry

.

Eur Heart J

2020

;

41

:

347

–

56

.

10.1093/eurheartj/ehz660

409

Liu

Y

,

Song

J

,

Wang

W

,

Zhang

K

,

Qi

Y

,

Yang

J

, et al.

Association of ejection fraction with mortality and cardiovascular events in patients with coronary artery disease

.

ESC Heart Fail

2022

;

9

:

3461

–

8

.

410

Thuijs

D

,

Milojevic

M

,

Stone

GW

,

Puskas

JD

,

Serruys

PW

,

Sabik

JF

, et al.

Impact of left ventricular ejection fraction on clinical outcomes after left main coronary artery revascularization: results from the randomized EXCEL trial

.

Eur J Heart Fail

2020

;

22

:

871

–

9

.

411

Abidov

A

,

Rozanski

A

,

Hachamovitch

R

,

Hayes

SW

,

Aboul-Enein

F

,

Cohen

I

, et al.

Prognostic significance of dyspnea in patients referred for cardiac stress testing

.

N Engl J Med

2005

;

353

:

1889

–

98

.

412

Myers

J

,

Prakash

M

,

Froelicher

V

,

Do

D

,

Partington

S

,

Atwood

JE

.

Exercise capacity and mortality among men referred for exercise testing

.

N Engl J Med

2002

;

346

:

793

–

801

.

413

Sipilä

K

,

Tikkakoski

A

,

Alanko

S

,

Haarala

A

,

Hernesniemi

J

,

Lyytikäinen

L-P

, et al.

Combination of low blood pressure response, low exercise capacity and slow heart rate recovery during an exercise test significantly increases mortality risk

.

Ann Med

2019

;

51

:

390

–

6

.

10.1080/07853890.2019.1684550

414

Salokari

E

,

Laukkanen

JA

,

Lehtimaki

T

,

Kurl

S

,

Kunutsor

S

,

Zaccardi

F

, et al.

The Duke treadmill score with bicycle ergometer: exercise capacity is the most important predictor of cardiovascular mortality

.

Eur J Prev Cardiol

2019

;

26

:

199

–

207

.

10.1177/2047487318804618

415

Williams

MC

,

Kwiecinski

J

,

Doris

M

,

McElhinney

P

,

D’Souza

MS

,

Cadet

S

, et al.

Low-attenuation noncalcified plaque on coronary computed tomography angiography predicts myocardial infarction: results from the multicenter SCOT-HEART trial (Scottish Computed Tomography of the HEART)

.

Circulation

2020

;

141

:

1452

–

62

.

10.1161/CIRCULATIONAHA.119.044720

416

Mortensen

MB

,

Dzaye

O

,

Steffensen

FH

,

Bøtker

HE

,

Jensen

JM

,

Rønnow Sand

NP

, et al.

Impact of plaque burden versus stenosis on ischemic events in patients with coronary atherosclerosis

.

J Am Coll Cardiol

2020

;

76

:

2803

–

13

.

10.1016/j.jacc.2020.10.021

417

van Rosendael

AR

,

Bax

AM

,

Smit

JM

,

van den Hoogen

IJ

,

Ma

X

,

Al’Aref

S

, et al.

Clinical risk factors and atherosclerotic plaque extent to define risk for major events in patients without obstructive coronary artery disease: the long-term coronary computed tomography angiography CONFIRM registry

.

Eur Heart J Cardiovasc Imaging

2020

;

21

:

479

–

88

.

418

Sharir

T

,

Germano

G

,

Kang

X

,

Lewin

HC

,

Miranda

R

,

Cohen

I

, et al.

Prediction of myocardial infarction versus cardiac death by gated myocardial perfusion SPECT: risk stratification by the amount of stress-induced ischemia and the poststress ejection fraction

.

J Nucl Med

2001

;

42

:

831

–

7

.

10.1016/j.jacc.2013.03.080

419

Hachamovitch

R

,

Rozanski

A

,

Shaw

LJ

,

Stone

GW

,

Thomson

LEJ

,

Friedman

JD

, et al.

Impact of ischaemia and scar on the therapeutic benefit derived from myocardial revascularization vs. medical therapy among patients undergoing stress-rest myocardial perfusion scintigraphy

.

Eur Heart J

2011

;

32

:

1012

–

24

.

10.1093/eurheartj/ehq500

420

Lipinski

MJ

,

McVey

CM

,

Berger

JS

,

Kramer

CM

,

Salerno

M

.

Prognostic value of stress cardiac magnetic resonance imaging in patients with known or suspected coronary artery disease: a systematic review and meta-analysis

.

J Am Coll Cardiol

2013

;

62

:

826

–

38

.

421

Patel

KK

,

Spertus

JA

,

Chan

PS

,

Sperry

BW

,

Thompson

RC

,

Al Badarin

F

, et al.

Extent of myocardial ischemia on positron emission tomography and survival benefit with early revascularization

.

J Am Coll Cardiol

2019

;

74

:

1645

–

54

.

10.1016/j.jacc.2019.07.055

422

Azadani

PN

,

Miller

RJH

,

Sharir

T

,

Diniz

MA

,

Hu

L-H

,

Otaki

Y

, et al.

Impact of early revascularization on major adverse cardiovascular events in relation to automatically quantified ischemia

.

JACC Cardiovasc Imaging

2021

;

14

:

644

–

53

.

10.1016/j.jcmg.2020.05.039

423

Sharir

T

,

Hollander

I

,

Hemo

B

,

Tsamir

J

,

Yefremov

N

,

Bojko

A

, et al.

Survival benefit of coronary revascularization after myocardial perfusion SPECT: the role of ischemia

.

J Nucl Cardiol

2021

;

28

:

1676

–

87

.

10.1007/s12350-019-01932-4

424

Ciampi

Q

,

Zagatina

A

,

Cortigiani

L

,

Wierzbowska-Drabik

K

,

Kasprzak

JD

,

Haberka

M

, et al.

Prognostic value of stress echocardiography assessed by the ABCDE protocol

.

Eur Heart J

2021

;

42

:

3869

–

78

.

10.1093/eurheartj/ehab493

425

Picano

E

,

Pierard

L

,

Peteiro

J

,

Djordjevic-Dikic

A

,

Sade

LE

,

Cortigiani

L

, et al.

The clinical use of stress echocardiography in chronic coronary syndromes and beyond coronary artery disease: a clinical consensus statement from the European Association of Cardiovascular Imaging of the ESC

.

Eur Heart J Cardiovasc Imaging

2023

;

25

:

e65

–

90

.

10.1093/ehjci/jead250

10.1016/j.jcin.2013.10.017

426

Mancini

GBJ

,

Hartigan

PM

,

Shaw

LJ

,

Berman

DS

,

Hayes

SW

,

Bates

ER

, et al.

Predicting outcome in the COURAGE trial (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation): coronary anatomy versus ischemia

.

JACC Cardiovasc Interv

2014

;

7

:

195

–

201

.

427

Weintraub

WS

,

Hartigan

PM

,

Mancini

GBJ

,

Teo

KK

,

Maron

DJ

,

Spertus

JA

, et al.

Effect of coronary anatomy and myocardial ischemia on long-term survival in patients with stable ischemic heart disease

.

Circ Cardiovasc Qual Outcomes

2019

;

12

:

e005079

.

10.1161/circoutcomes.118.005079

428

Al-Mallah

MH

,

Dilsizian

V

.

The impact of revascularization on mortality: a debate on patient selection bias vs entry bias

.

J Am Coll Cardiol

2022

;

80

:

216

–

8

.

10.1016/j.jacc.2022.04.051

429

Adjedj

J

,

De Bruyne

B

,

Floré

V

,

Di Gioia

G

,

Ferrara

A

,

Pellicano

M

, et al.

Significance of intermediate values of fractional flow reserve in patients with coronary artery disease

.

Circulation

2016

;

133

:

502

–

8

.

10.1161/circulationaha.115.018747

430

Fournier

S

,

Collet

C

,

Xaplanteris

P

,

Zimmermann

FM

,

Toth

GG

,

Tonino

PAL

, et al.

Global fractional flow reserve value predicts 5-year outcomes in patients with coronary atherosclerosis but without ischemia

.

J Am Heart Assoc

2020

;

9

:

e017729

.

10.1161/jaha.120.017729

431

Lee

JM

,

Koo

BK

,

Shin

ES

,

Nam

C-W

,

Doh

J-H

,

Hwang

D

, et al.

Clinical implications of three-vessel fractional flow reserve measurement in patients with coronary artery disease

.

Eur Heart J

2018

;

39

:

945

–

51

.

10.1093/eurheartj/ehx458

432

Collet

C

,

Miyazaki

Y

,

Ryan

N

,

Asano

T

,

Tenekecioglu

E

,

Sonck

J

, et al.

Fractional flow reserve derived from computed tomographic angiography in patients with multivessel CAD

.

J Am Coll Cardiol

2018

;

71

:

2756

–

69

.

10.1016/j.jacc.2018.02.053

433

Asano

T

,

Katagiri

Y

,

Chang

CC

,

Kogame

N

,

Chichareon

P

,

Takahashi

K

, et al.

Angiography-derived fractional flow reserve in the SYNTAX II trial: feasibility, diagnostic performance of quantitative flow ratio, and clinical prognostic value of functional SYNTAX score derived from quantitative flow ratio in patients with 3-vessel disease

.

JACC Cardiovasc Interv

2019

;

12

:

259

–

70

.

10.1016/j.jcin.2018.09.023

434

Zhang

R

,

Song

C

,

Guan

C

,

Liu

Q

,

Wang

C

,

Xie

L

, et al.

Prognostic value of quantitative flow ratio based functional SYNTAX score in patients with left main or multivessel coronary artery disease

.

Circ Cardiovasc Interv

2020

;

13

:

e009155

.

10.1161/circinterventions.120.009155

435

Shaw

LJ

,

Berman

DS

,

Picard

MH

,

Friedrich

MG

,

Kwong

RY

,

Stone

GW

, et al.

Comparative definitions for moderate-severe ischemia in stress nuclear, echocardiography, and magnetic resonance imaging

.

JACC Cardiovasc Imaging

2014

;

7

:

593

–

604

.

10.1016/j.jcmg.2013.10.021

436

Anderson

L

,

Brown

JP

,

Clark

AM

,

Dalal

H

,

Rossau

HKK

,

Bridges

C

, et al.

Patient education in the management of coronary heart disease

.

Cochrane Database Syst Rev

2017

;

6

:

CD008895

.

10.1002/14651858.CD008895.pub3

437

Collado-Mateo

D

,

Lavin-Perez

AM

,

Penacoba

C

,

Del Coso

J

,

Leyton-Román

M

,

Luque-Casado

A

, et al.

Key factors associated with adherence to physical exercise in patients with chronic diseases and older adults: an umbrella review

.

Int J Environ Res Public Health

2021

;

18

:

2023

.

10.3390/ijerph18042023

438

Kohler

AK

,

Jaarsma

T

,

Tingstrom

P

,

Nilsson

S

.

The effect of problem-based learning after coronary heart disease—a randomised study in primary health care (COR-PRIM)

.

BMC Cardiovasc Disord

2020

;

20

:

370

.

10.1186/s12872-020-01647-2

439

Alzaman

N

,

Wartak

SA

,

Friderici

J

,

Rothberg

MB

.

Effect of patients’ awareness of CVD risk factors on health-related behaviors

.

South Med J

2013

;

106

:

606

–

9

.

10.1097/SMJ.0000000000000013

440

Riegel

B

,

Jaarsma

T

,

Stromberg

A

.

A middle-range theory of self-care of chronic illness

.

ANS Adv Nurs Sci

2012

;

35

:

194

–

204

.

10.1097/ANS.0b013e318261b1ba

441

Astin

F

,

Lucock

M

,

Jennings

CS

.

Heart and mind: behavioural cardiology demystified for the clinician

.

Heart

2019

;

105

:

881

–

8

.

10.1136/heartjnl-2016-310750

442

Sheeran

P

,

Harris

PR

,

Epton

T

.

Does heightening risk appraisals change people’s intentions and behavior? A meta-analysis of experimental studies

.

Psychol Bull

2014

;

140

:

511

–

43

.

443

Zwack

CC

,

Smith

C

,

Poulsen

V

,

Raffoul

N

,

Redfern

J

.

Information needs and communication strategies for people with coronary heart disease: a scoping review

.

Int J Environ Res Public Health

2023

;

20

:

1723

.

10.3390/ijerph20031723

444

Navar

AM

,

Wang

TY

,

Mi

X

,

Robinson

JG

,

Virani

SS

,

Roger

VL

, et al.

Influence of cardiovascular risk communication tools and presentation formats on patient perceptions and preferences

.

JAMA Cardiol

2018

;

3

:

1192

–

9

.

10.1001/jamacardio.2018.3680

445

Whitmore

K

,

Zhou

Z

,

Chapman

N

,

Huynh

Q

,

Magnussen

CG

,

Sharman

JE

, et al.

Impact of patient visualization of cardiovascular images on modification of cardiovascular risk factors: systematic review and meta-analysis

.

JACC Cardiovasc Imaging

2023

;

16

:

1069

–

81

.

10.1016/j.jcmg.2023.03.007

446

Rossello

X

,

Dorresteijn

JA

,

Janssen

A

,

Lambrinou

E

,

Scherrenberg

M

,

Bonnefoy-Cudraz

E

, et al.

Risk prediction tools in cardiovascular disease prevention: a report from the ESC Prevention of CVD Programme led by the European Association of Preventive Cardiology (EAPC) in collaboration with the Acute Cardiovascular Care Association (ACCA) and the Association of Cardiovascular Nursing and Allied Professions (ACNAP)

.

Eur J Prev Cardiol

2019

;

26

:

1534

–

44

.

10.1177/2047487319846715

447

Critchley

J

,

Capewell

S

.

Smoking cessation for the secondary prevention of coronary heart disease

.

Cochrane Database Syst Rev

2004

:

CD003041

.

10.1002/14651858.CD003041.pub2

10.1002/14651858.CD006886.pub2

448

Barth

J

,

Jacob

T

,

Daha

I

,

Critchley

JA

.

Psychosocial interventions for smoking cessation in patients with coronary heart disease

.

Cochrane Database Syst Rev

2015

;

7

:

CD006886

.

10.1146/annurev-med-111314-033712

449

Prochaska

JJ

,

Benowitz

NL

.

The past, present, and future of nicotine addiction therapy

.

Annu Rev Med

2016

;

67

:

467

–

86

.

450

Suissa

K

,

Lariviere

J

,

Eisenberg

MJ

,

Eberg

M

,

Gore

GC

,

Grad

R

, et al.

Efficacy and safety of smoking cessation interventions in patients with cardiovascular disease: a network meta-analysis of randomized controlled trials

.

Circ Cardiovasc Qual Outcomes

2017

;

10

:

e002458

.

10.1161/CIRCOUTCOMES.115.002458

451

Lindson

N

,

Chepkin

SC

,

Ye

W

,

Fanshawe

TR

,

Bullen

C

,

Hartmann-Boyce

J

.

Different doses, durations and modes of delivery of nicotine replacement therapy for smoking cessation

.

Cochrane Database Syst Rev

2019

;

4

:

CD013308

.

10.1002/14651858.CD013308

452

Mills

EJ

,

Thorlund

K

,

Eapen

S

,

Wu

P

,

Prochaska

JJ

.

Cardiovascular events associated with smoking cessation pharmacotherapies: a network meta-analysis

.

Circulation

2014

;

129

:

28

–

41

.

10.1161/CIRCULATIONAHA.113.003961

453

Kavousi

M

,

Pisinger

C

,

Barthelemy

JC

,

De Smedt

D

,

Koskinas

K

,

Marques-Vidal

P

, et al.

Electronic cigarettes and health with special focus on cardiovascular effects: position paper of the European Association of Preventive Cardiology (EAPC)

.

Eur J Prev Cardiol

2020

;

28

:

1552

–

66

.

10.1177/2047487320941993

10.1002/14651858.CD010216.pub4

454

Qasim

H

,

Karim

ZA

,

Rivera

JO

,

Khasawneh

FT

,

Alshbool

FZ

.

Impact of electronic cigarettes on the cardiovascular system

.

J Am Heart Assoc

2017

;

6

:

e006353

.

10.1161/JAHA.117.006353

455

Hartmann-Boyce

J

,

McRobbie

H

,

Lindson

N

,

Bullen

C

,

Begh

R

,

Theodoulou

A

, et al.

Electronic cigarettes for smoking cessation

.

Cochrane Database Syst Rev

2020

;

10

:

CD010216

.

456

Abu Jad

AA

,

Ravanavena

A

,

Ravindra

C

,

Igweonu-Nwakile

EO

,

Ali

S

,

Paul

S

, et al.

Adverse effects of cannabinoids and tobacco consumption on the cardiovascular system: a systematic review

.

Cureus

2022

;

14

:

e29208

.

457

Schwartz

BG

,

Rezkalla

S

,

Kloner

RA

.

Cardiovascular effects of cocaine

.

Circulation

2010

;

122

:

2558

–

69

.

10.1161/CIRCULATIONAHA.110.940569

458

Singleton

JH

,

Abner

EL

,

Akpunonu

PD

,

Kucharska-Newton

AM

.

Association of nonacute opioid use and cardiovascular diseases: a scoping review of the literature

.

J Am Heart Assoc

2021

;

10

:

e021260

.

10.1161/JAHA.121.021260

459

DeFilippis

EM

,

Bajaj

NS

,

Singh

A

,

Malloy

R

,

Givertz

MM

,

Blankstein

R

, et al.

Marijuana use in patients with cardiovascular disease: JACC review topic of the week

.

J Am Coll Cardiol

2020

;

75

:

320

–

32

.

10.1016/j.jacc.2019.11.025

460

McNeely

J

,

Cleland

CM

,

Strauss

SM

,

Palamar

JJ

,

Rotrosen

J

,

Saitz

R

.

Validation of self-administered single-item screening questions (SISQS) for unhealthy alcohol and drug use in primary care patients

.

J Gen Intern Med

2015

;

30

:

1757

–

64

.

10.1007/s11606-015-3391-6

461

Khan

SS

,

Ning

H

,

Wilkins

JT

,

Allen

N

,

Carnethon

M

,

Berry

JD

, et al.

Association of body mass index with lifetime risk of cardiovascular disease and compression of morbidity

.

JAMA Cardiol

2018

;

3

:

280

–

7

.

10.1001/jamacardio.2018.0022

462

Pack

QR

,

Rodriguez-Escudero

JP

,

Thomas

RJ

,

Ades

PA

,

West

CP

,

Somers

VK

, et al.

The prognostic importance of weight loss in coronary artery disease: a systematic review and meta-analysis

.

Mayo Clin Proc

2014

;

89

:

1368

–

77

.

10.1016/j.mayocp.2014.04.033

463

Strelitz

J

,

Lawlor

ER

,

Wu

Y

,

Estlin

A

,

Nandakumar

G

,

Ahern

AL

, et al.

Association between weight change and incidence of cardiovascular disease events and mortality among adults with type 2 diabetes: a systematic review of observational studies and behavioural intervention trials

.

Diabetologia

2022

;

65

:

424

–

39

.

10.1007/s00125-021-05605-1

464

Rubino

DM

,

Greenway

FL

,

Khalid

U

,

O’Neil

PM

,

Rosenstock

J

,

Sørrig

R

, et al.

Effect of weekly subcutaneous semaglutide vs daily liraglutide on body weight in adults with overweight or obesity without diabetes: the STEP 8 randomized clinical trial

.

JAMA

2022

;

327

:

138

–

50

.

10.1001/jama.2021.23619

465

Lincoff

AM

,

Brown-Frandsen

K

,

Colhoun

HM

,

Deanfield

J

,

Emerson

SS

,

Esbjerg

S

, et al.

Semaglutide and cardiovascular outcomes in obesity without diabetes

.

N Engl J Med

2023

;

389

:

2221

–

32

.

10.1056/NEJMoa2307563

466

Jastreboff

AM

,

Aronne

LJ

,

Ahmad

NN

,

Wharton

S

,

Connery

L

,

Alves

B

, et al.

Tirzepatide once weekly for the treatment of obesity

.

N Engl J Med

2022

;

387

:

205

–

16

.

10.1056/NEJMoa2206038

467

Garvey

WT

,

Frias

JP

,

Jastreboff

AM

,

le Roux

CW

,

Sattar

N

,

Aizenberg

D

, et al.

Tirzepatide once weekly for the treatment of obesity in people with type 2 diabetes (SURMOUNT-2): a double-blind, randomised, multicentre, placebo-controlled, phase 3 trial

.

Lancet

2023

;

402

:

613

–

26

.

10.1016/S0140-6736(23)01200-X

468

Lopez-Jimenez

F

,

Bhatia

S

,

Collazo-Clavell

ML

,

Sarr

MG

,

Somers

VK

.

Safety and efficacy of bariatric surgery in patients with coronary artery disease

.

Mayo Clin Proc

2005

;

80

:

1157

–

62

.

469

De Bacquer

D

,

Jennings

CS

,

Mirrakhimov

E

,

Lovic

D

,

Bruthans

J

,

De Smedt

D

, et al.

Potential for optimizing management of obesity in the secondary prevention of coronary heart disease

.

Eur Heart J Qual Care Clin Outcomes

2022

;

8

:

568

–

76

.

10.1093/ehjqcco/qcab043

470

Wood

AM

,

Kaptoge

S

,

Butterworth

AS

,

Willeit

P

,

Warnakula

S

,

Bolton

T

, et al.

Risk thresholds for alcohol consumption: combined analysis of individual-participant data for 599

912 current drinkers in 83 prospective studies

.

Lancet

2018

;

391

:

1513

–

23

.

10.1016/S0140-6736(18)30134-X

471

Biddinger

KJ

,

Emdin

CA

,

Haas

ME

,

Wang

M

,

Hindy

G

,

Ellinor

PT

, et al.

Association of habitual alcohol intake with risk of cardiovascular disease

.

JAMA Netw Open

2022

;

5

:

e223849

.

10.1001/jamanetworkopen.2022.3849

472

Tully

PJ

,

Ang

SY

,

Lee

EJ

,

Bendig

E

,

Bauereiß

N

,

Bengel

J

, et al.

Psychological and pharmacological interventions for depression in patients with coronary artery disease

.

Cochrane Database Syst Rev

2021

;

12

:

CD008012

.

10.1002/14651858.CD008012.pub4

473

Kraus

WE

,

Powell

KE

,

Haskell

WL

,

Janz

KF

,

Campbell

WW

,

Jakicic

JM

, et al.

Physical activity, all-cause and cardiovascular mortality, and cardiovascular disease

.

Med Sci Sports Exerc

2019

;

51

:

1270

–

81

.

10.1249/MSS.0000000000001939

474

Hupin

D

,

Roche

F

,

Gremeaux

V

,

Chatard

J-C

,

Oriol

M

,

Gaspoz

J-M

, et al.

Even a low-dose of moderate-to-vigorous physical activity reduces mortality by 22% in adults aged ≥60 years: a systematic review and meta-analysis

.

Br J Sports Med

2015

;

49

:

1262

–

7

.

10.1136/bjsports-2014-094306

475

Arem

H

,

Moore

SC

,

Patel

A

,

Hartge

P

,

Berrington de Gonzalez

A

,

Visvanathan

K

, et al.

Leisure time physical activity and mortality: a detailed pooled analysis of the dose-response relationship

.

JAMA Intern Med

2015

;

175

:

959

–

67

.

10.1001/jamainternmed.2015.0533

476

Bull

FC

,

Al-Ansari

SS

,

Biddle

S

,

Borodulin

K

,

Buman

MP

,

Cardon

G

, et al.

World Health Organization 2020 guidelines on physical activity and sedentary behaviour

.

Br J Sports Med

2020

;

54

:

1451

–

62

.

10.1136/bjsports-2020-102955

477

O’Donovan

G

,

Lee

IM

,

Hamer

M

,

Stamatakis

E

.

Association of “weekend warrior” and other leisure time physical activity patterns with risks for all-cause, cardiovascular disease, and cancer mortality

.

JAMA Intern Med

2017

;

177

:

335

–

42

.

10.1001/jamainternmed.2016.8014

478

Jakicic

JM

,

Kraus

WE

,

Powell

KE

,

Campbell

WW

,

Janz

KF

,

Troiano

RP

, et al.

Association between bout duration of physical activity and health: systematic review

.

Med Sci Sports Exerc

2019

;

51

:

1213

–

9

.

10.1249/MSS.0000000000001933

479

Ekelund

U

,

Tarp

J

,

Steene-Johannessen

J

,

Hansen

BH

,

Jefferis

B

,

Fagerland

MW

, et al.

Dose-response associations between accelerometry measured physical activity and sedentary time and all cause mortality: systematic review and harmonised meta-analysis

.

BMJ

2019

;

366

:

l4570

.

480

Anderson

L

,

Thompson

DR

,

Oldridge

N

,

Zwisler

A-D

,

Rees

K

,

Martin

N

, et al.

Exercise-based cardiac rehabilitation for coronary heart disease

.

Cochrane Database Syst Rev

2016

;

1

:

CD001800

.

10.1002/14651858.CD001800.pub3

10.1016/j.mayocp.2017.07.019

481

Santiago de Araujo Pio

C

,

Marzolini

S

,

Pakosh

M

,

Grace

SL

.

Effect of cardiac rehabilitation dose on mortality and morbidity: a systematic review and meta-regression analysis

.

Mayo Clin Proc

2017

;

92

:

1644

–

59

.

482

Salzwedel

A

,

Jensen

K

,

Rauch

B

,

Doherty

P

,

Metzendorf

M-I

,

Hackbusch

M

, et al.

Effectiveness of comprehensive cardiac rehabilitation in coronary artery disease patients treated according to contemporary evidence based medicine: update of the Cardiac Rehabilitation Outcome Study (CROS-II)

.

Eur J Prev Cardiol

2020

;

27

:

1756

–

74

.

10.1177/2047487320905719

483

Dibben

G

,

Faulkner

J

,

Oldridge

N

,

Rees

K

,

Thompson

DR

,

Zwisler

A-D

, et al.

Exercise-based cardiac rehabilitation for coronary heart disease

.

Cochrane Database Syst Rev

2021

;

11

:

CD001800

.

10.1002/14651858.CD001800.pub4

484

Ambrosetti

M

,

Abreu

A

,

Corra

U

,

Davos

CH

,

Hansen

D

,

Frederix

I

, et al.

Secondary prevention through comprehensive cardiovascular rehabilitation: from knowledge to implementation. 2020 update. A position paper from the Secondary Prevention and Rehabilitation Section of the European Association of Preventive Cardiology

.

Eur J Prev Cardiol

2020

;

28

:

460

–

95

.

10.1177/2047487320913379

10.1007/s40279-018-0930-4

485

Hansen

D

,

Abreu

A

,

Ambrosetti

M

,

Cornelissen

V

,

Gevaert

A

,

Kemps

H

, et al.

Exercise intensity assessment and prescription in cardiovascular rehabilitation and beyond: why and how: a position statement from the Secondary Prevention and Rehabilitation Section of the European Association of Preventive Cardiology

.

Eur J Prev Cardiol

2022

;

29

:

230

–

45

.

10.1093/eurjpc/zwab007

486

Hansen

D

,

Niebauer

J

,

Cornelissen

V

,

Barna

O

,

Neunhäuserer

D

,

Stettler

C

, et al.

Exercise prescription in patients with different combinations of cardiovascular disease risk factors: a consensus statement from the EXPERT working group

.

Sports Med

2018

;

48

:

1781

–

97

.

487

Abell

B

,

Glasziou

P

,

Hoffmann

T

.

The contribution of individual exercise training components to clinical outcomes in randomised controlled trials of cardiac rehabilitation: a systematic review and meta-regression

.

Sports Med Open

2017

;

3

:

19

.

10.1186/s40798-017-0086-z

488

Sanchez-Delgado

JC

,

Camargo Sepulveda

DC

,

Cardona Zapata

A

,

Franco Pico

MY

,

Santos Blanco

LM

,

Jácome Hortúa

AM

, et al.

The effects of maintenance cardiac rehabilitation: a systematic review

.

J Cardiopulm Rehabil Prev

2020

;

40

:

224

–

44

.

10.1097/HCR.0000000000000520

489

Piepoli

MF

,

Corra

U

,

Dendale

P

,

Frederix

I

,

Prescott

E

,

Schmid

JP

, et al.

Challenges in secondary prevention after acute myocardial infarction: a call for action

.

Eur J Prev Cardiol

2016

;

23

:

1994

–

2006

.

10.1177/2047487316663873

490

Gomes-Neto

M

,

Duraes

AR

,

Reis

H

,

Neves

VR

,

Martinez

BP

,

Carvalho

VO

.

High-intensity interval training versus moderate-intensity continuous training on exercise capacity and quality of life in patients with coronary artery disease: a systematic review and meta-analysis

.

Eur J Prev Cardiol

2017

;

24

:

1696

–

707

.

10.1177/2047487317728370

491

Franssen

WMA

,

Franssen

G

,

Spaas

J

,

Solmi

F

,

Eijnde

BO

.

Can consumer wearable activity tracker-based interventions improve physical activity and cardiometabolic health in patients with chronic diseases? A systematic review and meta-analysis of randomised controlled trials

.

Int J Behav Nutr Phys Act

2020

;

17

:

57

.

10.1186/s12966-020-00955-2

492

Santiago de Araujo Pio

C

,

Chaves

GS

,

Davies

P

,

Taylor

RS

,

Grace

SL

.

Interventions to promote patient utilisation of cardiac rehabilitation

.

Cochrane Database Syst Rev

2019

;

2

:

CD007131

.

10.1002/14651858.CD007131.pub4

493

Anderson

L

,

Sharp

GA

,

Norton

RJ

,

Dalal

H

,

Dean

SG

,

Jolly

K

, et al.

Home-based versus centre-based cardiac rehabilitation

.

Cochrane Database Syst Rev

2017

;

6

:

CD007130

.

10.1002/14651858.CD007130.pub4

494

Jin

K

,

Khonsari

S

,

Gallagher

R

,

Gallagher

P

,

Clark

AM

,

Freedman

B

, et al.

Telehealth interventions for the secondary prevention of coronary heart disease: a systematic review and meta-analysis

.

Eur J Cardiovasc Nurs

2019

;

18

:

260

–

71

.

10.1177/1474515119826510

495

Cruz-Cobo

C

,

Bernal-Jimenez

MA

,

Vazquez-Garcia

R

,

Santi-Cano

MJ

.

Effectiveness of mHealth interventions in the control of lifestyle and cardiovascular risk factors in patients after a coronary event: systematic review and meta-analysis

.

JMIR Mhealth Uhealth

2022

;

10

:

e39593

.

496

Hamilton

SJ

,

Mills

B

,

Birch

EM

,

Thompson

SC

.

Smartphones in the secondary prevention of cardiovascular disease: a systematic review

.

BMC Cardiovasc Disord

2018

;

1

:

25

.

10.1186/s12872-018-0764-x

10.1007/s11936-018-0667-2

497

Kissel

CK

,

Nikoletou

D

.

Cardiac rehabilitation and exercise prescription in symptomatic patients with non-obstructive coronary artery disease—a systematic review

.

Curr Treat Options Cardiovasc Med

2018

;

20

:

78

.

498

Keteyian

SJ

,

Brawner

CA

,

Savage

PD

,

Ehrman

JK

,

Schairer

J

,

Divine

G

, et al.

Peak aerobic capacity predicts prognosis in patients with coronary heart disease

.

Am Heart J

2008

;

156

:

292

–

300

.

10.1016/j.ahj.2008.03.017

499

Critchley

JA

,

Capewell

S

.

Mortality risk reduction associated with smoking cessation in patients with coronary heart disease: a systematic review

.

JAMA

2003

;

290

:

86

–

97

.

10.1001/jama.290.1.86

500

Held

C

,

Hadziosmanovic

N

,

Aylward

PE

,

Hagström

E

,

Hochman

JS

,

Stewart

RAH

, et al.

Body mass index and association with cardiovascular outcomes in patients with stable coronary heart disease—a STABILITY substudy

.

J Am Heart Assoc

2022

;

11

:

e023667

.

10.1161/JAHA.121.023667

501

Stewart

RA

,

Wallentin

L

,

Benatar

J

,

Danchin

N

,

Hagström

E

,

Held

C

, et al.

Dietary patterns and the risk of major adverse cardiovascular events in a global study of high-risk patients with stable coronary heart disease

.

Eur Heart J

2016

;

37

:

1993

–

2001

.

10.1093/eurheartj/ehw125

502

Stewart

RAH

,

Held

C

,

Hadziosmanovic

N

,

Armstrong

PW

,

Cannon

CP

,

Granger

CB

, et al.

Physical activity and mortality in patients with stable coronary heart disease

.

J Am Coll Cardiol

2017

;

70

:

1689

–

700

.

10.1016/j.jacc.2017.08.017

503

Artinian

NT

,

Fletcher

GF

,

Mozaffarian

D

,

Kris-Etherton

P

,

Van Horn

L

,

Lichtenstein

AH

, et al.

Interventions to promote physical activity and dietary lifestyle changes for cardiovascular risk factor reduction in adults: a scientific statement from the American Heart Association

.

Circulation

2010

;

122

:

406

–

41

.

10.1161/CIR.0b013e3181e8edf1

504

Ferrari

R

,

Pavasini

R

,

Camici

PG

,

Crea

F

,

Danchin

N

,

Pinto

F

, et al.

Anti-anginal drugs-beliefs and evidence: systematic review covering 50 years of medical treatment

.

Eur Heart J

2019

;

40

:

190

–

4

.

10.1093/eurheartj/ehy504

505

Belsey

J

,

Savelieva

I

,

Mugelli

A

,

Camm

AJ

.

Relative efficacy of antianginal drugs used as add-on therapy in patients with stable angina: a systematic review and meta-analysis

.

Eur J Prev Cardiol

2015

;

22

:

837

–

48

.

10.1177/2047487314533217

506

Pavasini

R

,

Camici

PG

,

Crea

F

,

Danchin

N

,

Fox

K

,

Manolis

AJ

, et al.

Anti-anginal drugs: systematic review and clinical implications

.

Int J Cardiol

2019

;

283

:

55

–

63

.

10.1016/j.ijcard.2018.12.008

507

Tardif

JC

,

Ford

I

,

Tendera

M

,

Bourassa

MG

,

Fox

K

;

INITIATIVE Investigators

.

Efficacy of ivabradine, a new selective I_f inhibitor, compared with atenolol in patients with chronic stable angina

.

Eur Heart J

2005

;

26

:

2529

–

36

.

10.1093/eurheartj/ehi586

508

Ruzyllo

W

,

Tendera

M

,

Ford

I

,

Fox

KM

.

Antianginal efficacy and safety of ivabradine compared with amlodipine in patients with stable effort angina pectoris: a 3-month randomised, double-blind, multicentre, noninferiority trial

.

Drugs

2007

;

67

:

393

–

405

.

10.2165/00003495-200767030-00005

509

Fox

K

,

Ford

I

,

Steg

PG

,

Tardif

J-C

,

Tendera

M

,

Ferrari

R

, et al.

Ivabradine in stable coronary artery disease without clinical heart failure

.

N Engl J Med

2014

;

371

:

1091

–

9

.

10.1056/NEJMoa1406430

510

Sorbets

E

,

Steg

PG

,

Young

R

,

Danchin

N

,

Greenlaw

N

,

Ford

I

, et al.

Beta-blockers, calcium antagonists, and mortality in stable coronary artery disease: an international cohort study

.

Eur Heart J

2019

;

40

:

1399

–

407

.

10.1093/eurheartj/ehy811

511

Steg

PG

,

Greenlaw

N

,

Tendera

M

,

Tardif

J-C

,

Ferrari

R

,

Al-Zaibag

M

, et al.

Prevalence of anginal symptoms and myocardial ischemia and their effect on clinical outcomes in outpatients with stable coronary artery disease: data from the International Observational CLARIFY Registry

.

JAMA Intern Med

2014

;

174

:

1651

–

9

.

10.1001/jamainternmed.2014.3773

512

Ford

TJ

,

Berry

C

.

Angina: contemporary diagnosis and management

.

Heart

2020

;

106

:

387

–

98

.

10.1136/heartjnl-2018-314661

513

Ferrari

R

,

Camici

PG

,

Crea

F

,

Danchin

N

,

Fox

K

,

Maggioni

AP

, et al.

Expert consensus document: a ‘diamond’ approach to personalized treatment of angina

.

Nat Rev Cardiol

2018

;

15

:

120

–

32

.

10.1038/nrcardio.2017.131

514

Fihn

SD

,

Gardin

JM

,

Abrams

J

,

Berra

K

,

Blankenship

JC

,

Dallas

AP

, et al.

2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS Guideline for the diagnosis and management of patients with stable ischemic heart disease: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, and the American College of Physicians, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons

.

J Am Coll Cardiol

2012

;

60

:

e44

–

164

.

10.1016/j.jacc.2012.07.013

515

Manolis

AJ

,

Boden

WE

,

Collins

P

,

Dechend

R

,

Kallistratos

MS

,

Lopez Sendon

J

, et al.

State of the art approach to managing angina and ischemia: tailoring treatment to the evidence

.

Eur J Intern Med

2021

;

92

:

40

–

7

.

10.1016/j.ejim.2021.08.003

516

Bertero

E

,

Heusch

G

,

Munzel

T

,

Maack

C

.

A pathophysiological compass to personalize antianginal drug treatment

.

Nat Rev Cardiol

2021

;

18

:

838

–

52

.

10.1038/s41569-021-00573-w

517

Jouven

X

,

Empana

JP

,

Schwartz

PJ

,

Desnos

M

,

Courbon

D

,

Ducimetière

P

.

Heart-rate profile during exercise as a predictor of sudden death

.

N Engl J Med

2005

;

352

:

1951

–

8

.

518

Shu

DF

,

Dong

BR

,

Lin

XF

,

Wu

TX

,

Liu

GJ

.

Long-term beta blockers for stable angina: systematic review and meta-analysis

.

Eur J Prev Cardiol

2012

;

19

:

330

–

41

.

10.1177/1741826711409325

519

Freemantle

N

,

Cleland

J

,

Young

P

,

Mason

J

,

Harrison

J

.

β Blockade after myocardial infarction: systematic review and meta regression analysis

.

BMJ

1999

;

318

:

1730

–

7

.

10.1136/bmj.318.7200.1730

520

Martínez-Milla

J

,

Raposeiras-Roubín

S

,

Pascual-Figal

DA

,

Ibáñez

B

.

Role of beta-blockers in cardiovascular disease in 2019

.

Rev Esp Cardiol (Engl Ed)

2019

;

72

:

844

–

52

.

10.1016/j.rec.2019.04.014

521

Dahl Aarvik

M

,

Sandven

I

,

Dondo

TB

,

Gale

CP

,

Ruddox

V

,

Munkhaugen

J

, et al.

Effect of oral beta-blocker treatment on mortality in contemporary post-myocardial infarction patients: a systematic review and meta-analysis

.

Eur Heart J Cardiovasc Pharmacother

2019

;

5

:

12

–

20

.

10.1093/ehjcvp/pvy034

522

Rossello

X

,

Raposeiras-Roubin

S

,

Latini

R

,

Dominguez-Rodriguez

A

,

Barrabés

JA

,

Sánchez

PL

, et al.

Rationale and design of the pragmatic clinical trial tREatment with Beta-blockers after myOcardial infarction withOut reduced ejection fracTion (REBOOT)

.

Eur Heart J Cardiovasc Pharmacother

2022

;

8

:

291

–

301

.

10.1093/ehjcvp/pvab060

523

Raposeiras-Roubín

S

,

Abu-Assi

E

,

Redondo-Diéguez

A

,

González-Ferreiro

R

,

López-López

A

,

Bouzas-Cruz

N

, et al.

Prognostic benefit of beta-blockers after acute coronary syndrome with preserved systolic function. Still relevant today?

Rev Esp Cardiol (Engl Ed)

2015

;

68

:

585

–

91

.

10.1016/j.rec.2014.07.028

524

Dondo

TB

,

Hall

M

,

West

RM

,

Jernberg

T

,

Lindahl

B

,

Bueno

H

, et al.

β-Blockers and mortality after acute myocardial infarction in patients without heart failure or ventricular dysfunction

.

J Am Coll Cardiol

2017

;

69

:

2710

–

20

.

10.1016/j.jacc.2017.03.578

525

Kim

J

,

Kang

D

,

Park

H

,

Kang

M

,

Park

TK

,

Lee

JM

, et al.

Long-term β-blocker therapy and clinical outcomes after acute myocardial infarction in patients without heart failure: nationwide cohort study

.

Eur Heart J

2020

;

41

:

3521

–

9

.

10.1093/eurheartj/ehaa376

526

McDonagh

TA

,

Metra

M

,

Adamo

M

,

Gardner

RS

,

Baumbach

A

,

Böhm

M

, et al.

2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: developed by the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) With the special contribution of the Heart Failure Association (HFA) of the ESC

.

Eur Heart J

2021

;

42

:

3599

–

726

.

10.1093/eurheartj/ehab368

527

Watanabe

H

,

Ozasa

N

,

Morimoto

T

,

Shiomi

H

,

Bingyuan

B

,

Suwa

S

, et al.

Long-term use of carvedilol in patients with ST-segment elevation myocardial infarction treated with primary percutaneous coronary intervention

.

PLoS One

2018

;

13

:

e0199347

.

10.1371/journal.pone.0199347

528

Munkhaugen

J

,

Ruddox

V

,

Halvorsen

S

,

Dammen

T

,

Fagerland

MW

,

Hernæs

KH

, et al.

BEtablocker Treatment After acute Myocardial Infarction in revascularized patients without reduced left ventricular ejection fraction (BETAMI): rationale and design of a prospective, randomized, open, blinded end point study

.

Am Heart J

2019

;

208

:

37

–

46

.

10.1016/j.ahj.2018.10.005

529

Kristensen

AMD

,

Bovin

A

,

Zwisler

AD

,

Cerquira

C

,

Torp-Pedersen

C

,

Bøtker

HE

, et al.

Design and rationale of the Danish trial of beta-blocker treatment after myocardial infarction without reduced ejection fraction: study protocol for a randomized controlled trial

.

Trials

2020

;

21

:

415

.

10.1186/s13063-020-4214-6

530

Yndigegn

T

,

Lindahl

B

,

Alfredsson

J

,

Benatar

J

,

Brandin

L

,

Erlinge

D

, et al.

Design and rationale of randomized evaluation of decreased usage of beta-blockers after acute myocardial infarction (REDUCE-AMI)

.

Eur Heart J Cardiovasc Pharmacother

2023

;

9

:

192

–

7

.

10.1093/ehjcvp/pvac070

531

Rossello

X

,

Pocock

SJ

,

Julian

DG

.

Long-term use of cardiovascular drugs: challenges for research and for patient care

.

J Am Coll Cardiol

2015

;

66

:

1273

–

85

.

10.1016/j.jacc.2015.07.018

532

Puymirat

E

,

Riant

E

,

Aissaoui

N

,

Soria

A

,

Ducrocq

G

,

Coste

P

, et al.

β Blockers and mortality after myocardial infarction in patients without heart failure: multicentre prospective cohort study

.

BMJ

2016

;

354

:

i4801

.

533

Ishak

D

,

Aktaa

S

,

Lindhagen

L

,

Alfredsson

J

,

Dondo

TB

,

Held

C

, et al.

Association of beta-blockers beyond 1 year after myocardial infarction and cardiovascular outcomes

.

Heart

2023

;

109

:

1159

–

65

.

10.1136/heartjnl-2022-322115

534

Neumann

A

,

Maura

G

,

Weill

A

,

Alla

F

,

Danchin

N

.

Clinical events after discontinuation of beta-blockers in patients without heart failure optimally treated after acute myocardial infarction: a cohort study on the French healthcare databases

.

Circ Cardiovasc Qual Outcomes

2018

;

11

:

e004356

.

10.1161/CIRCOUTCOMES.117.004356

535

Zeitouni

M

,

Kerneis

M

,

Lattuca

B

,

Guedeney

P

,

Cayla

G

,

Collet

J-P

, et al.

Do patients need lifelong β-blockers after an uncomplicated myocardial infarction?

Am J Cardiovasc Drugs

2019

;

19

:

431

–

8

.

10.1007/s40256-019-00338-4

536

van de Ven

LL

,

Vermeulen

A

,

Tans

JG

,

Tans

AC

,

Liem

KL

,

Lageweg

NC

, et al.

Which drug to choose for stable angina pectoris: a comparative study between bisoprolol and nitrates

.

Int J Cardiol

1995

;

47

:

217

–

23

.

10.1016/0167-5273(94)02194-n

537

Ueberbacher

HJ

,

Patyna

WD

,

Krepp

P

,

Puespoek

J

,

Neuhaus

R

,

Hilbich

K

, et al.

[Randomized, double-blind comparison of isosorbide-5-mononitrate and delayed-action nifedipine in patients with stable exertional angina. Multicenter Study Group]

.

Schweiz Med Wochenschr

1991

;

121

:

1836

–

40

.

10.1016/0735-1097(94)00436-t

538

Davies

RF

,

Habibi

H

,

Klinke

WP

,

Dessain

P

,

Nadeau

C

,

Phaneuf

DC

, et al.

Effect of amlodipine, atenolol and their combination on myocardial ischemia during treadmill exercise and ambulatory monitoring. Canadian Amlodipine/Atenolol in Silent Ischemia Study (CASIS) Investigators

.

J Am Coll Cardiol

1995

;

25

:

619

–

25

.

539

Klein

WW

,

Jackson

G

,

Tavazzi

L

.

Efficacy of monotherapy compared with combined antianginal drugs in the treatment of chronic stable angina pectoris: a meta-analysis

.

Coron Artery Dis

2002

;

13

:

427

–

36

.

10.1097/00019501-200212000-00008

540

Wei

J

,

Wu

T

,

Yang

Q

,

Chen

M

,

Ni

J

,

Huang

D

.

Nitrates for stable angina: a systematic review and meta-analysis of randomized clinical trials

.

Int J Cardiol

2011

;

146

:

4

–

12

.

10.1016/j.ijcard.2010.05.019

541

Fox

K

,

Ford

I

,

Steg

PG

,

Tendera

M

,

Robertson

M

,

Ferrari

R

, et al.

Heart rate as a prognostic risk factor in patients with coronary artery disease and left-ventricular systolic dysfunction (BEAUTIFUL): a subgroup analysis of a randomised controlled trial

.

Lancet

2008

;

372

:

817

–

21

.

10.1016/s0140-6736(08)61171-x

542

Fox

K

,

Ford

I

,

Steg

PG

,

Tendera

M

,

Robertson

M

,

Ferrari

R

, et al.

Relationship between ivabradine treatment and cardiovascular outcomes in patients with stable coronary artery disease and left ventricular systolic dysfunction with limiting angina: a subgroup analysis of the randomized, controlled BEAUTIFUL trial

.

Eur Heart J

2009

;

30

:

2337

–

45

.

10.1093/eurheartj/ehp358

543

Jiang

J

,

Li

Y

,

Zhou

Y

,

Li

X

,

Li

H

,

Tang

B

, et al.

Oral nicorandil reduces ischemic attacks in patients with stable angina: a prospective, multicenter, open-label, randomized, controlled study

.

Int J Cardiol

2016

;

224

:

183

–

7

.

10.1016/j.ijcard.2016.08.305

544

Horinaka

S

,

Yabe

A

,

Yagi

H

,

Ishimitsu

T

,

Yamazaki

T

,

Suzuki

S

, et al.

Effects of nicorandil on cardiovascular events in patients with coronary artery disease in the Japanese Coronary Artery Disease (JCAD) study

.

Circ J

2010

;

74

:

503

–

9

.

10.1253/circj.cj-09-0649

545

Zhu

WL

,

Shan

YD

,

Guo

JX

,

Wei

J-P

,

Yang

X-C

,

Li

T-D

, et al.

Double-blind, multicenter, active-controlled, randomized clinical trial to assess the safety and efficacy of orally administered nicorandil in patients with stable angina pectoris in China

.

Circ J

2007

;

71

:

826

–

33

.

546

IONA study group

.

Effect of nicorandil on coronary events in patients with stable angina: the Impact Of Nicorandil in Angina (IONA) randomised trial

.

Lancet

2002

;

359

:

1269

–

75

.

10.1016/s0140-6736(02)08265-x

10.1097/00005344-199206203-00013

547

Di Somma

S

,

Liguori

V

,

Petitto

M

,

Carotenuto

A

,

Bokor

D

,

de Divitiis

O

, et al.

A double-blind comparison of nicorandil and metoprolol in stable effort angina pectoris

.

Cardiovasc Drugs Ther

1993

;

7

:

119

–

23

.

548

Döring

G

.

Antianginal and anti-ischemic efficacy of nicorandil in comparison with isosorbide-5-mononitrate and isosorbide dinitrate: results from two multicenter, double-blind, randomized studies with stable coronary heart disease patients

.

J Cardiovasc Pharmacol

1992

;

20 Suppl 3

:

S74

–

81

.

549

Zhao

Y

,

Peng

L

,

Luo

Y

,

Li

S

,

Zheng

Z

,

Dong

R

, et al.

Trimetazidine improves exercise tolerance in patients with ischemic heart disease: a meta-analysis

.

Herz

2016

;

41

:

514

–

22

.

10.1007/s00059-015-4392-2

550

Peng

S

,

Zhao

M

,

Wan

J

,

Fang

Q

,

Fang

D

,

Li

K

.

The efficacy of trimetazidine on stable angina pectoris: a meta-analysis of randomized clinical trials

.

Int J Cardiol

2014

;

177

:

780

–

5

.

10.1016/j.ijcard.2014.10.149

551

Beltrame

JF

.

Ivabradine and the SIGNIFY conundrum

.

Eur Heart J

2015

;

36

:

3297

–

9

.

10.1093/eurheartj/ehv368

552

Dittrich

H

,

Henneke

KH

,

Pohlmann

M

,

Pongratz

G

,

Bachmann

K

.

Provocation of left ventricular outflow tract obstruction in patients with hypertrophic cardiomyopathy. Comparison of orthostasis testing and nitrate application

.

Int J Card Imaging

1996

;

12

:

249

–

55

.

553

Stauffer

JC

,

Ruiz

V

,

Morard

JD

.

Subaortic obstruction after sildenafil in a patient with hypertrophic cardiomyopathy

.

N Engl J Med

1999

;

341

:

700

–

1

.

10.1056/NEJM199908263410916

554

Glikson

M

,

Nielsen

JC

,

Kronborg

MB

,

Michowitz

Y

,

Auricchio

A

,

Barbash

IM

, et al.

2021 ESC Guidelines on cardiac pacing and cardiac resynchronization therapy

.

Eur Heart J

2021

;

42

:

3427

–

520

.

10.1093/eurheartj/ehab364

555

Davies

A

,

Fox

K

,

Galassi

AR

,

Banai

S

,

Ylä-Herttuala

S

,

Lüscher

TF

.

Management of refractory angina: an update

.

Eur Heart J

2021

;

42

:

269

–

83

.

10.1093/eurheartj/ehaa820

556

Valgimigli

M

,

Bueno

H

,

Byrne

RA

,

Collet

J-P

,

Costa

F

,

Jeppsson

A

, et al.

2017 ESC focused update on dual antiplatelet therapy in coronary artery disease developed in collaboration with EACTS: the Task Force for dual antiplatelet therapy in coronary artery disease of the European Society of Cardiology (ESC) and of the European Association for Cardio-Thoracic Surgery (EACTS)

.

Eur Heart J

2018

;

39

:

213

–

60

.

10.1093/eurheartj/ehx419

557

Juul-Moller

S

,

Edvardsson

N

,

Jahnmatz

B

,

Rosén

A

,

Sørensen

S

,

Omblus

R

.

Double-blind trial of aspirin in primary prevention of myocardial infarction in patients with stable chronic angina pectoris. The Swedish Angina Pectoris Aspirin Trial (SAPAT) Group

.

Lancet

1992

;

340

:

1421

–

5

.

10.1016/0140-6736(92)92619-q

558

Antithrombotic Trialists’ (ATT) Collaboration

;

Baigent

C

,

Blackwell

L

,

Collins

R

,

Emberson

J

,

Godwin

J

, et al.

Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials

.

Lancet

2009

;

373

:

1849

–

60

.

10.1016/s0140-6736(09)60503-1

559

Antithrombotic Trialists’ Collaboration

.

Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients

.

BMJ

2002

;

324

:

71

–

86

.

10.1136/bmj.324.7329.71

10.1016/j.jacc.2023.04.051

560

Patrono

C

,

Garcia Rodriguez

LA

,

Landolfi

R

,

Baigent

C

.

Low-dose aspirin for the prevention of atherothrombosis

.

N Engl J Med

2005

;

353

:

2373

–

83

.

561

Jones

WS

,

Mulder

H

,

Wruck

LM

,

Pencina

MJ

,

Kripalani

S

,

Muñoz

D

, et al.

Comparative effectiveness of aspirin dosing in cardiovascular disease

.

N Engl J Med

2021

;

384

:

1981

–

90

.

10.1056/NEJMoa2102137

562

Gragnano

F

,

Cao

D

,

Pirondini

L

,

Franzone

A

,

Kim

H-S

,

von Scheidt

M

, et al.

P2Y₁₂ inhibitor or aspirin monotherapy for secondary prevention of coronary events

.

J Am Coll Cardiol

2023

;

82

:

89

–

105

.

563

Chiarito

M

,

Sanz-Sanchez

J

,

Cannata

F

,

Cao

D

,

Sturla

M

,

Panico

C

, et al.

Monotherapy with a P2Y₁₂ inhibitor or aspirin for secondary prevention in patients with established atherosclerosis: a systematic review and meta-analysis

.

Lancet

2020

;

395

:

1487

–

95

.

10.1016/S0140-6736(20)30315-9

564

CAPRIE Steering Committee

.

A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE)

.

Lancet

1996

;

348

:

1329

–

39

.

10.1016/s0140-6736(96)09457-3

10.1016/S0140-6736(21)01063-1

565

Koo

BK

,

Kang

J

,

Park

KW

,

Rhee

T-M

,

Yang

H-M

,

Won

K-B

, et al.

Aspirin versus clopidogrel for chronic maintenance monotherapy after percutaneous coronary intervention (HOST-EXAM): an investigator-initiated, prospective, randomised, open-label, multicentre trial

.

Lancet

2021

;

397

:

2487

–

96

.

566

Kang

J

,

Park

KW

,

Lee

H

,

Hwang

D

,

Yang

H-M

,

Rha

S-W

, et al.

Aspirin versus clopidogrel for long-term maintenance monotherapy after percutaneous coronary intervention: the HOST-EXAM Extended study

.

Circulation

2023

;

147

:

108

–

17

.

10.1161/circulationaha.122.062770

567

Gurbel

PA

,

Bliden

KP

,

Butler

K

,

Tantry

US

,

Gesheff

T

,

Wei

C

, et al.

Randomized double-blind assessment of the ONSET and OFFSET of the antiplatelet effects of ticagrelor versus clopidogrel in patients with stable coronary artery disease: the ONSET/OFFSET study

.

Circulation

2009

;

120

:

2577

–

85

.

10.1161/CIRCULATIONAHA.109.912550

568

Storey

RF

,

Angiolillo

DJ

,

Patil

SB

,

Desai

B

,

Ecob

R

,

Husted

S

, et al.

Inhibitory effects of ticagrelor compared with clopidogrel on platelet function in patients with acute coronary syndromes: the PLATO (PLATelet inhibition and patient Outcomes) PLATELET substudy

.

J Am Coll Cardiol

2010

;

56

:

1456

–

62

.

10.1016/j.jacc.2010.03.100

569

Wallentin

L

,

Becker

RC

,

Budaj

A

,

Cannon

CP

,

Emanuelsson

H

,

Held

C

, et al.

Ticagrelor versus clopidogrel in patients with acute coronary syndromes

.

N Engl J Med

2009

;

361

:

1045

–

57

.

10.1056/NEJMoa0904327

570

Vranckx

P

,

Valgimigli

M

,

Juni

P

,

Hamm

C

,

Steg

PG

,

Heg

D

, et al.

Ticagrelor plus aspirin for 1 month, followed by ticagrelor monotherapy for 23 months vs aspirin plus clopidogrel or ticagrelor for 12 months, followed by aspirin monotherapy for 12 months after implantation of a drug-eluting stent: a multicentre, open-label, randomised superiority trial

.

Lancet

2018

;

392

:

940

–

9

.

10.1016/S0140-6736(18)31858-0

571

Franzone

A

,

McFadden

E

,

Leonardi

S

,

Piccolo

R

,

Vranckx

P

,

Serruys

PW

, et al.

ticagrelor alone versus dual antiplatelet therapy from 1 month after drug-eluting coronary stenting

.

J Am Coll Cardiol

2019

;

74

:

2223

–

34

.

10.1016/j.jacc.2019.08.1038

572

Ono

M

,

Hara

H

,

Kawashima

H

,

Gao

C

,

Wang

R

,

Wykrzykowska

JJ

, et al.

Ticagrelor monotherapy versus aspirin monotherapy at 12 months after percutaneous coronary intervention: a landmark analysis of the GLOBAL LEADERS trial

.

EuroIntervention

2022

;

18

:

e377

–

88

.

10.4244/EIJ-D-21-00870

573

Mehran

R

,

Baber

U

,

Sharma

SK

,

Cohen

DJ

,

Angiolillo

DJ

,

Briguori

C

, et al.

Ticagrelor with or without aspirin in high-risk patients after PCI

.

N Engl J Med

2019

;

381

:

2032

–

42

.

10.1056/NEJMoa1908419

574

O’Donoghue

ML

,

Murphy

SA

,

Sabatine

MS

.

The safety and efficacy of aspirin discontinuation on a background of a P2Y₁₂ inhibitor in patients after percutaneous coronary intervention: a systematic review and meta-analysis

.

Circulation

2020

;

142

:

538

–

45

.

10.1161/CIRCULATIONAHA.120.046251

575

Vranckx

P

,

Valgimigli

M

,

Windecker

S

,

Steg

P

,

Hamm

C

,

Jüni

P

, et al.

Long-term ticagrelor monotherapy versus standard dual antiplatelet therapy followed by aspirin monotherapy in patients undergoing biolimus-eluting stent implantation: rationale and design of the GLOBAL LEADERS trial

.

EuroIntervention

2016

;

12

:

1239

–

45

.

576

Kogame

N

,

Guimaraes

PO

,

Modolo

R

,

De Martino

F

,

Tinoco

J

,

Ribeiro

EE

, et al.

Aspirin-free prasugrel monotherapy following coronary artery stenting in patients with stable CAD: the ASET Pilot study

.

JACC Cardiovasc Interv

2020

;

13

:

2251

–

62

.

10.1016/j.jcin.2020.06.023

577

Mega

JL

,

Close

SL

,

Wiviott

SD

,

Shen

L

,

Hockett

RD

,

Brandt

JT

, et al.

Cytochrome P450 genetic polymorphisms and the response to prasugrel: relationship to pharmacokinetic, pharmacodynamic, and clinical outcomes

.

Circulation

2009

;

119

:

2553

–

60

.

10.1161/circulationaha.109.851949

578

O’Donoghue

ML

,

Braunwald

E

,

Antman

EM

,

Murphy

SA

,

Bates

ER

,

Rozenman

Y

, et al.

Pharmacodynamic effect and clinical efficacy of clopidogrel and prasugrel with or without a proton-pump inhibitor: an analysis of two randomised trials

.

Lancet

2009

;

374

:

989

–

97

.

10.1016/S0140-6736(09)61525-7

579

Teng

R

,

Oliver

S

,

Hayes

MA

,

Butler

K

.

Absorption, distribution, metabolism, and excretion of ticagrelor in healthy subjects

.

Drug Metab Dispos

2010

;

38

:

1514

–

21

.

10.1124/dmd.110.032250

580

Giorgi

MA

,

Cohen Arazi

H

,

Gonzalez

CD

,

Di Girolamo

G

.

Beyond efficacy: pharmacokinetic differences between clopidogrel, prasugrel and ticagrelor

.

Expert Opin Pharmacother

2011

;

12

:

1285

–

95

.

10.1517/14656566.2011.550573

581

Tantry

US

,

Bonello

L

,

Aradi

D

,

Price

MJ

,

Jeong

Y-H

,

Angiolillo

DJ

, et al.

Consensus and update on the definition of on-treatment platelet reactivity to adenosine diphosphate associated with ischemia and bleeding

.

J Am Coll Cardiol

2013

;

62

:

2261

–

73

.

10.1016/j.jacc.2013.07.101

582

Parker

WA

,

Storey

RF

.

Antithrombotic therapy for patients with chronic coronary syndromes

.

Heart

2021

;

107

:

925

–

33

.

10.1136/heartjnl-2020-316914

583

Silvain

J

,

Lattuca

B

,

Beygui

F

,

Rangé

G

,

Motovska

Z

,

Dillinger

J-G

, et al.

Ticagrelor versus clopidogrel in elective percutaneous coronary intervention (ALPHEUS): a randomised, open-label, phase 3b trial

.

Lancet

2020

;

396

:

1737

–

44

.

10.1016/S0140-6736(20)32236-4

584

Steg

PG

,

Bhatt

DL

,

Simon

T

,

Fox

K

,

Mehta

SR

,

Harrington

RA

, et al.

Ticagrelor in patients with stable coronary disease and diabetes

.

N Engl J Med

2019

;

381

:

1309

–

20

.

10.1056/NEJMoa1908077

585

Hahn

JY

,

Song

YB

,

Oh

JH

,

Chun

WJ

,

Park

YH

,

Jang

WJ

, et al.

Effect of P2Y12 inhibitor monotherapy vs dual antiplatelet therapy on cardiovascular events in patients undergoing percutaneous coronary intervention: the SMART-CHOICE randomized clinical trial

.

JAMA

2019

;

321

:

2428

–

37

.

10.1001/jama.2019.8146

586

Watanabe

H

,

Domei

T

,

Morimoto

T

,

Natsuaki

M

,

Shiomi

H

,

Toyota

T

, et al.

Effect of 1-month dual antiplatelet therapy followed by clopidogrel vs 12-month dual antiplatelet therapy on cardiovascular and bleeding events in patients receiving PCI: the STOPDAPT-2 randomized clinical trial

.

JAMA

2019

;

321

:

2414

–

27

.

10.1001/jama.2019.8145

587

Valgimigli

M

,

Frigoli

E

,

Heg

D

,

Tijssen

J

,

Jüni

P

,

Vranckx

P

, et al.

Dual antiplatelet therapy after PCI in patients at high bleeding risk

.

N Engl J Med

2021

;

385

:

1643

–

55

.

10.1056/NEJMoa2108749

588

Hong

SJ

,

Kim

JS

,

Hong

SJ

,

Lim

D-S

,

Lee

S-Y

,

Yun

KH

, et al.

1-Month dual-antiplatelet therapy followed by aspirin monotherapy after polymer-free drug-coated stent implantation: one-month DAPT trial

.

JACC Cardiovasc Interv

2021

;

14

:

1801

–

11

.

10.1016/j.jcin.2021.06.003

589

Costa

F

,

van Klaveren

D

,

James

S

,

Heg

D

,

Räber

L

,

Feres

F

, et al.

Derivation and validation of the predicting bleeding complications in patients undergoing stent implantation and subsequent dual antiplatelet therapy (PRECISE-DAPT) score: a pooled analysis of individual-patient datasets from clinical trials

.

Lancet

2017

;

389

:

1025

–

34

.

10.1016/S0140-6736(17)30397-5

590

Urban

P

,

Mehran

R

,

Colleran

R

,

Angiolillo

DJ

,

Byrne

RA

,

Capodanno

D

, et al.

Defining high bleeding risk in patients undergoing percutaneous coronary intervention: a consensus document from the Academic Research Consortium for High Bleeding Risk

.

Eur Heart J

2019

;

40

:

2632

–

53

.

10.1093/eurheartj/ehz372

591

Costa

F

,

Montalto

C

,

Branca

M

,

Hong

S-J

,

Watanabe

H

,

Franzone

A

, et al.

Dual antiplatelet therapy duration after percutaneous coronary intervention in high bleeding risk: a meta-analysis of randomized trials

.

Eur Heart J

2023

;

44

:

954

–

68

.

10.1093/eurheartj/ehac706

592

Mauri

L

,

Kereiakes

DJ

,

Yeh

RW

,

Driscoll-Shempp

P

,

Cutlip

DE

,

Steg

PG

, et al.

Twelve or 30 months of dual antiplatelet therapy after drug-eluting stents

.

N Engl J Med

2014

;

371

:

2155

–

66

.

10.1056/NEJMoa1409312

593

Bonaca

MP

,

Bhatt

DL

,

Cohen

M

,

Steg

PG

,

Storey

RF

,

Jensen

EC

, et al.

Long-term use of ticagrelor in patients with prior myocardial infarction

.

N Engl J Med

2015

;

372

:

1791

–

800

.

10.1056/NEJMoa1500857

594

Eikelboom

JW

,

Connolly

SJ

,

Bosch

J

,

Dagenais

GR

,

Hart

RG

,

Shestakovska

O

, et al.

Rivaroxaban with or without aspirin in stable cardiovascular disease

.

N Engl J Med

2017

;

377

:

1319

–

30

.

10.1056/NEJMoa1709118

595

Bhatt

DL

,

Bonaca

MP

,

Bansilal

S

,

Angiolillo

DJ

,

Cohen

M

,

Storey

RF

, et al.

Reduction in ischemic events with ticagrelor in diabetic patients with prior myocardial infarction in PEGASUS-TIMI 54

.

J Am Coll Cardiol

2016

;

67

:

2732

–

40

.

10.1016/j.jacc.2016.03.529

596

Bonaca

MP

,

Bhatt

DL

,

Storey

RF

,

Steg

PG

,

Cohen

M

,

Kuder

J

, et al.

Ticagrelor for prevention of ischemic events after myocardial infarction in patients with peripheral artery disease

.

J Am Coll Cardiol

2016

;

67

:

2719

–

28

.

10.1016/j.jacc.2016.03.524

597

Bansilal

S

,

Bonaca

MP

,

Cornel

JH

,

Storey

RF

,

Bhatt

DL

,

Steg

PG

, et al.

Ticagrelor for secondary prevention of atherothrombotic events in patients with multivessel coronary disease

.

J Am Coll Cardiol

2018

;

71

:

489

–

96

.

10.1016/j.jacc.2017.11.050

598

Anand

SS

,

Bosch

J

,

Eikelboom

JW

,

Connolly

SJ

,

Diaz

R

,

Widimsky

P

, et al.

Rivaroxaban with or without aspirin in patients with stable peripheral or carotid artery disease: an international, randomised, double-blind, placebo-controlled trial

.

Lancet

2018

;

391

:

219

–

29

.

10.1016/S0140-6736(17)32409-1

599

Mega

JL

,

Simon

T

,

Collet

JP

,

Anderson

JL

,

Antman

EM

,

Bliden

K

, et al.

Reduced-function CYP2C19 genotype and risk of adverse clinical outcomes among patients treated with clopidogrel predominantly for PCI: a meta-analysis

.

JAMA

2010

;

304

:

1821

–

30

.

10.1001/jama.2010.1543

600

Pereira

NL

,

Rihal

C

,

Lennon

R

,

Marcus

G

,

Shrivastava

S

,

Bell

MR

, et al.

Effect of CYP2C19 genotype on ischemic outcomes during oral P2Y₁₂ inhibitor therapy: a meta-analysis

.

JACC Cardiovasc Interv

2021

;

14

:

739

–

50

.

10.1016/j.jcin.2021.01.024

601

Sibbing

D

,

Aradi

D

,

Jacobshagen

C

,

Gross

L

,

Trenk

D

,

Geisler

T

, et al.

Guided de-escalation of antiplatelet treatment in patients with acute coronary syndrome undergoing percutaneous coronary intervention (TROPICAL-ACS): a randomised, open-label, multicentre trial

.

Lancet

2017

;

390

:

1747

–

57

.

10.1016/S0140-6736(17)32155-4

602

Claassens

DMF

,

Vos

GJA

,

Bergmeijer

TO

,

Hermanides

RS

,

van ’t Hof

AWJ

,

van der Harst

P

, et al.

A genotype-guided strategy for oral P2Y₁₂ inhibitors in primary PCI

.

N Engl J Med

2019

;

381

:

1621

–

31

.

10.1056/NEJMoa1907096

603

Price

MJ

,

Angiolillo

DJ

,

Teirstein

PS

,

Lillie

E

,

Manoukian

SV

,

Berger

PB

, et al.

Platelet reactivity and cardiovascular outcomes after percutaneous coronary intervention: a time-dependent analysis of the Gauging Responsiveness with A VerifyNow P2Y12 assay: Impact on Thrombosis and Safety (GRAVITAS) trial

.

Circulation

2011

;

124

:

1132

–

7

.

10.1161/circulationaha.111.029165

604

Collet

JP

,

Silvain

J

,

Barthélémy

O

,

Rangé

G

,

Cayla

G

,

Van Belle

E

, et al.

Dual-antiplatelet treatment beyond 1 year after drug-eluting stent implantation (ARCTIC-Interruption): a randomised trial

.

Lancet

2014

;

384

:

1577

–

85

.

10.1016/s0140-6736(14)60612-7

605

Cayla

G

,

Cuisset

T

,

Silvain

J

,

Leclercq

F

,

Manzo-Silberman

S

,

Saint-Etienne

C

, et al.

Platelet function monitoring to adjust antiplatelet therapy in elderly patients stented for an acute coronary syndrome (ANTARCTIC): an open-label, blinded-endpoint, randomised controlled superiority trial

.

Lancet

2016

;

388

:

2015

–

22

.

10.1016/s0140-6736(16)31323-x

606

Sibbing

D

,

Aradi

D

,

Jacobshagen

C

,

Gross

L

,

Trenk

D

,

Geisler

T

, et al.

A randomised trial on platelet function-guided de-escalation of antiplatelet treatment in ACS patients undergoing PCI. Rationale and design of the Testing Responsiveness to Platelet Inhibition on Chronic Antiplatelet Treatment for Acute Coronary Syndromes (TROPICAL-ACS) Trial

.

Thromb Haemost

2017

;

117

:

188

–

95

.

607

Pereira

NL

,

Farkouh

ME

,

So

D

,

Lennon

R

,

Geller

N

,

Mathew

V

, et al.

Effect of genotype-guided oral P2Y12 inhibitor selection vs conventional clopidogrel therapy on ischemic outcomes after percutaneous coronary intervention: the TAILOR-PCI randomized clinical trial

.

JAMA

2020

;

324

:

761

–

71

.

10.1001/jama.2020.12443

608

Ingraham

BS

,

Farkouh

ME

,

Lennon

RJ

,

So

D

,

Goodman

SG

,

Geller

N

, et al.

Genetic-guided oral P2Y₁₂ inhibitor selection and cumulative ischemic events after percutaneous coronary intervention

.

JACC Cardiovasc Interv

2023

;

16

:

816

–

25

.

10.1016/j.jcin.2023.01.356

609

Hurlen

M

,

Abdelnoor

M

,

Smith

P

,

Erikssen

J

,

Arnesen

H

.

Warfarin, aspirin, or both after myocardial infarction

.

N Engl J Med

2002

;

347

:

969

–

74

.

610

van Es

RF

,

Jonker

JJ

,

Verheugt

FW

,

Deckers

JW

,

Grobbee

DE

;

Antithrombotics in the Secondary Preventionof Events in Coronary Thrombosis-2 (ASPECT-2) Research Group

.

Aspirin and coumadin after acute coronary syndromes (the ASPECT-2 study): a randomised controlled trial

.

Lancet

2002

;

360

:

109

–

13

.

10.1016/S0140-6736(02)09409-6

611

Sixty Plus Reinfarction Study Research Group

.

A double-blind trial to assess long-term oral anticoagulant therapy in elderly patients after myocardial infarction. Report of the Sixty Plus Reinfarction Study Research Group

.

Lancet

1980

;

2

:

989

–

94

.

10.1016/S0140-6736(80)92154-6

10.1016/S0140-6736(09)61751-7

612

Sorensen

R

,

Hansen

ML

,

Abildstrom

SZ

,

Hvelplund

A

,

Andersson

C

,

Jørgensen

C

, et al.

Risk of bleeding in patients with acute myocardial infarction treated with different combinations of aspirin, clopidogrel, and vitamin K antagonists in Denmark: a retrospective analysis of nationwide registry data

.

Lancet

2009

;

374

:

1967

–

74

.

613

Hindricks

G

,

Potpara

T

,

Dagres

N

,

Arbelo

E

,

Bax

JJ

,

Blomström-Lundqvist

C

, et al.

2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS): the Task Force for the diagnosis and management of atrial fibrillation of the European Society of Cardiology (ESC) Developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC

.

Eur Heart J

2021

;

42

:

373

–

498

.

10.1093/eurheartj/ehaa612

614

Valgimigli

M

,

Costa

F

,

Lokhnygina

Y

,

Clare

RM

,

Wallentin

L

,

Moliterno

DJ

, et al.

Trade-off of myocardial infarction vs. bleeding types on mortality after acute coronary syndrome: lessons from the Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome (TRACER) randomized trial

.

Eur Heart J

2017

;

38

:

804

–

10

.

10.1093/eurheartj/ehw525

615

Dewilde

WJ

,

Oirbans

T

,

Verheugt

FW

,

Kelder

JC

,

De Smet

BJGL

,

Herrman

J-P

, et al.

Use of clopidogrel with or without aspirin in patients taking oral anticoagulant therapy and undergoing percutaneous coronary intervention: an open-label, randomised, controlled trial

.

Lancet

2013

;

381

:

1107

–

15

.

10.1016/S0140-6736(12)62177-1

616

Gibson

CM

,

Mehran

R

,

Bode

C

,

Halperin

J

,

Verheugt

FW

,

Wildgoose

P

, et al.

Prevention of bleeding in patients with atrial fibrillation undergoing PCI

.

N Engl J Med

2016

;

375

:

2423

–

34

.

10.1056/NEJMoa1611594

617

Cannon

CP

,

Bhatt

DL

,

Oldgren

J

,

Lip

GYH

,

Ellis

SG

,

Kimura

T

, et al.

Dual antithrombotic therapy with dabigatran after PCI in atrial fibrillation

.

N Engl J Med

2017

;

377

:

1513

–

24

.

10.1056/NEJMoa1708454

618

Vranckx

P

,

Valgimigli

M

,

Eckardt

L

,

Tijssen

J

,

Lewalter

T

,

Gargiulo

G

, et al.

Edoxaban-based versus vitamin K antagonist-based antithrombotic regimen after successful coronary stenting in patients with atrial fibrillation (ENTRUST-AF PCI): a randomised, open-label, phase 3b trial

.

Lancet

2019

;

394

:

1335

–

43

.

10.1016/S0140-6736(19)31872-0

619

Lopes

RD

,

Heizer

G

,

Aronson

R

,

Vora

AN

,

Massaro

T

,

Mehran

R

, et al.

Antithrombotic therapy after acute coronary syndrome or PCI in atrial fibrillation

.

N Engl J Med

2019

;

380

:

1509

–

24

.

10.1056/NEJMoa1817083

620

Galli

M

,

Andreotti

F

,

Porto

I

,

Crea

F

.

Intracranial haemorrhages vs. stent thromboses with direct oral anticoagulant plus single antiplatelet agent or triple antithrombotic therapy: a meta-analysis of randomized trials in atrial fibrillation and percutaneous coronary intervention/acute coronary syndrome patients

.

Europace

2020

;

22

:

538

–

46

.

10.1093/europace/euz345

621

Gargiulo

G

,

Goette

A

,

Tijssen

J

,

Eckardt

L

,

Lewalter

T

,

Vranckx

P

, et al.

Safety and efficacy outcomes of double vs. triple antithrombotic therapy in patients with atrial fibrillation following percutaneous coronary intervention: a systematic review and meta-analysis of non-vitamin K antagonist oral anticoagulant-based randomized clinical trials

.

Eur Heart J

2019

;

40

:

3757

–

67

.

10.1093/eurheartj/ehz732

622

Alexander

JH

,

Wojdyla

D

,

Vora

AN

,

Thomas

L

,

Granger

CB

,

Goodman

SG

, et al.

Risk/benefit tradeoff of antithrombotic therapy in patients with atrial fibrillation early and late after an acute coronary syndrome or percutaneous coronary intervention: insights from AUGUSTUS

.

Circulation

2020

;

141

:

1618

–

27

.

10.1161/CIRCULATIONAHA.120.046534

623

Lip

GYH

,

Collet

JP

,

Haude

M

,

Byrne

R

,

Chung

EH

,

Fauchier

L

, et al.

2018 Joint European consensus document on the management of antithrombotic therapy in atrial fibrillation patients presenting with acute coronary syndrome and/or undergoing percutaneous cardiovascular interventions: a joint consensus document of the European Heart Rhythm Association (EHRA), European Society of Cardiology Working Group on Thrombosis, European Association of Percutaneous Cardiovascular Interventions (EAPCI), and European Association of Acute Cardiac Care (ACCA) endorsed by the Heart Rhythm Society (HRS), Asia-Pacific Heart Rhythm Society (APHRS), Latin America Heart Rhythm Society (LAHRS), and Cardiac Arrhythmia Society of Southern Africa (CASSA)

.

Europace

2019

;

21

:

192

–

3

.

10.1093/europace/euy174

624

Oldgren

J

,

Steg

PG

,

Hohnloser

SH

,

Lip

GYH

,

Kimura

T

,

Nordaby

M

, et al.

Dabigatran dual therapy with ticagrelor or clopidogrel after percutaneous coronary intervention in atrial fibrillation patients with or without acute coronary syndrome: a subgroup analysis from the RE-DUAL PCI trial

.

Eur Heart J

2019

;

40

:

1553

–

62

.

10.1093/eurheartj/ehz059

625

Rubboli

A

.

Oral anticoagulation alone for concomitant stable coronary artery disease and atrial fibrillation: a definitive strategy?

Int J Cardiol

2018

;

264

:

95

–

6

.

10.1016/j.ijcard.2018.04.023

626

Patti

G

,

Pecen

L

,

Lucerna

M

,

Huber

K

,

Rohla

M

,

Renda

G

, et al.

Outcomes of anticoagulated patients with atrial fibrillation treated with or without antiplatelet therapy—a pooled analysis from the PREFER in AF and PREFER in AF PROLONGATON registries

.

Int J Cardiol

2018

;

270

:

160

–

6

.

10.1016/j.ijcard.2018.06.098

627

Yasuda

S

,

Kaikita

K

,

Akao

M

,

Ako

J

,

Matoba

T

,

Nakamura

M

, et al.

Antithrombotic therapy for atrial fibrillation with stable coronary disease

.

N Engl J Med

2019

;

381

:

1103

–

13

.

10.1056/NEJMoa1904143

628

Konstantinides

SV

,

Meyer

G

,

Becattini

C

,

Bueno

H

,

Geersing

G-J

,

Harjola

V-P

, et al.

2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS)

.

Eur Heart J

2020

;

41

:

543

–

603

.

10.1093/eurheartj/ehz405

629

Bjorklund

E

,

Nielsen

SJ

,

Hansson

EC

,

Karlsson

M

,

Wallinder

A

,

Martinsson

A

, et al.

Secondary prevention medications after coronary artery bypass grafting and long-term survival: a population-based longitudinal study from the SWEDEHEART registry

.

Eur Heart J

2020

;

41

:

1653

–

61

.

10.1093/eurheartj/ehz714

630

Mangano

DT

.

Multicenter Study of Perioperative Ischemia Research Group. Aspirin and mortality from coronary bypass surgery

.

N Engl J Med

2002

;

347

:

1309

–

17

.

631

Sousa-Uva

M

,

Storey

R

,

Huber

K

,

Falk

V

,

Leite-Moreira

AF

,

Amour

J

, et al.

Expert position paper on the management of antiplatelet therapy in patients undergoing coronary artery bypass graft surgery

.

Eur Heart J

2014

;

35

:

1510

–

4

.

10.1093/eurheartj/ehu158

632

Sousa-Uva

M

,

Head

SJ

,

Milojevic

M

,

Collet

J-P

,

Landoni

G

,

Castella

M

, et al.

2017 EACTS Guidelines on perioperative medication in adult cardiac surgery

.

Eur J Cardiothorac Surg

2018

;

53

:

5

–

33

.

633

Shaw

JR

,

Li

N

,

Vanassche

T

,

Coppens

M

,

Spyropoulos

AC

,

Syed

S

, et al.

Predictors of preprocedural direct oral anticoagulant levels in patients having an elective surgery or procedure

.

Blood Adv

2020

;

4

:

3520

–

7

.

10.1182/bloodadvances.2020002335

634

Steffel

J

,

Collins

R

,

Antz

M

,

Cornu

P

,

Desteghe

L

,

Haeusler

KG

, et al.

2021 European Heart Rhythm Association practical guide on the use of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation

.

Europace

2021

;

23

:

1612

–

76

.

10.1093/europace/euab065

635

Sandner

S

,

Redfors

B

,

Angiolillo

DJ

,

Audisio

K

,

Fremes

SE

,

Janssen

PWA

, et al.

Association of dual antiplatelet therapy with ticagrelor with vein graft failure after coronary artery bypass graft surgery: a systematic review and meta-analysis

.

JAMA

2022

;

328

:

554

–

62

.

10.1001/jama.2022.11966

636

Kulik

A

,

Le May

MR

,

Voisine

P

,

Tardif

J-C

,

DeLarochelliere

R

,

Naidoo

S

, et al.

Aspirin plus clopidogrel versus aspirin alone after coronary artery bypass grafting: the clopidogrel after surgery for coronary artery disease (CASCADE) trial

.

Circulation

2010

;

122

:

2680

–

7

.

10.1161/CIRCULATIONAHA.110.978007

637

Zhao

Q

,

Zhu

Y

,

Xu

Z

,

Cheng

Z

,

Mei

J

,

Chen

X

, et al.

Effect of ticagrelor plus aspirin, ticagrelor alone, or aspirin alone on saphenous vein graft patency 1 year after coronary artery bypass grafting: a randomized clinical trial

.

JAMA

2018

;

319

:

1677

–

86

.

10.1001/jama.2018.3197

638

Filardo

G

,

Damiano

RJ

Jr,

Ailawadi

G

,

Thourani

VH

,

Pollock

BD

,

Sass

DM

, et al.

Epidemiology of new-onset atrial fibrillation following coronary artery bypass graft surgery

.

Heart

2018

;

104

:

985

–

92

.

10.1136/heartjnl-2017-312150

639

Benedetto

U

,

Gaudino

MF

,

Dimagli

A

,

Gerry

S

,

Gray

A

,

Lees

B

, et al.

Postoperative atrial fibrillation and long-term risk of stroke after isolated coronary artery bypass graft surgery

.

Circulation

2020

;

142

:

1320

–

9

.

10.1161/CIRCULATIONAHA.120.046940

640

Taha

A

,

Nielsen

SJ

,

Franzen

S

,

Rezk

M

,

Ahlsson

A

,

Friberg

L

, et al.

Stroke risk stratification in patients with postoperative atrial fibrillation after coronary artery bypass grafting

.

J Am Heart Assoc

2022

;

11

:

e024703

.

10.1161/JAHA.121.024703

641

Butt

JH

,

Xian

Y

,

Peterson

ED

,

Olsen

PS

,

Rørth

R

,

Gundlund

A

, et al.

Long-term thromboembolic risk in patients with postoperative atrial fibrillation after coronary artery bypass graft surgery and patients with nonvalvular atrial fibrillation

.

JAMA Cardiol

2018

;

3

:

417

–

24

.

10.1001/jamacardio.2018.0405

642

Taha

A

,

Nielsen

SJ

,

Bergfeldt

L

,

Ahlsson

A

,

Friberg

L

,

Björck

S

, et al.

New-onset atrial fibrillation after coronary artery bypass grafting and long-term outcome: a population-based nationwide study from the SWEDEHEART registry

.

J Am Heart Assoc

2021

;

10

:

e017966

.

10.1161/JAHA.120.017966

643

Abraham

NS

,

Hlatky

MA

,

Antman

EM

,

Bhatt

DL

,

Bjorkman

DJ

,

Clark

CB

, et al.

ACCF/ACG/AHA 2010 Expert Consensus Document on the concomitant use of proton pump inhibitors and thienopyridines: a focused update of the ACCF/ACG/AHA 2008 expert consensus document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use: a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents

.

Circulation

2010

;

122

:

2619

–

33

.

10.1161/CIR.0b013e318202f701

644

Abraham

NS

,

Noseworthy

PA

,

Inselman

J

,

Herrin

J

,

Yao

X

,

Sangaralingham

LR

, et al.

Risk of gastrointestinal bleeding increases with combinations of antithrombotic agents and patient age

.

Clin Gastroenterol Hepatol

2020

;

18

:

337

–

46.e19

.

10.1016/j.cgh.2019.05.017

645

Li

L

,

Geraghty

OC

,

Mehta

Z

,

Rothwell

PM

, on behalf of the

Oxford Vascular Study

.

Age-specific risks, severity, time course, and outcome of bleeding on long-term antiplatelet treatment after vascular events: a population-based cohort study

.

Lancet

2017

;

390

:

490

–

9

.

10.1016/S0140-6736(17)30770-5

646

Moayyedi

P

,

Eikelboom

JW

,

Bosch

J

,

Connolly

SJ

,

Dyal

L

,

Shestakovska

O

, et al.

Safety of proton pump inhibitors based on a large, multi-year, randomized trial of patients receiving rivaroxaban or aspirin

.

Gastroenterology

2019

;

157

:

682

–

91.e2

.

10.1053/j.gastro.2019.05.056

647

Ahn

HJ

,

Lee

SR

,

Choi

EK

,

Rhee

TM

,

Kwon

S

,

Oh

S

, et al.

Protective effect of proton-pump inhibitor against gastrointestinal bleeding in patients receiving oral anticoagulants: a systematic review and meta-analysis

.

Br J Clin Pharmacol

2022

;

88

:

4676

–

87

.

648

Shang

YS

,

Zhong

PY

,

Ma

Y

,

Bai

N

,

Niu

Y

,

Wang

Z-L

.

Efficacy and safety of proton pump inhibitors in patients with coronary artery diseases receiving oral antiplatelet agents and/or anticoagulants: a systematic review and meta-analysis

.

J Cardiovasc Pharmacol

2022

;

80

:

1

–

12

.

10.1097/fjc.0000000000001284

649

Lin

Y

,

Cai

Z

,

Dong

S

,

Liu

H

,

Pang

X

,

Chen

Q

, et al.

Comparative efficacy and safety of antiplatelet or anticoagulant therapy in patients with chronic coronary syndromes after percutaneous coronary intervention: a network meta-analysis of randomized controlled trials

.

Front Pharmacol

2022

;

13

:

992376

.

10.3389/fphar.2022.992376

650

Valgimigli

M

,

Campo

G

,

Monti

M

,

Vranckx

P

,

Percoco

G

,

Tumscitz

C

, et al.

Short- versus long-term duration of dual-antiplatelet therapy after coronary stenting: a randomized multicenter trial

.

Circulation

2012

;

125

:

2015

–

26

.

10.1161/CIRCULATIONAHA.111.071589

651

Gwon

HC

,

Hahn

JY

,

Park

KW

,

Song

YB

,

Chae

IH

,

Lim

DS

, et al.

Six-month versus 12-month dual antiplatelet therapy after implantation of drug-eluting stents: the Efficacy of Xience/Promus Versus Cypher to Reduce Late Loss After Stenting (EXCELLENT) randomized, multicenter study

.

Circulation

2012

;

125

:

505

–

13

.

10.1161/CIRCULATIONAHA.111.059022

652

Schulz-Schupke

S

,

Byrne

RA

,

Ten Berg

JM

,

Neumann

FJ

,

Han

Y

,

Adriaenssens

T

, et al.

ISAR-SAFE: a randomized, double-blind, placebo-controlled trial of 6 vs. 12 months of clopidogrel therapy after drug-eluting stenting

.

Eur Heart J

2015

;

36

:

1252

–

63

.

10.1093/eurheartj/ehu523

653

Han

Y

,

Xu

B

,

Xu

K

,

Guan

C

,

Jing

Q

,

Zheng

Q

, et al.

Six versus 12 months of dual antiplatelet therapy after implantation of biodegradable polymer sirolimus-eluting stent: randomized substudy of the I-LOVE-IT 2 trial

.

Circ Cardiovasc Interv

2016

;

9

:

e003145

.

10.1161/CIRCINTERVENTIONS.115.003145

654

Hong

SJ

,

Shin

DH

,

Kim

JS

,

Kim

BK

,

Ko

YG

,

Choi

D

, et al.

6-Month versus 12-month dual-antiplatelet therapy following long everolimus-eluting stent implantation: the IVUS-XPL randomized clinical trial

.

JACC Cardiovasc Interv

2016

;

9

:

1438

–

46

.

10.1016/j.jcin.2016.04.036

655

Kim

BK

,

Hong

MK

,

Shin

DH

,

Nam

CM

,

Kim

JS

,

Ko

YG

, et al.

A new strategy for discontinuation of dual antiplatelet therapy: the RESET Trial (REal Safety and Efficacy of 3-month dual antiplatelet Therapy following Endeavor zotarolimus-eluting stent implantation)

.

J Am Coll Cardiol

2012

;

60

:

1340

–

8

.

10.1016/j.jacc.2012.06.043

656

Feres

F

,

Costa

RA

,

Abizaid

A

,

Leon

MB

,

Marin-Neto

JA

,

Botelho

RV

, et al.

Three vs twelve months of dual antiplatelet therapy after zotarolimus-eluting stents: the OPTIMIZE randomized trial

.

JAMA

2013

;

310

:

2510

–

22

.

10.1001/jama.2013.282183

657

Valgimigli

M

,

Gragnano

F

,

Branca

M

,

Franzone

A

,

Baber

U

,

Jang

Y

, et al.

P2Y12 inhibitor monotherapy or dual antiplatelet therapy after coronary revascularisation: individual patient level meta-analysis of randomised controlled trials

.

BMJ

2021

;

373

:

n1332

.

658

Ruff

CT

,

Giugliano

RP

,

Braunwald

E

,

Hoffman

EB

,

Deenadayalu

N

,

Ezekowitz

MD

, et al.

Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials

.

Lancet

2014

;

383

:

955

–

62

.

10.1016/S0140-6736(13)62343-0

659

Potpara

TS

,

Mujovic

N

,

Proietti

M

,

Dagres

N

,

Hindricks

G

,

Collet

JP

, et al.

Revisiting the effects of omitting aspirin in combined antithrombotic therapies for atrial fibrillation and acute coronary syndromes or percutaneous coronary interventions: meta-analysis of pooled data from the PIONEER AF-PCI, RE-DUAL PCI, and AUGUSTUS trials

.

Europace

2020

;

22

:

33

–

46

.

10.1093/europace/euz259

660

Wallentin

L

,

Yusuf

S

,

Ezekowitz

MD

,

Alings

M

,

Flather

M

,

Franzosi

MG

, et al.

Efficacy and safety of dabigatran compared with warfarin at different levels of international normalised ratio control for stroke prevention in atrial fibrillation: an analysis of the RE-LY trial

.

Lancet

2010

;

376

:

975

–

83

.

10.1016/S0140-6736(10)61194-4

661

Fiedler

KA

,

Maeng

M

,

Mehilli

J

,

Schulz-Schüpke

S

,

Byrne

RA

,

Sibbing

D

, et al.

Duration of triple therapy in patients requiring oral anticoagulation after drug-eluting stent implantation: the ISAR-TRIPLE trial

.

J Am Coll Cardiol

2015

;

65

:

1619

–

29

.

10.1016/j.jacc.2015.02.050

662

Proietti

M

,

Airaksinen

KEJ

,

Rubboli

A

,

Schlitt

A

,

Kiviniemi

T

,

Karjalainen

PP

, et al.

Time in therapeutic range and major adverse outcomes in atrial fibrillation patients undergoing percutaneous coronary intervention: the Atrial Fibrillation Undergoing Coronary Artery Stenting (AFCAS) registry

.

Am Heart J

2017

;

190

:

86

–

93

.

10.1016/j.ahj.2017.05.016

663

McDowell

TY

,

Lawrence

J

,

Florian

J

,

Southworth

MR

,

Grant

S

,

Stockbridge

N

.

Relationship between international normalized ratio and outcomes in modern trials with warfarin controls

.

Pharmacotherapy

2018

;

38

:

899

–

906

.

664

Bhatt

DL

,

Cryer

BL

,

Contant

CF

,

Cohen

M

,

Lanas

A

,

Schnitzer

TJ

, et al.

Clopidogrel with or without omeprazole in coronary artery disease

.

N Engl J Med

2010

;

363

:

1909

–

17

.

10.1056/NEJMoa1007964

665

Lanas

A

,

Garcia-Rodriguez

LA

,

Arroyo

MT

,

Gomollon

F

,

Feu

F

,

Gonzalez-Perez

A

, et al.

Risk of upper gastrointestinal ulcer bleeding associated with selective cyclo-oxygenase-2 inhibitors, traditional non-aspirin non-steroidal anti-inflammatory drugs, aspirin and combinations

.

Gut

2006

;

55

:

1731

–

8

.

10.1136/gut.2005.080754

666

Scally

B

,

Emberson

JR

,

Spata

E

,

Reith

C

,

Davies

K

,

Halls

H

, et al.

Effects of gastroprotectant drugs for the prevention and treatment of peptic ulcer disease and its complications: a meta-analysis of randomised trials

.

Lancet Gastroenterol Hepatol

2018

;

3

:

231

–

41

.

10.1016/S2468-1253(18)30037-2

667

Cea Soriano

L

,

Fowkes

FGR

,

Allum

AM

,

Johansson

S

,

Garcia Rodriguez

LA

.

Predictors of bleeding in patients with symptomatic peripheral artery disease: a cohort study using the health improvement network in the United Kingdom

.

Thromb Haemost

2018

;

118

:

1101

–

12

.

10.1055/s-0038-1646923

668

Han

Y

,

Liao

Z

,

Li

Y

,

Zhao

X

,

Ma

S

,

Bao

D

, et al.

Magnetically controlled capsule endoscopy for assessment of antiplatelet therapy-induced gastrointestinal injury

.

J Am Coll Cardiol

2022

;

79

:

116

–

28

.

10.1016/j.jacc.2021.10.028

669

Ference

BA

,

Ginsberg

HN

,

Graham

I

,

Ray

KK

,

Packard

CJ

,

Bruckert

E

, et al.

Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel

.

Eur Heart J

2017

;

38

:

2459

–

72

.

10.1093/eurheartj/ehx144

670

Cholesterol Treatment Trialists’ (CTT) Collaboration

;

Baigent

C

,

Blackwell

L

,

Emberson

J

,

Holland

LE

,

Reith

C

, et al.

Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170

000 participants in 26 randomised trials

.

Lancet

2010

;

376

:

1670

–

81

.

10.1016/s0140-6736(10)61350-5

671

Cholesterol Treatment Trialists’ (CTT) Collaboration

;

Fulcher

J

,

O’Connell

R

,

Voysey

M

,

Emberson

J

,

Blackwell

L

, et al.

Efficacy and safety of LDL-lowering therapy among men and women: meta-analysis of individual data from 174

000 participants in 27 randomised trials

.

Lancet

2015

;

385

:

1397

–

405

.

10.1016/s0140-6736(14)61368-4

672

Ridker

PM

,

Mora

S

,

Rose

L

;

Jupiter Trial Study Group

.

Percent reduction in LDL cholesterol following high-intensity statin therapy: potential implications for guidelines and for the prescription of emerging lipid-lowering agents

.

Eur Heart J

2016

;

37

:

1373

–

9

.

10.1093/eurheartj/ehw046

673

Ray

KK

,

Molemans

B

,

Schoonen

WM

,

Giovas

P

,

Bray

S

,

Kiru

G

, et al.

EU-wide cross-sectional observational study of lipid-modifying therapy use in secondary and primary care: the DA VINCI study

.

Eur J Prev Cardiol

2021

;

28

:

1279

–

89

.

10.1093/eurjpc/zwaa047

674

Cannon

CP

,

Blazing

MA

,

Giugliano

RP

,

McCagg

A

,

White

JA

,

Theroux

P

, et al.

Ezetimibe added to statin therapy after acute coronary syndromes

.

N Engl J Med

2015

;

372

:

2387

–

97

.

10.1056/NEJMoa1410489

675

Sabatine

MS

,

Giugliano

RP

,

Keech

AC

,

Honarpour

N

,

Wiviott

SD

,

Murphy

SA

, et al.

Evolocumab and clinical outcomes in patients with cardiovascular disease

.

N Engl J Med

2017

;

376

:

1713

–

22

.

10.1056/NEJMoa1615664

676

Schwartz

GG

,

Steg

PG

,

Szarek

M

,

Bhatt

DL

,

Bittner

VA

,

Diaz

R

, et al.

Alirocumab and cardiovascular outcomes after acute coronary syndrome

.

N Engl J Med

2018

;

379

:

2097

–

107

.

10.1056/NEJMoa1801174

677

O’Donoghue

ML

,

Giugliano

RP

,

Wiviott

SD

,

Atar

D

,

Keech

A

,

Kuder

JF

, et al.

Long-term evolocumab in patients with established atherosclerotic cardiovascular disease

.

Circulation

2022

;

146

:

1109

–

19

.

10.1161/CIRCULATIONAHA.122.061620

678

Ballantyne

CM

,

Laufs

U

,

Ray

KK

,

Leiter

LA

,

Bays

HE

,

Goldberg

AC

, et al.

Bempedoic acid plus ezetimibe fixed-dose combination in patients with hypercholesterolemia and high CVD risk treated with maximally tolerated statin therapy

.

Eur J Prev Cardiol

2020

;

27

:

593

–

603

.

10.1177/2047487319864671

679

Ray

KK

,

Bays

HE

,

Catapano

AL

,

Lalwani

ND

,

Bloedon

LT

,

Sterling

LR

, et al.

Safety and efficacy of bempedoic acid to reduce LDL cholesterol

.

N Engl J Med

2019

;

380

:

1022

–

32

.

10.1056/NEJMoa1803917

680

Nissen

SE

,

Lincoff

AM

,

Brennan

D

,

Ray

KK

,

Mason

D

,

Kastelein

JJP

, et al.

Bempedoic acid and cardiovascular outcomes in statin-intolerant patients

.

New Engl J Med

2023

;

388

:

1353

–

64

.

10.1056/NEJMoa2215024

681

Ray

KK

,

Wright

RS

,

Kallend

D

,

Koenig

W

,

Leiter

LA

,

Raal

FJ

, et al.

Two phase 3 trials of inclisiran in patients with elevated LDL cholesterol

.

N Engl J Med

2020

;

382

:

1507

–

19

.

10.1056/NEJMoa1912387

682

Patti

G

,

Cannon

CP

,

Murphy

SA

,

Mega

S

,

Pasceri

V

,

Briguori

C

, et al.

Clinical benefit of statin pretreatment in patients undergoing percutaneous coronary intervention: a collaborative patient-level meta-analysis of 13 randomized studies

.

Circulation

2011

;

123

:

1622

–

32

.

10.1161/CIRCULATIONAHA.110.002451

683

SOLVD Investigators

;

Yusuf

S

,

Pitt

B

,

Davis

CE

,

Hood

WB

,

Cohn

JN

.

Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure

.

N Engl J Med

1991

;

325

:

293

–

302

.

10.1056/NEJM199108013250501

684

Pfeffer

MA

,

Braunwald

E

,

Moye

LA

,

Basta

L

,

Brown

EJ

,

Cuddy

TE

, et al.

Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction — results of the survival and ventricular enlargement trial. The SAVE Investigators

.

N Engl J Med

1992

;

327

:

669

–

77

.

10.1056/NEJM199209033271001

685

Flather

MD

,

Yusuf

S

,

Kober

L

,

Pfeffer

M

,

Hall

A

,

Murray

G

, et al.

Long-term ACE-inhibitor therapy in patients with heart failure or left-ventricular dysfunction: a systematic overview of data from individual patients. ACE-Inhibitor Myocardial Infarction Collaborative Group

.

Lancet

2000

;

355

:

1575

–

81

.

10.1016/s0140-6736(00)02212-1

686

Heart Outcomes Prevention Evaluation Study Investigators

;

Yusuf

S

,

Sleight

P

,

Pogue

J

,

Bosch

J

,

Davies

R

, et al.

Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients

.

N Engl J Med

2000

;

342

:

145

–

53

.

10.1056/NEJM200001203420301

687

Fox

KM

;

EURopean trial On reduction of cardiac events with Perindopril in stable coronary Artery disease Investigators

.

Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: randomised, double-blind, placebo-controlled, multicentre trial (the EUROPA study)

.

Lancet

2003

;

362

:

782

–

8

.

10.1016/s0140-6736(03)14286-9

688

Wiviott

SD

,

Raz

I

,

Bonaca

MP

,

Mosenzon

O

,

Kato

ET

,

Cahn

A

, et al.

Dapagliflozin and cardiovascular outcomes in type 2 diabetes

.

N Engl J Med

2019

;

380

:

347

–

57

.

10.1056/NEJMoa1812389

689

Patel

A

;

ADVANCE Collaborative Group

;

MacMahon

S

,

Chalmers

J

,

Neal

B

,

Woodward

M

, et al.

Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial

.

Lancet

2007

;

370

:

829

–

40

.

10.1016/S0140-6736(07)61303-8

690

Braunwald

E

,

Domanski

MJ

,

Fowler

SE

,

Geller

NL

,

Gersh

BJ

,

Hsia

J

, et al.

Angiotensin-converting-enzyme inhibition in stable coronary artery disease

.

N Engl J Med

2004

;

351

:

2058

–

68

.

691

Bangalore

S

,

Fakheri

R

,

Wandel

S

,

Toklu

B

,

Wandel

J

,

Messerli

FH

.

Renin angiotensin system inhibitors for patients with stable coronary artery disease without heart failure: systematic review and meta-analysis of randomized trials

.

BMJ

2017

;

356

:

j4

.

692

Prosser

HC

,

Peck

KY

,

Dinh

D

,

Roberts

L

,

Chandrasekhar

J

,

Brennan

A

, et al.

Role of renin-angiotensin system antagonists on long-term mortality post-percutaneous coronary intervention in reduced and preserved ejection fraction

.

Clin Res Cardiol

2022

;

111

:

776

–

86

.

10.1007/s00392-021-01985-x

693

McMurray

JJ

,

Packer

M

,

Desai

AS

,

Gong

J

,

Lefkowitz

MP

,

Rizkala

AR

, et al.

Angiotensin-neprilysin inhibition versus enalapril in heart failure

.

N Engl J Med

2014

;

371

:

993

–

1004

.

10.1056/NEJMoa1409077

694

Mogensen

UM

,

Kober

L

,

Kristensen

SL

,

Jhund

PS

,

Gong

J

,

Lefkowitz

MP

, et al.

The effects of sacubitril/valsartan on coronary outcomes in PARADIGM-HF

.

Am Heart J

2017

;

188

:

35

–

41

.

10.1016/j.ahj.2017.02.034

695

Zinman

B

,

Wanner

C

,

Lachin

JM

,

Fitchett

D

,

Bluhmki

E

,

Hantel

S

, et al.

Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes

.

N Engl J Med

2015

;

373

:

2117

–

28

.

10.1056/NEJMoa1504720

696

Neal

B

,

Perkovic

V

,

Matthews

DR

,

Mahaffey

KW

,

Fulcher

G

,

Meininger

G

, et al.

Rationale, design and baseline characteristics of the CANagliflozin cardioVascular Assessment Study–Renal (CANVAS-R): a randomized, placebo-controlled trial

.

Diabetes Obes Metab

2017

;

19

:

387

–

93

.

697

Cannon

CP

,

Pratley

R

,

Dagogo-Jack

S

,

Mancuso

J

,

Huyck

S

,

Masiukiewicz

U

, et al.

Cardiovascular outcomes with ertugliflozin in type 2 diabetes

.

N Engl J Med

2020

;

383

:

1425

–

35

.

10.1056/NEJMoa2004967

698

McGuire

DK

,

Shih

WJ

,

Cosentino

F

,

Charbonnel

B

,

Cherney

DZI

,

Dagogo-Jack

S

, et al.

Association of SGLT2 inhibitors with cardiovascular and kidney outcomes in patients with type 2 diabetes: a meta-analysis

.

JAMA Cardiol

2021

;

6

:

148

–

58

.

10.1001/jamacardio.2020.4511

699

Mudaliar

S

,

Alloju

S

,

Henry

RR

.

Can a shift in fuel energetics explain the beneficial cardiorenal outcomes in the EMPA-REG OUTCOME study? A unifying hypothesis

.

Diabetes Care

2016

;

39

:

1115

–

22

.

700

Neal

B

,

Perkovic

V

,

Mahaffey

KW

,

de Zeeuw

D

,

Fulcher

G

,

Erondu

N

, et al.

Canagliflozin and cardiovascular and renal events in type 2 diabetes

.

N Engl J Med

2017

;

377

:

644

–

57

.

10.1056/NEJMoa1611925

701

Uthman

L

,

Baartscheer

A

,

Bleijlevens

B

,

Schumacher

CA

,

Fiolet

JWT

,

Koeman

A

, et al.

Class effects of SGLT2 inhibitors in mouse cardiomyocytes and hearts: inhibition of Na⁺/H⁺ exchanger, lowering of cytosolic Na⁺ and vasodilation

.

Diabetologia

2018

;

61

:

722

–

6

.

10.1007/s00125-017-4509-7

702

Lopaschuk

GD

,

Verma

S

.

Mechanisms of cardiovascular benefits of sodium glucose co-transporter 2 (SGLT2) inhibitors: a state-of-the-art review

.

JACC Basic Transl Sci

2020

;

5

:

632

–

44

.

10.1016/j.jacbts.2020.02.004

703

Kristensen

SL

,

Rorth

R

,

Jhund

PS

,

Docherty

KF

,

Sattar

N

,

Preiss

D

, et al.

Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials

.

Lancet Diabetes Endocrinol

2019

;

7

:

776

–

85

.

10.1016/S2213-8587(19)30249-9

704

McMurray

JJV

,

Solomon

SD

,

Inzucchi

SE

,

Køber

L

,

Kosiborod

MN

,

Martinez

FA

, et al.

Dapagliflozin in patients with heart failure and reduced ejection fraction

.

N Engl J Med

2019

;

381

:

1995

–

2008

.

10.1056/NEJMoa1911303

705

Packer

M

,

Anker

SD

,

Butler

J

,

Filippatos

G

,

Pocock

SJ

,

Carson

P

, et al.

Cardiovascular and renal outcomes with empagliflozin in heart failure

.

N Engl J Med

2020

;

383

:

1413

–

24

.

10.1056/NEJMoa2022190

706

Anker

SD

,

Butler

J

,

Filippatos

G

,

Ferreira

JP

,

Bocchi

E

,

Böhm

M

, et al.

Empagliflozin in heart failure with a preserved ejection fraction

.

N Engl J Med

2021

;

385

:

1451

–

61

.

10.1056/NEJMoa2107038

707

Solomon

SD

,

McMurray

JJV

,

Claggett

B

,

de Boer

RA

,

DeMets

D

,

Hernandez

AF

, et al.

Dapagliflozin in heart failure with mildly reduced or preserved ejection fraction

.

N Engl J Med

2022

;

387

:

1089

–

98

.

10.1056/NEJMoa2206286

708

Razuk

V

,

Chiarito

M

,

Cao

D

,

Nicolas

J

,

Pivato

CA

,

Camaj

A

, et al.

SGLT-2 inhibitors and cardiovascular outcomes in patients with and without a history of heart failure: a systematic review and meta-analysis

.

Eur Heart J Cardiovasc Pharmacother

2022

;

8

:

557

–

67

.

10.1093/ehjcvp/pvac001

709

McDonagh

TA

,

Metra

M

,

Adamo

M

,

Gardner

RS

,

Baumbach

A

,

Böhm

M

, et al.

2023 Focused update of the 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: developed by the task force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) wth the special contribution of the Heart Failure Association (HFA) of the ESC

.

Eur Heart J

2023

;

44

:

3627

–

39

.

10.1093/eurheartj/ehad195

710

Gerstein

HC

,

Sattar

N

,

Rosenstock

J

,

Ramasundarahettige

C

,

Pratley

R

,

Lopes

RD

, et al.

Cardiovascular and renal outcomes with efpeglenatide in type 2 diabetes

.

N Engl J Med

2021

;

385

:

896

–

907

.

10.1056/NEJMoa2108269

711

Sattar

N

,

Lee

MMY

,

Kristensen

SL

,

Branch

KRH

,

Del Prato

S

,

Khurmi

NS

, et al.

Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of randomised trials

.

Lancet Diabetes Endocrinol

2021

;

9

:

653

–

62

.

10.1016/S2213-8587(21)00203-5

712

Ridker

PM

,

Everett

BM

,

Thuren

T

,

MacFadyen

JG

,

Chang

WH

,

Ballantyne

C

, et al.

Antiinflammatory therapy with canakinumab for atherosclerotic disease

.

N Engl J Med

2017

;

377

:

1119

–

31

.

10.1056/NEJMoa1707914

713

Ridker

PM

,

Everett

BM

,

Pradhan

A

,

MacFadyen

JG

,

Solomon

DH

,

Zaharris

E

, et al.

Low-dose methotrexate for the prevention of atherosclerotic events

.

N Engl J Med

2019

;

380

:

752

–

62

.

10.1056/NEJMoa1809798

714

Tardif

JC

,

Kouz

S

,

Waters

DD

,

Bertrand

OF

,

Diaz

R

,

Maggioni

AP

, et al.

Efficacy and safety of low-dose colchicine after myocardial infarction

.

N Engl J Med

2019

;

381

:

2497

–

505

.

10.1056/NEJMoa1912388

715

Nidorf

SM

,

Fiolet

ATL

,

Mosterd

A

,

Eikelboom

JW

,

Schut

A

,

Opstal

TSJ

, et al.

Colchicine in patients with chronic coronary disease

.

N Engl J Med

2020

;

383

:

1838

–

47

.

10.1056/NEJMoa2021372

716

Andreis

A

,

Imazio

M

,

Piroli

F

,

Avondo

S

,

Casula

M

,

Paneva

E

, et al.

Efficacy and safety of colchicine for the prevention of major cardiovascular and cerebrovascular events in patients with coronary artery disease: a systematic review and meta-analysis on 12

869 patients

.

Eur J Prev Cardiol

2022

;

28

:

1916

–

25

.

10.1093/eurjpc/zwab045

717

Abdallah

MS

,

Wang

K

,

Magnuson

EA

,

Osnabrugge

RL

,

Kappetein

AP

,

Morice

MC

, et al.

Quality of life after surgery or DES in patients with 3-vessel or left main disease

.

J Am Coll Cardiol

2017

;

69

:

2039

–

50

.

10.1016/j.jacc.2017.02.031

718

Bittl

JA

,

He

Y

,

Jacobs

AK

,

Yancy

CW

,

Normand

SLT

;

American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines

.

Bayesian methods affirm the use of percutaneous coronary intervention to improve survival in patients with unprotected left main coronary artery disease

.

Circulation

2013

;

127

:

2177

–

85

.

10.1161/CIRCULATIONAHA.112.000646

719

Yusuf

S

,

Zucker

D

,

Passamani

E

,

Peduzzi

P

,

Takaro

T

,

Fisher

LD

, et al.

Effect of coronary artery bypass graft surgery on survival: overview of 10-year results from randomised trials by the Coronary Artery Bypass Graft Surgery Trialists Collaboration

.

Lancet

1994

;

344

:

563

–

70

.

10.1016/s0140-6736(94)91963-1

720

Takaro

T

,

Peduzzi

P

,

Detre

KM

,

Hultgren

HN

,

Murphy

ML

,

van der Bel-Kahn

J

, et al.

Survival in subgroups of patients with left main coronary artery disease. Veterans Administration Cooperative Study of surgery for coronary arterial occlusive disease

.

Circulation

1982

;

66

:

14

–

22

.

10.1161/01.cir.66.1.14

721

Talano

JV

,

Scanlon

PJ

,

Meadows

WR

,

Kahn

M

,

Pifarre

R

,

Gunnar

RM

.

Influence of surgery on survival in 145 patients with left main coronary artery disease

.

Circulation

1975

;

52

:

I105

–

111

.

10.1016/S0140-6736(82)91200-4

722

European Coronary Surgery Study Group

.

Long-term results of prospective randomised study of coronary artery bypass surgery in stable angina pectoris. European Coronary Surgery Study Group

.

Lancet

1982

;

320

:

1173

–

80

.

723

Coronary artery surgery study (CASS).

A randomized trial of coronary artery bypass surgery. Survival data

.

Circulation

1983

;

68

:

939

–

50

.

10.1161/01.CIR.68.5.939

10.1056/nejm198411223112102

724

Veterans Administration Coronary Artery Bypass Surgery Cooperative Study Group

.

Eleven-year survival in the Veterans Administration randomized trial of coronary bypass surgery for stable angina

.

New Engl J Med

1984

;

311

:

1333

–

9

.

10.1016/j.jacc.2021.05.010

725

Windecker

S

,

Stortecky

S

,

Stefanini

GG

,

daCosta

BR

,

Rutjes

AW

,

Di Nisio

M

, et al.

Revascularisation versus medical treatment in patients with stable coronary artery disease: network meta-analysis

.

BMJ

2014

;

348

:

g3859

.

726

Miller

RJH

,

Bonow

RO

,

Gransar

H

,

Park

R

,

Slomka

PJ

,

Friedman

JD

, et al.

Percutaneous or surgical revascularization is associated with survival benefit in stable coronary artery disease

.

Eur Heart J Cardiovasc Imaging

2020

;

21

:

961

–

70

.

10.1093/ehjci/jeaa083

727

Doenst

T

,

Bonow

RO

,

Bhatt

DL

,

Falk

V

,

Gaudino

M

.

Improving terminology to describe coronary artery procedures: JACC review topic of the week

.

J Am Coll Cardiol

2021

;

78

:

180

–

8

.

728

Head

SJ

,

Milojevic

M

,

Daemen

J

,

Ahn

JM

,

Boersma

E

,

Christiansen

EH

, et al.

Mortality after coronary artery bypass grafting versus percutaneous coronary intervention with stenting for coronary artery disease: a pooled analysis of individual patient data

.

Lancet

2018

;

391

:

939

–

48

.

10.1016/s0140-6736(18)30423-9

729

Perera

D

,

Clayton

T

,

O’Kane

PD

,

Greenwood

JP

,

Weerackody

R

,

Ryan

M

, et al.

Percutaneous revascularization for ischemic left ventricular dysfunction

.

N Engl J Med

2022

;

387

:

1351

–

60

.

10.1056/NEJMoa2206606

730

Sabatine

MS

,

Bergmark

BA

,

Murphy

SA

,

O’Gara

PT

,

Smith

PK

,

Serruys

PW

, et al.

Percutaneous coronary intervention with drug-eluting stents versus coronary artery bypass grafting in left main coronary artery disease: an individual patient data meta-analysis

.

Lancet

2021

;

398

:

2247

–

57

.

10.1016/s0140-6736(21)02334-5

731

Serruys

PW

,

Ono

M

,

Garg

S

,

Hara

H

,

Kawashima

H

,

Pompilio

G

, et al.

Percutaneous coronary revascularization: JACC historical breakthroughs in perspective

.

J Am Coll Cardiol

2021

;

78

:

384

–

407

.

10.1016/j.jacc.2021.05.024

732

Bangalore

S

,

Maron David

J

,

Stone Gregg

W

,

Hochman Judith

S

.

Routine revascularization versus initial medical therapy for stable ischemic heart disease

.

Circulation

2020

;

142

:

841

–

57

.

10.1161/CIRCULATIONAHA.120.048194

733

Soares

A

,

Boden

WE

,

Hueb

W

,

Brooks

MM

,

Vlachos

HEA

,

O’Fee

K

, et al.

Death and myocardial infarction following initial revascularization versus optimal medical therapy in chronic coronary syndromes with myocardial ischemia: a systematic review and meta-analysis of contemporary randomized controlled trials

.

J Am Heart Assoc

2021

;

10

:

e019114

.

10.1161/JAHA.120.019114

734

Kumar

A

,

Doshi

R

,

Khan

SU

,

Shariff

M

,

Baby

J

,

Majmundar

M

, et al.

Revascularization or optimal medical therapy for stable ischemic heart disease: a Bayesian meta-analysis of contemporary trials

.

Cardiovasc Revasc Med

2022

;

40

:

42

–

7

.

10.1016/j.carrev.2021.12.005

735

Wang

HY

,

Xu

B

,

Dou

K

,

Guan

C

,

Song

L

,

Huang

Y

, et al.

Implications of periprocedural myocardial biomarker elevations and commonly used MI definitions after left main PCI

.

JACC Cardiovasc Interv

2021

;

14

:

1623

–

34

.

10.1016/j.jcin.2021.05.006

736

Bulluck

H

,

Paradies

V

,

Barbato

E

,

Baumbach

A

,

Bøtker

HE

,

Capodanno

D

, et al.

Prognostically relevant periprocedural myocardial injury and infarction associated with percutaneous coronary interventions: a Consensus Document of the ESC Working Group on Cellular Biology of the Heart and European Association of Percutaneous Cardiovascular Interventions (EAPCI)

.

Eur Heart J

2021

;

42

:

2630

–

42

.

10.1093/eurheartj/ehab271

737

Chaitman

BR

,

Alexander

KP

,

Cyr

DD

,

Berger

JS

,

Reynolds

HR

,

Bangalore

S

, et al.

Myocardial infarction in the ISCHEMIA Trial: impact of different definitions on incidence, prognosis, and treatment comparisons

.

Circulation

2021

;

143

:

790

–

804

.

10.1161/circulationaha.120.047987

738

Redfors

B

,

Stone

GW

,

Alexander

JH

,

Bates

ER

,

Bhatt

DL

,

Biondi-Zoccai

G

, et al.

Outcomes according to coronary revascularization modality in the ISCHEMIA trial

.

J Am Coll Cardiol

2024

;

83

:

549

–

58

.

10.1016/j.jacc.2023.11.002

739

Navarese

EP

,

Lansky

AJ

,

Farkouh

ME

,

Grzelakowska

K

,

Bonaca

MP

,

Gorog

DA

, et al.

Effects of elective coronary revascularization vs medical therapy alone on noncardiac mortality: a meta-analysis

.

JACC Cardiovasc Interv

2023

;

16

:

1144

–

56

.

10.1016/j.jcin.2023.02.030

740

Vedin

O

,

Lam

CSP

,

Koh

AS

,

Benson

L

,

Teng

THK

,

Tay

WT

, et al.

Significance of ischemic heart disease in patients with heart failure and preserved, midrange, and reduced ejection fraction: a nationwide cohort study

.

Circ Heart Fail

2017

;

10

:

e003875

.

10.1161/circheartfailure.117.003875

741

Panza

JA

,

Chrzanowski

L

,

Bonow

RO

.

Myocardial viability assessment before surgical revascularization in ischemic cardiomyopathy: JACC review topic of the week

.

J Am Coll Cardiol

2021

;

78

:

1068

–

77

.

10.1016/j.jacc.2021.07.004

742

Rahimtoola

SH

,

Dilsizian

V

,

Kramer

CM

,

Marwick

TH

,

Vanoverschelde

JL

.

Chronic ischemic left ventricular dysfunction: from pathophysiology to imaging and its integration into clinical practice

.

JACC Cardiovasc Imaging

2008

;

1

:

536

–

55

.

10.1016/j.jcmg.2008.05.009

743

Kunadian

V

,

Zaman

A

,

Qiu

W

.

Revascularization among patients with severe left ventricular dysfunction: a meta-analysis of observational studies

.

Eur J Heart Fail

2011

;

13

:

773

–

84

.

10.1093/eurjhf/hfr037

744

Allman

KC

,

Shaw

LJ

,

Hachamovitch

R

,

Udelson

JE

.

Myocardial viability testing and impact of revascularization on prognosis in patients with coronary artery disease and left ventricular dysfunction: a meta-analysis

.

J Am Coll Cardiol

2002

;

39

:

1151

–

8

.

10.1016/s0735-1097(02)01726-6

745

Beanlands

RS

,

Nichol

G

,

Huszti

E

,

Humen

D

,

Racine

N

,

Freeman

M

, et al.

F-18-fluorodeoxyglucose positron emission tomography imaging-assisted management of patients with severe left ventricular dysfunction and suspected coronary disease: a randomized, controlled trial (PARR-2)

.

J Am Coll Cardiol

2007

;

50

:

2002

–

12

.

10.1016/j.jacc.2007.09.006

746

Mc Ardle

B

,

Shukla

T

,

Nichol

G

,

deKemp

RA

,

Bernick

J

,

Guo

A

, et al.

Long-term follow-up of outcomes with F-18-fluorodeoxyglucose positron emission tomography imaging-assisted management of patients with severe left ventricular dysfunction secondary to coronary disease

.

Circ Cardiovasc Imaging

2016

;

9

:

e004331

.

10.1161/circimaging.115.004331

747

D’Egidio

G

,

Nichol

G

,

Williams

KA

,

Guo

A

,

Garrard

L

,

deKemp

R

, et al.

Increasing benefit from revascularization is associated with increasing amounts of myocardial hibernation: a substudy of the PARR-2 trial

.

JACC Cardiovasc Imaging

2009

;

2

:

1060

–

8

.

10.1016/j.jcmg.2009.02.017

748

Ling

LF

,

Marwick

TH

,

Flores

DR

,

Jaber

WA

,

Brunken

RC

,

Cerqueira

MD

, et al.

Identification of therapeutic benefit from revascularization in patients with left ventricular systolic dysfunction: inducible ischemia versus hibernating myocardium

.

Circ Cardiovasc Imaging

2013

;

6

:

363

–

72

.

10.1161/circimaging.112.000138

749

Petrie

MC

,

Jhund

PS

,

She

L

,

Adlbrecht

C

,

Doenst

T

,

Panza

JA

, et al.

Ten-year outcomes after coronary artery bypass grafting according to age in patients with heart failure and left ventricular systolic dysfunction: an analysis of the extended follow-up of the STICH Trial (Surgical Treatment for Ischemic Heart Failure)

.

Circulation

2016

;

134

:

1314

–

24

.

10.1161/CIRCULATIONAHA.116.024800

750

Panza

JA

,

Ellis

AM

,

Al-Khalidi

HR

,

Holly

TA

,

Berman

DS

,

Oh

JK

, et al.

Myocardial viability and long-term outcomes in ischemic cardiomyopathy

.

N Engl J Med

2019

;

381

:

739

–

48

.

10.1056/NEJMoa1807365

751

Wolff

G

,

Dimitroulis

D

,

Andreotti

F

,

Kołodziejczak

M

,

Jung

C

,

Scicchitano

P

, et al.

Survival benefits of invasive versus conservative strategies in heart failure in patients with reduced ejection fraction and coronary artery disease: a meta-analysis

.

Circ Heart Fail

2017

;

10

:

e003255

.

10.1161/circheartfailure.116.003255

752

Sun

LY

,

Gaudino

M

,

Chen

RJ

,

Bader Eddeen

A

,

Ruel

M

.

Long-term outcomes in patients with severely reduced left ventricular ejection fraction undergoing percutaneous coronary intervention vs coronary artery bypass grafting

.

JAMA Cardiol

2020

;

5

:

631

–

41

.

10.1001/jamacardio.2020.0239

753

Völz

S

,

Redfors

B

,

Angerås

O

,

Ioanes

D

,

Odenstedt

J

,

Koul

S

, et al.

Long-term mortality in patients with ischaemic heart failure revascularized with coronary artery bypass grafting or percutaneous coronary intervention: insights from the Swedish Coronary Angiography and Angioplasty Registry (SCAAR)

.

Eur Heart J

2021

;

42

:

2657

–

64

.

10.1093/eurheartj/ehab273

754

Ono

M

,

Garg

S

,

Onuma

Y

,

Serruys

PW

.

Coronary artery bypass grafting versus percutaneous coronary intervention in ischaemic heart failure. Can reliable treatment decisions in high-risk patients be based on non-randomized data?

Eur Heart J

2021

;

42

:

2665

–

9

.

10.1093/eurheartj/ehab349

755

Perera

D

,

Ryan

M

,

Morgan

HP

,

Greenwood

JP

,

Petrie

MC

,

Dodd

M

, et al.

Viability and outcomes with revascularization or medical therapy in ischemic ventricular dysfunction: a prespecified secondary analysis of the REVIVED-BCIS2 trial

.

JAMA Cardiol

2023

;

8

:

1154

–

61

.

10.1001/jamacardio.2023.3803

756

Ryan

M

,

Morgan

H

,

Chiribiri

A

,

Nagel

E

,

Cleland

J

,

Perera

D

.

Myocardial viability testing: all STICHed up, or about to be REVIVED?

Eur Heart J

2022

;

43

:

118

–

26

.

10.1093/eurheartj/ehab729

757

Shaw

LJ

,

Berman

DS

,

Maron

DJ

,

Mancini

GBJ

,

Hayes

SW

,

Hartigan

PM

, et al.

Optimal medical therapy with or without percutaneous coronary intervention to reduce ischemic burden: results from the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial nuclear substudy

.

Circulation

2008

;

117

:

1283

–

91

.

10.1161/circulationaha.107.743963

758

Gaudino

M

,

Andreotti

F

,

Kimura

T

.

Current concepts in coronary artery revascularisation

.

Lancet

2023

;

401

:

1611

–

28

.

10.1016/S0140-6736(23)00459-2

759

Kim

T

,

Kang

DY

,

Kim

S

,

Lee

JH

,

Kim

AR

,

Lee

YJ

, et al.

Impact of complete or incomplete revascularization for left main coronary disease: the extended PRECOMBAT study

.

JACC Asia

2023

;

3

:

65

–

74

.

10.1016/j.jacasi.2022.10.007

760

Farooq

V

,

Serruys

PW

,

Bourantas

CV

,

Zhang

Y

,

Muramatsu

T

,

Feldman

T

, et al.

Quantification of incomplete revascularization and its association with five-year mortality in the synergy between percutaneous coronary intervention with taxus and cardiac surgery (SYNTAX) trial validation of the residual SYNTAX score

.

Circulation

2013

;

128

:

141

–

51

.

10.1161/CIRCULATIONAHA.113.001803

761

Gallinoro

E

,

Paolisso

P

,

Di Gioia

G

,

Bermpeis

K

,

Fernandez-Peregrina

E

,

Candreva

A

, et al.

Deferral of coronary revascularization in patients with reduced ejection fraction based on physiological assessment: impact on long-term survival

.

J Am Heart Assoc

2022

;

11

:

e026656

.

10.1161/JAHA.122.026656

762

Ahn

JM

,

Park

DW

,

Lee

CW

,

Chang

M

,

Cavalcante

R

,

Sotomi

Y

, et al.

Comparison of stenting versus bypass surgery according to the completeness of revascularization in severe coronary artery disease: patient-level pooled analysis of the SYNTAX, PRECOMBAT, and BEST trials

.

JACC Cardiovasc Interv

2017

;

10

:

1415

–

24

.

10.1016/j.jcin.2017.04.037

763

Girerd

N

,

Magne

J

,

Rabilloud

M

,

Charbonneau

E

,

Mohamadi

S

,

Pibarot

P

, et al.

The impact of complete revascularization on long-term survival is strongly dependent on age

.

Ann Thorac Surg

2012

;

94

:

1166

–

72

.

10.1016/j.athoracsur.2012.05.023

764

Werner

GS

,

Martin-Yuste

V

,

Hildick-Smith

D

,

Boudou

N

,

Sianos

G

,

Gelev

V

, et al.

A randomized multicentre trial to compare revascularization with optimal medical therapy for the treatment of chronic total coronary occlusions

.

Eur Heart J

2018

;

39

:

2484

–

93

.

10.1093/eurheartj/ehy220

765

Lee

SW

,

Lee

PH

,

Ahn

JM

,

Park

DW

,

Yun

SC

,

Han

S

, et al.

Randomized trial evaluating percutaneous coronary intervention for the treatment of chronic total occlusion

.

Circulation

2019

;

139

:

1674

–

83

.

10.1161/CIRCULATIONAHA.118.031313

766

Simsek

B

,

Kostantinis

S

,

Karacsonyi

J

,

Alaswad

K

,

Megaly

M

,

Karmpaliotis

D

, et al.

A systematic review and meta-analysis of clinical outcomes of patients undergoing chronic total occlusion percutaneous coronary intervention

.

J Invasive Cardiol

2022

;

34

:

E763

–

75

.

10.1161/CIRCULATIONAHA.120.046289

767

Werner

GS

,

Hildick-Smith

D

,

Martin Yuste

V

,

Boudou

N

,

Sianos

G

,

Gelev

V

, et al.

Three-year outcomes of a randomized multicentre trial comparing revascularization and optimal medical therapy for chronic total coronary occlusions (EuroCTO)

.

EuroIntervention

2023

;

19

:

571

–

9

.

10.4244/eij-d-23-00312

768

Takahashi

K

,

Serruys

PW

,

Gao

C

,

Ono

M

,

Wang

R

,

Thuijs

DJFM

, et al.

Ten-year all-cause death according to completeness of revascularization in patients with three-vessel disease or left main coronary artery disease: insights from the SYNTAX Extended survival study

.

Circulation

2021

;

144

:

96

–

109

.

769

Leviner

DB

,

Torregrossa

G

,

Puskas

JD

.

Incomplete revascularization: what the surgeon needs to know

.

Ann Cardiothorac Surg

2018

;

7

:

463

–

9

.

10.21037/acs.2018.06.07

770

Gaba

P

,

Gersh

BJ

,

Ali

ZA

,

Moses

JW

,

Stone

GW

.

Complete versus incomplete coronary revascularization: definitions, assessment and outcomes

.

Nat Rev Cardiol

2021

;

18

:

155

–

68

.

10.1038/s41569-020-00457-5

771

Lamy

A

,

Eikelboom

J

,

Sheth

T

,

Connolly

S

,

Bosch

J

,

Fox

KAA

, et al.

Rivaroxaban, aspirin, or both to prevent early coronary bypass graft occlusion: the COMPASS-CABG study

.

J Am Coll Cardiol

2019

;

73

:

121

–

30

.

10.1016/j.jacc.2018.10.048

772

Xenogiannis

I

,

Zenati

M

,

Bhatt

DL

,

Rao

SV

,

Rodés-Cabau

J

,

Goldman

S

, et al.

Saphenous vein graft failure: from pathophysiology to prevention and treatment strategies

.

Circulation

2021

;

144

:

728

–

45

.

10.1161/CIRCULATIONAHA.120.052163

773

Han

Z

,

Zhang

G

,

Chen

Y

.

Early asymptomatic graft failure in coronary artery bypass grafting: a study based on computed tomography angiography analysis

.

J Cardiothorac Surg

2023

;

18

:

98

.

10.1186/s13019-023-02199-0

774

Head

SJ

,

Borgermann

J

,

Osnabrugge

RL

,

Kieser

TM

,

Falk

V

,

Taggart

DP

, et al.

Coronary artery bypass grafting: Part 2—optimizing outcomes and future prospects

.

Eur Heart J

2013

;

34

:

2873

–

86

.

10.1093/eurheartj/eht284

775

Stone

GW

.

Multivessel PCI on its 40th anniversary: finally a match for CABG?

Eur Heart J

2017

;

38

:

3135

–

8

.

10.1093/eurheartj/ehx528

776

Osnabrugge

RL

,

Speir

AM

,

Head

SJ

,

Fonner

CE

,

Fonner

E

,

Kappetein

AP

, et al.

Performance of EuroSCORE II in a large US database: implications for transcatheter aortic valve implantation

.

Eur J Cardiothorac Surg

2014

;

46

:

400

–

8

; discussion 408.

777

Thuijs

D

,

Habib

RH

,

Head

SJ

,

Puskas

JD

,

Taggart

DP

,

Stone

GW

, et al.

Prognostic performance of the Society of Thoracic Surgeons risk score in patients with left main coronary artery disease undergoing revascularisation: a post hoc analysis of the EXCEL trial

.

EuroIntervention

2020

;

16

:

36

–

43

.

10.4244/EIJ-D-19-00417

778

Reichart

D

,

Rosato

S

,

Nammas

W

,

Onorati

F

,

Dalén

M

,

Castro

L

, et al.

Clinical frailty scale and outcome after coronary artery bypass grafting

.

Eur J Cardiothorac Surg

2018

;

54

:

1102

–

9

.

779

Zhang

YJ

,

Iqbal

J

,

Campos

CM

,

Klaveren

DV

,

Bourantas

CV

,

Dawkins

KD

, et al.

Prognostic value of site SYNTAX score and rationale for combining anatomic and clinical factors in decision making: insights from the SYNTAX trial

.

J Am Coll Cardiol

2014

;

64

:

423

–

32

.

10.1016/j.jacc.2014.05.022

780

Bonaros

N

,

Van Craenenbroeck

E

.

A good operation is not enough, when it comes to frail patients

.

Eur J Cardiothorac Surg

2023

;

64

:

ezad205

.

10.1093/ejcts/ezad205

781

Sianos

G

,

Morel

MA

,

Kappetein

AP

,

Morice

MC

,

Colombo

A

,

Dawkins

K

, et al.

The SYNTAX score: an angiographic tool grading the complexity of coronary artery disease

.

EuroIntervention

2005

;

1

:

219

–

27

.

10.1093/eurheartj/ehad476

782

Byrne

RA

,

Fremes

S

,

Capodanno

D

,

Czerny

M

,

Doenst

T

,

Emberson

JR

, et al.

2022 Joint ESC/EACTS review of the 2018 guideline recommendations on the revascularization of left main coronary artery disease in patients at low surgical risk and anatomy suitable for PCI or CABG

.

Eur Heart J

2023

;

44

:

4310

–

20

.

783

Calburean

PA

,

Grebenisan

P

,

Nistor

IA

,

Pal

K

,

Vacariu

V

,

Drincal

RK

, et al.

Prediction of 3-year all-cause and cardiovascular cause mortality in a prospective percutaneous coronary intervention registry: machine learning model outperforms conventional clinical risk scores

.

Atherosclerosis

2022

;

350

:

33

–

40

.

10.1016/j.atherosclerosis.2022.03.028

784

Farooq

V

,

van Klaveren

D

,

Steyerberg

EW

,

Meliga

E

,

Vergouwe

Y

,

Chieffo

A

, et al.

Anatomical and clinical characteristics to guide decision making between coronary artery bypass surgery and percutaneous coronary intervention for individual patients: development and validation of SYNTAX score II

.

Lancet

2013

;

381

:

639

–

50

.

10.1016/s0140-6736(13)60108-7

785

Escaned

J

,

Collet

C

,

Ryan

N

,

Luigi De Maria

G

,

Walsh

S

,

Sabate

M

, et al.

Clinical outcomes of state-of-the-art percutaneous coronary revascularization in patients with de novo three vessel disease: 1-year results of the SYNTAX II study

.

Eur Heart J

2017

;

38

:

3124

–

34

.

10.1093/eurheartj/ehx512

786

Cavalcante

R

,

Sotomi

Y

,

Mancone

M

,

Whan Lee

C

,

Ahn

JM

,

Onuma

Y

, et al.

Impact of the SYNTAX scores I and II in patients with diabetes and multivessel coronary disease: a pooled analysis of patient level data from the SYNTAX, PRECOMBAT, and BEST trials

.

Eur Heart J

2017

;

38

:

1969

–

77

.

10.1093/eurheartj/ehx138

787

Hara

H

,

Shiomi

H

,

van Klaveren

D

,

Kent

DM

,

Steyerberg

EW

,

Garg

S

, et al.

External validation of the SYNTAX score II 2020

.

J Am Coll Cardiol

2021

;

78

:

1227

–

38

.

10.1016/j.jacc.2021.07.027

788

Modolo

R

,

Chichareon

P

,

van Klaveren

D

,

Dressler

O

,

Zhang

Y

,

Sabik

JF

, et al.

Impact of non-respect of SYNTAX score II recommendation for surgery in patients with left main coronary artery disease treated by percutaneous coronary intervention: an EXCEL substudy

.

Eur J Cardiothorac Surg

2020

;

57

:

676

–

83

.

789

Takahashi

K

,

Serruys

PW

,

Fuster

V

,

Farkouh

ME

,

Spertus

JA

,

Cohen

DJ

, et al.

Redevelopment and validation of the SYNTAX score II to individualise decision making between percutaneous and surgical revascularisation in patients with complex coronary artery disease: secondary analysis of the multicentre randomised controlled SYNTAXES trial with external cohort validation

.

Lancet

2020

;

396

:

1399

–

412

.

10.1016/S0140-6736(20)32114-0

790

De Silva

K

,

Morton

G

,

Sicard

P

,

Chong

E

,

Indermuehle

A

,

Clapp

B

, et al.

Prognostic utility of BCIS myocardial jeopardy score for classification of coronary disease burden and completeness of revascularization

.

Am J Cardiol

2013

;

111

:

172

–

7

.

10.1016/j.amjcard.2012.09.012

791

Kapoor

JR

,

Gienger

AL

,

Ardehali

R

,

Varghese

R

,

Perez

MV

,

Sundaram

V

, et al.

Isolated disease of the proximal left anterior descending artery comparing the effectiveness of percutaneous coronary interventions and coronary artery bypass surgery

.

JACC Cardiovasc Interv

2008

;

1

:

483

–

91

.

10.1016/j.jcin.2008.07.001

792

Thiele

H

,

Neumann-Schniedewind

P

,

Jacobs

S

,

Boudriot

E

,

Walther

T

,

Mohr

FW

, et al.

Randomized comparison of minimally invasive direct coronary artery bypass surgery versus sirolimus-eluting stenting in isolated proximal left anterior descending coronary artery stenosis

.

J Am Coll Cardiol

2009

;

53

:

2324

–

31

.

10.1016/j.jacc.2009.03.032

793

Blazek

S

,

Holzhey

D

,

Jungert

C

,

Borger

MA

,

Fuernau

G

,

Desch

S

, et al.

Comparison of bare-metal stenting with minimally invasive bypass surgery for stenosis of the left anterior descending coronary artery: 10-year follow-up of a randomized trial

.

JACC Cardiovasc Interv

2013

;

6

:

20

–

6

.

10.1016/j.jcin.2012.09.008

794

Blazek

S

,

Rossbach

C

,

Borger

MA

,

Fuernau

G

,

Desch

S

,

Eitel

I

, et al.

Comparison of sirolimus-eluting stenting with minimally invasive bypass surgery for stenosis of the left anterior descending coronary artery: 7-year follow-up of a randomized trial

.

JACC Cardiovasc Interv

2015

;

8

:

30

–

8

.

10.1016/j.jcin.2014.08.006

795

Thuijs

D

,

Kappetein

AP

,

Serruys

PW

,

Mohr

FW

,

Morice

MC

,

Mack

MJ

, et al.

Percutaneous coronary intervention versus coronary artery bypass grafting in patients with three-vessel or left main coronary artery disease: 10-year follow-up of the multicentre randomised controlled SYNTAX trial

.

Lancet

2019

;

394

:

1325

–

34

.

10.1016/s0140-6736(19)31997-x

796

Gianoli

M

,

de Jong

AR

,

Jacob

KA

,

Namba

HF

,

van der Kaaij

NP

,

van der Harst

P

, et al.

Minimally invasive surgery or stenting for left anterior descending artery disease—meta-analysis

.

Int J Cardiol Heart Vasc

2022

;

40

:

101046

.

10.1016/j.ijcha.2022.101046

797

Patel

NC

,

Hemli

JM

,

Seetharam

K

,

Singh

VP

,

Scheinerman

SJ

,

Pirelli

L

, et al.

Minimally invasive coronary bypass versus percutaneous coronary intervention for isolated complex stenosis of the left anterior descending coronary artery

.

J Thorac Cardiovasc Surg

2022

;

163

:

1839

–

46.e1

.

10.1016/j.jtcvs.2020.04.171

798

Serruys

PW

,

Morice

MC

,

Kappetein

AP

,

Colombo

A

,

Holmes

DR

,

Mack

MJ

, et al.

Percutaneous coronary intervention versus coronary-artery bypass grafting for severe coronary artery disease

.

N Engl J Med

2009

;

360

:

961

–

72

.

10.1056/NEJMoa0804626

799

Giacoppo

D

,

Colleran

R

,

Cassese

S

,

Frangieh

AH

,

Wiebe

J

,

Joner

M

, et al.

Percutaneous coronary intervention vs coronary artery bypass grafting in patients with left main coronary artery stenosis: a systematic review and meta-analysis

.

JAMA Cardiol

2017

;

2

:

1079

–

88

.

10.1001/jamacardio.2017.2895

800

Palmerini

T

,

Serruys

P

,

Kappetein

AP

,

Genereux

P

,

Riva

DD

,

Reggiani

LB

, et al.

Clinical outcomes with percutaneous coronary revascularization vs coronary artery bypass grafting surgery in patients with unprotected left main coronary artery disease: a meta-analysis of 6 randomized trials and 4,686 patients

.

Am Heart J

2017

;

190

:

54

–

63

.

10.1016/j.ahj.2017.05.005

801

Farkouh

ME

,

Domanski

M

,

Sleeper

LA

,

Siami

FS

,

Dangas

G

,

Mack

M

, et al.

Strategies for multivessel revascularization in patients with diabetes

.

N Engl J Med

2012

;

367

:

2375

–

84

.

10.1056/NEJMoa1211585

802

Ahmad

Y

,

Howard

JP

,

Arnold

AD

,

Cook

CM

,

Prasad

M

,

Ali

ZA

, et al.

Mortality after drug-eluting stents vs. coronary artery bypass grafting for left main coronary artery disease: a meta-analysis of randomized controlled trials

.

Eur Heart J

2020

;

41

:

3228

–

35

.

10.1093/eurheartj/ehaa135

803

Kuno

T

,

Ueyama

H

,

Rao

SV

,

Cohen

MG

,

Tamis-Holland

JE

,

Thompson

C

, et al.

Percutaneous coronary intervention or coronary artery bypass graft surgery for left main coronary artery disease: a meta-analysis of randomized trials

.

Am Heart J

2020

;

227

:

9

–

10

.

10.1016/j.ahj.2020.06.001

804

D’Ascenzo

F

,

De Filippo

O

,

Elia

E

,

Doronzo

MP

,

Omedè

P

,

Montefusco

A

, et al.

Percutaneous vs. surgical revascularization for patients with unprotected left main stenosis: a meta-analysis of 5-year follow-up randomized controlled trials

.

Eur Heart J Qual Care Clin Outcomes

2021

;

7

:

476

–

85

.

10.1093/ehjqcco/qcaa041

805

Hildick-Smith

D

,

Egred

M

,

Banning

A

,

Brunel

P

,

Ferenc

M

,

Hovasse

T

, et al.

The European bifurcation club Left Main Coronary Stent study: a randomized comparison of stepwise provisional vs. systematic dual stenting strategies (EBC MAIN)

.

Eur Heart J

2021

;

42

:

3829

–

39

.

10.1093/eurheartj/ehab283

806

Kandzari

DE

,

Gershlick

AH

,

Serruys

PW

,

Leon

MB

,

Morice

MC

,

Simonton

CA

, et al.

Outcomes among patients undergoing distal left main percutaneous coronary intervention

.

Circ Cardiovasc Interv

2018

;

11

:

e007007

.

10.1161/CIRCINTERVENTIONS.118.007007

807

Choi

KH

,

Song

YB

,

Lee

JM

,

Park

TK

,

Yang

JH

,

Hahn

JY

, et al.

Prognostic effects of treatment strategies for left main versus non-left main bifurcation percutaneous coronary intervention with current-generation drug-eluting stent

.

Circ Cardiovasc Interv

2020

;

13

:

e008543

.

10.1161/CIRCINTERVENTIONS.119.008543

808

Ninomiya

K

,

Serruys

PW

,

Garg

S

,

Gao

C

,

Masuda

S

,

Lunardi

M

, et al.

Predicted and observed mortality at 10 years in patients with bifurcation lesions in the SYNTAX trial

.

JACC Cardiovasc Interv

2022

;

15

:

1231

–

42

.

10.1016/j.jcin.2022.04.025

809

Wang

HY

,

Zhang

R

,

Dou

K

,

Huang

Y

,

Xie

L

,

Qiao

Z

, et al.

Left main bifurcation stenting: impact of residual ischaemia on cardiovascular mortality

.

Eur Heart J

2023

;

44

:

4324

–

36

.

10.1093/eurheartj/ehad318

810

Holm

NR

,

Andreasen

LN

,

Neghabat

O

,

Laanmets

P

,

Kumsars

I

,

Bennett

J

, et al.

OCT or angiography guidance for PCI in complex bifurcation lesions

.

N Engl J Med

2023

;

389

:

1477

–

87

.

10.1056/NEJMoa2307770

811

Xu

B

,

Redfors

B

,

Yang

Y

,

Qiao

S

,

Wu

Y

,

Chen

J

, et al.

Impact of operator experience and volume on outcomes after left main coronary artery percutaneous coronary intervention

.

JACC Cardiovasc Interv

2016

;

9

:

2086

–

93

.

10.1016/j.jcin.2016.08.011

812

Kinnaird

T

,

Gallagher

S

,

Anderson

R

,

Sharp

A

,

Farooq

V

,

Ludman

P

, et al.

Are higher operator volumes for unprotected left main stem percutaneous coronary intervention associated with improved patient outcomes? A survival analysis of 6724 procedures from the British Cardiovascular Intervention Society National Database

.

Circ Cardiovasc Interv

2020

;

13

:

e008782

.

10.1161/CIRCINTERVENTIONS.119.008782

813

Morice

MC

,

Serruys

PW

,

Kappetein

AP

,

Feldman

TE

,

Ståhle

E

,

Colombo

A

, et al.

Five-year outcomes in patients with left main disease treated with either percutaneous coronary intervention or coronary artery bypass grafting in the Synergy Between Percutaneous Coronary Intervention with Taxus and Cardiac Surgery Trial

.

Circulation

2014

;

129

:

2388

–

94

.

10.1161/CIRCULATIONAHA.113.006689

814

Park

SJ

,

Kim

YH

,

Park

DW

,

Yun

SC

,

Ahn

JM

,

Song

HG

, et al.

Randomized trial of stents versus bypass surgery for left main coronary artery disease

.

N Engl J Med

2011

;

364

:

1718

–

27

.

10.1056/NEJMoa1100452

815

Ahn

JM

,

Roh

JH

,

Kim

YH

,

Park

DW

,

Yun

SC

,

Lee

PH

, et al.

Randomized trial of stents versus bypass surgery for left main coronary artery disease: 5-year outcomes of the PRECOMBAT study

.

J Am Coll Cardiol

2015

;

65

:

2198

–

206

.

10.1016/j.jacc.2015.03.033

816

Park

DW

,

Ahn

JM

,

Park

H

,

Yun

SC

,

Kang

DY

,

Lee

PH

, et al.

Ten-year outcomes after drug-eluting stents versus coronary artery bypass grafting for left main coronary disease: extended follow-up of the PRECOMBAT trial

.

Circulation

2020

;

141

:

1437

–

46

.

10.1161/CIRCULATIONAHA.120.046039

817

Morice

MC

,

Serruys

PW

,

Kappetein

AP

,

Feldman

TE

,

Ståhle

E

,

Colombo

A

, et al.

Outcomes in patients with de novo left main disease treated with either percutaneous coronary intervention using paclitaxel-eluting stents or coronary artery bypass graft treatment in the Synergy Between Percutaneous Coronary Intervention with TAXUS and Cardiac Surgery (SYNTAX) trial

.

Circulation

2010

;

121

:

2645

–

53

.

10.1161/circulationaha.109.899211

818

Kappetein

AP

,

Feldman

TE

,

Mack

MJ

,

Morice

MC

,

Holmes

DR

,

Ståhle

E

, et al.

Comparison of coronary bypass surgery with drug-eluting stenting for the treatment of left main and/or three-vessel disease: 3-year follow-up of the SYNTAX trial

.

Eur Heart J

2011

;

32

:

2125

–

34

.

10.1093/eurheartj/ehr213

819

Makikallio

T

,

Holm

NR

,

Lindsay

M

,

Spence

MS

,

Erglis

A

,

Menown

IBA

, et al.

Percutaneous coronary angioplasty versus coronary artery bypass grafting in treatment of unprotected left main stenosis (NOBLE): a prospective, randomised, open-label, non-inferiority trial

.

Lancet

2016

;

388

:

2743

–

52

.

10.1016/S0140-6736(16)32052-9

820

Holm

NR

,

Makikallio

T

,

Lindsay

MM

,

Spence

MS

,

Erglis

A

,

Menown

IBA

, et al.

Percutaneous coronary angioplasty versus coronary artery bypass grafting in the treatment of unprotected left main stenosis: updated 5-year outcomes from the randomised, non-inferiority NOBLE trial

.

Lancet

2020

;

395

:

191

–

9

.

10.1016/S0140-6736(19)32972-1

821

Stone

GW

,

Sabik

JF

,

Serruys

PW

,

Simonton

CA

,

Généreux

P

,

Puskas

J

, et al.

Everolimus-eluting stents or bypass surgery for left main coronary artery disease

.

N Engl J Med

2016

;

375

:

2223

–

35

.

10.1056/NEJMoa1610227

822

Stone

GW

,

Kappetein

AP

,

Sabik

JF

,

Pocock

SJ

,

Morice

MC

,

Puskas

J

, et al.

Five-year outcomes after PCI or CABG for left main coronary disease

.

N Engl J Med

2019

;

381

:

1820

–

30

.

10.1056/NEJMoa1909406

823

Mohr

FW

,

Morice

MC

,

Kappetein

AP

,

Feldman

TE

,

Ståhle

E

,

Colombo

A

, et al.

Coronary artery bypass graft surgery versus percutaneous coronary intervention in patients with three-vessel disease and left main coronary disease: 5-year follow-up of the randomised, clinical SYNTAX trial

.

Lancet

2013

;

381

:

629

–

38

.

10.1016/S0140-6736(13)60141-5

824

Farkouh

ME

,

Domanski

M

,

Dangas

GD

,

Godoy

LC

,

Mack

MJ

,

Siami

FS

, et al.

Long-term survival following multivessel revascularization in patients with diabetes: the FREEDOM follow-on study

.

J Am Coll Cardiol

2019

;

73

:

629

–

38

.

10.1016/j.jacc.2018.11.001

825

Parasca

CA

,

Head

SJ

,

Milojevic

M

,

Mack

MJ

,

Serruys

PW

,

Morice

MC

, et al.

Incidence, characteristics, predictors, and outcomes of repeat revascularization after percutaneous coronary intervention and coronary artery bypass grafting: the SYNTAX trial at 5 years

.

JACC Cardiovasc Interv

2016

;

9

:

2493

–

507

.

10.1016/j.jcin.2016.09.044

826

van Nunen

LX

,

Zimmermann

FM

,

Tonino

PA

,

Barbato

E

,

Baumbach

A

,

Engstrøm

T

, et al.

Fractional flow reserve versus angiography for guidance of PCI in patients with multivessel coronary artery disease (FAME): 5-year follow-up of a randomised controlled trial

.

Lancet

2015

;

386

:

1853

–

60

.

10.1016/S0140-6736(15)00057-4

827

Zimmermann

FM

,

Ding

VY

,

Pijls

NHJ

,

Piroth

Z

,

van Straten

AHM

,

Szekely

L

, et al.

Fractional flow reserve-guided pci or coronary bypass surgery for 3-vessel coronary artery disease: 3-year follow-up of the FAME 3 trial

.

Circulation

2023

;

148

:

950

–

8

.

10.1161/CIRCULATIONAHA.123.065770

828

Piroth

Z

,

Otsuki

H

,

Zimmermann

FM

,

Ferenci

T

,

Keulards

DCJ

,

Yeung

AC

, et al.

Prognostic value of measuring fractional flow reserve after percutaneous coronary intervention in patients with complex coronary artery disease: insights from the FAME 3 trial

.

Circ Cardiovasc Interv

2022

;

15

:

884

–

91

.

10.1161/CIRCINTERVENTIONS.122.012542

829

Collison

D

,

Didagelos

M

,

Aetesam-Ur-Rahman

M

,

Copt

S

,

McDade

R

,

McCartney

P

, et al.

Post-stenting fractional flow reserve vs coronary angiography for optimization of percutaneous coronary intervention (TARGET-FFR)

.

Eur Heart J

2021

;

42

:

4656

–

68

.

10.1093/eurheartj/ehab449

830

Patel

MR

,

Jeremias

A

,

Maehara

A

,

Matsumura

M

,

Zhang

Z

,

Schneider

J

, et al.

1-Year outcomes of blinded physiological assessment of residual ischemia after successful PCI: DEFINE PCI trial

.

JACC Cardiovasc Interv

2022

;

15

:

52

–

61

.

10.1016/j.jcin.2021.09.042

831

Hwang

D

,

Koo

BK

,

Zhang

J

,

Park

J

,

Yang

S

,

Kim

M

, et al.

Prognostic implications of fractional flow reserve after coronary stenting: a systematic review and meta-analysis

.

JAMA Netw Open

2022

;

5

:

e2232842

.

10.1001/jamanetworkopen.2022.32842

832

Collet

C

,

Johnson Nils

P

,

Mizukami

T

,

Fearon

WF

,

Berry

C

,

Sonck

J

, et al.

Impact of post-PCI FFR stratified by coronary artery

.

JACC Cardiovasc Interv

2023

;

16

:

2396

–

408

.

10.1016/j.jcin.2023.08.018

833

Dai

N

,

Yuan

S

,

Dou

K

,

Zhang

R

,

Hu

N

,

He

J

, et al.

Prognostic implications of prestent pullback pressure gradient and poststent quantitative flow ratio in patients undergoing percutaneous coronary intervention

.

J Am Heart Assoc

2022

;

11

:

e024903

.

10.1161/JAHA.121.024903

834

Dai

N

,

Tang

X

,

Chen

Z

,

Huang

D

,

Duan

S

,

Qian

J

, et al.

Pre-stenting angiography-FFR based physiological map provides virtual intervention and predicts physiological and clinical outcomes

.

Catheter Cardiovasc Interv

2023

;

101

:

1053

–

61

.

835

Kikuta

Y

,

Cook

CM

,

Sharp

ASP

,

Salinas

P

,

Kawase

Y

,

Shiono

Y

, et al.

Pre-angioplasty instantaneous wave-free ratio pullback predicts hemodynamic outcome in humans with coronary artery disease: primary results of the international multicenter iFR GRADIENT registry

.

JACC Cardiovasc Interv

2018

;

11

:

757

–

67

.

10.1016/j.jcin.2018.03.005

836

Biscaglia

S

,

Verardi

FM

,

Tebaldi

M

,

Guiducci

V

,

Caglioni

S

,

Campana

R

, et al.

QFR-based virtual PCI or conventional angiography to guide PCI: the AQVA trial

.

JACC Cardiovasc Interv

2023

;

16

:

783

–

94

.

10.1016/j.jcin.2022.10.054

837

Bouisset

F

,

Ohashi

H

,

Andreini

D

,

Collet

C

. (September 19, 2023)

Role of coronary computed tomography angiography to optimise percutaneous coronary intervention outcomes

.

Heart

2024

;

110

:

1056

–

1062

838

Sonck

J

,

Nagumo

S

,

Norgaard

BL

,

Otake

H

,

Ko

B

,

Zhang

J

, et al.

Clinical validation of a virtual planner for coronary interventions based on coronary CT angiography

.

JACC Cardiovasc Imaging

2022

;

15

:

1242

–

55

. doi: doi:

10.1016/j.jcmg.2022.02.003

839

Van Belle

E

,

Raposo

L

,

Bravo Baptista

S

,

Vincent

F

,

Porouchani

S

,

Cosenza

A

, et al.

Impact of an interactive CT/FFR(CT) interventional planner on coronary artery disease management decision making

.

JACC Cardiovasc Imaging

2021

;

14

:

1068

–

70

.

10.1016/j.jcmg.2020.09.040

840

Lee

JM

,

Choi

KH

,

Song

YB

,

Lee

JY

,

Lee

SJ

,

Lee

SY

, et al.

Intravascular imaging-guided or angiography-guided complex PCI

.

N Engl J Med

2023

;

388

:

1668

–

79

.

10.1056/NEJMoa2216607

841

Ali

ZA

,

Landmesser

U

,

Maehara

A

,

Matsumura

M

,

Shlofmitz

RA

,

Guagliumi

G

, et al.

Optical coherence tomography-guided versus angiography-guided PCI

.

N Engl J Med

2023

;

389

:

1466

–

76

.

10.1056/NEJMoa2305861

842

Sabik

JF

III,

Blackstone

EH

,

Gillinov

AM

,

Banbury

MK

,

Smedira

NG

,

Lytle

BW

.

Influence of patient characteristics and arterial grafts on freedom from coronary reoperation

.

J Thorac Cardiovasc Surg

2006

;

131

:

90

–

8

.

10.1016/j.jtcvs.2005.05.024

843

Locker

C

,

Schaff

HV

,

Dearani

JA

,

Joyce

LD

,

Park

SJ

,

Burkhart

HM

, et al.

Multiple arterial grafts improve late survival of patients undergoing coronary artery bypass graft surgery: analysis of 8622 patients with multivessel disease

.

Circulation

2012

;

126

:

1023

–

30

.

10.1161/CIRCULATIONAHA.111.084624

844

Lowenstern

A

,

Wu

J

,

Bradley

SM

,

Fanaroff

AC

,

Tcheng

JE

,

Wang

TY

.

Current landscape of hybrid revascularization: a report from the NCDR CathPCI Registry

.

Am Heart J

2019

;

215

:

167

–

77

.

10.1016/j.ahj.2019.06.014

845

Ganyukov

VI

,

Kochergin

NA

,

Shilov

AA

,

Tarasov

RS

,

Skupien

J

,

Kozyrin

KA

, et al.

Randomized clinical trial of surgical versus percutaneous versus hybrid multivessel coronary revascularization: 3 years’ follow-up

.

JACC Cardiovasc Interv

2021

;

14

:

1163

–

5

.

10.1016/j.jcin.2021.02.037

846

Makoul

G

,

Clayman

ML

.

An integrative model of shared decision making in medical encounters

.

Patient Educ Couns

2006

;

60

:

301

–

12

.

10.1016/j.pec.2005.06.010

847

Mulley

AG

,

Trimble

C

,

Elwyn

G

.

Stop the silent misdiagnosis: patients’ preferences matter

.

BMJ

2012

;

345

:

e6572

.

848

Hughes

TM

,

Merath

K

,

Chen

Q

,

Sun

S

,

Palmer

E

,

Idrees

JJ

, et al.

Association of shared decision-making on patient-reported health outcomes and healthcare utilization

.

Am J Surg

2018

;

216

:

7

–

12

.

10.1016/j.amjsurg.2018.01.011

849

Nuis

RJ

,

Jadoon

A

,

van Dalen

BM

,

Dulfer

K

,

Snelder

SM

,

Yazdi

MT

, et al.

Patient perspectives on left main stem revascularization strategies, the OPINION-2 study

.

J Cardiol

2021

;

77

:

271

–

8

.

10.1016/j.jjcc.2020.09.009

850

Oudkerk Pool

MD

,

Hooglugt

JQ

,

Schijven

MP

,

Mulder

BJM

,

Bouma

BJ

,

de Winter

RJ

, et al.

Review of digitalized patient education in cardiology: a future ahead?

Cardiology

2021

;

146

:

263

–

71

.

851

Lincoln

TE

,

Buddadhumaruk

P

,

Arnold

RM

,

Scheunemann

LP

,

Ernecoff

NC

,

Chang

CCH

, et al.

Association between shared decision-making during family meetings and surrogates’ trust in their ICU physician

.

Chest

2023

;

163

:

1214

–

24

.

10.1016/j.chest.2022.10.028

852

Ayton

DR

,

Barker

AL

,

Peeters

G

,

Berkovic

DE

,

Lefkovits

J

,

Brennan

A

, et al.

Exploring patient-reported outcomes following percutaneous coronary intervention: a qualitative study

.

Health Expect

2018

;

21

:

457

–

65

.

853

Kipp

R

,

Lehman

J

,

Israel

J

,

Edwards

N

,

Becker

T

,

Raval

AN

.

Patient preferences for coronary artery bypass graft surgery or percutaneous intervention in multivessel coronary artery disease

.

Catheter Cardiovasc Interv

2013

;

82

:

212

–

8

.

854

Witberg

G

,

Segev

A

,

Barac

YD

,

Raanani

E

,

Assali

A

,

Finkelstein

A

, et al.

Heart team/guidelines discordance is associated with increased mortality: data from a national survey of revascularization in patients with complex coronary artery disease

.

Circ Cardiovasc Interv

2021

;

14

:

e009686

.

10.1161/circinterventions.120.009686

855

Patterson

T

,

McConkey

HZR

,

Ahmed-Jushuf

F

,

Moschonas

K

,

Nguyen

H

,

Karamasis

GV

, et al.

Long-term outcomes following heart team revascularization recommendations in complex coronary artery disease

.

J Am Heart Assoc

2019

;

8

:

e011279

.

10.1161/jaha.118.011279

856

Jonik

S

,

Marchel

M

,

Huczek

Z

,

Kochman

J

,

Wilimski

R

,

Kuśmierczyk

M

, et al.

An individualized approach of multidisciplinary heart team for myocardial revascularization and valvular heart disease—state of art

.

J Pers Med

2022

;

12

:

705

.

857

McKeown

L

,

Hong

YA

,

Kreps

GL

,

Xue

H

.

Trends and differences in perceptions of patient-centered communication among adults in the US

.

Patient Educ Couns

2023

;

106

:

128

–

34

.

10.1016/j.pec.2022.10.010

858

Tsang

MB

,

Schwalm

JD

,

Gandhi

S

,

Sibbald

MG

,

Gafni

A

,

Mercuri

M

, et al.

Comparison of heart team vs interventional cardiologist recommendations for the treatment of patients with multivessel coronary artery disease

.

JAMA Netw Open

2020

;

3

:

e2012749

.

10.1001/jamanetworkopen.2020.12749

859

Dzavik

V

,

Ghali

WA

,

Norris

C

,

Mitchell

LB

,

Koshal

A

,

Saunders

LD

, et al.

Long-term survival in 11,661 patients with multivessel coronary artery disease in the era of stenting: a report from the Alberta Provincial Project for Outcome Assessment in Coronary Heart Disease (APPROACH) investigators

.

Am Heart J

2001

;

142

:

119

–

26

.

10.1067/mhj.2001.116072

860

Lee

PH

,

Ahn

JM

,

Chang

M

,

Baek

S

,

Yoon

SH

,

Kang

SJ

, et al.

Left main coronary artery disease: secular trends in patient characteristics, treatments, and outcomes

.

J Am Coll Cardiol

2016

;

68

:

1233

–

46

.

10.1016/j.jacc.2016.05.089

861

Panza

JA

,

Velazquez

EJ

,

She

L

,

Smith

PK

,

Nicolau

JC

,

Favaloro

RR

, et al.

Extent of coronary and myocardial disease and benefit from surgical revascularization in ischemic LV dysfunction [Corrected]

.

J Am Coll Cardiol

2014

;

64

:

553

–

61

.

10.1016/j.jacc.2014.04.064

862

Sullivan

PG

,

Wallach

JD

,

Ioannidis

JP

.

Meta-analysis comparing established risk prediction models (EuroSCORE II, STS Score, and ACEF Score) for perioperative mortality during cardiac surgery

.

Am J Cardiol

2016

;

118

:

1574

–

82

.

10.1016/j.amjcard.2016.08.024

863

Ad

N

,

Holmes

SD

,

Patel

J

,

Pritchard

G

,

Shuman

DJ

,

Halpin

L

.

Comparison of EuroSCORE II, original EuroSCORE, and the Society of Thoracic Surgeons Risk Score in cardiac surgery patients

.

Ann Thorac Surg

2016

;

102

:

573

–

9

.

10.1016/j.athoracsur.2016.01.105

864

Sinha

S

,

Dimagli

A

,

Dixon

L

,

Gaudino

M

,

Caputo

M

,

Vohra

HA

, et al.

Systematic review and meta-analysis of mortality risk prediction models in adult cardiac surgery

.

Interact Cardiovasc Thorac Surg

2021

;

33

:

673

–

86

.

10.1093/icvts/ivab151

865

Scudeler

TL

,

Farkouh

ME

,

Hueb

W

,

Rezende

PC

,

Campolina

AG

,

Martins

EB

, et al.

Coronary atherosclerotic burden assessed by SYNTAX scores and outcomes in surgical, percutaneous or medical strategies: a retrospective cohort study

.

BMJ Open

2022

;

12

:

e062378

.

10.1136/bmjopen-2022-062378

866

Kuno

T

,

Kiyohara

Y

,

Maehara

A

,

Ueyama

HA

,

Kampaktsis

PN

,

Takagi

H

, et al.

Comparison of intravascular imaging, functional, or angiographically guided coronary intervention

.

J Am Coll Cardiol

2023

;

82

:

2167

–

76

.

10.1016/j.jacc.2023.09.823

867

Chen

H

,

Hong

L

,

Xi

G

,

Wang

H

,

Hu

J

,

Liu

Q

, et al.

Prognostic value of quantitative flow ratio in patients with coronary heart disease after percutaneous coronary intervention therapy: a meta-analysis

.

Front Cardiovasc Med

2023

;

10

:

1164290

.

10.3389/fcvm.2023.1164290

868

Agarwal

SK

,

Kasula

S

,

Hacioglu

Y

,

Ahmed

Z

,

Uretsky

BF

,

Hakeem

A

.

Utilizing post-intervention fractional flow reserve to optimize acute results and the relationship to long-term outcomes

.

JACC Cardiovasc Interv

2016

;

9

:

1022

–

31

.

10.1016/j.jcin.2016.01.046

869

Milojevic

M

,

Serruys

PW

,

Sabik

JF

,

Kandzari

DE

,

Schampaert

E

,

van Boven

AJ

, et al.

Bypass surgery or stenting for left main coronary artery disease in patients with diabetes

.

J Am Coll Cardiol

2019

;

73

:

1616

–

28

.

10.1016/j.jacc.2019.01.037

870

Gaudino

M

,

Audisio

K

,

Hueb

WA

,

Stone

GW

,

Farkouh

ME

,

Di Franco

A

, et al.

Coronary artery bypass grafting versus medical therapy in patients with stable coronary artery disease: an individual patient data pooled meta-analysis of randomized trials

.

J Thorac Cardiovasc Surg

2024

;

167

:

1022

–

32.e14

.

10.1016/j.jtcvs.2022.06.003

871

Bari 2D Study Group

;

Frye

RL

,

August

P

,

Brooks

MM

,

Hardison

RM

,

Kelsey

SF

, et al.

A randomized trial of therapies for type 2 diabetes and coronary artery disease

.

N Engl J Med

2009

;

360

:

2503

–

15

.

10.1056/NEJMoa0805796

872

Park

DW

,

Kim

YH

,

Song

HG

,

Ahn

JM

,

Kim

WJ

,

Lee

JY

, et al.

Long-term outcome of stents versus bypass surgery in diabetic and nondiabetic patients with multivessel or left main coronary artery disease: a pooled analysis of 5775 individual patient data

.

Circ Cardiovasc Interv

2012

;

5

:

467

–

75

.

10.1161/circinterventions.112.969915

873

Kamalesh

M

,

Sharp

TG

,

Tang

XC

,

Shunk

K

,

Ward

HB

,

Walsh

J

, et al.

Percutaneous coronary intervention versus coronary bypass surgery in United States veterans with diabetes

.

J Am Coll Cardiol

2013

;

61

:

808

–

16

.

10.1016/j.jacc.2012.11.044

874

Kappetein

AP

,

Head

SJ

,

Morice

MC

,

Banning

AP

,

Serruys

PW

,

Mohr

FW

, et al.

Treatment of complex coronary artery disease in patients with diabetes: 5-year results comparing outcomes of bypass surgery and percutaneous coronary intervention in the SYNTAX trial

.

Eur J Cardiothorac Surg

2013

;

43

:

1006

–

13

.

875

Booth

J

,

Clayton

T

,

Pepper

J

,

Nugara

F

,

Flather

M

,

Sigwart

U

, et al.

Randomized, controlled trial of coronary artery bypass surgery versus percutaneous coronary intervention in patients with multivessel coronary artery disease: six-year follow-up from the Stent or Surgery Trial (SoS)

.

Circulation

2008

;

118

:

381

–

8

.

10.1161/circulationaha.107.739144

876

Park

SJ

,

Ahn

JM

,

Kim

YH

,

Park

DW

,

Yun

SC

,

Lee

JY

, et al.

Trial of everolimus-eluting stents or bypass surgery for coronary disease

.

N Engl J Med

2015

;

372

:

1204

–

12

.

10.1056/NEJMoa1415447

877

Hueb

WA

,

Bellotti

G

,

de Oliveira

SA

,

Arie

S

,

de Albuquerque

CP

,

Jatene

AD

, et al.

The Medicine, Angioplasty or Surgery Study (MASS): a prospective, randomized trial of medical therapy, balloon angioplasty or bypass surgery for single proximal left anterior descending artery stenoses

.

J Am Coll Cardiol

1995

;

26

:

1600

–

5

.

10.1016/0735-1097(95)00384-3

878

Aziz

O

,

Rao

C

,

Panesar

SS

,

Jones

C

,

Morris

S

,

Darzi

A

, et al.

Meta-analysis of minimally invasive internal thoracic artery bypass versus percutaneous revascularisation for isolated lesions of the left anterior descending artery

.

BMJ

2007

;

334

:

617

.

10.1136/bmj.39106.476215.BE

879

Deppe

A-C

,

Liakopoulos

OJ

,

Kuhn

EW

,

Slottosch

I

,

Scherner

M

,

Choi

YH

, et al.

Minimally invasive direct coronary bypass grafting versus percutaneous coronary intervention for single-vessel disease: a meta-analysis of 2885 patients

.

Eur J Cardiothorac Surg

2015

;

47

:

397

–

406

.

880

Crespo-Leiro

MG

,

Anker

SD

,

Maggioni

AP

,

Coats

AJ

,

Filippatos

G

,

Ruschitzka

F

, et al.

European Society of Cardiology Heart Failure Long-Term Registry (ESC-HF-LT): 1-year follow-up outcomes and differences across regions

.

Eur J Heart Fail

2016

;

18

:

613

–

25

.

881

Fox

KF

,

Cowie

MR

,

Wood

DA

,

Coats

AJ

,

Gibbs

JS

,

Underwood

SR

, et al.

Coronary artery disease as the cause of incident heart failure in the population

.

Eur Heart J

2001

;

22

:

228

–

36

.

10.1053/euhj.2000.2289

882

Groenewegen

A

,

Rutten

FH

,

Mosterd

A

,

Hoes

AW

.

Epidemiology of heart failure

.

Eur J Heart Fail

2020

;

22

:

1342

–

56

.

883

Shah

SJ

,

Lam

CSP

,

Svedlund

S

,

Saraste

A

,

Hage

C

,

Tan

RS

, et al.

Prevalence and correlates of coronary microvascular dysfunction in heart failure with preserved ejection fraction: PROMIS-HFpEF

.

Eur Heart J

2018

;

39

:

3439

–

50

.

10.1093/eurheartj/ehy531

884

Yang

JH

,

Obokata

M

,

Reddy

YNV

,

Redfield

MM

,

Lerman

A

,

Borlaug

BA

.

Endothelium-dependent and independent coronary microvascular dysfunction in patients with heart failure with preserved ejection fraction

.

Eur J Heart Fail

2020

;

22

:

432

–

41

.

885

Sinha

A

,

Rahman

H

,

Webb

A

,

Shah

AM

,

Perera

D

.

Untangling the pathophysiologic link between coronary microvascular dysfunction and heart failure with preserved ejection fraction

.

Eur Heart J

2021

;

42

:

4431

–

41

.

10.1093/eurheartj/ehab653

886

Crea

F

,

Bairey Merz

CN

,

Beltrame

JF

,

Kaski

JC

,

Ogawa

H

,

Ong

P

, et al.

The parallel tales of microvascular angina and heart failure with preserved ejection fraction: a paradigm shift

.

Eur Heart J

2017

;

38

:

473

–

7

.

10.1093/eurheartj/ehw461

887

Rush

CJ

,

Berry

C

,

Oldroyd

KG

,

Rocchiccioli

JP

,

Lindsay

MM

,

Touyz

RM

, et al.

Prevalence of coronary artery disease and coronary microvascular dysfunction in patients with heart failure with preserved ejection fraction

.

JAMA Cardiol

2021

;

6

:

1130

–

43

.

10.1001/jamacardio.2021.1825

888

Arnold

JR

,

Kanagala

P

,

Budgeon

CA

,

Jerosch-Herold

M

,

Gulsin

G

,

Singh

A

, et al.

Prevalence and prognostic significance of microvascular dysfunction in heart failure with preserved ejection fraction

.

JACC Cardiovasc Imaging

2022

;

15

:

1001

–

11

.

10.1016/j.jcmg.2021.11.022

889

Lin

X

,

Wu

G

,

Wang

S

,

Huang

J

.

The prevalence of coronary microvascular dysfunction (CMD) in heart failure with preserved ejection fraction (HFpEF): a systematic review and meta-analysis

.

Heart Fail Rev

2024

;

29

:

405

–

16

.

10.1007/s10741-023-10362-x

890

Paolisso

P

,

Gallinoro

E

,

Belmonte

M

,

Bertolone

DT

,

Bermpeis

K

,

De Colle

C

, et al.

Coronary microvascular dysfunction in patients with heart failure: characterization of patterns in HFrEF versus HFpEF

.

Circ Heart Fail

2023

;

17

:

e010805

.

10.1161/circheartfailure.123.010805

891

Taqueti

VR

,

Solomon

SD

,

Shah

AM

,

Desai

AS

,

Groarke

JD

,

Osborne

MT

, et al.

Coronary microvascular dysfunction and future risk of heart failure with preserved ejection fraction

.

Eur Heart J

2018

;

39

:

840

–

9

.

10.1093/eurheartj/ehx721

892

Paulus

WJ

,

Tschöpe

C

.

A novel paradigm for heart failure with preserved ejection fraction: comorbidities drive myocardial dysfunction and remodeling through coronary microvascular endothelial inflammation

.

J Am Coll Cardiol

2013

;

62

:

263

–

71

.

10.1016/j.jacc.2013.02.092

893

Sicari

R

,

Nihoyannopoulos

P

,

Evangelista

A

,

Kasprzak

J

,

Lancellotti

P

,

Poldermans

D

, et al.

Stress echocardiography expert consensus statement—executive summary: European Association of Echocardiography (EAE) (a registered branch of the ESC)

.

Eur Heart J

2009

;

30

:

278

–

89

.

10.1093/eurheartj/ehn492

894

Garbi

M

,

McDonagh

T

,

Cosyns

B

,

Bucciarelli-Ducci

C

,

Edvardsen

T

,

Kitsiou

A

, et al.

Appropriateness criteria for cardiovascular imaging use in heart failure: report of literature review

.

Eur Heart J Cardiovasc Imaging

2015

;

16

:

147

–

53

.

895

Ghostine

S

,

Caussin

C

,

Habis

M

,

Habib

Y

,

Clement

C

,

Sigal-Cinqualbre

A

, et al.

Non-invasive diagnosis of ischaemic heart failure using 64-slice computed tomography

.

Eur Heart J

2008

;

29

:

2133

–

40

.

10.1093/eurheartj/ehn072

896

Andreini

D

,

Pontone

G

,

Bartorelli

AL

,

Agostoni

P

,

Mushtaq

S

,

Bertella

E

, et al.

Sixty-four-slice multidetector computed tomography: an accurate imaging modality for the evaluation of coronary arteries in dilated cardiomyopathy of unknown etiology

.

Circ Cardiovasc Imaging

2009

;

2

:

199

–

205

.

10.1161/circimaging.108.822809

897

van den Boogert

TPW

,

Claessen

B

,

van Randen

A

,

van Schuppen

J

,

Boekholdt

SM

,

Beijk

MAM

, et al.

Implementation of CT coronary angiography as an alternative to invasive coronary angiography in the diagnostic work-up of non-coronary cardiac surgery, cardiomyopathy, heart failure and ventricular arrhythmias

.

J Clin Med

2021

;

10

:

2374

.

898

Chow

BJW

,

Coyle

D

,

Hossain

A

,

Laine

M

,

Hanninen

H

,

Ukkonen

H

, et al.

Computed tomography coronary angiography for patients with heart failure (CTA-HF): a randomized controlled trial (IMAGE-HF 1C)

.

Eur Heart J Cardiovasc Imaging

2021

;

22

:

1083

–

90

.

10.1093/ehjci/jeaa109

899

Fox

K

,

Ford

I

,

Steg

PG

,

Tendera

M

,

Ferrari

R

;

BEAUTIFUL Investigators

.

Ivabradine for patients with stable coronary artery disease and left-ventricular systolic dysfunction (BEAUTIFUL): a randomised, double-blind, placebo-controlled trial

.

Lancet

2008

;

372

:

807

–

16

.

10.1016/S0140-6736(08)61170-8

900

Vitale

C

,

Wajngaten

M

,

Sposato

B

,

Gebara

O

,

Rossini

P

,

Fini

M

, et al.

Trimetazidine improves left ventricular function and quality of life in elderly patients with coronary artery disease

.

Eur Heart J

2004

;

25

:

1814

–

21

.

10.1016/j.ehj.2004.06.034

901

Wilson

SR

,

Scirica

BM

,

Braunwald

E

,

Murphy

SA

,

Karwatowska-Prokopczuk

E

,

Buros

JL

, et al.

Efficacy of ranolazine in patients with chronic angina observations from the randomized, double-blind, placebo-controlled MERLIN-TIMI (metabolic efficiency with ranolazine for less ischemia in non-ST-segment elevation acute coronary syndromes) 36 trial

.

J Am Coll Cardiol

2009

;

53

:

1510

–

6

.

10.1016/j.jacc.2009.01.037

902

Cohn

JN

,

Ziesche

S

,

Smith

R

,

Anand

I

,

Dunkman

WB

,

Loeb

H

, et al.

Effect of the calcium antagonist felodipine as supplementary vasodilator therapy in patients with chronic heart failure treated with enalapril

.

Circulation

1997

;

96

:

856

–

63

.

10.1161/01.CIR.96.3.856

903

Branch

KR

,

Probstfield

JL

,

Eikelboom

JW

,

Bosch

J

,

Maggioni

AP

,

Cheng

RK

, et al.

Rivaroxaban with or without aspirin in patients with heart failure and chronic coronary or peripheral artery disease

.

Circulation

2019

;

140

:

529

–

37

.

10.1161/circulationaha.119.039609

904

Mehra

MR

,

Vaduganathan

M

,

Fu

M

,

Ferreira

JP

,

Anker

SD

,

Cleland

JGF

, et al.

A comprehensive analysis of the effects of rivaroxaban on stroke or transient ischaemic attack in patients with heart failure, coronary artery disease, and sinus rhythm: the COMMANDER HF trial

.

Eur Heart J

2019

;

40

:

3593

–

602

.

10.1093/eurheartj/ehz427

905

Chieffo

A

,

Dudek

D

,

Hassager

C

,

Combes

A

,

Gramegna

M

,

Halvorsen

S

, et al.

Joint EAPCI/ACVC expert consensus document on percutaneous ventricular assist devices

.

Eur Heart J Acute Cardiovasc Care

2021

;

10

:

570

–

83

.

10.1093/ehjacc/zuab015

906

O’Neill

WW

,

Kleiman

NS

,

Moses

J

,

Henriques

JPS

,

Dixon

S

,

Massaro

J

, et al.

A prospective, randomized clinical trial of hemodynamic support with Impella 2.5 versus intra-aortic balloon pump in patients undergoing high-risk percutaneous coronary intervention: the PROTECT II study

.

Circulation

2012

;

126

:

1717

–

27

.

10.1161/CIRCULATIONAHA.112.098194

907

O’Neill

WW

,

Anderson

M

,

Burkhoff

D

,

Grines

CL

,

Kapur

NK

,

Lansky

AJ

, et al.

Improved outcomes in patients with severely depressed LVEF undergoing percutaneous coronary intervention with contemporary practices

.

Am Heart J

2022

;

248

:

139

–

49

.

10.1016/j.ahj.2022.02.006

908

Morgan

H

,

Ryan

M

,

Briceno

N

,

Modi

B

,

Rahman

H

,

Arnold

S

, et al.

Coronary jeopardy score predicts ischemic etiology in patients with left ventricular systolic dysfunction

.

J Invasive Cardiol

2022

;

34

:

E683

–

5

.

909

Taylor

RS

,

Walker

S

,

Smart

NA

,

Piepoli

MF

,

Warren

FC

,

Ciani

O

, et al.

Impact of exercise rehabilitation on exercise capacity and quality-of-life in heart failure: individual participant meta-analysis

.

J Am Coll Cardiol

2019

;

73

:

1430

–

43

.

10.1016/j.jacc.2018.12.072

910

Kitzman

DW

,

Brubaker

PH

,

Herrington

DM

,

Morgan

TM

,

Stewart

KP

,

Hundley

WG

, et al.

Effect of endurance exercise training on endothelial function and arterial stiffness in older patients with heart failure and preserved ejection fraction: a randomized, controlled, single-blind trial

.

J Am Coll Cardiol

2013

;

62

:

584

–

92

.

10.1016/j.jacc.2013.04.033

911

Kitzman

DW

,

Brubaker

P

,

Morgan

T

,

Haykowsky

M

,

Hundley

G

,

Kraus

WE

, et al.

Effect of caloric restriction or aerobic exercise training on peak oxygen consumption and quality of life in obese older patients with heart failure with preserved ejection fraction: a randomized clinical trial

.

JAMA

2016

;

315

:

36

–

46

.

10.1001/jama.2015.17346

912

Pfeffer

MA

,

Swedberg

K

,

Granger

CB

,

Held

P

,

McMurray

JJV

,

Michelson

EL

, et al.

Effects of candesartan on mortality and morbidity in patients with chronic heart failure: the CHARM-Overall programme

.

Lancet

2003

;

362

:

759

–

66

.

10.1016/s0140-6736(03)14282-1

913

Pfeffer

MA

,

McMurray

JJ

,

Velazquez

EJ

,

Rouleau

JL

,

Køber

L

,

Maggioni

AP

, et al.

Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both

.

N Engl J Med

2003

;

349

:

1893

–

906

.

914

Granger

CB

,

McMurray

JJ

,

Yusuf

S

,

Held

P

,

Michelson

EL

,

Olofsson

B

, et al.

Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function intolerant to angiotensin-converting-enzyme inhibitors: the CHARM-Alternative trial

.

Lancet

2003

;

362

:

772

–

6

.

10.1016/S0140-6736(03)14284-5

915

Faris

R

,

Flather

M

,

Purcell

H

,

Henein

M

,

Poole-Wilson

P

,

Coats

A

.

Current evidence supporting the role of diuretics in heart failure: a meta analysis of randomised controlled trials

.

Int J Cardiol

2002

;

82

:

149

–

58

.

10.1016/s0167-5273(01)00600-3

916

Moss

AJ

,

Zareba

W

,

Hall

WJ

,

Klein

H

,

Wilber

DJ

,

Cannom

DS

, et al.

Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction

.

N Engl J Med

2002

;

346

:

877

–

83

.

917

Antiarrhythmics versus Implantable Defibrillators (AVID) Investigators

.

A comparison of antiarrhythmic-drug therapy with implantable defibrillators in patients resuscitated from near-fatal ventricular arrhythmias

.

N Engl J Med

1997

;

337

:

1576

–

84

.

10.1056/NEJM199711273372202

10.1161/circulationaha.119.041595

918

Connolly

SJ

,

Hallstrom

AP

,

Cappato

R

,

Schron

EB

,

Kuck

KH

,

Zipes

DP

, et al.

Meta-analysis of the implantable cardioverter defibrillator secondary prevention trials. AVID, CASH and CIDS studies. Antiarrhythmics vs Implantable Defibrillator study. Cardiac Arrest Study Hamburg. Canadian Implantable Defibrillator Study

.

Eur Heart J

2000

;

21

:

2071

–

8

.

10.1053/euhj.2000.2476

919

Kuck

KH

,

Cappato

R

,

Siebels

J

,

Ruppel

R

.

Randomized comparison of antiarrhythmic drug therapy with implantable defibrillators in patients resuscitated from cardiac arrest: the Cardiac Arrest Study Hamburg (CASH)

.

Circulation

2000

;

102

:

748

–

54

.

10.1161/01.cir.102.7.748

920

Bardy

GH

,

Lee

KL

,

Mark

DB

,

Poole

JE

,

Packer

DL

,

Boineau

R

, et al.

Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure

.

N Engl J Med

2005

;

352

:

225

–

37

.

921

Moss

AJ

,

Hall

WJ

,

Cannom

DS

,

Klein

H

,

Brown

MW

,

Daubert

JP

, et al.

Cardiac-resynchronization therapy for the prevention of heart-failure events

.

N Engl J Med

2009

;

361

:

1329

–

38

.

10.1056/NEJMoa0906431

922

Cleland

JG

,

Abraham

WT

,

Linde

C

,

Gold

MR

,

Young

JB

,

Claude Daubert

J

, et al.

An individual patient meta-analysis of five randomized trials assessing the effects of cardiac resynchronization therapy on morbidity and mortality in patients with symptomatic heart failure

.

Eur Heart J

2013

;

34

:

3547

–

56

.

10.1093/eurheartj/eht290

923

Brignole

M

,

Botto

G

,

Mont

L

,

Iacopino

S

,

De Marchi

G

,

Oddone

D

, et al.

Cardiac resynchronization therapy in patients undergoing atrioventricular junction ablation for permanent atrial fibrillation: a randomized trial

.

Eur Heart J

2011

;

32

:

2420

–

9

.

10.1093/eurheartj/ehr162

924

Stavrakis

S

,

Garabelli

P

,

Reynolds

DW

.

Cardiac resynchronization therapy after atrioventricular junction ablation for symptomatic atrial fibrillation: a meta-analysis

.

Europace

2012

;

14

:

1490

–

7

.

10.1093/europace/eus193

925

Curtis

AB

,

Worley

SJ

,

Adamson

PB

,

Chung

ES

,

Niazi

I

,

Sherfesee

L

, et al.

Biventricular pacing for atrioventricular block and systolic dysfunction

.

N Engl J Med

2013

;

368

:

1585

–

93

.

10.1056/NEJMoa1210356

926

Rahman

H

,

Ryan

M

,

Lumley

M

,

Modi

B

,

McConkey

H

,

Ellis

H

, et al.

Coronary microvascular dysfunction is associated with myocardial ischemia and abnormal coronary perfusion during exercise

.

Circulation

2019

;

140

:

1805

–

16

.

927

Lee

SH

,

Shin

D

,

Lee

JM

,

van de Hoef

TP

,

Hong

D

,

Choi

KH

, et al.

Clinical relevance of ischemia with nonobstructive coronary arteries according to coronary microvascular dysfunction

.

J Am Heart Assoc

2022

;

11

:

e025171

.

10.1161/JAHA.121.025171

928

Reynolds

HR

,

Diaz

A

,

Cyr

DD

,

Shaw

LJ

,

Mancini

GBJ

,

Leipsic

J

, et al.

Ischemia with nonobstructive coronary arteries: insights from the ISCHEMIA trial

.

JACC Cardiovasc Imaging

2023

;

16

:

63

–

74

.

10.1016/j.jcmg.2022.06.015

929

Jespersen

L

,

Hvelplund

A

,

Abildstrom

SZ

,

Pedersen

F

,

Galatius

S

,

Madsen

JK

, et al.

Stable angina pectoris with no obstructive coronary artery disease is associated with increased risks of major adverse cardiovascular events

.

Eur Heart J

2012

;

33

:

734

–

44

.

10.1093/eurheartj/ehr331

930

Aziz

A

,

Hansen

HS

,

Sechtem

U

,

Prescott

E

,

Ong

P

.

Sex-related differences in vasomotor function in patients with angina and unobstructed coronary arteries

.

J Am Coll Cardiol

2017

;

70

:

2349

–

58

.

10.1016/j.jacc.2017.09.016

931

Boerhout

CKM

,

de Waard

GA

,

Lee

JM

,

Mejia-Renteria

H

,

Lee

SH

,

Jung

JH

, et al.

Prognostic value of structural and functional coronary microvascular dysfunction in patients with non-obstructive coronary artery disease; from the multicentre international ILIAS registry

.

EuroIntervention

2022

;

18

:

719

–

28

.

10.4244/eij-d-22-00043

932

Ong

P

,

Camici

PG

,

Beltrame

JF

,

Crea

F

,

Shimokawa

H

,

Sechtem

U

, et al.

International standardization of diagnostic criteria for microvascular angina

.

Int J Cardiol

2018

;

250

:

16

–

20

.

10.1016/j.ijcard.2017.08.068

933

Mejia-Renteria

H

,

van der Hoeven

N

,

van de Hoef

TP

,

Heemelaar

J

,

Ryan

N

,

Lerman

A

, et al.

Targeting the dominant mechanism of coronary microvascular dysfunction with intracoronary physiology tests

.

Int J Cardiovasc Imaging

2017

;

33

:

1041

–

59

.

10.1007/s10554-017-1136-9

934

Mygind

ND

,

Michelsen

MM

,

Pena

A

,

Frestad

D

,

Dose

N

,

Aziz

A

, et al.

Coronary microvascular function and cardiovascular risk factors in women with angina pectoris and no obstructive coronary artery disease: the iPOWER study

.

J Am Heart Assoc

2016

;

5

:

e003064

.

10.1161/JAHA.115.003064

935

Pepine

CJ

,

Anderson

RD

,

Sharaf

BL

,

Reis

SE

,

Smith

KM

,

Handberg

EM

, et al.

Coronary microvascular reactivity to adenosine predicts adverse outcome in women evaluated for suspected ischemia results from the National Heart, Lung and Blood Institute WISE (Women’s Ischemia Syndrome Evaluation) study

.

J Am Coll Cardiol

2010

;

55

:

2825

–

32

.

10.1016/j.jacc.2010.01.054

936

Murthy

VL

,

Naya

M

,

Taqueti

VR

,

Foster

CR

,

Gaber

M

,

Hainer

J

, et al.

Effects of sex on coronary microvascular dysfunction and cardiac outcomes

.

Circulation

2014

;

129

:

2518

–

27

.

10.1161/CIRCULATIONAHA.113.008507

937

Demir

OM

,

Boerhout

CKM

,

de Waard

GA

,

van de Hoef

TP

,

Patel

N

,

Beijk

MAM

, et al.

Comparison of doppler flow velocity and thermodilution derived indexes of coronary physiology

.

JACC Cardiovasc Interv

2022

;

15

:

1060

–

70

.

10.1016/j.jcin.2022.03.015

938

Zeiher

AM

,

Schächinger

V

,

Minners

J

.

Long-term cigarette smoking impairs endothelium-dependent coronary arterial vasodilator function

.

Circulation

1995

;

92

:

1094

–

100

.

10.1161/01.CIR.92.5.1094

939

Sara

JD

,

Widmer

RJ

,

Matsuzawa

Y

,

Lennon

RJ

,

Lerman

LO

,

Lerman

A

.

Prevalence of coronary microvascular dysfunction among patients with chest pain and nonobstructive coronary artery disease

.

JACC Cardiovasc Interv

2015

;

8

:

1445

–

53

.

10.1016/j.jcin.2015.06.017

940

Chhabra

L

,

Kowlgi

NG

.

Low incidence of diabetes mellitus in coronary microvascular dysfunction: an intriguing association

.

JACC Cardiovasc Interv

2016

;

9

:

395

–

6

.

10.1016/j.jcin.2015.11.017

941

Ishimori

ML

,

Martin

R

,

Berman

DS

,

Goykhman

P

,

Shaw

LJ

,

Shufelt

C

, et al.

Myocardial ischemia in the absence of obstructive coronary artery disease in systemic lupus erythematosus

.

JACC Cardiovasc Imaging

2011

;

4

:

27

–

33

.

10.1016/j.jcmg.2010.09.019

942

Recio-Mayoral

A

,

Rimoldi

OE

,

Camici

PG

,

Kaski

JC

.

Inflammation and microvascular dysfunction in cardiac syndrome X patients without conventional risk factors for coronary artery disease

.

JACC Cardiovasc Imaging

2013

;

6

:

660

–

7

.

10.1016/j.jcmg.2012.12.011

943

Fairweather

D

.

Sex differences in inflammation during atherosclerosis

.

Clin Med Insights Cardiol

2014

;

8

:

49

–

59

.

944

Recio-Mayoral

A

,

Mason

JC

,

Kaski

JC

,

Rubens

MB

,

Harari

OA

,

Camici

PG

.

Chronic inflammation and coronary microvascular dysfunction in patients without risk factors for coronary artery disease

.

Eur Heart J

2009

;

30

:

1837

–

43

.

10.1093/eurheartj/ehp205

945

Konst

RE

,

Elias-Smale

SE

,

Lier

A

,

Bode

C

,

Maas

AH

.

Different cardiovascular risk factors and psychosocial burden in symptomatic women with and without obstructive coronary artery disease

.

Eur J Prev Cardiol

2019

;

26

:

657

–

9

.

10.1177/2047487318814298

946

van der Meer

RE

,

Maas

AH

.

The role of mental stress in ischaemia with no obstructive coronary artery disease and coronary vasomotor disorders

.

Eur Cardiol

2021

;

16

:

e37

.

947

Suda

A

,

Takahashi

J

,

Hao

K

,

Kikuchi

Y

,

Shindo

T

,

Ikeda

S

, et al.

Coronary functional abnormalities in patients with angina and nonobstructive coronary artery disease

.

J Am Coll Cardiol

2019

;

74

:

2350

–

60

.

10.1016/j.jacc.2019.08.1056

948

Vrints

CJ

,

Bult

H

,

Hitter

E

,

Herman

AG

,

Snoeck

JP

.

Impaired endothelium-dependent cholinergic coronary vasodilation in patients with angina and normal coronary arteriograms

.

J Am Coll Cardiol

1992

;

19

:

21

–

31

.

10.1016/0735-1097(92)90046-p

949

Beltrame

JF

,

Sasayama

S

,

Maseri

A

.

Racial heterogeneity in coronary artery vasomotor reactivity: differences between Japanese and Caucasian patients

.

J Am Coll Cardiol

1999

;

33

:

1442

–

52

.

10.1016/s0735-1097(99)00073-x

950

Sueda

S

,

Kohno

H

,

Fukuda

H

,

Ochi

N

,

Kawada

H

,

Hayashi

Y

, et al.

Frequency of provoked coronary spasms in patients undergoing coronary arteriography using a spasm provocation test via intracoronary administration of ergonovine

.

Angiology

2004

;

55

:

403

–

11

.

10.1177/000331970405500407

951

Hung

MY

,

Hsu

KH

,

Hung

MJ

,

Cheng

CW

,

Cherng

WJ

.

Interactions among gender, age, hypertension and C-reactive protein in coronary vasospasm

.

Eur J Clin Invest

2010

;

40

:

1094

–

103

.

10.1111/j.1365-2362.2010.02360.x

952

Gulati

M

,

Khan

N

,

George

M

,

Berry

C

,

Chieffo

A

,

Camici

PG

, et al.

Ischemia with no obstructive coronary artery disease (INOCA): a patient self-report quality of life survey from INOCA international

.

Int J Cardiol

2023

;

371

:

28

–

39

.

10.1016/j.ijcard.2022.09.047

953

Shaw

LJ

,

Merz

CN

,

Pepine

CJ

,

Reis

SE

,

Bittner

V

,

Kip

KE

, et al.

The economic burden of angina in women with suspected ischemic heart disease: results from the National Institutes of Health–National Heart, Lung, and Blood Institute–sponsored Women’s Ischemia Syndrome Evaluation

.

Circulation

2006

;

114

:

894

–

904

.

10.1161/circulationaha.105.609990

954

Shaw

LJ

,

Shaw

RE

,

Merz

CN

,

Brindis

RG

,

Klein

LW

,

Nallamothu

B

, et al.

Impact of ethnicity and gender differences on angiographic coronary artery disease prevalence and in-hospital mortality in the American College of Cardiology–National Cardiovascular Data Registry

.

Circulation

2008

;

117

:

1787

–

801

.

10.1161/CIRCULATIONAHA.107.726562

955

Gulati

M

,

Cooper-DeHoff

RM

,

McClure

C

,

Johnson

BD

,

Shaw

LJ

,

Handberg

EM

, et al.

Adverse cardiovascular outcomes in women with nonobstructive coronary artery disease: a report from the Women’s Ischemia Syndrome Evaluation Study and the St James Women Take Heart Project

.

Arch Intern Med

2009

;

169

:

843

–

50

.

10.1001/archinternmed.2009.50

956

Min

JK

,

Dunning

A

,

Lin

FY

,

Achenbach

S

,

Al-Mallah

M

,

Budoff

MJ

, et al.

Age- and sex-related differences in all-cause mortality risk based on coronary computed tomography angiography findings results from the International Multicenter CONFIRM (coronary CT angiography evaluation for clinical outcomes: an international multicenter registry) of 23,854 patients without known coronary artery disease

.

J Am Coll Cardiol

2011

;

58

:

849

–

60

.

10.1016/j.jacc.2011.02.074

957

Jespersen

L

,

Abildstrom

SZ

,

Hvelplund

A

,

Madsen

JK

,

Galatius

S

,

Pedersen

F

, et al.

Burden of hospital admission and repeat angiography in angina pectoris patients with and without coronary artery disease: a registry-based cohort study

.

PLoS One

2014

;

9

:

e93170

.

10.1371/journal.pone.0093170

958

Radico

F

,

Zimarino

M

,

Fulgenzi

F

,

Ricci

F

,

Di Nicola

M

,

Jespersen

L

, et al.

Determinants of long-term clinical outcomes in patients with angina but without obstructive coronary artery disease: a systematic review and meta-analysis

.

Eur Heart J

2018

;

39

:

2135

–

46

.

10.1093/eurheartj/ehy185

959

Maddox

TM

,

Stanislawski

MA

,

Grunwald

GK

,

Bradley

SM

,

Ho

PM

,

Tsai

TT

, et al.

Nonobstructive coronary artery disease and risk of myocardial infarction

.

JAMA

2014

;

312

:

1754

–

63

.

10.1001/jama.2014.14681

960

Kelshiker

MA

,

Seligman

H

,

Howard

JP

,

Rahman

H

,

Foley

M

,

Nowbar

AN

, et al.

Coronary flow reserve and cardiovascular outcomes: a systematic review and meta-analysis

.

Eur Heart J

2022

;

43

:

1582

–

93

.

10.1093/eurheartj/ehab775

961

Boerhout

CKM

,

Lee

JM

,

de Waard

GA

,

Mejia-Renteria

H

,

Lee

SH

,

Jung

JH

, et al.

Microvascular resistance reserve: diagnostic and prognostic performance in the ILIAS registry

.

Eur Heart J

2023

;

44

:

2862

–

9

.

10.1093/eurheartj/ehad378

962

Zhou

W

,

Lee Jonan Chun

Y

,

Leung Siu

T

,

Lai

A

,

Lee

TF

,

Chiang

JB

, et al.

Long-term prognosis of patients with coronary microvascular disease using stress perfusion cardiac magnetic resonance

.

JACC Cardiovasc Imaging

2021

;

14

:

602

–

11

.

10.1016/j.jcmg.2020.09.034

963

Lanza

GA

,

Sestito

A

,

Sgueglia

GA

,

Infusino

F

,

Manolfi

M

,

Crea

F

, et al.

Current clinical features, diagnostic assessment and prognostic determinants of patients with variant angina

.

Int J Cardiol

2007

;

118

:

41

–

7

.

10.1016/j.ijcard.2006.06.016

964

Taqueti

VR

,

Di Carli

MF

.

Coronary microvascular disease pathogenic mechanisms and therapeutic options: JACC state-of-the-art review

.

J Am Coll Cardiol

2018

;

72

:

2625

–

41

.

10.1016/j.jacc.2018.09.042

965

Sidik

NP

,

Stanley

B

,

Sykes

R

,

Morrow

AJ

,

Bradley

CP

,

McDermott

M

, et al.

Invasive endotyping in patients with angina and no obstructive coronary artery disease: a randomized controlled trial

.

Circulation

2024

;

149

:

7

–

23

.

10.1161/CIRCULATIONAHA.123.064751

966

Rahman

H

,

Demir

OM

,

Khan

F

,

Ryan

M

,

Ellis

H

,

Mills

MT

, et al.

Physiological stratification of patients with angina due to coronary microvascular dysfunction

.

J Am Coll Cardiol

2020

;

75

:

2538

–

49

.

10.1016/j.jacc.2020.03.051

967

Belmonte

M

,

Pijls

NHJ

,

Bertolone

DT

,

Bertolone

DT

,

Keulards

DCJ

,

Viscusi

MM

, et al.

Measuring absolute coronary flow and microvascular resistance by thermodilution

.

J Am Coll Cardiol

2024

;

83

:

699

–

709

.

10.1016/j.jacc.2023.12.014

968

Feenstra

RGT

,

Woudstra

J

,

Bijloo

I

,

Vink

CEM

,

Boerhout

CKM

,

de Waard

GA

, et al.

Post-spastic flow recovery time to document vasospasm induced ischemia during acetylcholine provocation testing

.

Int J Cardiol Heart Vasc

2023

;

47

:

101220

.

10.1016/j.ijcha.2023.101220

969

Sueda

S

,

Kohno

H

,

Fukuda

H

,

Ochi

N

,

Kawada

H

,

Hayashi

Y

, et al.

Induction of coronary artery spasm by two pharmacological agents: comparison between intracoronary injection of acetylcholine and ergonovine

.

Coron Artery Dis

2003

;

14

:

451

–

7

.

10.1097/00019501-200309000-00006

970

Montone

RA

,

Rinaldi

R

,

Del Buono

MG

,

Gurgoglione

F

,

La Vecchia

G

,

Russo

M

, et al.

Safety and prognostic relevance of acetylcholine testing in patients with stable myocardial ischaemia or myocardial infarction and non-obstructive coronary arteries

.

EuroIntervention

2022

;

18

:

e666

–

76

.

10.4244/eij-d-21-00971

971

Takahashi

T

,

Samuels

BA

,

Li

W

,

Parikh

MA

,

Wei

J

,

Moses

JW

, et al.

Safety of provocative testing with intracoronary acetylcholine and implications for standard protocols

.

J Am Coll Cardiol

2022

;

79

:

2367

–

78

.

10.1016/j.jacc.2022.03.385

972

Montone

RA

,

Niccoli

G

,

Fracassi

F

,

Russo

M

,

Gurgoglione

F

,

Cammà

G

, et al.

Patients with acute myocardial infarction and non-obstructive coronary arteries: safety and prognostic relevance of invasive coronary provocative tests

.

Eur Heart J

2018

;

39

:

91

–

8

.

10.1093/eurheartj/ehx667

973

Layland

J

,

Carrick

D

,

Lee

M

,

Oldroyd

K

,

Berry

C

.

Adenosine: physiology, pharmacology, and clinical applications

.

JACC Cardiovasc Interv

2014

;

7

:

581

–

91

.

10.1016/j.jcin.2014.02.009

974

Mizukami

T

,

Sonck

J

,

Gallinoro

E

,

Kodeboina

M

,

Canvedra

A

,

Nagumo

S

, et al.

Duration of hyperemia with intracoronary administration of papaverine

.

J Am Heart Assoc

2021

;

10

:

e018562

.

10.1161/JAHA.120.018562

975

Kern

MJ

,

Deligonul

U

,

Serota

H

,

Gudipati

C

,

Buckingham

T

.

Ventricular arrhythmia due to intracoronary papaverine: analysis of QT intervals and coronary vasodilatory reserve

.

Cathet Cardiovasc Diagn

1990

;

19

:

229

–

36

.

10.1002/ccd.1810190402

976

Nakayama

M

,

Tanaka

N

,

Sakoda

K

,

Hokama

Y

,

Hoshino

K

,

Kimura

Y

, et al.

Papaverine-induced polymorphic ventricular tachycardia during coronary flow reserve study of patients with moderate coronary artery disease—analysis of ECG data

.

Circ J

2015

;

79

:

530

–

6

.

10.1253/circj.CJ-14-1118

977

Beltrame

JF

,

Tavella

R

,

Jones

D

,

Zeitz

C

.

Management of ischaemia with non-obstructive coronary arteries (INOCA)

.

BMJ

2021

;

375

:

e060602

.

10.1136/bmj-2021-060602

978

Ford

TJ

,

Stanley

B

,

Sidik

N

,

Good

R

,

Rocchiccioli

P

,

McEntegart

M

, et al.

1-Year outcomes of angina management guided by invasive coronary function testing (CorMicA)

.

JACC Cardiovasc Interv

2020

;

13

:

33

–

45

.

10.1016/j.jcin.2019.11.001

979

Kaski

JC

,

Crea

F

,

Gersh

BJ

,

Camici

PG

.

Reappraisal of ischemic heart disease

.

Circulation

2018

;

138

:

1463

–

80

.

10.1161/CIRCULATIONAHA.118.031373

980

Sinha

A

,

Rahman

H

,

Douiri

A

,

Demir

OM

,

De Silva

K

,

Clapp

B

, et al.

ChaMP-CMD: a phenotype-blinded, randomized controlled, cross-over trial

.

Circulation

2024

;

149

:

36

–

47

.

10.1161/CIRCULATIONAHA.123.066680

981

Jansen

TPJ

,

Konst

RE

,

de Vos

A

,

Paradies

V

,

Teerenstra

S

,

van den Oord

SCH

, et al.

Efficacy of diltiazem to improve coronary vasomotor dysfunction in ANOCA: the EDIT-CMD randomized clinical trial

.

JACC Cardiovasc Imaging

2022

;

15

:

1473

–

84

.

10.1016/j.jcmg.2022.03.012

982

Guarini

G

,

Huqi

A

,

Morrone

D

,

Capozza

P

,

Todiere

G

,

Marzilli

M

.

Pharmacological approaches to coronary microvascular dysfunction

.

Pharmacol Ther

2014

;

144

:

283

–

302

.

10.1016/j.pharmthera.2014.06.008

983

Cattaneo

M

,

Porretta

AP

,

Gallino

A

.

Ranolazine: drug overview and possible role in primary microvascular angina management

.

Int J Cardiol

2015

;

181

:

376

–

81

.

10.1016/j.ijcard.2014.12.055

984

Imran

TF

,

Malapero

R

,

Qavi

AH

,

Hasan

Z

,

de la Torre

B

,

Patel

YR

, et al.

Efficacy of spinal cord stimulation as an adjunct therapy for chronic refractory angina pectoris

.

Int J Cardiol

2017

;

227

:

535

–

42

.

10.1016/j.ijcard.2016.10.105

985

Lee

BK

,

Lim

HS

,

Fearon

WF

,

Yong

AS

,

Yamada

R

,

Tanaka

S

, et al.

Invasive evaluation of patients with angina in the absence of obstructive coronary artery disease

.

Circulation

2015

;

131

:

1054

–

60

.

10.1161/CIRCULATIONAHA.114.012636

986

Shufelt

CL

,

Thomson

LE

,

Goykhman

P

,

Agarwal

M

,

Mehta

PK

,

Sedlak

T

, et al.

Cardiac magnetic resonance imaging myocardial perfusion reserve index assessment in women with microvascular coronary dysfunction and reference controls

.

Cardiovasc Diagn Ther

2013

;

3

:

153

–

60

.

10.3978/j.issn.2223-3652.2013.08.02

10.1161/CIRCULATIONAHA.112.001345

987

Echavarria-Pinto

M

,

Escaned

J

,

Macias

E

,

Medina

M

,

Gonzalo

N

,

Petraco

R

, et al.

Disturbed coronary hemodynamics in vessels with intermediate stenoses evaluated with fractional flow reserve: a combined analysis of epicardial and microcirculatory involvement in ischemic heart disease

.

Circulation

2013

;

128

:

2557

–

66

.

988

Kaski

JC

,

Rosano

G

,

Gavrielides

S

,

Chen

L

.

Effects of angiotensin-converting enzyme inhibition on exercise-induced angina and ST segment depression in patients with microvascular angina

.

J Am Coll Cardiol

1994

;

23

:

652

–

7

.

10.1016/0735-1097(94)90750-1

989

Erdamar

H

,

Sen

N

,

Tavil

Y

,

Yazc

HU

,

Turfan

M

,

Poyraz

F

, et al.

The effect of nebivolol treatment on oxidative stress and antioxidant status in patients with cardiac syndrome-X

.

Coron Artery Dis

2009

;

20

:

238

–

44

.

10.1097/mca.0b013e32830936bb

990

Kayaalti

F

,

Kalay

N

,

Basar

E

,

Mavili

E

,

Duran

M

,

Ozdogru

I

, et al.

Effects of nebivolol therapy on endothelial functions in cardiac syndrome X

.

Heart Vessels

2010

;

25

:

92

–

6

.

10.1007/s00380-009-1170-1

991

Antman

E

,

Muller

J

,

Goldberg

S

,

MacAlpin

R

,

Rubenfire

M

,

Tabatznik

B

, et al.

Nifedipine therapy for coronary-artery spasm. Experience in 127 patients

.

N Engl J Med

1980

;

302

:

1269

–

73

.

10.1056/nejm198006053022301

992

Johnson

SM

,

Mauritson

DR

,

Willerson

JT

,

Hillis

LD

.

A controlled trial of verapamil for Prinzmetal’s variant angina

.

N Engl J Med

1981

;

304

:

862

–

6

.

10.1056/nejm198104093041502

993

Ginsburg

R

,

Lamb

IH

,

Schroeder

JS

,

Hu

M

,

Harrison

DC

.

Randomized double-blind comparison of nifedipine and isosorbide dinitrate therapy in variant angina pectoris due to coronary artery spasm

.

Am Heart J

1982

;

103

:

44

–

8

.

10.1016/0002-8703(82)90527-0

994

Pesola

A

,

Lauro

A

,

Gallo

R

,

Madeo

A

,

Cosentino

G

.

Efficacy of diltiazem in variant angina. Results of a double-blind crossover study in CCU by Holter monitoring. The possible occurrence of a withdrawal syndrome

.

G Ital Cardiol

1987

;

17

:

329

–

39

.

10.1016/0735–1097(93)90310-w

995

Chahine

RA

,

Feldman

RL

,

Giles

TD

,

Nicod

P

,

Raizner

AE

,

Weiss

RJ

, et al.

Randomized placebo-controlled trial of amlodipine in vasospastic angina. Amlodipine Study 160 Group

.

J Am Coll Cardiol

1993

;

21

:

1365

–

70

.

996

Oikawa

Y

,

Matsuno

S

,

Yajima

J

,

Nakamura

M

,

Ono

T

,

Ishiwata

S

, et al.

Effects of treatment with once-daily nifedipine CR and twice-daily benidipine on prevention of symptomatic attacks in patients with coronary spastic angina pectoris—Adalat Trial vs Coniel in Tokyo against Coronary Spastic Angina (ATTACK CSA)

.

J Cardiol

2010

;

55

:

238

–

47

.

10.1016/j.jjcc.2009.11.005

997

Aschermann

M

,

Bultas

J

,

Karetová

D

,

Kölbel

F

,

Kozáková

M

,

Simper

D

.

Randomized double-blind comparison of isosorbide dinitrate and nifedipine in variant angina pectoris

.

Am J Cardiol

1990

;

65

:

J46

–

9

.

10.1016/0002-9149(90)91312-t

10.1016/j.jcin.2021.10.003

998

Seitz

A

,

Feenstra

R

,

Konst

RE

,

Martínez Pereyra

V

,

Beck

S

,

Beijk

MAM

, et al.

Acetylcholine rechallenge: a first step toward tailored treatment in patients with coronary artery spasm

.

JACC Cardiovasc Interv

2022

;

15

:

65

–

75

.

999

Nishigaki

K

,

Inoue

Y

,

Yamanouchi

Y

,

Fukumoto

Y

,

Yasuda

S

,

Sueda

S

, et al.

Prognostic effects of calcium channel blockers in patients with vasospastic angina—a meta-analysis

.

Circ J

2010

;

74

:

1943

–

50

.

10.1253/circj.cj-10-0292

1000

Winniford

MD

,

Gabliani

G

,

Johnson

SM

,

Mauritson

DR

,

Fulton

KL

,

Hillis

LD

.

Concomitant calcium antagonist plus isosorbide dinitrate therapy for markedly active variant angina

.

Am Heart J

1984

;

108

:

1269

–

73

.

10.1016/0002-8703(84)90752-x

1001

Gu

SZ

,

Beska

B

,

Chan

D

,

Neely

D

,

Batty

JA

,

Adams-Hall

J

, et al.

Cognitive decline in older patients with non-ST elevation acute coronary syndrome

.

J Am Heart Assoc

2019

;

8

:

e011218

.

10.1161/jaha.118.011218

1002

Beska

B

,

Coakley

D

,

MacGowan

G

,

Adams-Hall

J

,

Wilkinson

C

,

Kunadian

V

.

Frailty and quality of life after invasive management for non-ST elevation acute coronary syndrome

.

Heart

2022

;

108

:

203

–

11

.

10.1136/heartjnl-2021-319064

1003

Beska

B

,

Mills

GB

,

Ratcovich

H

,

Wilkinson

C

,

Damluji

AA

,

Kunadian

V

.

Impact of multimorbidity on long-term outcomes in older adults with non-ST elevation acute coronary syndrome in the North East of England: a multi-centre cohort study of patients undergoing invasive care

.

BMJ Open

2022

;

12

:

e061830

.

10.1136/bmjopen-2022-061830

1004

Mills

GB

,

Ratcovich

H

,

Adams-Hall

J

,

Beska

B

,

Kirkup

E

,

Raharjo

DE

, et al.

Is the contemporary care of the older persons with acute coronary syndrome evidence-based?

Eur Heart J Open

2022

;

2

:

oeab044

.

10.1093/ehjopen/oeab044

1005

Ratcovich

H

,

Beska

B

,

Mills

G

,

Holmvang

L

,

Adams-Hall

J

,

Stevenson

H

, et al.

Five-year clinical outcomes in patients with frailty aged ≥75 years with non-ST elevation acute coronary syndrome undergoing invasive management

.

Eur Heart J Open

2022

;

2

:

oeac035

.

10.1093/ehjopen/oeac035

1006

Sinclair

H

,

Batty

JA

,

Qiu

W

,

Kunadian

V

.

Engaging older patients in cardiovascular research: observational analysis of the ICON-1 study

.

Open Heart

2016

;

3

:

e000436

.

10.1136/openhrt-2016-000436

1007

Mas-Llado

C

,

Gonzalez-Del-Hoyo

M

,

Siquier-Padilla

J

,

Blaya-Peña

L

,

Coughlan

JJ

,

García de la Villa

B

, et al.

Representativeness in randomised clinical trials supporting acute coronary syndrome guidelines

.

Eur Heart J Qual Care Clin Outcomes

2023

;

9

:

796

–

805

.

10.1093/ehjqcco/qcad007

1008

Rossello

X

,

Ferreira

JP

,

Caimari

F

,

Lamiral

Z

,

Sharma

A

,

Mehta

C

, et al.

Influence of sex, age and race on coronary and heart failure events in patients with diabetes and post-acute coronary syndrome

.

Clin Res Cardiol

2021

;

110

:

1612

–

24

.

10.1007/s00392-021-01859-2

10.1016/S0140-6736(17)32713-7

1009

Varenne

O

,

Cook

S

,

Sideris

G

,

Kedev

S

,

Cuisset

T

,

Carrié

D

, et al.

Drug-eluting stents in elderly patients with coronary artery disease (SENIOR): a randomised single-blind trial

.

Lancet

2018

;

391

:

41

–

50

.

10.1016/s0140-6736(21)00684-x

1010

Chung

K

,

Wilkinson

C

,

Veerasamy

M

,

Kunadian

V

.

Frailty scores and their utility in older patients with cardiovascular disease

.

Interv Cardiol

2021

;

16

:

e05

.

1011

Vogel

B

,

Acevedo

M

,

Appelman

Y

,

Bairey Merz

CN

,

Chieffo

A

,

Figtree

GA

, et al.

The Lancet women and cardiovascular disease Commission: reducing the global burden by 2030

.

Lancet

2021

;

397

:

2385

–

438

.

10.1016/j.jacc.2021.07.066

1012

Gaudino

M

,

Di Franco

A

,

Cao

D

,

Giustino

G

,

Bairey Merz

CN

,

Fremes

SE

, et al.

Sex-related outcomes of medical, percutaneous, and surgical interventions for coronary artery disease: JACC focus seminar 3/7

.

J Am Coll Cardiol

2022

;

79

:

1407

–

25

.

10.1136/heartjnl-2021-320533

1013

Jackson

J

,

Alkhalil

M

,

Ratcovich

H

,

Wilkinson

C

,

Mehran

R

,

Kunadian

V

.

Evidence base for the management of women with non-ST elevation acute coronary syndrome

.

Heart

2022

;

108

:

1682

–

9

.

10.1016/j.jacc.2014.02.529

1014

Ahmed

R

,

Dunford

J

,

Mehran

R

,

Robson

S

,

Kunadian

V

.

Pre-eclampsia and future cardiovascular risk among women: a review

.

J Am Coll Cardiol

2014

;

63

:

1815

–

22

.

10.1093/eurheartj/ehaa1044

1015

Maas

A

,

Rosano

G

,

Cifkova

R

,

Chieffo

A

,

van Dijken

D

,

Hamoda

H

, et al.

Cardiovascular health after menopause transition, pregnancy disorders, and other gynaecologic conditions: a consensus document from European cardiologists, gynaecologists, and endocrinologists

.

Eur Heart J

2021

;

42

:

967

–

84

.

10.1016/s2468-2667(19)30155-0

1016

Zhu

D

,

Chung

HF

,

Dobson

AJ

,

Pandeya

N

,

Giles

GG

,

Bruinsma

F

, et al.

Age at natural menopause and risk of incident cardiovascular disease: a pooled analysis of individual patient data

.

Lancet Public Health

2019

;

4

:

e553

–

64

.

10.1161/cir.0000000000000961

1017

Parikh

NI

,

Gonzalez

JM

,

Anderson

CAM

,

Judd

SE

,

Rexrode

KM

,

Hlatky

MA

, et al.

Adverse pregnancy outcomes and cardiovascular disease risk: unique opportunities for cardiovascular disease prevention in women: a scientific statement from the American Heart Association

.

Circulation

2021

;

143

:

e902

–

16

.

10.1016/j.rec.2021.05.006

1018

Rossello

X

,

Mas-Lladó

C

,

Pocock

S

,

Vicent

L

,

van de Werf

F

,

Chin

CT

, et al.

Sex differences in mortality after an acute coronary syndrome increase with lower country wealth and higher income inequality

.

Rev Esp Cardiol (Engl Ed)

2022

;

75

:

392

–

400

.

10.1161/hcq.0000000000000089

1019

Sims

M

,

Kershaw

KN

,

Breathett

K

,

Jackson

EA

,

Lewis

LM

,

Mujahid

MS

, et al.

Importance of housing and cardiovascular health and well-being: a scientific statement from the American Heart Association

.

Circ Cardiovasc Qual Outcomes

2020

;

13

:

e000089

.

10.1136/heartjnl-2018-313959

1020

Wilkinson

C

,

Bebb

O

,

Dondo

TB

,

Munyombwe

T

,

Casadei

B

,

Clarke

S

, et al.

Sex differences in quality indicator attainment for myocardial infarction: a nationwide cohort study

.

Heart

2019

;

105

:

516

–

23

.

10.1016/j.jacc.2020.01.056

1021

Kosmidou

I

,

Leon

MB

,

Zhang

Y

,

Serruys

PW

,

von Birgelen

C

,

Smits

PC

, et al.

Long-term outcomes in women and men following percutaneous coronary intervention

.

J Am Coll Cardiol

2020

;

75

:

1631

–

40

.

1022

Angraal

S

,

Khera

R

,

Wang

Y

,

Lu

Y

,

Jean

R

,

Dreyer

RP

, et al.

Sex and race differences in the utilization and outcomes of coronary artery bypass grafting among medicare beneficiaries, 1999–2014

.

J Am Heart Assoc

2018

;

7

:

e009014

.

10.1161/JAHA.118.009014

10.1016/j.jacc.2019.09.065

1023

Sarma

AA

,

Braunwald

E

,

Cannon

CP

,

Guo

J

,

Im

KA

,

Antman

EM

, et al.

Outcomes of women compared with men after non-ST-segment elevation acute coronary syndromes

.

J Am Coll Cardiol

2019

;

74

:

3013

–

22

.

10.1001/jamacardio.2019.4296

1024

Chichareon

P

,

Modolo

R

,

Kerkmeijer

L

,

Tomaniak

M

,

Kogame

N

,

Takahashi

K

, et al.

Association of sex with outcomes in patients undergoing percutaneous coronary intervention: a subgroup analysis of the GLOBAL LEADERS randomized clinical trial

.

JAMA Cardiol

2020

;

5

:

21

–

9

.

10.1016/j.ijcha.2022.101118

1025

Ratcovich

H

,

Alkhalil

M

,

Beska

B

,

Holmvang

L

,

Lawless

M

,

Gede Dennis Sukadana

I

, et al.

Sex differences in long-term outcomes in older adults undergoing invasive treatment for non-ST elevation acute coronary syndrome: an ICON-1 sub-study

.

Int J Cardiol Heart Vasc

2022

;

42

:

101118

.

1026

Rossouw

JE

,

Anderson

GL

,

Prentice

RL

,

LaCroix

AZ

,

Kooperberg

C

,

Stefanick

ML

, et al.

Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial

.

JAMA

2002

;

288

:

321

–

33

.

10.1001/jama.288.3.321

1027

Urban

P

,

Meredith

IT

,

Abizaid

A

,

Pocock

SJ

,

Carrié

D

,

Naber

C

, et al.

Polymer-free drug-coated coronary stents in patients at high bleeding risk

.

N Engl J Med

2015

;

373

:

2038

–

47

.

10.1056/NEJMoa1503943

1028

Windecker

S

,

Latib

A

,

Kedhi

E

,

Kirtane

AJ

,

Kandzari

DE

,

Mehran

R

, et al.

Polymer-based or polymer-free stents in patients at high bleeding risk

.

N Engl J Med

2020

;

382

:

1208

–

18

.

10.1056/NEJMoa1910021

10.1016/j.jcin.2021.04.043

1029

Angiolillo

DJ

,

Cao

D

,

Baber

U

,

Sartori

S

,

Zhang

Z

,

Dangas

G

, et al.

Impact of age on the safety and efficacy of ticagrelor monotherapy in patients undergoing PCI

.

JACC Cardiovasc Interv

2021

;

14

:

1434

–

46

.

10.1093/eurheartj/ehab702

1030

Escaned

J

,

Cao

D

,

Baber

U

,

Nicolas

J

,

Sartori

S

,

Zhang

Z

, et al.

Ticagrelor monotherapy in patients at high bleeding risk undergoing percutaneous coronary intervention: TWILIGHT-HBR

.

Eur Heart J

2021

;

42

:

4624

–

34

.

10.1016/j.jcin.2021.07.016

1031

Mehran

R

,

Cao

D

,

Angiolillo

DJ

,

Bangalore

S

,

Bhatt

DL

,

Ge

J

, et al.

3- or 1-Month DAPT in patients at high bleeding risk undergoing everolimus-eluting stent implantation

.

JACC Cardiovasc Interv

2021

;

14

:

1870

–

83

.

10.1016/j.jacc.2021.08.074

1032

Valgimigli

M

,

Cao

D

,

Angiolillo

DJ

,

Bangalore

S

,

Bhatt

DL

,

Ge

J

, et al.

Duration of dual antiplatelet therapy for patients at high bleeding risk undergoing PCI

.

J Am Coll Cardiol

2021

;

78

:

2060

–

72

.

10.1016/j.autrev.2021.102925

1033

Restivo

V

,

Candiloro

S

,

Daidone

M

,

Norrito

R

,

Cataldi

M

,

Minutolo

G

, et al.

Systematic review and meta-analysis of cardiovascular risk in rheumatological disease: symptomatic and non-symptomatic events in rheumatoid arthritis and systemic lupus erythematosus

.

Autoimmun Rev

2022

;

21

:

102925

.

10.1093/rheumatology/keac210

1034

Kerola

AM

,

Kazemi

A

,

Rollefstad

S

,

Lillegraven

S

,

Sexton

J

,

Wibetoe

G

, et al.

All-cause and cause-specific mortality in rheumatoid arthritis, psoriatic arthritis and axial spondyloarthritis: a nationwide registry study

.

Rheumatology (Oxford)

2022

;

61

:

4656

–

66

.

1035

Zöller

B

,

Li

X

,

Sundquist

J

,

Sundquist

K

.

Risk of subsequent ischemic and hemorrhagic stroke in patients hospitalized for immune-mediated diseases: a nationwide follow-up study from Sweden

.

BMC Neurol

2012

;

12

:

41

.

10.1186/1471–2377-12-41

10.1371/journal.pone.0033442

1036

Zöller

B

,

Li

X

,

Sundquist

J

,

Sundquist

K

.

Risk of subsequent coronary heart disease in patients hospitalized for immune-mediated diseases: a nationwide follow-up study from Sweden

.

PLoS One

2012

;

7

:

e33442

.

10.1093/rheumatology/kes169

1037

Kuo

CF

,

Yu

KH

,

See

LC

,

Chou

IJ

,

Ko

YS

,

Chang

HC

, et al.

Risk of myocardial infarction among patients with gout: a nationwide population-based study

.

Rheumatology (Oxford)

2013

;

52

:

111

–

7

.

10.1136/annrheumdis-2013-204838

1038

Cervera

R

,

Serrano

R

,

Pons-Estel

GJ

,

Ceberio-Hualde

L

,

Shoenfeld

Y

,

de Ramón

E

, et al.

Morbidity and mortality in the antiphospholipid syndrome during a 10-year period: a multicentre prospective study of 1000 patients

.

Ann Rheum Dis

2015

;

74

:

1011

–

8

.

10.1136/annrheumdis-2017-211663

1039

Alenghat

FJ

.

The prevalence of atherosclerosis in those with inflammatory connective tissue disease by race, age, and traditional risk factors

.

Sci Rep

2016

;

6

:

20303

.

1040

Tektonidou

MG

,

Lewandowski

LB

,

Hu

J

,

Dasgupta

A

,

Ward

MM

.

Survival in adults and children with systemic lupus erythematosus: a systematic review and Bayesian meta-analysis of studies from 1950 to 2016

.

Ann Rheum Dis

2017

;

76

:

2009

–

16

.

10.1093/rheumatology/key028

1041

Aouba

A

,

Gonzalez Chiappe

S

,

Eb

M

,

Delmas

C

,

de Boysson

H

,

Bienvenu

B

, et al.

Mortality causes and trends associated with giant cell arteritis: analysis of the French national death certificate database (1980–2011)

.

Rheumatology (Oxford)

2018

;

57

:

1047

–

55

.

10.1093/rheumatology/kex338

1042

Houben

E

,

Penne

EL

,

Voskuyl

AE

,

van der Heijden

JW

,

Otten

RHJ

,

Boers

M

, et al.

Cardiovascular events in anti-neutrophil cytoplasmic antibody-associated vasculitis: a meta-analysis of observational studies

.

Rheumatology (Oxford)

2018

;

57

:

555

–

62

.

10.1093/rheumatology/kez229

1043

Houben

E

,

Mendel

A

,

van der Heijden

JW

,

Simsek

S

,

Bax

WA

,

Carette

S

, et al.

Prevalence and management of cardiovascular risk factors in ANCA-associated vasculitis

.

Rheumatology (Oxford)

2019

;

58

:

2333

–

5

.

10.1097/md.0000000000023009

1044

Cen

X

,

Feng

S

,

Wei

S

,

Yan

L

,

Sun

L

.

Systemic sclerosis and risk of cardiovascular disease: a PRISMA-compliant systemic review and meta-analysis of cohort studies

.

Medicine (Baltimore)

2020

;

99

:

e23009

.

10.7326/0003-4819-144-4-200602210-00006

1045

Chung

CP

,

Oeser

A

,

Raggi

P

,

Gebretsadik

T

,

Shintani

AK

,

Sokka

T

, et al.

Increased coronary-artery atherosclerosis in rheumatoid arthritis: relationship to disease duration and cardiovascular risk factors

.

Arthritis Rheum

2005

;

52

:

3045

–

53

.

1046

Roman

MJ

,

Moeller

E

,

Davis

A

,

Paget

SA

,

Crow

MK

,

Lockshin

MD

, et al.

Preclinical carotid atherosclerosis in patients with rheumatoid arthritis

.

Ann Intern Med

2006

;

144

:

249

–

56

.

1047

Kobayashi

H

,

Giles

JT

,

Polak

JF

,

Blumenthal

RS

,

Leffell

MS

,

Szklo

M

, et al.

Increased prevalence of carotid artery atherosclerosis in rheumatoid arthritis is artery-specific

.

J Rheumatol

2010

;

37

:

730

–

9

.

10.3899/jrheum.090670

1048

Giles

JT

,

Post

WS

,

Blumenthal

RS

,

Polak

J

,

Petri

M

,

Gelber

AC

, et al.

Longitudinal predictors of progression of carotid atherosclerosis in rheumatoid arthritis

.

Arthritis Rheum

2011

;

63

:

3216

–

25

.

1049

Ajeganova

S

,

de Faire

U

,

Jogestrand

T

,

Frostegård

J

,

Hafström

I

.

Carotid atherosclerosis, disease measures, oxidized low-density lipoproteins, and atheroprotective natural antibodies for cardiovascular disease in early rheumatoid arthritis—an inception cohort study

.

J Rheumatol

2012

;

39

:

1146

–

54

.

10.3899/jrheum.111334

10.1186/s13075-016-1074-2

1050

Lucke

M

,

Messner

W

,

Kim

ES

,

Husni

ME

.

The impact of identifying carotid plaque on addressing cardiovascular risk in psoriatic arthritis

.

Arthritis Res Ther

2016

;

18

:

178

.

10.1016/j.semarthrit.2008.01.012

1051

Fischer

K

,

Przepiera-Będzak

H

,

Brzosko

I

,

Sawicki

M

,

Walecka

A

,

Brzosko

M

.

Anti-phosphatidylethanolamine and anti-phosphatidylserine antibodies—association with renal involvement, atherosclerosis, cardiovascular manifestations, Raynaud phenomenon and disease activity in Polish patients with systemic lupus erythematosus

.

Biomolecules

2022

;

12

:

1328

.

1052

Gonzalez-Juanatey

C

,

Llorca

J

,

Martin

J

,

Gonzalez-Gay

MA

.

Carotid intima-media thickness predicts the development of cardiovascular events in patients with rheumatoid arthritis

.

Semin Arthritis Rheum

2009

;

38

:

366

–

71

.

10.1136/annrheumdis-2020-217595

1053

Evans

MR

,

Escalante

A

,

Battafarano

DF

,

Freeman

GL

,

O’Leary

DH

,

del Rincón

I

.

Carotid atherosclerosis predicts incident acute coronary syndromes in rheumatoid arthritis

.

Arthritis Rheum

2011

;

63

:

1211

–

20

.

1054

Lam

SHM

,

Cheng

IT

,

Li

EK

,

Wong

P

,

Lee

J

,

Yip

RML

, et al.

DAPSA, carotid plaque and cardiovascular events in psoriatic arthritis: a longitudinal study

.

Ann Rheum Dis

2020

;

79

:

1320

–

6

.

10.1161/strokeaha.114.006091

1055

Gupta

A

,

Kesavabhotla

K

,

Baradaran

H

,

Kamel

H

,

Pandya

A

,

Giambrone

AE

, et al.

Plaque echolucency and stroke risk in asymptomatic carotid stenosis: a systematic review and meta-analysis

.

Stroke

2015

;

46

:

91

–

7

.

10.1016/j.ijcard.2016.08.129

1056

Semb

AG

,

Ikdahl

E

,

Hisdal

J

,

Olsen

IC

,

Rollefstad

S

.

Exploring cardiovascular disease risk evaluation in patients with inflammatory joint diseases

.

Int J Cardiol

2016

;

223

:

331

–

6

.