2019 ESC Guidelines for the diagnosis and management of chronic coronary syndromes: The Task Force for the diagnosis and management of chronic coronary syndromes of the European Society of Cardiology (ESC)

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. These forms were compiled into one file and can be found on the ESC website (http://www.escardio.org/guidelines). Any changes in declarations of interest that arise during the writing period were notified to the ESC and updated. The Task Force received its entire financial support from the ESC without any involvement from the healthcare industry.

The ESC CPG supervises and coordinates the preparation of new Guidelines. The Committee is also responsible for the endorsement process of these Guidelines. The ESC Guidelines undergo extensive review by the CPG and external experts. After appropriate revisions the Guidelines are approved by all the experts involved in the Task Force. The finalized document is approved by the CPG for publication in the European Heart Journal. The Guidelines were developed after careful consideration of the scientific and medical knowledge and the evidence available at the time of their dating.

The task of developing ESC Guidelines also includes the creation of educational tools and implementation programmes for the recommendations including condensed pocket guideline versions, summary slides, booklets with essential messages, summary cards for non-specialists and an electronic version for digital applications (smartphones, etc.). These versions are abridged and thus, for more detailed information, the user should always access to the full text version of the Guidelines, which is freely available via the ESC website and hosted on the EHJ website. The National Societies of the ESC are encouraged to endorse, translate and implement all ESC Guidelines. Implementation programmes are needed because it has been shown that the outcome of disease may be favourably influenced by the thorough application of clinical recommendations.

Health professionals are encouraged to take the ESC Guidelines fully into account when exercising their clinical judgment, as well as in the determination and the implementation of preventive, diagnostic or therapeutic medical strategies. However, the ESC Guidelines do not override in any way whatsoever the individual responsibility of health professionals to make appropriate and accurate decisions in consideration of each patient's health condition and in consultation with that patient or the patient's caregiver where appropriate and/or necessary. It is also the health professional's responsibility to verify the rules and regulations applicable in each country to drugs and devices at the time of prescription.

2 Introduction

Coronary artery disease (CAD) is a pathological process characterized by atherosclerotic plaque accumulation in the epicardial arteries, whether obstructive or non-obstructive. This process can be modified by lifestyle adjustments, pharmacological therapies, and invasive interventions designed to achieve disease stabilization or regression. The disease can have long, stable periods but can also become unstable at any time, typically due to an acute atherothrombotic event caused by plaque rupture or erosion. However, the disease is chronic, most often progressive, and hence serious, even in clinically apparently silent periods. The dynamic nature of the CAD process results in various clinical presentations, which can be conveniently categorized as either acute coronary syndromes (ACS) or chronic coronary syndromes (CCS). The Guidelines presented here refer to the management of patients with CCS. The natural history of CCS is illustrated in Figure 1.

Figure 1

Schematic illustration of the natural history of chronic coronary syndromes. ACE = angiotensin-converting enzyme; ACS = acute coronary syndromes; CCS = chronic coronary syndromes; MI = myocardial infarction.

The most frequently encountered clinical scenarios in patients with suspected or established CCS are: (i) patients with suspected CAD and ‘stable’ anginal symptoms, and/or dyspnoea (see section 3); (ii) patients with new onset of heart failure (HF) or left ventricular (LV) dysfunction and suspected CAD (see section 4); (iii) asymptomatic and symptomatic patients with stabilized symptoms <1 year after an ACS, or patients with recent revascularization (see section 5.1); (iv) asymptomatic and symptomatic patients >1 year after initial diagnosis or revascularization (see section 5.2); (v) patients with angina and suspected vasospastic or microvascular disease (see section 6); and (vi) asymptomatic subjects in whom CAD is detected at screening (see section 7).

All of these scenarios are classified as a CCS but involve different risks for future cardiovascular events [e.g. death or myocardial infarction (MI)], and the risk may change over time. Development of an ACS may acutely destabilize each of these clinical scenarios. The risk may increase as a consequence of insufficiently controlled cardiovascular risk factors, suboptimal lifestyle modifications and/or medical therapy, or unsuccessful revascularization. Alternatively, the risk may decrease as a consequence of appropriate secondary prevention and successful revascularization. Hence, CCS are defined by the different evolutionary phases of CAD, excluding situations in which an acute coronary artery thrombosis dominates the clinical presentation (i.e. ACS).

In the present Guidelines, each section deals with the main clinical scenarios of CCS. This structure aims to simplify the use of the Guidelines in clinical practice. Additional information, tables, figures, and references are available in the Supplementary Data on the ESC website (www.escardio.org) as well as in The ESC Textbook of Cardiovascular Medicine.

2.1 What is new in the 2019 Guidelines?

New/revised concepts in 2019

The Guidelines have been revised to focus on CCS instead of stable CAD.

This change emphasizes the fact that the clinical presentations of CAD can be categorized as either ACS or CCS. CAD is a dynamic process of atherosclerotic plaque accumulation and functional alterations of coronary circulation that can be modified by lifestyle, pharmacological therapies, and revascularization, which result in disease stabilization or regression.

In the current Guidelines on CCS, six clinical scenarios most frequently encountered in patients are identified: (i) patients with suspected CAD and ‘stable’ anginal symptoms, and/or dyspnoea; (ii) patients with new onset of HF or LV dysfunction and suspected CAD; (iii) asymptomatic and symptomatic patients with stabilized symptoms <1 year after an ACS or patients with recent revascularization; (iv) asymptomatic and symptomatic patients >1 year after initial diagnosis or revascularization; (v) patients with angina and suspected vasospastic or microvascular disease; (vi) asymptomatic subjects in whom CAD is detected at screening.

The PTP of CAD based on age, gender and nature of symptoms have undergone major revisions. In addition, we introduced a new phrase 'Clinical likelihood of CAD' that utilizes also various risk factors of CAD as PTP modifiers. The application of various diagnostic tests in different patient groups to rule-in or rule-out CAD have been updated.

The Guidelines emphasize the crucial role of healthy lifestyle behaviours and other preventive actions in decreasing the risk of subsequent cardiovascular events and mortality.

ACS = acute coronary syndromes; CAD = coronary artery disease; CCS = chronic coronary syndromes; HF = heart failure; LV = left ventricular; PTP = pre-test probability.

New/revised concepts in 2019

The Guidelines have been revised to focus on CCS instead of stable CAD.

This change emphasizes the fact that the clinical presentations of CAD can be categorized as either ACS or CCS. CAD is a dynamic process of atherosclerotic plaque accumulation and functional alterations of coronary circulation that can be modified by lifestyle, pharmacological therapies, and revascularization, which result in disease stabilization or regression.

In the current Guidelines on CCS, six clinical scenarios most frequently encountered in patients are identified: (i) patients with suspected CAD and ‘stable’ anginal symptoms, and/or dyspnoea; (ii) patients with new onset of HF or LV dysfunction and suspected CAD; (iii) asymptomatic and symptomatic patients with stabilized symptoms <1 year after an ACS or patients with recent revascularization; (iv) asymptomatic and symptomatic patients >1 year after initial diagnosis or revascularization; (v) patients with angina and suspected vasospastic or microvascular disease; (vi) asymptomatic subjects in whom CAD is detected at screening.

The PTP of CAD based on age, gender and nature of symptoms have undergone major revisions. In addition, we introduced a new phrase 'Clinical likelihood of CAD' that utilizes also various risk factors of CAD as PTP modifiers. The application of various diagnostic tests in different patient groups to rule-in or rule-out CAD have been updated.

The Guidelines emphasize the crucial role of healthy lifestyle behaviours and other preventive actions in decreasing the risk of subsequent cardiovascular events and mortality.

ACS = acute coronary syndromes; CAD = coronary artery disease; CCS = chronic coronary syndromes; HF = heart failure; LV = left ventricular; PTP = pre-test probability.

^aClass of recommendation.

ACE = angiotensin-converting enzyme; ACS = acute coronary syndromes; AF = atrial fibrillation; b.i.d. = bis in die (twice a day); CAD = coronary artery disease; CCS = chronic coronary syndromes; CHA₂DS₂-VASc = Cardiac failure, Hypertension, Age ≥75 [Doubled], Diabetes, Stroke [Doubled] – Vascular disease, Age 65–74 and Sex category [Female]; CTA = computed tomography angiography; CVD = cardiovascular disease; HF = heart failure; IMT = intima−media thickness; LV = left ventricular; NOAC = non-vitamin K antagonist oral anticoagulant; OAC = oral anticoagulant; o.d. = omni die (once a day); PCI = percutaneous coronary intervention; PCSK9 = proprotein convertase subtilisin-kexin type 9; VKA = vitamin K antagonist.

^aClass of recommendation.

BP = blood pressure; CAD = coronary artery disease; CCB = calcium channel blocker; CFR = coronary flow reserve; CMR = cardiac magnetic resonance; DHP-CCB = dihydropyridine calcium channel blockers; ECG = electrocardiogram; FFR = fractional flow reserve; iwFR = instantaneous wave-free ratio (instant flow reserve); LAD = left anterior descending; PET = positron emission tomography; PTP = pre-test probability.

3 Patients with angina and/or dyspnoea, and suspected coronary artery disease

3.1 Basic assessment, diagnosis, and risk assessment

The general approach for the initial diagnostic management of patients with angina and suspected obstructive CAD is presented in Figure 2. The diagnostic management approach includes six steps. The first step is to assess the symptoms and signs, to identify patients with possible unstable angina or other forms of ACS (step 1). In patients without unstable angina or other ACS, the next step is to evaluate the patient’s general condition and quality of life (step 2). Comorbidities that could potentially influence therapeutic decisions are assessed and other potential causes of the symptoms are considered. Step 3 includes basic testing and assessment of LV function. Thereafter, the clinical likelihood of obstructive CAD is estimated (step 4) and, on this basis, diagnostic testing is offered to selected patients to establish the diagnosis of CAD (step 5). Once a diagnosis of obstructive CAD has been confirmed, the patient’s event risk will be determined (step 6) as it has a major impact on the subsequent therapeutic decisions.

Figure 2

$Approach for the initial diagnostic management of patients with angina and suspected coronary artery disease. ACS = acute coronary syndrome; BP = blood pressure; CAD = coronary artery disease; CTA = computed tomography angiography; ECG = electrocardiogram; FFR = fractional flow reserve; iwFR = instantaneous wave-free ratio; LVEF = left ventricular ejection fraction. aIf the diagnosis of CAD is uncertain, establishing a diagnosis using non-invasive functional imaging for myocardial ischaemia before treatment may be reasonable. bMay be omitted in very young and healthy patients with a high suspicion of an extracardiac cause of chest pain, and in multimorbid patients in whom the echocardiography result has no consequence for further patient management. cConsider exercise ECG to assess symptoms, arrhythmias, exercise tolerance, BP response, and event risk in selected patients. dAbility to exercise, individual test-related risks, and likelihood of obtaining diagnostic test result. eHigh clinical likelihood and symptoms inadequately responding to medical treatment, high event risk based on clinical evaluation (such as ST-segment depression, combined with symptoms at a low workload or systolic dysfunction indicating CAD), or uncertain diagnosis on non-invasive testing. fFunctional imaging for myocardial ischaemia if coronary CTA has shown CAD of uncertain grade or is non-diagnostic. gConsider also angina without obstructive disease in the epicardial coronary arteries (see section 6).$

Approach for the initial diagnostic management of patients with angina and suspected coronary artery disease. ACS = acute coronary syndrome; BP = blood pressure; CAD = coronary artery disease; CTA = computed tomography angiography; ECG = electrocardiogram; FFR = fractional flow reserve; iwFR = instantaneous wave-free ratio; LVEF = left ventricular ejection fraction. ^aIf the diagnosis of CAD is uncertain, establishing a diagnosis using non-invasive functional imaging for myocardial ischaemia before treatment may be reasonable. ^bMay be omitted in very young and healthy patients with a high suspicion of an extracardiac cause of chest pain, and in multimorbid patients in whom the echocardiography result has no consequence for further patient management. ^cConsider exercise ECG to assess symptoms, arrhythmias, exercise tolerance, BP response, and event risk in selected patients. ^dAbility to exercise, individual test-related risks, and likelihood of obtaining diagnostic test result. ^eHigh clinical likelihood and symptoms inadequately responding to medical treatment, high event risk based on clinical evaluation (such as ST-segment depression, combined with symptoms at a low workload or systolic dysfunction indicating CAD), or uncertain diagnosis on non-invasive testing. ^fFunctional imaging for myocardial ischaemia if coronary CTA has shown CAD of uncertain grade or is non-diagnostic. ^gConsider also angina without obstructive disease in the epicardial coronary arteries (see section 6).

After these steps, appropriate therapies are to be initiated, which include lifestyle management (see section 3.2), medical therapy (see section 3.3), and revascularization when indicated (see section 3.4).

3.1.1. Step 1: Symptoms and signs

A careful history is the cornerstone of the diagnosis of angina. It is possible to achieve a high degree of certainty on a diagnosis based on history alone, although physical examination and objective tests are most often necessary to confirm the diagnosis, exclude alternative diagnoses, and assess the severity of underlying disease. The history should include any manifestation of cardiovascular disease (CVD) and risk factors (i.e. family history of CVD, dyslipidaemia, diabetes, hypertension, smoking, and other lifestyle factors).

The characteristics of discomfort related to myocardial ischaemia (angina pectoris) may be divided into four categories: location, character, duration, and relationship to exertion, and other exacerbating or relieving factors. The discomfort caused by myocardial ischaemia is usually located in the chest, near the sternum, but may be felt anywhere from the epigastrium to the lower jaw or teeth, between the shoulder blades, or in either arm to the wrist and fingers. The discomfort is often described as pressure, tightness, or heaviness; sometimes strangling, constricting, or burning. It may be useful to ask the patient directly about the presence of ‘discomfort’ as many do not feel ‘pain’ or ‘pressure’ in their chest. Shortness of breath may accompany angina, and chest discomfort may also be accompanied by less-specific symptoms such as fatigue or faintness, nausea, burning, restlessness, or a sense of impending doom. Shortness of breath may be the sole symptom of CAD and it may be difficult to differentiate this from shortness of breath caused by other conditions.

The duration of the discomfort is brief—≤10 min in the majority of cases, and more commonly just a few minutes or less—and chest pain lasting for seconds is unlikely to be due to CAD. An important characteristic is the relationship to exercise. Symptoms classically appear or become more severe with increased levels of exertion—such as walking up an incline or against a breeze, or in cold weather—and rapidly disappear within a few minutes when these causal factors abate. Exacerbations of symptoms after a heavy meal or after waking up in the morning are classic features of angina. Angina may paradoxically be reduced with further exercise (walk-through angina) or on second exertion (warm-up angina).¹ Sublingual nitrates rapidly relieve angina. Symptoms are unrelated to respiration or position. The angina threshold, and hence symptoms, may vary considerably from day to day and even during the same day.

Definitions of typical and atypical angina are summarized in Table 3. The classification, although subjective, is practical and of proven value in determining the likelihood of obstructive CAD.²^,³ Studies published since 2015 have reported that the majority of patients suspected of having CAD present with atypical or non-anginal chest pain,^4–6 with as few as 10 − 15% presenting with typical angina.³^,⁷^,⁸ The Canadian Cardiovascular Society classification is still widely used as a grading system for angina,⁹ to quantify the threshold at which symptoms occur in relation to physical activities (Table 4).

Table 3

Traditional clinical classification of suspected anginal symptoms

Typical angina

Meets the following three characteristics: (i) Constricting discomfort in the front of the chest or in the neck, jaw, shoulder, or arm; (ii) Precipitated by physical exertion; (iii) Relieved by rest or nitrates within 5 min.

Atypical angina

Meets two of these characteristics.

Non-anginal chest pain

Meets only one or none of these characteristics.

Table 4

Grading of effort angina severity according to the Canadian Cardiovascular Society

Grade	Description of angina severity
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 cold, in 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 normal pace and conditions.
IV	Angina at rest	No exertion needed to trigger angina.

Grade	Description of angina severity
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 cold, in 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 normal pace and conditions.
IV	Angina at rest	No exertion needed to trigger angina.

Table 4

Grading of effort angina severity according to the Canadian Cardiovascular Society

Grade	Description of angina severity
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 cold, in 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 normal pace and conditions.
IV	Angina at rest	No exertion needed to trigger angina.

Grade	Description of angina severity
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 cold, in 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 normal pace and conditions.
IV	Angina at rest	No exertion needed to trigger angina.

Physical examination of a patient with suspected CAD is important to assess the presence of anaemia, hypertension, valvular heart disease, hypertrophic cardiomyopathy, or arrhythmias. It is also recommended that practitioners obtain the body mass index (BMI) and search for evidence of non-coronary vascular disease, which may be asymptomatic [includes palpation of peripheral pulses, and auscultation of carotid and femoral arteries, as well as assessment of the ankle−brachial index (ABI)], and other signs of 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 CAD more unlikely. One should also try to reproduce the symptoms by palpation¹⁰ and test the effect of sublingual nitroglycerin in order to classify the symptoms (Table 3).

3.1.1.1 Stable vs. unstable angina

Unstable angina may present in one of three ways: (i) as rest angina, i.e. pain of characteristic nature and location occurring at rest and for prolonged periods (>20 min); (ii) new-onset angina, i.e. recent (2 months) onset of moderate-to-severe angina (Canadian Cardiovascular Society grade II or III); or (iii) crescendo angina, i.e. previous angina, which progressively increases in severity and intensity, and at a lower threshold, over a short period of time. Management of angina fulfilling these criteria is dealt with in the ESC Guidelines for the management of ACS.¹¹^,¹² New-onset angina is generally regarded as unstable angina; however, if angina occurs for the first time with heavy exertion and subsides at rest, the suspected condition falls under the definition of CCS rather than unstable angina. In patients with unstable angina identified as being at low risk, it is recommended that the diagnostic and prognostic algorithms presented in these Guidelines be applied once the period of instability has subsided.¹¹ Low-risk patients with unstable angina are characterized by no recurrence of angina, no signs of HF, no abnormalities in the initial or subsequent electrocardiogram (ECG), and no rise in troponin levels.¹¹ In this setting, a non-invasive diagnostic strategy is recommended before deciding on an invasive strategy. Based on the definition above, stable and unstable angina may overlap, and many CCS patients pass through a period of experiencing unstable angina.

3.1.1.2 Distinction between symptoms caused by epicardial vs. microvascular/vasospastic disease

A distinction between symptoms caused by an epicardial stenosis and symptoms caused by microvascular or vasospastic disease cannot be made with reasonable certainty. Reliance on ischaemia testing or depiction of the coronary anatomy is often unavoidable to exclude obstructive CAD, which can be absent in symptomatic patients.¹³^,¹⁴ A diagnostic workup for microvascular or vasospastic disease is discussed in section 6 of these Guidelines.

3.1.2 Step 2: Comorbidities and other causes of symptoms

Before any testing is considered, one must assess the patient’s general health, comorbidities, and quality of life. If revascularization is unlikely to be an acceptable option, further testing may be reduced to a clinically indicated minimum and appropriate therapy should be instituted, which may include a trial of antianginal medication even if a diagnosis of CAD has not been fully demonstrated. Non-invasive functional imaging for ischaemia may be an option if there is need to verify the diagnosis (Figure 2).

If the pain is clearly non-anginal, other diagnostic testing may be indicated to identify gastrointestinal, pulmonary, or musculoskeletal causes of chest pain. Nevertheless, these patients should also receive Guideline-based risk-factor modification based on commonly applied risk charts such as SCORE (Systematic COronary Risk Evaluation) (www.heartscore.org).¹⁵

3.1.3 Step 3: Basic testing

Basic (first-line) testing in patients with suspected CAD includes standard laboratory biochemical testing, a resting ECG, possible ambulatory ECG monitoring, resting echocardiography, and, in selected patients, a chest X-ray. Such testing can be done on an outpatient basis.

3.1.3.1 Biochemical tests

Laboratory investigations are used to identify possible causes of ischaemia, to establish cardiovascular risk factors and associated conditions, and to determine prognosis. Haemoglobin as part of a full blood count and—where there is a clinical suspicion of a thyroid disorder—thyroid hormone levels provide information related to possible causes of ischaemia. Fasting plasma glucose and glycated haemoglobin (HbA1c) should be measured in every patient with suspected CAD. If both are inconclusive, an additional oral glucose tolerance test is recommended.¹⁶ Knowledge of glucose metabolism is important because of the well-recognized association between diabetes and adverse cardiovascular outcome. Patients with diabetes should be managed according to specific Guidelines.¹⁵^,¹⁶ A lipid profile, including total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol (LDL-C), and triglycerides, should also be evaluated in any patient with suspected CAD to establish the patient’s risk profile and ascertain the need for treatment.¹⁵^,¹⁷ To characterize severe dyslipidaemia or follow-up on high triglyceridaemia, fasting values are recommended.¹⁷

Peripheral artery disease (PAD) and renal dysfunction increase the likelihood of CAD, and have a negative impact on prognosis.^18–20 Hence, baseline renal function should be evaluated with estimation of the glomerular filtration rate (GFR). It may also be reasonable to measure the uric acid level, as hyperuricaemia is a frequent comorbid condition and may also 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 Guidelines for ACS without persistent ST-segment elevation.¹¹ If high-sensitivity assays are employed, low levels of troponin can be detected in many patients with stable angina. Increased troponin levels are associated with adverse outcome^21–25 and small studies have indicated a possible incremental value in diagnosing CAD,²⁶^,²⁷ but larger trials are needed to verify the utility of systematic assessment in patients suspected of CAD. While multiple biomarkers may be useful for prognostication (see section 5), they do not yet have a role in diagnosing obstructive CAD.

Basic biochemistry testing in the initial diagnostic management of patients with suspected coronary artery disease

ACS = acute coronary syndromes; CAD = coronary artery disease; CCS = chronic coronary syndromes; HbA1c = glycated haemoglobin; LDL-C = low-density lipoprotein cholesterol.

a

Class of recommendation.

b

Level of evidence.

3.1.3.2 Resting electrocardiogram and ambulatory monitoring

The paradigm of diagnosing myocardial ischaemia has, for almost a century, been based on the detection of repolarization abnormalities, mainly in the form of ST-segment depressions. Thus, the resting 12 lead ECG remains an indispensable component of the initial evaluation of a patient with chest pain without an obviously non-cardiac cause. Two scenarios of clinical evaluation are encountered: (i) a patient without symptoms of chest pain or discomfort, and (ii) a patient with ongoing anginal symptoms.

The former situation is far more prevalent and a normal resting ECG is frequently recorded. However, even in the absence of repolarization abnormalities, an ECG can demonstrate indirect signs of CAD, such as signs of previous MI (pathological Q waves) or conduction abnormalities [mainly left bundle branch block (LBBB) and impairment of atrioventricular conduction]. Atrial fibrillation (AF) is a frequent finding in patients with chest pain (usually atypical). ST-segment depression during supraventricular tachyarrhythmias is not predictive of obstructive CAD.^36–39

The ECG can be crucial for diagnosing myocardial ischaemia if dynamic ST-segment changes are recorded during ongoing angina. The diagnosis of Prinzmetal and vasospastic angina is based on the detection of typical transient ST-segment elevation or depression during an angina attack (usually at rest).

Long-term ambulatory ECG monitoring and recording should not be used to replace exercise testing; however, 12 lead ECG monitoring can be considered in selected patients to detect anginal episodes unrelated to physical exercise. Ambulatory ECG monitoring may reveal evidence of silent myocardial ischaemia in patients with CCS, but rarely adds relevant diagnostic or prognostic information that cannot be derived from stress testing.⁴⁰ ECG changes suggesting ischaemia on ambulatory ECG monitoring are very frequent in women, but do not correlate with findings during stress testing.⁴¹ Most importantly, therapeutic strategies targeting silent ischaemia detected by ambulatory monitoring have not demonstrated clear survival benefits.⁴²^,⁴³

Resting electrocardiogram in the initial diagnostic management of patients with suspected coronary artery disease

CAD = coronary artery disease; CCS = chronic coronary syndromes; ECG = electrocardiogram.

a

Class of recommendation.

b

Level of evidence.

Ambulatory electrocardiogram monitoring in the initial diagnostic management of patients with suspected coronary artery disease

CAD = coronary artery disease; CCS = chronic coronary syndromes; ECG = electrocardiogram.

a

Class of recommendation.

b

Level of evidence.

3.1.3.3 Echocardiography and magnetic resonance imaging at rest

An echocardiographic study will provide important information about cardiac function and anatomy. LV ejection fraction (LVEF) is often normal in patients with CCS.⁴⁴ A decreased LV function and/or regional wall motion abnormalities may increase the suspicion of ischaemic myocardial damage,⁴⁵ and a pattern of LV dysfunction following the theoretical distribution territory of the coronary arteries is typical in patients who have already had an MI.⁴⁶^,⁴⁷ The detection of regional wall motion abnormalities can challenging by visual assessment, and detection of early systolic lengthening, decreased systolic shortening, or post-systolic shortening by strain imaging techniques might be helpful in patients with apparently normal LV function but with clinical suspicion of CCS.^48–50 Decreased diastolic LV function has been reported to be an early sign of ischaemic myocardial dysfunction and could also be indicative of microvascular dysfunction.⁵¹^,⁵²

Echocardiography is an important clinical tool for the exclusion of alternative causes of chest pain and also aids in diagnosing concurrent cardiac diseases, such as valvular heart diseases, HF, and most cardiomyopathies,⁵³ but it is important to remember that these diseases often coexist with obstructive CAD. The use of an echocardiographic contrast agent can be useful in patients with poor acoustic windows.⁵⁴

Cardiac magnetic resonance (CMR) may be considered in patients with suspected CAD when the echocardiogram (having used contrast) is inconclusive.⁵⁵ CMR will provide useful information on cardiac anatomy and systolic cardiac function, similar to that from an echocardiogram, in patients with no contraindications for CMR. CMR can assess global and regional function,⁵⁶ and the use of late gadolinium enhancement CMR can reveal a typical pattern of scarred myocardium in patients who have already experienced an MI.⁵⁷

Assessment of LV function is important in all patients for risk stratification (see Supplementary Datasection 3.2) and should therefore be performed in all symptomatic patients with suspected CAD. Management of patients with either angina or HF symptoms, with reduced LVEF <40% or a mid-range reduced LVEF of 40−49%, is described in section 4 of the Guidelines.

Resting echocardiography and cardiac magnetic resonance in the initial diagnostic management of patients with suspected coronary artery disease

CAD = coronary artery disease; CCS = chronic coronary syndromes; CMR = cardiac magnetic resonance imaging; LVEF = left ventricular ejection fraction.

a

Class of recommendation.

b

Level of evidence.

3.1.3.4 Chest X-ray

Chest X-ray is frequently used in the assessment of patients with chest pain. However, in CCS, it does not provide specific information for diagnosis or event risk stratification. The test may occasionally be helpful in assessing patients with suspected HF. Chest X-ray may also be useful in patients with pulmonary problems, which often accompany CAD, or to rule-out another cause of chest pain in atypical presentations.

Chest X-ray in the initial diagnostic management of patients with suspected coronary artery disease

HF = heart failure.

a

Class of recommendation.

b

Level of evidence.

3.1.4 Step 4: Assessment of pre-test probability and clinical likelihood of coronary artery disease

The performance of the available methods in diagnosing obstructive CAD (i.e. the likelihood that the patient has disease if the test is abnormal, and the likelihood that the patient does not have disease if the test is normal) depends on the prevalence of disease in the population studied and, thus, the likelihood that a given patient will actually have CAD. Diagnostic testing is most useful when the likelihood is intermediate. When likelihood is high, a large number of patients need to be studied to identify the few patients that do not have disease, and a negative test result can seldom rule out the presence of obstructive CAD (i.e. the negative predictive value is low). When the likelihood is low, a negative test can rule out the disease, but the lower the likelihood, the higher the likelihood of a false-positive test (i.e. a positive test in the absence of obstructive CAD). In patients at the extreme ends of the probability range, it is therefore reasonable to refrain from diagnostic testing, and assume that the patient does or does not have obstructive CAD based on clinical evaluation alone.

The likelihood of obstructive CAD is influenced by the prevalence of the disease in the population studied, as well as by clinical features of an individual patient. A simple predictive model can be used to estimate the pre-test probability (PTP) of obstructive CAD based on age, sex, and the nature of symptoms.⁵⁹ In the previous version of these Guidelines,⁶⁰ estimation of the PTP was based on data gathered by Genders et al.,⁶¹ which updated previous data from Diamond and Forrester.⁵⁹ Notably, the prevalence of disease for a given constellation of age, sex, and nature of symptoms was lower than in the Diamond and Forrester data. Since the previous version of the Guidelines was published, several studies have indicated that the prevalence of obstructive disease among patients with suspected CAD is lower than in the previous update.⁷^,⁸^,⁶²^,⁶³

A pooled analysis⁶⁴ of three contemporary study cohorts, including patients evaluated for suspected CAD,⁷^,⁸^,⁶² has indicated that the PTP based on age, sex, and symptoms is approximately one-third of that predicted by the model used in the previous version of the Guidelines.⁵⁷^,⁶² Overestimation of PTP is an important contributory factor to a low diagnostic yield of non-invasive and invasive testing. The new set of PTPs presented in Table 5 may substantially reduce the need for non-invasive and invasive tests in patients with suspected stable CAD. The table now also includes patients presenting with dyspnoea as their main symptom. However, it should be noted that the PTPs presented in Table 5 (as well as the PTP table in the previous version of the Guidelines) are based mainly on patients from countries with low CVD risk, and may vary between regions and countries.

Table 5

Pre-test probabilities of obstructive coronary artery disease in 15 815 symptomatic patients according to age, sex, and the nature of symptoms in a pooled analysis⁶⁴ of contemporary data⁷^,⁸^,⁶²

CAD = coronary artery disease; PTP = pre-test probability.

a

In addition to the classic Diamond and Forrester classes,⁵⁹ patients with dyspnoea only or dyspnoea as the primary symptom are included. The regions shaded dark green denote the groups in which non-invasive testing is most beneficial (PTP >15%). The regions shaded light green denote the groups with PTPs of CAD between 5–15%, in which testing for diagnosis may be considered after assessing the overall clinical likelihood based on the modifiers of PTPs presented in Figure 3.

Application of the new PTPs (Table 5) has important consequences for the referral of patients for diagnostic testing. If diagnostic testing was deferred in patients with a new PTP <15%, this would result in a large increase in the proportion of patients for whom diagnostic testing was not recommended, because more patients are classified as having a PTP <15%. In data derived from the PROMISE (Prospective Multicenter Imaging Study for Evaluation of Chest Pain) trial, 50% of patients previously classified as having an intermediate likelihood of obstructive CAD were reclassified to a PTP <15% according to the new PTP.⁶² In data derived from the pooled analysis⁶⁴ (Table 5), 57% of all patients were classified to a PTP <15%.

Studies have shown that outcomes in patients classified with the new PTP <15% is good (annual risk of cardiovascular death or MI is <1%).⁷^,⁶² Hence, it is safe to defer routine testing in patients with PTP <15%, thus reducing unnecessary procedures and costs.

Recent studies have also demonstrated that, when tested, the true observed prevalence of obstructive CAD has been <5% in patients who had a PTP <15% according to the 2013 version of these Guidelines.⁷^,⁶³ Therefore, this Task Force recognizes that the performance of diagnostic testing in patients with a new PTP of 5 − 15% more closely reflects current clinical practice and may be considered, particularly if symptoms are limiting and require clarification.⁷^,⁶³ Patient preference, local resources and the availability of tests, clinical judgement, and appropriate patient information remain important when making a decision to proceed with non-invasive diagnostic testing for an individual patient when the PTP is 5 − 15%, and the higher likelihood of a false-positive test must be considered. Patients with a PTP ≤5% can be assumed to have such a low probability of disease that diagnostic testing should be performed only for compelling reasons. Implementation of the new PTPs also indicates that patients should not be routinely referred directly to invasive assessment unless clinical or other data indicate a high likelihood of obstructive CAD.

Clinical models that incorporate information on risk factors for CVD, resting ECG changes, or coronary calcification have improved the identification of patients with obstructive CAD compared with age, sex, and symptoms alone.³^,⁷^,⁶⁰^,^65–68 Therefore, the presence of risk factors for CVD (such as family history of CVD, dyslipidaemia, diabetes, hypertension, smoking, and other lifestyle factors) that increase the probability of obstructive CAD can be used as modifiers of the PTP estimate. If available, Q-wave, ST-segment, or T-wave changes on the ECG, LV dysfunction suggestive of ischaemia, and findings on exercise ECG, as well as information on coronary calcium obtained by computed tomography (CT), can be used to improve estimations of the PTP of obstructive CAD.³^,⁶⁹ In particular, the absence of coronary calcium (Agatston score = 0) is associated with a low prevalence of obstructive CAD (<5%), and low risk of death or non-fatal MI (<1% annual risk).⁶⁹^,⁷⁰ However, it should be noted that coronary calcium imaging does not exclude coronary stenosis caused by a non-calcified atherosclerotic lesion,⁷⁰ and the presence of coronary calcium is a weak predictor of obstructive CAD.⁶⁹ Although the optimal use of these factors in improving PTP assessment has not yet been established, they should be considered in addition to the PTP based on sex, age, and the nature of symptoms to determine the overall clinical likelihood of obstructive CAD, as summarized in Figure 3. This is particularly important in refining the likelihood of CAD patients with a PTP of 5–15% based on age, sex, and the nature of symptoms.

Figure 3

Determinants of the clinical likelihood of obstructive coronary artery disease. CAD = coronary artery disease; CT = computed tomography, CVD = cardiovascular disease, ECG = electrocardiogram, LV = left ventricular; PTP = pre-test probability. ^aWhen available.

3.1.5 Step 5: Selecting appropriate testing

In patients in whom revascularization is futile due to comorbidities and overall quality of life, the diagnosis of CAD can be made clinically and only medical therapy is required. If the diagnosis of CAD is uncertain, establishing a diagnosis using non-invasive functional imaging for myocardial ischaemia before treatment is reasonable (Figure 2).

In a patient with a high clinical likelihood of CAD, symptoms unresponsive to medical therapy or typical 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 invasive coronary angiography (ICA) without further diagnostic testing is a reasonable option. Under such circumstances, the indication for revascularization should be based on appropriate invasive confirmation of the haemodynamic significance of a stenosis.⁷¹^,⁷²

In other patients in whom CAD cannot be excluded by clinical assessment alone, non-invasive diagnostic tests are recommended to establish the diagnosis and assess the event risk. The current Guidelines recommend the use of either non-invasive functional imaging of ischaemia or anatomical imaging using coronary CT angiography (CTA) as the initial test for diagnosing CAD.

3.1.5.1 Functional non-invasive tests

Functional non-invasive tests for the diagnosis of obstructive CAD are designed to detect myocardial ischaemia through ECG changes, wall motion abnormalities by stress CMR or stress echocardiography, or perfusion changes by single-photon emission CT (SPECT), positron emission tomography (PET), myocardial contrast echocardiography, or contrast CMR. Ischaemia can be provoked by exercise or pharmacological stressors, either by increased myocardial work and oxygen demand, or by heterogeneity in myocardial perfusion by vasodilatation. Non-invasive functional tests are associated with high accuracy for the detection of flow-limiting coronary stenosis compared with invasive functional testing [fractional flow reserve (FFR)].⁷³ However, lower-grade coronary atherosclerosis not linked with ischaemia remains undetected by functional testing and, in the presence of a negative functional test, patients should receive risk-factor modification based on commonly applied risk charts and recommendations.

3.1.5.2 Anatomical non-invasive evaluation

Anatomical non-invasive evaluation, by visualizing the coronary artery lumen and wall using an intravenous contrast agent, can be performed with coronary CTA, which provides high accuracy for the detection of obstructive coronary stenoses defined by ICA,⁷³ because both tests are based on anatomy. However, stenoses estimated to be 50–90% by visual inspection are not necessarily functionally significant, i.e. they do not always induce myocardial ischaemia.⁷³^,⁷⁴ Therefore, either non-invasive or invasive functional testing is recommended for further evaluation of angiographic stenosis detected by coronary CTA or invasive angiography, unless a very high-grade (>90% diameter stenosis) stenosis is detected via invasive angiography. The presence or absence of non-obstructive coronary atherosclerosis on coronary CTA provides prognostic information, and can be used to guide preventive therapy.⁷⁵ The SCOT-HEART (Scottish Computed Tomography of the HEART) trial demonstrated a significantly lower rate of the combined endpoint of cardiovascular death or non-fatal MI (2.3 vs. 3.9% during 5 year follow-up) in patients in whom coronary CTA was performed in addition to routine testing, which consisted predominantly of exercise ECG.⁶ Other randomized, prospective clinical trials have demonstrated that diagnostic testing with coronary CTA is associated with clinical outcomes similar to those for functional imaging in patients with suspected CAD.⁴^,⁶^,⁷⁶ In patients with extensive CAD, coronary CTA complemented by CT-based FFR was non-inferior to ICA and FFR for decision-making, and the identification of targets for revascularization.⁷⁷

3.1.5.3 Role of the exercise electrocardiogram

Exercise ECG has inferior diagnostic performance compared with diagnostic imaging tests, and has limited power to rule-in or rule-out obstructive CAD.⁷³ Since the publication of the previous version of these Guidelines, randomized clinical trials (RCTs) have compared the effects of diagnostic strategies based on exercise ECG or an imaging diagnostic test⁶^,⁷⁸^,⁷⁹ on clinical outcomes. These studies have shown that the addition of coronary CTA⁵^,⁶^,⁷⁸^,⁸⁰ or functional imaging⁷⁹ clarifies the diagnosis, enables the targeting of preventive therapies and interventions, and potentially reduces the risk of MI compared with an exercise ECG. Some, although not all, registry studies have also shown similar benefits regarding the use of an imaging diagnostic test in patients treated in everyday clinical practice.⁸¹^,⁸² Therefore, these Guidelines recommend the use of an imaging diagnostic test instead of exercise ECG as the initial test for to diagnose obstructive CAD.

An exercise ECG alone may be considered as an alternative to diagnose obstructive CAD if imaging tests are not available, keeping in mind the risk of false-negative and false-positive test results.⁷³^,⁸³ An exercise ECG is of no diagnostic value in patients with ECG abnormalities 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 who are being treated with digitalis). An exercise ECG provides complementary clinically useful information beyond ECG changes and valuable prognostic information. Therefore, application of an exercise ECG may be considered in selected patients to complement clinical evaluation for the assessment of symptoms, ST-segment changes, exercise tolerance, arrhythmias, blood pressure (BP) response, and event risk.

3.1.5.4 Selection of diagnostic tests

Either a functional or anatomical test can be used to establish a diagnosis of obstructive CAD. A summary of the main diagnostic pathways is displayed in Figure 4. For revascularization decisions, information on both anatomy and ischaemia is needed.

Figure 4

Main diagnostic pathways in symptomatic patients with suspected obstructive coronary artery disease. Depending on clinical conditions and the healthcare environment, patient workup can start with either of three options: non-invasive testing, coronary computed tomography angiography, or invasive coronary angiography. Through each pathway, both functional and anatomical information is gathered to inform an appropriate diagnostic and therapeutic strategy. Risk-factor modification should be considered in all patients. CAD = coronary artery disease; CTA = computed tomography angiography; ECG = electrocardiogram; LV = left ventricular. ^aConsider microvascular angina. ^bAntianginal medications and/or risk-factor modification.

3.1.5.5 The impact of clinical likelihood on the selection of a diagnostic test

Each non-invasive diagnostic test has a particular range of clinical likelihood of obstructive CAD where the usefulness of its application is maximal. The likelihood ratios of the tests constitute useful parameters of their abilities to correctly classify patients, and can be used to facilitate the selection of the most useful test in any given patient.⁷³^,⁸⁴ Given a clinical likelihood of obstructive CAD and the likelihood ratio of a particular test, one can assess the post-test probability of obstructive CAD after performing such a test. Using this approach, one can estimate the optimal ranges of clinical likelihood for each test, where they can reclassify patients from intermediate to either low or high post-test probability of CAD (Figure 5).⁷³

Figure 5

$Ranges of clinical likelihood of coronary artery disease in which a given test can rule-in (red) or rule-out (green) obstructive coronary artery disease. (A) Reference standard is anatomical assessment using invasive coronary angiography. (B) Reference standard is functional assessment using fractional flow reserve. Note in (B) that the data with stress echocardiography and single-photon emission computed tomography are more limited than with the other techniques.73 The crosshairs mark the mean values and their 95% confidence intervals. Figure adapted from Knuuti et al.73 CAD = coronary artery disease; CMR = cardiac magnetic resonance; CTA = computed tomography angiography; ECG = electrocardiogram; FFR = fractional flow reserve; ICA = invasive coronary angiography; PET = positron emission tomography; SPECT = single-photon emission computed tomography.$

Ranges of clinical likelihood of coronary artery disease in which a given test can rule-in (red) or rule-out (green) obstructive coronary artery disease. (A) Reference standard is anatomical assessment using invasive coronary angiography. (B) Reference standard is functional assessment using fractional flow reserve. Note in (B) that the data with stress echocardiography and single-photon emission computed tomography are more limited than with the other techniques.⁷³ The crosshairs mark the mean values and their 95% confidence intervals. Figure adapted from Knuuti et al.⁷³ CAD = coronary artery disease; CMR = cardiac magnetic resonance; CTA = computed tomography angiography; ECG = electrocardiogram; FFR = fractional flow reserve; ICA = invasive coronary angiography; PET = positron emission tomography; SPECT = single-photon emission computed tomography.

Coronary CTA is the preferred test in patients with a lower range of clinical likelihood of CAD, no previous diagnosis of CAD, and characteristics associated with a high likelihood of good image quality. It detects subclinical coronary atherosclerosis, but can also accurately rule out both anatomically and functionally significant CAD (Figure 5). It has higher accuracy values when low clinical likelihood populations are subjected to examination.⁸⁵ Trials evaluating outcomes after coronary CTA to date have mostly included patients with a low clinical likelihood.⁴^,⁵

The non-invasive functional tests for ischaemia typically have better rule-in power. In outcome trials, functional imaging tests have been associated with fewer referrals for downstream ICA compared with a strategy relying on anatomical imaging.⁵⁵^,⁷⁶^,⁸⁶ Before revascularization decisions can be made, functional evaluation of ischaemia (either non-invasive or invasive) is required in most patients. Therefore, functional non-invasive testing may be preferred in patients at the higher end of the range of clinical likelihood if revascularization is likely or the patient has previously diagnosed CAD.

Patients in whom CAD is suspected, but who have a very low clinical likelihood (≤5%) of CAD, should have other cardiac causes of chest pain excluded and their cardiovascular risk factors adjusted, based on a risk-score assessment. In patients with repeated, unprovoked attacks of anginal symptoms mainly at rest, vasospastic angina should be considered, diagnosed, and treated appropriately (see section 6).

In addition to diagnostic accuracy and clinical likelihood, the selection of a non-invasive test depends on other patient characteristics, local expertise, and the availability of tests. Some diagnostic tests may perform better in some patients than others. For example, irregular heart rate and the presence of extensive coronary calcification are associated with increased likelihood of non-diagnostic image quality of coronary CTA, and it is not recommended in such patients.⁸⁵ Stress echocardiography or SPECT perfusion imaging can be combined with dynamic exercise testing, and may be preferred if additional information available from the exercise test, such as exercise tolerance or heart rate response to exercise, is considered important. Exercise ECG cannot be used for diagnostic purposes in the presence of ECG abnormalities that prevent the evaluation of ischaemia. Risks related to different diagnostic tests need to be weighed against the benefits to the individual.⁸⁷ For example, exposure to ionizing radiation associated with coronary CTA and nuclear perfusion imaging needs to be taken into account, especially in young individuals.⁸⁷ Similarly, contraindications to pharmacological stressors and contrast agents (iodine-based contrast agents and gadolinium-based chelates) need to be taken into account. When testing is used appropriately, the clinical benefit from accurate diagnosis and therapy exceeds the projected risks of testing itself.⁸⁷

3.1.5.6 Invasive testing

For diagnostic purposes, ICA is only necessary in patients with suspected CAD in cases of inconclusive non-invasive testing or, exceptionally, in patients from particular professions, due to regulatory issues.⁸⁸ However, ICA may be indicated if non-invasive assessment suggests high event risk for determination of options for revascularization.⁸⁸

In a patient with a high clinical likelihood of CAD, and symptoms unresponsive to medical therapy or with typical angina at a low level of exercise, and initial clinical evaluation indicates a high event risk, early ICA without previous non-invasive risk stratification may be reasonable to identify lesions potentially amenable to revascularization (Figure 4). Invasive functional assessment should complement ICA, especially in patients with coronary stenoses of 50 − 90% or multivessel disease, given the frequent mismatch between the angiographic and haemodynamic severities of coronary stenoses.^89–91 Systematic integration of ICA with FFR has been shown to result in changes to the management strategies of 30 − 50% of patients undergoing elective ICA.⁹²^,⁹³ Methods used to perform ICA have improved substantially, resulting in a reduction of complication rates with rapid ambulation. This is especially true for ICA performed via the radial artery.⁹⁴ The composite rate of major complications associated with routine femoral diagnostic catheterization—mainly bleeding requiring blood transfusions—is still 0.5–2%.⁹⁵ The composite rate of death, MI, or stroke is of the order of 0.1–0.2%.⁹⁶ ICA should not be performed in patients with angina who refuse invasive procedures, prefer to avoid revascularization, who are not candidates for percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG), or in whom revascularization is not expected to improve functional status or quality of life. Intracoronary techniques for the diagnostic assessment of coronary anatomy are briefly mentioned in the Supplementary Data of this document.

Use of diagnostic imaging tests in the initial diagnostic management of symptomatic patients with suspected coronary artery disease

CAD = coronary artery disease; CT = computed tomography; CTA = computed tomography angiography.

a

Class of recommendation.

b

Level of evidence

c

Stress echocardiography, stress cardiac magnetic resonance, single-photon emission CT, or positron emission tomography.

d

Characteristics determining ability to exercise, likelihood of good image quality, expected radiation exposure, and risks or contraindications.

Use of exercise electrocardiogram in the initial diagnostic management of patients with suspected coronary artery disease

BP = blood pressure; CAD = coronary artery disease; ECG = electrocardiogram.

a

Class of recommendation.

b

Level of evidence.

c

When this information will have an impact on diagnostic strategy or management.

3.1.6 Step 6: Assessment of event risk

Assessment of event risk is recommended in every patient being evaluated for suspected CAD or with a newly diagnosed CAD, as it has major impacts on therapy decisions. The process of risk stratification serves to identify patients at high event risk who will benefit from revascularization beyond the amelioration of symptoms. Event risk stratification is usually based on the assessments used to make a diagnosis of CAD. All patients should undergo cardiovascular event risk stratification using clinical evaluation, the assessment of LV function by resting echocardiography, and, in the majority of cases, non-invasive assessment of ischaemia or coronary anatomy. Although the diagnostic value of an exercise ECG is limited,⁷³ the occurrence of ST-segment depression at a low workload combined with exertional symptoms (angina or dyspnoea), low exercise capacity, complex ventricular ectopy, or arrhythmias and abnormal BP response are markers of a high risk of cardiac mortality.^97–100 Patients with typical angina and LV systolic dysfunction in a pattern that indicates CAD are also at high risk of cardiac mortality.¹⁰¹ ICA for risk stratification will only be required in a selected subgroup of patients and additional FFR may be required for event risk stratification as appropriate (Figure 4). Risk assessment in patients with HF and LV dysfunction, asymptomatic patients with known CAD, and patients with recurrent symptoms after previous coronary intervention is discussed in sections 4 and 5.

3.1.6.1 Definition of levels of risk

In patients with established CCS, the risk of annual cardiac mortality is used to describe the event risk. As in the previous version of the Guidelines,⁶⁰ high event risk is defined as a cardiac mortality rate >3% per year and low event risk as a cardiac mortality rate <1% per year. The definitions of high event risk based on findings of diagnostic tests in symptomatic patients or in patients with established CCS are shown in Table 6.

Table 6

Definitions of high event risk for different test modalities in patients with established chronic coronary syndromes^a^102–104

Exercise ECG

Cardiovascular mortality >3% per year according to Duke Treadmill Score

SPECT or PET perfusion imaging

Area of ischaemia ≥10% of the left ventricle myocardium

Stress echocardiography

≥3 of 16 segments with stress-induced hypokinesia or akinesia

CMR

≥2 of 16 segments with stress perfusion defects or ≥3 dobutamine-induced dysfunctional segments

Coronary CTA or ICA

Three-vessel disease with proximal stenoses, LM disease, or proximal anterior descending disease

Invasive functional testing

FFR ≤0.8, iwFR ≤0.89

CTA = computed tomography angiography; CMR = cardiac magnetic resonance; ECG = electrocardiogram; FFR = fractional flow reserve; ICA = invasive coronary angiography; iwFR = instantaneous wave-free ration (instant flow reserve); LM = left main; PET = positron emission tomography; SPECT; single-photon emission computed tomography.

a

For detailed explanations, refer to the Supplementary Data.

Notably, the level of risk is different from the risk assessment based on SCORE in asymptomatic individuals without diabetes who are apparently healthy (see section 7). SCORE defines 10 year cardiovascular mortality in asymptomatic subjects. Differences in these risk-assessment tools and the scales are illustrated in Figure 6. The findings of different test modalities that correspond to high event risk are presented in Table 6 and are discussed in more detail in the Supplementary Data (sections 1.1 and 1.2).^102–104 For all non-invasive tests presented in Table 6, a normal test result is associated with a low event risk.¹⁰⁵

Figure 6

Comparison of risk assessments in asymptomatic apparently healthy subjects (primary prevention) and patients with established chronic coronary syndromes (secondary prevention). Note that in asymptomatic subjects (left panel), SCORE estimates 10 year cardiovascular mortality, while in symptomatic patients (right panel), annual cardiac mortality is estimated. CCS = chronic coronary syndromes; SCORE = Systematic COronary Risk Evaluation.

Recommendations on risk assessment

CAD = coronary artery disease; CTA = computed tomography angiography; ECG = electrocardiogram; FFR = fractional flow reserve; ICA = invasive coronary angiography; iwFR = instantaneous wave-free ratio; LM = left main; LV = left ventricular; LVEF = LV ejection fraction.

a

Class of recommendation.

b

Level of evidence.

3.2 Lifestyle management

3.2.1 General management of patients with coronary artery disease

General management of CCS aims to reduce symptoms and improve prognosis through appropriate medications and interventions, and to control risk factors including lifestyle behaviours. Optimal medical therapy in the COURAGE (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation) trial included the promotion of medication adherence, behavioural counselling, and support for the managing lifestyle risk factors delivered by nurse case managers.¹¹⁷ Achievement of optimal management may be best accomplished through a multidisciplinary team approach that can provide tailored and flexible support to patients.

Patient-reported outcome measures can provide relevant and systematic information about patients’ symptoms, functioning, and concerns. Patient-reported outcome measures are increasingly being implemented sequentially in healthcare, and have been shown to improve clinical care and patient experiences, communication between providers and patients (including sensitive subjects), save time in consultations, and improve provider satisfaction.¹¹⁸

3.2.2 Lifestyle modification and control of risk factors

Implementing healthy lifestyle behaviours decreases the risk of subsequent cardiovascular events and mortality, and is additional to appropriate secondary prevention therapy. Lifestyle recommendations and interventions are described in more detail in the 2016 ESC Guidelines on CVD prevention in clinical practice.¹⁵ Lifestyle factors are important and the implementation of healthy behaviours (including smoking cessation, recommended physical activity, a healthy diet, and maintaining a healthy weight; see Table 7) significantly decreases the risk of future cardiovascular events and death, even when controlling for evidence-based secondary prevention therapy and interventions.^119–122 Benefits are evident as early as 6 months after an index event.¹¹⁹

Table 7

Lifestyle recommendations for patients with chronic coronary syndromes

Lifestyle factor
Smoking cessation	Use pharmacological and behavioural strategies to help patients quit smoking. Avoid passive smoking.
Healthy diet	Diet high in vegetables, fruit, and wholegrains. Limit saturated fat to <10% of total intake. Limit alcohol to <100 g/week or 15 g/day.
Physical activity	30 − 60 min moderate physical activity most days, but even irregular activity is beneficial.
Healthy weight	Obtain and maintain a healthy weight (<25 kg/m²), or reduce weight through recommended energy intake and increased physical activity.
Other	Take medications as prescribed. Sexual activity is low risk for stable patients not symptomatic at low-to-moderate activity levels.

Lifestyle factor
Smoking cessation	Use pharmacological and behavioural strategies to help patients quit smoking. Avoid passive smoking.
Healthy diet	Diet high in vegetables, fruit, and wholegrains. Limit saturated fat to <10% of total intake. Limit alcohol to <100 g/week or 15 g/day.
Physical activity	30 − 60 min moderate physical activity most days, but even irregular activity is beneficial.
Healthy weight	Obtain and maintain a healthy weight (<25 kg/m²), or reduce weight through recommended energy intake and increased physical activity.
Other	Take medications as prescribed. Sexual activity is low risk for stable patients not symptomatic at low-to-moderate activity levels.

Table 7

Lifestyle recommendations for patients with chronic coronary syndromes

Lifestyle factor
Smoking cessation	Use pharmacological and behavioural strategies to help patients quit smoking. Avoid passive smoking.
Healthy diet	Diet high in vegetables, fruit, and wholegrains. Limit saturated fat to <10% of total intake. Limit alcohol to <100 g/week or 15 g/day.
Physical activity	30 − 60 min moderate physical activity most days, but even irregular activity is beneficial.
Healthy weight	Obtain and maintain a healthy weight (<25 kg/m²), or reduce weight through recommended energy intake and increased physical activity.
Other	Take medications as prescribed. Sexual activity is low risk for stable patients not symptomatic at low-to-moderate activity levels.

Lifestyle factor
Smoking cessation	Use pharmacological and behavioural strategies to help patients quit smoking. Avoid passive smoking.
Healthy diet	Diet high in vegetables, fruit, and wholegrains. Limit saturated fat to <10% of total intake. Limit alcohol to <100 g/week or 15 g/day.
Physical activity	30 − 60 min moderate physical activity most days, but even irregular activity is beneficial.
Healthy weight	Obtain and maintain a healthy weight (<25 kg/m²), or reduce weight through recommended energy intake and increased physical activity.
Other	Take medications as prescribed. Sexual activity is low risk for stable patients not symptomatic at low-to-moderate activity levels.

Primary care providers have an important role to play in prevention. The primary care arm of the EUROACTION cluster randomized trial demonstrated that a nurse-co-ordinated programme in primary care was more effective in helping patients achieve lifestyle and risk-factor goals than usual care.¹²³ Practice nurses in the Netherlands were found to be as effective as general practitioners in decreasing cardiovascular risk in another randomized study.¹²³

3.2.2.1 Smoking

Smoking cessation improves the prognosis in patients with CCS, including a 36% risk reduction in mortality for those who quit.¹²⁴ Measures to promote smoking cessation include brief advice, counselling and behavioural interventions, and pharmacological therapy including nicotine replacement. Patients should also avoid passive smoking.

Brief advice, relative to no treatment, doubles the likelihood of smoking cessation in the short-term, but more intensive advice and support (behavioural interventions, telephone support, or self-help measures) is more effective than brief advice, especially if continued over 1 month.¹²⁵^,¹²⁶ All forms of nicotine-replacement therapy, bupropion, and varenicline are more effective in increasing smoking cessation than control, and combining behavioural and pharmacological approaches is effective and highly recommended.¹²⁵ A network meta-analysis of 63 clinical trials (including eight trials in CVD patients) found no increase in major adverse cardiovascular events linked to nicotine-replacement therapy, bupropion, or varenicline.¹²⁷ Nicotine-replacement therapy was associated with minor events such as arrhythmias and angina, and bupropion appeared to have a protective effect against major adverse cardiovascular events.¹²⁷ The use of e-cigarettes is considered to be a reduced-harm alternative to conventional cigarettes, but they are not harm-free. Newer devices can deliver higher nicotine contents, and e-cigarettes emit other constituents such as carbonyls and fine and ultrafine particulates.¹²⁸ Although previous systematic reviews have found very limited and inconsistent evidence that e-cigarettes (primarily first-generation devices) are useful in improve smoking cessation compared with placebo or nicotine-replacement therapy, a recent large clinical trial found e-cigarettes to be more effective than nicotine-replacement therapy in smoking cessation.^129–133 In this randomised trial of 886 smokers, those assigned to e-cigarettes had a sustained 1 year abstinence rate of 18% compared with 9.9% for nicotine-replacement therapy [relative risk, 1.83; 95% confidence interval (CI) 1.30 to 2.58; P < 0.001].¹³³

In clinical encounters with smokers, clinicians should follow the ‘Five As’: ask about smoking, advise to quit, assess readiness to quit, assist with smoking cessation (pharmacological support and referral for behavioural counselling), and arrange follow-up (Figure 7).

Figure 7

The five As of smoking cessation.

3.2.2.2 Diet and alcohol

Unhealthy diets are a leading contributor to CAD and its progression, and changes to healthy eating patterns in patients with CCS have resulted in a reduction in mortality and cardiovascular events¹³⁴ (recommended diet characteristics are detailed in Table 8).

Table 8

Healthy diet characteristics^{134,137,141,142}

Characteristics
Increase consumption of fruits and vegetables (≥200 g each per day).
35–45 g of fibre per day, preferably from wholegrains.
Moderate consumption of nuts (30 g per day, unsalted).
1–2 servings of fish per week (one to be oily fish).
Limited lean meat, low-fat dairy products, and liquid vegetable oils.
Saturated fats to account for <10% of total energy intake; replace with polyunsaturated fats.
As little intake of trans unsaturated fats as possible, preferably no intake from processed food, and <1% of total energy intake.
≤5–6 g of salt per day.
If alcohol is consumed, limiting intake to ≤100 g/week or <15 g/day is recommended.
Avoid energy-dense foods such as sugar-sweetened soft drinks.

Characteristics
Increase consumption of fruits and vegetables (≥200 g each per day).
35–45 g of fibre per day, preferably from wholegrains.
Moderate consumption of nuts (30 g per day, unsalted).
1–2 servings of fish per week (one to be oily fish).
Limited lean meat, low-fat dairy products, and liquid vegetable oils.
Saturated fats to account for <10% of total energy intake; replace with polyunsaturated fats.
As little intake of trans unsaturated fats as possible, preferably no intake from processed food, and <1% of total energy intake.
≤5–6 g of salt per day.
If alcohol is consumed, limiting intake to ≤100 g/week or <15 g/day is recommended.
Avoid energy-dense foods such as sugar-sweetened soft drinks.

Table 8

Healthy diet characteristics^{134,137,141,142}

Characteristics
Increase consumption of fruits and vegetables (≥200 g each per day).
35–45 g of fibre per day, preferably from wholegrains.
Moderate consumption of nuts (30 g per day, unsalted).
1–2 servings of fish per week (one to be oily fish).
Limited lean meat, low-fat dairy products, and liquid vegetable oils.
Saturated fats to account for <10% of total energy intake; replace with polyunsaturated fats.
As little intake of trans unsaturated fats as possible, preferably no intake from processed food, and <1% of total energy intake.
≤5–6 g of salt per day.
If alcohol is consumed, limiting intake to ≤100 g/week or <15 g/day is recommended.
Avoid energy-dense foods such as sugar-sweetened soft drinks.

Characteristics
Increase consumption of fruits and vegetables (≥200 g each per day).
35–45 g of fibre per day, preferably from wholegrains.
Moderate consumption of nuts (30 g per day, unsalted).
1–2 servings of fish per week (one to be oily fish).
Limited lean meat, low-fat dairy products, and liquid vegetable oils.
Saturated fats to account for <10% of total energy intake; replace with polyunsaturated fats.
As little intake of trans unsaturated fats as possible, preferably no intake from processed food, and <1% of total energy intake.
≤5–6 g of salt per day.
If alcohol is consumed, limiting intake to ≤100 g/week or <15 g/day is recommended.
Avoid energy-dense foods such as sugar-sweetened soft drinks.

A Mediterranean dietary pattern high in fruit, vegetables, legumes, fibre, polyunsaturated fats, nuts, and fish, avoiding or limiting refined carbohydrates, red meat, dairy, and saturated fat, is advocated.^135–138 Although light-to-moderate alcohol intake (1–2 drinks per day) does not increase risk of MI, levels >100 g per week were associated with higher all-cause and other CVD mortality in a large individual-data meta-analysis.¹³⁹ The Global Burden of Disease 1990–2016 analysis concluded that zero alcohol intake was the level at which risk for death and disability was minimized.¹⁴⁰

3.2.2.3 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 (20 − 25 kg/m²). Obesity was associated with a shorter overall lifespan, and overweight was associated with developing CVD at an earlier age.¹⁴³ Waist circumference is a marker of central obesity and is strongly associated with developing CVD and diabetes. Waist circumference ≤94 cm for men (<90 cm for South Asian and Asian men) and ≤80 cm for women is recommended.

In subjects with CAD, intentional weight loss is associated with a significantly lower risk of adverse clinical outcomes.¹⁴⁴ Although there has been much argument regarding the relative benefits of low-fat vs. low-carbohydrate diets, Gardner et al.¹⁴⁵ found similar weight loss and benefits in patients randomized to either healthy low-fat or low-carbohydrate diets. This finding held, regardless of patients’ genotype patterns and baseline insulin secretion. Healthy diets with energy intake limited to the amount needed to obtain and maintain a healthy weight (BMI <25 kg/m²), and increasing physical activity, are recommended for weight management.

3.2.2.4 Physical activity

Exercise has been referred to as a ‘polypill’ due to its numerous beneficial effects on cardiovascular risk factors and cardiovascular system physiology.¹⁴⁶^,¹⁴⁷ Exercise improves angina through enhanced oxygen delivery to the myocardium, and increasing exercise capacity is an independent predictor of increased survival among men and women with CCS, even among those with a regimen consistent with evidence-based management.¹²²^,¹⁴⁷^,¹⁴⁸

Every 1 mL/kg/min increase in exercise peak oxygen consumption was associated with a 14–17% reduction of risk for cardiovascular and all-cause death in women and men.¹²²

Physical activity recommendations for patients with CCS are 30–60 min of moderate-intensity aerobic activity ≥5 days per week.¹⁴⁷ Even irregular leisure-time physical activity decreases mortality risk among previously sedentary patients,¹⁴⁹ and increasing activity is associated with lower cardiovascular mortality.¹⁵⁰ Previously sedentary patients will need support to work up to 30–60 min most days, reassurance that exercise is beneficial, and education regarding what to do if angina occurs while being active. Resistance exercises maintain muscle mass, strength, and function and, with aerobic activity, have benefits regarding insulin sensitivity and control of lipids and BP.

3.2.2.5 Cardiac rehabilitation

Exercise-based cardiac rehabilitation has consistently demonstrated its effectiveness in reducing cardiovascular mortality and hospitalizations compared with no exercise controls in patients with CAD, and this benefit persists into the modern era.^151–153 Most patients participating in cardiac rehabilitation are referred following an acute MI or after revascularization, with 0 − 24% of patients found to be referred for CCS in 12 European countries.¹⁵⁴ Importantly, the benefits of cardiac rehabilitation occur across diagnostic categories.^151–153

3.2.2.6 Psychosocial factors

Patients with heart disease have a two-fold increased risk of mood and anxiety disorders compared with people without heart disease.¹⁵⁵^,¹⁵⁶ Psychosocial stress, depression, and anxiety are associated with worse outcomes, and make it difficult for patients to make positive changes to their lifestyles or adhere to a therapeutic regimen. The ESC Prevention Guidelines recommend assessment for psychosocial risk factors.¹⁵ 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.^157–159

3.2.2.7 Environmental factors

Air pollutants are estimated to be one of the 10 leading risk factors for global mortality. Exposure to air pollution increases risk of MI, as well as hospitalization and death from heart failure, stroke, and arrhythmia.¹⁶⁰ Patients with CCS should avoid heavily traffic-congested areas. Air purifiers with high-efficiency particulate air (‘HEPA’) filters reduce indoor pollution, and wearing N95 respirator face masks in heavily polluted areas has been shown to be protective.¹⁶⁰ Environmental noise also increases the risk of CVD.¹⁶¹ Policies and regulations that reduce air pollution and environmental noise should be supported, and patients should be advised about these risks.

3.2.2.8 Sexual activity

Patients with CCS often worry about the cardiovascular risk associated with sexual activity and/or experience sexual dysfunction.¹⁶² The risk of triggering sudden death or an acute MI is very low, especially when sexual activity is with a stable partner in a familiar environment without stress, or excessive intake of food or alcohol beforehand.¹⁶³^,¹⁶⁴ Although sexual activity transiently increases the risk of MI, it is the cause of <1% of acute MIs and <1–1.7% of sudden deaths occur during sexual activity.¹⁶⁴ The energy expenditure during sexual activity is generally low-to-moderate (3 − 5 metabolic equivalents) and climbing two flights of stairs is often used as an equivalent activity in terms of energy expended.¹⁶³^,¹⁶⁴ Regular physical activity decreases the risk of adverse events during sexual activity.¹⁶⁵ Sexual dysfunction in patients with CCS includes decreased libido and sexual activity, and a high prevalence of erectile dysfunction. Sexual dysfunction may be caused by underlying vascular conditions, psychosocial factors, specific medications, number of medications, and changes in relationships.¹⁶⁶ Thiazide diuretics and beta-blockers (except nebivolol) may negatively influence erectile function, but studies published since 2011 have not found a consistent relationship between most contemporary cardiovascular medications and erectile dysfunction.¹⁶²^,¹⁶⁴^,¹⁶⁵ Phosphodiesterase-5 inhibitors to treat erectile dysfunction are generally safe in CCS patients, but should not be used in those taking nitrates.¹⁶⁴ Healthcare providers should ask patients about sexual activity, and offer advice and counselling.

3.2.2.9 Adherence and sustainability

Adherence to lifestyle modifications and to medications is a challenge. A systematic review of epidemiological studies indicated that a substantial proportion of patients do not adhere to cardiovascular medications, and that 9% of cardiovascular events in Europe were attributable to poor adherence.¹⁶⁷ In older men with ischaemic heart disease, greater adherence to medication guidelines appears to be positively associated with better clinical outcomes, independent of other conditions.¹⁶⁸ Polypharmacy plays a negative role in adherence to treatment,¹⁶⁹ and complexity of drug regimen is associated with non-adherence and higher rates of hospitalizations.¹⁷⁰ Drug prescriptions should prioritize medications that have proved their benefit with the highest level of evidence and those for whom the amplitude of benefit is largest. Simplifying medication regimens may help, and there is some evidence of benefits of cognitive educational strategies, electronically monitored feedback, and support by nurse case managers. Medication reviews by primary care providers may be helpful in patients with multiple comorbidities to minimize the risk of adverse interactions and to simplify medication regimens.¹¹⁷^,^171–173

Promoting behaviour change and medication adherence should be part of each clinical encounter in primary care and specialist follow-up, emphasising its importance, referring for support when needed, and congratulating patients for their achievements. Long-term support (intensive in the first 6 months, then every 6 months for 3 years) in the GOSPEL (Global secondary prevention strategies to limit event recurrence after myocardial infarction) trial resulted in significant improvements in risk factors, and decreases in several clinical mortality and morbidity endpoints.¹²¹ The Multicenter Lifestyle Demonstration Project showed that CCS patients could make intensive lifestyle changes and improve their risk factors and fitness, with changes sustained at 12 months.¹⁷⁴

3.2.2.10 Influenza vaccination

An annual influenza vaccination can improve prevention of acute MI in patients with CCS,¹⁷⁵^,¹⁷⁶ change HF prognosis,¹⁷⁷ and decrease cardiovascular mortality in adults aged ≥65 years.^178–180 Therefore, annual influenza vaccination is recommended for patients with CAD, especially in the elderly.

Recommendations on lifestyle management

CCS = chronic coronary syndrome; GPs = general practitioners.

a

Class of recommendation.

b

Level of evidence.

3.3 Pharmacological management

The aims of pharmacological management of CCS patients are to reduce angina symptoms and exercise-induced ischaemia, and to prevent cardiovascular events.

Immediate relief of anginal symptoms, or the prevention of symptoms under circumstances likely to elicit angina, is usually obtained with rapidly acting formulations of nitroglycerin. Anti-ischaemic drugs—but also lifestyle changes, regular exercise training, patient education, and revascularization—all play a role in minimizing or eradicating symptoms over the long-term (long-term prevention).

Prevention of cardiovascular events targets MI and death associated with CAD, and focuses primarily on reducing the incidence of acute thrombotic events and the development of ventricular dysfunction. Strategies include pharmacological and lifestyle interventions, as detailed in the 2016 European Guidelines on CVD prevention in clinical practice.¹⁵

3.3.1 Anti-ischaemic drugs

3.3.1.1 General strategy

Optimal treatment can be defined as the treatment that satisfactorily controls symptoms and prevents cardiac events associated with CCS, with maximal patient adherence and minimal adverse events.^188–191 However, there is no universal definition of an optimal treatment in patients with CCS, and drug therapies must be adapted to each patient’s characteristics and preferences.¹⁹² Initial drug therapy usually consists of one or two antianginal drugs, as necessary, plus drugs for secondary prevention of CVD.¹⁹³ The initial choice of antianginal drug(s) depends on the expected tolerance related to the individual patient’s profile and comorbidities, potential drug interactions with co-administered therapies, the patient’s preferences after being informed of potential adverse effects, and drug availability. Whether combination therapy with two antianginal drugs [e.g. a beta-blocker and a calcium channel blocker (CCB)] is superior to monotherapy with any class of antianginal drug in reducing clinical events remains unclear.^194–197

Beta-adrenergic blockers or CCBs are recommended as the first choice, although no RCT to date has compared this strategy to an alternative strategy using initial prescription of other anti-ischaemic drugs, or the combination of a beta-blocker and a CCB.¹⁹¹^,¹⁹⁵ The results of a network meta-analysis of 46 studies and 71 treatment comparisons supported the initial combination of a beta-blocker and a CCB.¹⁹⁸ The same meta-analysis suggested that several second-line add-on anti-ischaemic drugs (long-acting nitrates, ranolazine, trimetazidine, and, to a lesser extent, ivabradine) may prove beneficial in combination with a beta-blocker or a CCB as first-line therapy, while no data were available for nicorandil. However, it should be noted that the study pooled RCTs using endpoints of nitrate use, angina frequency, time to angina or to ST-segment depression, and total exercise time, and no study or meta-analysis has yet assessed with sufficient power the influence of combining a beta-blocker or a CCB with a second-line anti-ischaemic drug on morbidity or mortality events.¹⁹⁸ Regardless of the initial strategy, response to initial antianginal therapy should be reassessed after 2–4 weeks of treatment initiation.

3.3.1.2 Available drugs

Anti-ischaemic drugs have proved benefits regarding symptoms associated with myocardial ischaemia but do not prevent cardiovascular events in most patients with CCS. Supplementary Table 3 in the Supplementary Data summarizes the principal major side effects, contraindications, drug–drug interactions, and precautions relating to anti-ischaemic drugs. Supplementary Table 2 summarizes the main mechanisms of action of anti-ischaemic drugs.

Nitrates

Short-acting nitrates for acute effort angina

Sublingual and spray nitroglycerin formulations provide immediate relief of effort angina. Spray nitroglycerin acts more rapidly than sublingual nitroglycerin.¹⁹⁹ At the onset of angina symptoms, the patient should rest in a sitting position (standing promotes syncope, and lying down enhances venous return and preload) and take nitroglycerin (0.3–0.6 mg tablet sublingually and not swallowed, or 0.4 mg spray to the tongue and not swallowed or inhaled) every 5 min until the pain disappears, or a maximum of 1.2 mg has been taken within 15 min. During this time frame, if angina persists, immediate medical attention is needed. Nitroglycerin can be administered for prophylaxis before physical activities known to provoke angina. Isosorbide dinitrate (5 mg sublingually) has a slightly slower onset of action than nitroglycerin due to hepatic conversion to mononitrate. The effect of isosorbide dinitrate may last ≤1 h if the drug is taken sublingually or persist for several hours if the drug is taken by oral ingestion.

Long-acting nitrates for angina prophylaxis

Long-acting nitrate formulations (e.g. nitroglycerin, isosorbide dinitrate, and isosorbide mononitrate) should be considered as second-line therapy for angina relief when initial therapy with a beta-blocker or non-dihydropyridine (non-DHP) CCB is contraindicated, poorly tolerated, or insufficient to control symptoms. In fact, there is a paucity of data comparing nitrates with beta-blockers or CCB from which to draw firm conclusions about their relative efficacies.²⁰⁰ When taken over a prolonged period, long-acting nitrates provoke tolerance with loss of efficacy, which requires prescription of a nitrate-free or nitrate-low interval of ∼10–14 h.²⁰¹ Nitroglycerin can be administered orally or transdermally through slow-release patch systems. Bioavailability of isosorbide dinitrate depends on the interindividual variability in hepatic conversion and is generally lower than the bioavailability of isosorbide mononitrate (its active metabolite), which is 100% bioavailable. Titration of dose is essential with all formulations to obtain the maximal control of symptoms at a tolerable dose. Discontinuation should be tapered and not abrupt to avoid a rebound increase in angina.²⁰² The most common side effects are hypotension, headache, and flushing. Contraindications include hypertrophic obstructive cardiomyopathy, severe aortic valvular stenosis, and co-administration of phosphodiesterase inhibitors (e.g. sildenafil, tadalafil, or vardenafil) or riociguat.

Beta-blockers

The dose of beta-blockers should be adjusted to limit the heart rate to 55–60 b.p.m. (beats per minute) at rest.²⁰³^,²⁰⁴ Discontinuation should be tapered and not abrupt. Beta-blockers can be combined with DHP CCBs to reduce DHP-induced tachycardia, but with uncertain incremental clinical value.^205–208 Caution is warranted when a beta-blocker is combined with verapamil or diltiazem due to the potential for developing worsening of HF, excessive bradycardia, and/or atrioventricular block. Combination of a beta-blocker with a nitrate attenuates the reflex tachycardia of the latter. The principal side effects of beta-blockers are fatigue, depression, bradycardia, heart block, bronchospasm, peripheral vasoconstriction, postural hypotension, impotence, and masking of hypoglycaemia symptoms.

In certain patients with recent MI and those with chronic HF with reduced ejection fraction, beta-blockers have been associated with a significant reduction in mortality and/or cardiovascular events,^209–215 but the protective benefit in patients with CAD without prior MI or HF is less well established and lacks placebo-controlled trials.²¹⁶ A retrospective analysis of 21 860 matched patients from the REACH (REduction of Atherothrombosis for Continued Health) Registry showed no reduction in cardiovascular mortality with beta-blockers in patients with either CAD with risk factors only, known prior MI, or known CAD without MI.²¹⁷ In a retrospective national registry of 755 215 patients aged ≥65 years with a history of CAD without prior MI or HF with reduced ejection fraction undergoing elective PCI, beta-blocker use at discharge was not associated with any reduction in cardiovascular morbidity or mortality at 30 day and 3 year follow-up.²¹⁸ However, in patients with or without previous MI undergoing CABG, beta-blockers were associated with lower risk of long-term mortality and adverse cardiovascular events.²¹⁹ Other observational studies and meta-analyses have questioned the benefit of long-term (>1 year) beta-blocker therapy in patients with a previous MI.²¹⁶^,^220–224 This is still a matter for debate,²²⁵ and uncertainties remain on the comparative role of beta-blockers and angiotensin-converting enzyme (ACE) inhibitors.

Calcium channel blockers

While CCBs improve symptoms and myocardial ischaemia, they have not been shown to reduce major morbidity endpoints or mortality in patients with CCS.¹⁹²^,^226–228

Non-dihydropyridine agents (heart rate-lowering calcium channel blockers)

Verapamil. Verapamil has a large range of approved indications, including all varieties of angina (effort, vasospastic, and unstable), supraventricular tachycardias, and hypertension. Indirect evidence suggests good safety but with risks of heart block, bradycardia, and HF. Compared with metoprolol, the antianginal activity was similar.²²⁹ Compared with atenonol in hypertension with CAD, verapamil is associated with fewer cases of diabetes, fewer anginal attacks,²³⁰ and less psychological depression.²³¹ Beta-blockade combined with verapamil is not advised (due to risk of heart block).

Diltiazem. Diltiazem, with its low-side effect profile, has advantages compared with verapamil in the treatment of effort angina. Like verapamil, it acts by peripheral vasodilation, relief of exercise-induced coronary constriction, a modest negative inotropic effect, and sinus node inhibition. There have been no outcome studies comparing diltiazem and verapamil.

In some selected patients, non-DHP agents may be combined with beta-blockers for the treatment of angina. However, on such occasions they must be used under close monitoring of patients’ tolerance regarding excessive bradycardia or signs of HF. Use of non-DHP CCBs in patients with LV dysfunction is not advised.

Dihydropyridine agents

Long-acting nifedipine. This agent is a powerful arterial vasodilator with few serious side effects. Long-acting nifedipine has been especially well tested in hypertensive anginal patients when added to beta-blockade.²³² In the large placebo-controlled ACTION (A Coronary disease Trial Investigating Outcome with Nifedipine gastrointestinal therapeutic system) trial, addition of long-acting nifedipine [60 mg o.d. (once a day)] to conventional treatment of angina had no effect on major cardiovascular event-free survival. Long-acting nifedipine proved to be safe, and reduced the need for coronary angiography and cardiovascular interventions.²³² Relative contraindications to nifedipine are few (severe aortic stenosis, hypertrophic obstructive cardiomyopathy, or HF), and careful combination with beta-blockade is usually feasible and desirable. Vasodilatory side effects include headache and ankle oedema.

Amlodipine. The very long half-life of amlodipine and its good tolerability make it an effective once-a-day antianginal and antihypertensive agent, setting it apart from drugs that are taken either twice or three times daily. Side effects are few, mainly ankle oedema. In patients with CCS and normal BP (∼75% receiving a beta-blocker), amlodipine 10 mg/day reduced coronary revascularizations and hospitalizations for angina in a 24 month trial.²³³ Exercise-induced ischaemia is more effectively reduced by amlodipine, 5 mg titrated to 10 mg/day, than by the beta-blocker atenolol, 50 mg/day, and their combination is even better.²³⁴ However, the CCB–beta-blocker combination is often underused, even in some studies reporting ‘optimally treated’ stable effort angina.

Ivabradine

Ivabradine has been reported to be non-inferior to atenolol or amlodipine in the treatment of angina and ischaemia in patients with CCS.²³⁵^,²³⁶ Adding ivabradine 7.5 mg b.i.d. [bis in die (twice a day)] to atenolol therapy gave better control of heart rate and anginal symptoms.²³⁷ In 10 917 patients with limiting previous angina enrolled in the morbidity–mortality evaluation of the BEAUTIFUL (I_f Inhibitor Ivabradine in Patients With Coronary Artery Disease and Left Ventricular Dysfunction) trial, ivabradine did not reduce the composite primary endpoint of cardiovascular death, hospitalization with MI, or HF.²³⁸ Also, in the SIGNIFY (Study Assessing the Morbidity–Mortality Benefits of the I_f Inhibitor Ivabradine in Patients with Coronary Artery Disease) study, consisting of 19 102 patients with CAD without clinical HF and a heart rate ≥70 b.p.m., there was no significant difference between the ivabradine group and the placebo group in the incidence of the primary composite endpoint of death from cardiovascular causes or non-fatal MI.²³⁹ Ivabradine was associated with an increase in the incidence of the primary endpoint among 12 049 patients with activity-limiting angina but not among those without activity-limiting angina (P=0.02 for interaction). In 2014, the European Medicines Agency issued recommendations to reduce the risk of bradycardia and placed ivabradine under additional monitoring.²⁴⁰ In aggregate, these results support the use of ivabradine as a second-line drug in patients with CCS.

Nicorandil

Nicorandil is a nitrate derivative of nicotinamide, with antianginal effects similar to those of nitrates or beta-blockers.^241–244 Side effects include nausea, vomiting, and potentially severe oral, intestinal, and mucosal ulcerations.²⁴⁵

In the placebo-controlled IONA (Impact Of Nicorandil in Angina) trial (n = 5126), nicorandil significantly reduced the composite of coronary heart disease (CHD) death, non-fatal MI, or unplanned hospital admission for suspected anginal symptoms in patients with CCS, but there was no effect on death from ischaemic heart disease or non-fatal MI.²⁴⁶ These results support the use of nicorandil as a second-line drug in patients with CCS.

Ranolazine

Ranolazine is a selective inhibitor of the late inward sodium current. Side effects include dizziness, nausea, and constipation. In addition, ranolazine increases QTc, and should therefore be used carefully in patients with QT prolongation or on QT-prolonging drugs.

In a placebo-controlled trial of 6560 patients with non-ST-segment elevation ACS, the addition of ranolazine to standard treatment did not prove effective in reducing the primary efficacy endpoint of cardiovascular death, MI, or recurrent ischaemia.²⁴⁷ However, in the relatively large subgroup of patients with chronic angina (n = 3565), significant reductions in recurrent ischaemia, worsening angina, and intensification of antianginal therapy were observed.²⁴⁸ In another placebo-controlled trial of patients with diabetes and CAD receiving one or two antianginal drugs, ranolazine reduced angina and sublingual nitroglycerin use with good tolerability.²⁴⁹ In the RIVER-PCI (Ranolazine for Incomplete Vessel Revascularization Post‐Percutaneous Coronary Intervention) trial, ranolazine did not reduce the composite of ischaemia-driven revascularization or hospitalization without revascularization in 2651 patients with a history of chronic angina and incomplete revascularization after PCI, including those with and without PCI for a CAD indication, nor did it reduce angina symptoms at 1 year.²⁵⁰^,²⁵¹

These results support the use of ranolazine as a second-line drug in CCS patients with refractory angina despite commonly used antianginal agents such as beta-blockers, CCBs, and/or long-acting nitrates. Conversely, there is a lack of evidence to support the use of ranolazine in patients with CCS following PCI with incomplete revascularization.

Trimetazidine

Trimetazidine appears to have a haemodynamically neutral side effect profile.²⁵² Trimetazidine (35 mg b.i.d.) added to beta-blockade (atenolol) improved effort-induced myocardial ischaemia, as reviewed by the European Medicines Agency in June 2012.²⁵³^,²⁵⁴ It remains contraindicated in Parkinson’s disease and motion disorders, such as tremor (shaking), muscle rigidity, walking disorders, and restless leg syndrome. A 2014 meta-analysis of 13, mostly Chinese, studies consisting of 1628 patients showed that treatment with trimetazidine on top of other antianginal drugs was associated with a smaller weekly mean number of angina attacks, lower weekly nitroglycerin use, longer time to 1 mm ST-segment depression, higher total work, and longer exercise duration at peak exercise than treatment with the other antianginal drugs for stable angina pectoris.²⁵⁵ These results support the use of trimetazidine as a second-line drug in patients with CCS whose symptoms are not adequately controlled by, or who are intolerant to, other medicines for angina pectoris.

Allopurinol

In 2010, a randomized crossover study of 65 patients with CAD showed that allopurinol 600 mg/day increased times to ST-segment depression and to angina.²⁵⁶ An observational study of 29 298 episodes of incident allopurinol use found an association of allopurinol use with a reduction in the risk of incident MI in the elderly, particularly when used for >2 years.²⁵⁷ However, the role of allopurinol in reducing clinical events in CVD remains unclear.²⁵⁸

A stepwise strategy for anti-ischaemic drug therapy in CCS is proposed, depending on some baseline patient characteristics (Figure 8). Incomplete responses or poor tolerance at each step justify moving to the next step. The strategy must be adapted to each patient’s characteristics and preferences, and does not necessarily follow the steps indicated in the figure.

Figure 8

Suggested stepwise strategy for long term anti-ischaemic drug therapy in patients with chronic coronary syndromes and specific baseline characteristics. The proposed stepwise approach must be adapted to each patient's characteristics and preferences. Given the limited evidence on various combinations of drugs in different clinical conditions, the proposed options are only indicative of potential combinations and do not represent formal recommendations. BB = beta-blocker; bpm = beats per minute; CCB = [any class of] calcium channel blocker; DHP-CCB = dihydropyridine calcium channel blocker; HF = heart failure; LAN = long-acting nitrate; LV = left ventricular; non-DHP-CCB = non-dihydropyridine calcium channel blocker. ^aCombination of a BB with a DHP-CCB should be considered as first step; combination of a BB or a CCB with a second-line drug may be considered as a first step; ^bThe combination of a BB and non-DHP-CCB should initially use low doses of each drug under close monitoring of tolerance, particularly heart rate and blood pressure; ^cLow-dose BB or low-dose non-DHP-CCB should be used under close monitoring of tolerance, particularly heart rate and blood pressure; ^dIvabradine should not be combined with non-DHP-CCB; ^eConsider adding the drug chosen at step 2 to the drug tested at step 1 if blood pressure remains unchanged.

3.3.1.3 Patients with low blood pressure

In patients with low BP, it is recommended to start antianginal drugs at very low doses, with preferential use of drugs with no or limited effects on BP. A low-dose beta-blocker or low-dose non-DHP-CCB can be tested first under close monitoring of tolerance. Ivabradine (in patients with sinus rhythm), ranolazine, or trimetazidine can also be used.

3.3.1.4 Patients with low heart rate

Increased heart rate correlates linearly with cardiovascular events, and the benefit of heart-rate reduction as a treatment goal in subgroups of CCS patients has been demonstrated using various drugs.²⁰³^,^259–261 However, in patients with baseline bradycardia (e.g. heart rate <60 b.p.m.) heart rate-lowering drugs (beta-blockers, ivabradine, and heart-rate lowering CCBs) should be avoided or used with caution, and—if needed—started at very low doses. Antianginal drugs without heart rate-lowering effects should preferably be given.

Recommendations on anti-ischaemic drugs in patients with chronic coronary syndromes

BP = blood pressure; CCB = calcium channel blocker; CCS = chronic coronary syndromes; DHP-CCB = dihydropyridine calcium channel blocker.

a

Class of recommendation.

b

Level of evidence.

c

No demonstration of benefit on prognosis.

3.3.2 Event prevention

3.3.2.1 Antiplatelet drugs

Platelet activation and aggregation is the driver for symptomatic coronary thrombosis, forming the basis for the use of antiplatelet drugs in patients with CCS in view of a favourable balance between the prevention of ischaemic events and increased risk of bleeding. Dual antiplatelet therapy (DAPT) with aspirin and an oral P2Y₁₂ inhibitor is the mainstay of antithrombotic therapy after MI and/or PCI.

Low-dose aspirin

Aspirin acts via irreversible inhibition of platelet cyclooxygenase-1 and thus thromboxane production, which is normally complete with chronic dosing ≥75 mg/day. The gastrointestinal side effects of aspirin increase at higher doses, and current evidence supports a daily dose of 75–100 mg for the prevention of ischaemic events in CAD patients with or without a history of MI.^268–270 As cyclooxygenase-1 inhibition by aspirin is consistent and predictable in adherent patients, no platelet function testing is required to monitor individual response.²⁷¹ Although other non-selective non-steroidal anti-inflammatory drugs, such as ibuprofen, reversibly inhibit cyclooxygenase-1, their adverse effects on cardiovascular risk indicate that they cannot be recommended as an alternative treatment in patients with aspirin intolerance.²⁷²

Oral P2Y₁₂ inhibitors

P2Y₁₂ inhibitors block the platelet P2Y₁₂ receptor, which plays a key role in platelet activation and the amplification of arterial thrombus formation. Clopidogrel and prasugrel are thienopyridine prodrugs that irreversibly block P2Y₁₂ via active metabolites. Ticagrelor is a reversibly-binding P2Y₁₂ inhibitor that does not require metabolic activation.

The CAPRIE (Clopidogrel vs. Aspirin in Patients at Risk of Ischaemic Events) trial showed an overall slight benefit of clopidogrel compared with aspirin, with a similar safety profile, in preventing cardiovascular events in patients with previous MI, previous stroke, or PAD.²⁷³ Subgroup analysis suggested greater benefit of clopidogrel in patients with PAD. Despite its lesser antiplatelet efficacy, clopidogrel demonstrated equivalent efficacy to ticagrelor in patients with PAD.²⁷⁴ Clopidogrel is limited by variable pharmacodynamic effects related to variable efficiency of conversion to its active metabolite, partly associated with loss-of-function variants in the CYP2C19 gene, leading to a lack of efficacy in some patients.²⁷¹ Drugs that inhibit CYP2C19, such as omeprazole, may reduce the response to clopidogrel.²⁷⁵

Prasugrel has more rapid, more predictable, and, on average, greater antiplatelet effect compared with clopidogrel, and is not susceptible to drug interactions or the effect of CYP2C19 loss-of-function variants. Prasugrel has greater efficacy than clopidogrel in aspirin-treated patients with ACS undergoing PCI, but not in medically-managed patients with ACS.²⁷⁶^,²⁷⁷ Prasugrel has been associated with more non-fatal and fatal bleeding events than clopidogrel in ACS patients undergoing PCI, leading to apparent harm in those with a history of ischaemic stroke, and a lack of apparent benefit in those aged >75 years or with body weight <60 kg.²⁷⁶

Ticagrelor has the most predictable and consistently high level of P2Y₁₂ inhibition during maintenance therapy in adherent patients,²¹⁹ and also has more rapid onset, as well as more rapid and predictable offset of action compared with clopidogrel.^278–280 Ticagrelor as monotherapy appears to have similar efficacy and safety to aspirin monotherapy in patients with previous PCI.²⁸¹ Ticagrelor, with a 180 mg loading dose followed by 90 mg b.i.d., achieved greater reduction of ischaemic events compared with clopidogrel in aspirin-treated ACS patients, regardless of revascularization strategy, at the expense of more non-fatal bleeding.²⁸²^,²⁸³ Ticagrelor at doses of 90 or 60 mg b.i.d. reduced the 3 year combined incidence of MI, stroke, or cardiovascular death compared with placebo in stable aspirin-treated patients with a history of MI 1–3 years previously.²⁸⁴ Both ticagrelor doses increased non-fatal but not fatal bleeding. The equivalent efficacies and similar safeties of the two ticagrelor doses were explained by similar levels of platelet inhibition.²⁸⁵ Ticagrelor may cause dyspnoea, which is often transient and most often mild and tolerable, but occasionally necessitates switching to a thienopyridine.²⁸⁶^,²⁸⁷ Ticagrelor is metabolized via CYP3A, and consequently should not be used with strong CYP3A inhibitors or inducers.

The optimal timing of initiation of P2Y₁₂ inhibition before coronary angiography and possible PCI in patients with CCS is uncertain, but increasing use of a radial artery approach and clinical experience has allowed consideration of clopidogrel pre-treatment in patients who have a high chance of requiring PCI.²⁸⁴ Limited pharmacodynamic studies support the unlicensed use of prasugrel or ticagrelor in stable patients undergoing elective PCI who have a high risk of stent thrombosis, but the safety/efficacy balance of this approach, compared with clopidogrel, has not been established.²⁸⁸

Duration of dual antiplatelet therapy

After PCI for stable angina, 6 months of DAPT achieves the optimum balance of efficacy and safety in most patients.²⁸⁴ Premature discontinuation of a P2Y₁₂ inhibitor is associated with an increased risk of stent thrombosis and is discouraged.²⁸⁴ However, a shorter duration of DAPT may be considered in those at high risk of life-threatening bleeding in view of the very low risk of stent thrombosis after 1–3 months.²⁸⁴ On the basis of phase III trials, 12 months is the recommended default duration of DAPT after ACS, but shorter duration may again be considered in those at high bleeding risk.¹¹^,²⁸⁴ A DAPT study of patients undergoing PCI showed that extended therapy beyond 12 months with clopidogrel or prasugrel reduced ischaemic events and stent thrombosis, but without mortality benefit and at the expense of increased bleeding.²⁸⁹ A greater benefit of extended clopidogrel or prasugrel was seen in patients who were treated for MI.²⁹⁰

The PEGASUS-TIMI 54 (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 demonstrated that long-term therapy with ticagrelor 60 or 90 mg b.i.d., commenced in stable patients ≥1 year after MI, reduced ischaemic events at the expense of more non-fatal bleeding.²⁸⁴ The 60 mg dose appeared better tolerated and is approved in many countries for this indication. Subgroup analysis demonstrated greater absolute reductions in ischaemic events with long-term ticagrelor (60 mg b.i.d.) in higher-risk post-MI patients with diabetes, PAD, or multivessel CAD.^291–293

3.3.2.2 Anticoagulant drugs in sinus rhythm

Anticoagulant drugs inhibit the action and/or formation of thrombin, which plays a pivotal role in both coagulation and platelet activation. Consequently, anticoagulants have been shown to reduce the risk of arterial thrombotic events. The superior efficacy and safety of DAPT, compared with aspirin and anticoagulation, in preventing stent thrombosis led to the latter strategy being abandoned in favour of DAPT following PCI.²⁸⁴ Combination of antiplatelet therapy and standard anticoagulant doses of warfarin or apixaban for secondary prevention after ACS was associated with an unfavourable balance of efficacy and bleeding.²⁹⁴^,²⁹⁵ However, recently reported studies have renewed interest in combining lower anticoagulant doses with antiplatelet therapy.

Low-dose rivaroxaban

Rivaroxaban is a factor Xa inhibitor that has been studied at a low dose of 2.5 mg b.i.d. in several populations of patients in sinus rhythm, this dose being one-quarter of the standard dose used for anticoagulation in patients with AF. Rivaroxaban 2.5 mg b.i.d., compared with placebo, reduced the composite of MI, stroke, or cardiovascular death in stabilized patients treated predominantly with aspirin and clopidogrel following ACS, at the expense of increased bleeding but with evidence of a reduction in cardiovascular death.²⁹⁶ Subsequently, in the COMPASS (Cardiovascular Outcomes for People Using Anticoagulation Strategies) trial, the same regimen in combination with aspirin was compared with aspirin alone, as well as rivaroxaban 5 mg b.i.d. alone, in patients with CCS or PAD, and showed reduced ischaemic events at the expense of increased risk of predominantly non-fatal bleeding.²⁹⁷ Of note, the pre-specified significance thresholds for cardiovascular mortality and all-cause mortality were not met. Greater absolute risk reductions were seen in higher-risk patients with diabetes, PAD, or moderate chronic kidney disease (CKD), as well as current smokers. In GEMINI-ACS (A Study to Compare the Safety of Rivaroxaban Versus Acetylsalicylic Acid in Addition to Either Clopidogrel or Ticagrelor Therapy in Participants With Acute Coronary Syndrome), rivaroxaban 2.5 mg b.i.d. was compared with aspirin in patients treated with a P2Y₁₂ inhibitor who were stable following PCI. The results suggested similar safety of rivaroxaban to aspirin in this setting, but larger studies are required to substantiate this finding.²⁹⁸ In addition, the safety of performing PCI without aspirin pre-treatment is unknown.

3.3.2.3 Anticoagulant drugs in atrial fibrillation

Anticoagulant therapy is recommended in patients with AF and CCS for reduction of ischaemic stroke and other ischaemic events. Anticoagulants in AF patients have demonstrated superiority over aspirin monotherapy or clopidogrel-based DAPT for stroke prevention, and are therefore recommended for this indication.²⁹⁹ When oral anticoagulation is initiated in a patient with AF who is eligible for a non-vitamin K antagonist oral anticoagulant (NOAC; apixaban, dabigatran, edoxaban, or rivaroxaban), a NOAC is recommended in preference to a vitamin K antagonist (VKA).²⁹⁹

Combination anticoagulant and antiplatelet therapy following percutaneous coronary intervention for patients with atrial fibrillation or another indication for oral anticoagulation

No studies to date have specifically focused on CCS patients with AF undergoing PCI and clinical decisions must be based on clinical trials that have included a large proportion of patients with ACS. For peri-procedural management, it is recommended that interruption of VKA is avoided, if feasible, whereas it is recommended that NOAC therapy is stopped for 12–48 h before elective PCI, depending on renal function and the particular NOAC regimen.³⁰⁰ Radial artery access is preferred along with intraprocedural unfractionated heparin either at a standard dose (70–100 U/kg) or, in those with uninterrupted VKA, at a lower dose of 30–50 U/kg.³⁰⁰ Pre-treatment with aspirin 75–100 mg daily is recommended, and clopidogrel (300–600 mg loading dose if not on long-term maintenance therapy) is recommended in preference to prasugrel or ticagrelor.³⁰⁰ VKA-treated patients receiving aspirin and clopidogrel post-PCI should have a target international normalized ratio in the range of 2.0–2.5, aiming for high time in therapeutic range (>70%).³⁰⁰ Subsequent to post-PCI trials of different antithrombotic regimens considered in previous Guidelines,⁸⁸^,²⁸⁴ the AUGUSTUS trial (An Open-label, 2 × 2 Factorial, Randomized Controlled, Clinical Trial to Evaluate the Safety of Apixaban vs. Vitamin K Antagonist and Aspirin vs. Aspirin Placebo in Patients With Atrial Fibrillation and Acute Coronary Syndrome or Percutaneous Coronary Intervention) showed, firstly, that apixaban 5 mg b.i.d. (i.e. the licensed dose for thromboprophylaxis in AF) was associated with significantly less major or clinically relevant non-major bleeding than VKA; and, secondly, that aspirin, compared with placebo, was associated with significantly more bleeding, with the safest combination being apixaban and placebo in addition to P2Y₁₂ inhibitor (predominantly clopidogrel).³⁰¹ However, there were numerically, but not statistically significantly, more stent thrombosis events with placebo than with aspirin, and the trial was not powered to assess differences in these events between groups.³⁰¹ Consequently, when concerns about thrombotic risk prevail over concerns about bleeding risk, ≥1 month of triple therapy [oral anticoagulant (OAC), aspirin, and clopidogrel] is recommended to cover the period when the risk of stent thrombosis is presumed to exceed the risk of bleeding.³⁰⁰^,³⁰¹ There is currently limited evidence to support the use of OACs with ticagrelor or prasugrel as dual therapy after PCI as an alternative to triple therapy.³⁰⁰^,³⁰¹

Long-term combination therapy in patients with atrial fibrillation or another indication for anticoagulation

OAC monotherapy is generally recommended 6–12 months after PCI in patients with AF, as there is a lack of specific data supporting long-term treatment with an OAC and a single antiplatelet agent; however, in highly selected cases with high ischaemic risk, dual therapy with an OAC and aspirin or clopidogrel may be considered.³⁰⁰

3.3.2.4 Proton pump inhibitors

Proton pump inhibitors reduce the risk of gastrointestinal bleeding in patients treated with antiplatelet drugs and may be a useful adjunctive treatment for improving safety.²⁷⁵ Long-term proton pump inhibitor use is associated with hypomagnesaemia, but the role of monitoring serum magnesium levels is uncertain. Proton pump inhibitors that inhibit CYP2C19, particularly omeprazole and esomeprazole, may reduce the pharmacodynamic response to clopidogrel. Although this has not been shown to affect the risk of ischaemic events or stent thrombosis, co-administration of omeprazole or esomeprazole with clopidogrel is generally not recommended.

3.3.2.5 Cardiac surgery and antithrombotic therapy

Aspirin should normally be continued in patients with CCS undergoing elective cardiac surgery, and other antithrombotic drugs stopped at intervals according to their duration of action and indication (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 dose and renal function). Reloading of aspirin after CABG surgery may improve graft patency.³⁰² The role of DAPT or dual therapy with aspirin and rivaroxaban after CABG surgery is uncertain as large prospective studies are lacking. However, RCT results have suggested higher graft patency rates with DAPT compared with aspirin monotherapy.²⁸⁴^,³⁰³^,³⁰⁴

3.3.2.6 Non-cardiac surgery and antithrombotic therapy

Non-cardiac surgery is associated with an increased risk of MI. Following PCI, whenever possible, it is recommended to postpone elective surgery until the recommended course of DAPT has been completed. Usually, this will mean delaying surgery until 6 months after PCI, but surgery between 3–6 months may be considered by a multidisciplinary team, including an interventional cardiologist, if clinically indicated. In most types of surgery, aspirin should be continued as the benefit outweighs the bleeding risk, but this may not be appropriate for procedures associated with extremely high bleeding risk (intracranial procedures, transurethral prostatectomy, intraocular procedures, etc.).²⁸⁴ The COMPASS study included CCS patients with a history of peripheral revascularization procedures, and demonstrated benefits of aspirin and rivaroxaban 2.5 mg b.i.d. compared with aspirin alone, including reductions in major adverse limb events and mortality, suggesting the need to risk-stratify patients after non-cardiac vascular surgery for atherosclerotic disease.³⁰⁵^,³⁰⁶

Recommendations for event prevention I

AF = atrial fibrillation; b.i.d. = bis in die (twice a day); CAD = coronary artery disease; CCS = chronic coronary syndromes; CHA₂DS₂-VASc = Cardiac failure, Hypertension, Age ≥75 [Doubled], Diabetes, Stroke [Doubled] – Vascular disease, Age 65–74 and Sex category [Female]; CKD = chronic kidney disease; DAPT = dual antiplatelet therapy; eGFR = estimated glomerular filtration rate; HF = heart failure; MI = myocardial infarction; NOAC = non-vitamin K antagonist oral anticoagulant; OAC = oral anticoagulant; o.d. = omni die (once a day); PAD = peripheral artery disease; PCI = percutaneous coronary intervention; VKA = vitamin K antagonist.

a

Class of recommendation.

b

Level of evidence.

c

Diffuse multivessel CAD with at least one of the following: diabetes mellitus requiring medication, recurrent MI, PAD, or CKD with eGFR 15–59 mL/min/1.73 m².

d

Prior history of intracerebral haemorrhage or ischaemic stroke, history of other intracranial pathology, recent gastrointestinal bleeding or anaemia due to possible gastrointestinal blood loss, other gastrointestinal pathology associated with increased bleeding risk, liver failure, bleeding diathesis or coagulopathy, extreme old age or frailty, or renal failure requiring dialysis or with eGFR <15 mL/min/1.73 m².

e

At least one of the following: multivessel/diffuse CAD, diabetes mellitus requiring medication, recurrent MI, PAD, HF, or CKD with eGFR 15–59 mL/min/1.73 m².

f

See summary of product characteristics for reduced doses or contraindications for each NOAC in patients with CKD, body weight <60 kg, age >75–80 years, and/or drug interactions.

g

Congestive HF, hypertension, age ≥75 years (2 points), diabetes, prior stroke/transient ischaemic attack/embolus (2 points), vascular disease (CAD on imaging or angiography,³¹² prior MI, PAD, or aortic plaque), age 65–74 years, and female sex.

h

Risk of stent thrombosis encompasses (i) the risk of thrombosis occurring and (ii) the risk of death should stent thrombosis occur, both of which relate to anatomical, procedural, and clinical characteristics. Risk factors for CCS patients include stenting of left main stem, proximal LAD, or last remaining patent artery; suboptimal stent deployment; stent length >60 mm; diabetes mellitus; CKD; bifurcation with two stents implanted; treatment of chronic total occlusion; and previous stent thrombosis on adequate antithrombotic therapy.

Table 9

Treatment options for dual antithrombotic therapy in combination with aspirin 75 − 100 mg daily in patients who have a high^a or moderate^b risk of ischaemic events, and do not have a high bleeding risk^c

Drug option	Dose	Indication	Additional cautions	References
Clopidogrel	75 mg o.d.	Post-MI in patients who have tolerated DAPT for 1 year		²⁸⁹^,²⁹⁰
Prasugrel	10 mg o.d or 5 mg o.d.; if body weight <60 kg or age >75 years	Post-PCI for MI in patients who have tolerated DAPT for 1 year	Age >75 years	²⁸⁹^,²⁹⁰^,³¹³
Rivaroxaban	2.5 mg b.i.d.	Post-MI >1 year or multivessel CAD	Creatinine clearance 15 − 29 mL/min	²⁹⁷
Ticagrelor	60 mg b.i.d.	Post-MI in patients who have tolerated DAPT for 1 year		^291–293^,³⁰⁷^,³¹⁴

Drug option	Dose	Indication	Additional cautions	References
Clopidogrel	75 mg o.d.	Post-MI in patients who have tolerated DAPT for 1 year		²⁸⁹^,²⁹⁰
Prasugrel	10 mg o.d or 5 mg o.d.; if body weight <60 kg or age >75 years	Post-PCI for MI in patients who have tolerated DAPT for 1 year	Age >75 years	²⁸⁹^,²⁹⁰^,³¹³
Rivaroxaban	2.5 mg b.i.d.	Post-MI >1 year or multivessel CAD	Creatinine clearance 15 − 29 mL/min	²⁹⁷
Ticagrelor	60 mg b.i.d.	Post-MI in patients who have tolerated DAPT for 1 year		^291–293^,³⁰⁷^,³¹⁴

Treatment options are presented in alphabetical order.

b.i.d. = bis in die (twice a day); CAD = coronary artery disease; CKD = chronic kidney disease; DAPT = dual antiplatelet therapy; eGFR = estimated glomerular filtration rate; HF = heart failure; MI = myocardial infarction; o.d. = omni die (once a day); PAD = peripheral artery disease; PCI = percutaneous coronary intervention.

a

High risk of ischaemic events is defined as diffuse multivessel CAD with at least one of the following: diabetes mellitus requiring medication, recurrent MI, PAD, or CKD with eGFR 15 − 59 mL/min/1.73 m².

b

Moderately increased risk of ischaemic events is defined as at least one of the following: multivessel/diffuse CAD, diabetes mellitus requiring medication, recurrent MI, PAD, HF, or CKD with eGFR 15 − 59 mL/min/1.73 m².

c

High bleeding risk is defined as history of intracerebral haemorrhage or ischaemic stroke, history of other intracranial pathology, recent gastrointestinal bleeding or anaemia due to possible gastrointestinal blood loss, other gastrointestinal pathology associated with increased bleeding risk, liver failure, bleeding diathesis or coagulopathy, extreme old age or frailty, or renal failure requiring dialysis or with eGFR <15 mL/min/1.73 m².

Table 9

Treatment options for dual antithrombotic therapy in combination with aspirin 75 − 100 mg daily in patients who have a high^a or moderate^b risk of ischaemic events, and do not have a high bleeding risk^c

Drug option	Dose	Indication	Additional cautions	References
Clopidogrel	75 mg o.d.	Post-MI in patients who have tolerated DAPT for 1 year		²⁸⁹^,²⁹⁰
Prasugrel	10 mg o.d or 5 mg o.d.; if body weight <60 kg or age >75 years	Post-PCI for MI in patients who have tolerated DAPT for 1 year	Age >75 years	²⁸⁹^,²⁹⁰^,³¹³
Rivaroxaban	2.5 mg b.i.d.	Post-MI >1 year or multivessel CAD	Creatinine clearance 15 − 29 mL/min	²⁹⁷
Ticagrelor	60 mg b.i.d.	Post-MI in patients who have tolerated DAPT for 1 year		^291–293^,³⁰⁷^,³¹⁴

Drug option	Dose	Indication	Additional cautions	References
Clopidogrel	75 mg o.d.	Post-MI in patients who have tolerated DAPT for 1 year		²⁸⁹^,²⁹⁰
Prasugrel	10 mg o.d or 5 mg o.d.; if body weight <60 kg or age >75 years	Post-PCI for MI in patients who have tolerated DAPT for 1 year	Age >75 years	²⁸⁹^,²⁹⁰^,³¹³
Rivaroxaban	2.5 mg b.i.d.	Post-MI >1 year or multivessel CAD	Creatinine clearance 15 − 29 mL/min	²⁹⁷
Ticagrelor	60 mg b.i.d.	Post-MI in patients who have tolerated DAPT for 1 year		^291–293^,³⁰⁷^,³¹⁴

Treatment options are presented in alphabetical order.

b.i.d. = bis in die (twice a day); CAD = coronary artery disease; CKD = chronic kidney disease; DAPT = dual antiplatelet therapy; eGFR = estimated glomerular filtration rate; HF = heart failure; MI = myocardial infarction; o.d. = omni die (once a day); PAD = peripheral artery disease; PCI = percutaneous coronary intervention.

a

High risk of ischaemic events is defined as diffuse multivessel CAD with at least one of the following: diabetes mellitus requiring medication, recurrent MI, PAD, or CKD with eGFR 15 − 59 mL/min/1.73 m².

b

Moderately increased risk of ischaemic events is defined as at least one of the following: multivessel/diffuse CAD, diabetes mellitus requiring medication, recurrent MI, PAD, HF, or CKD with eGFR 15 − 59 mL/min/1.73 m².

c

High bleeding risk is defined as history of intracerebral haemorrhage or ischaemic stroke, history of other intracranial pathology, recent gastrointestinal bleeding or anaemia due to possible gastrointestinal blood loss, other gastrointestinal pathology associated with increased bleeding risk, liver failure, bleeding diathesis or coagulopathy, extreme old age or frailty, or renal failure requiring dialysis or with eGFR <15 mL/min/1.73 m².

3.3.3 Statins and other lipid-lowering drugs

Dyslipidaemia should be managed according to lipid guidelines with pharmacological and lifestyle intervention.³¹⁵ Patients with established CAD are regarded as being at very high risk for cardiovascular events and statin treatment must be considered, irrespective of LDL-C levels. The goal of treatment is to lower LDL-C by at least 50% from baseline and to <1.4 mmol/L (<55 mg/dL) although a lower target LDL-C of <1.0 mmol/L (<40 mg/dL) may be considered in patients who have experience a second vascular event within 2 years, not necessarily of the same type as the first event, whilst taking maximally tolerated statin-based therapy. When this level cannot be achieved, the addition of ezetimibe has been demonstrated to decrease cholesterol and cardiovascular events in post-ACS patients, and in those with diabetes,³¹⁶ with no further effect on mortality.³¹⁷ In addition to exercise, diet, and weight control, which should be recommended to all patients, dietary supplements including phytosterols may lower LDL-C to a lesser extent, but have not been shown to improve clinical outcomes.³¹⁸ These are also used in patients with intolerance to statins who constitute a group at higher risk for cardiovascular events.³¹⁹ Trials published since 2015 have demonstrated that proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors (evolocumab³²⁰ and alirocumab^321–323) are very effective at reducing cholesterol, lowering LDL-C in a stable fashion to ≤1.3 mmol/L (50 mg/dL). In outcomes trials, these agents have demonstrated a reduction of cardiovascular and mainly ischaemic events, with little or no impact on mortality.³²⁴ Very low levels of cholesterol are well tolerated and associated with fewer events,³²⁵ but the high cost of PCSK9 inhibitors, unaffordable for many health systems,³²⁶ and their unknown long-term safety have limited their use to date. Low-density lipoprotein apheresis and new therapies such as mipomersen and lomitapide need further research.

For patients undergoing PCI, high-dose atorvastatin has been shown to reduce the frequency of peri-procedural events in both statin-naïve patients and patients receiving chronic statin therapy.³²⁷

3.3.4 Renin−angiotensin−aldosterone system blockers

ACE inhibitors can reduce mortality, MI, stroke, and HF among patients with LV dysfunction,^328–330 previous vascular disease,^331–333 and high-risk diabetes.³³⁴ It is recommended that ACE inhibitors [or angiotensin receptor blockers (ARBs) in cases of intolerance] be considered for the treatment of patients with CCS with coexisting hypertension, LVEF ≤40%, diabetes, or CKD, unless contraindicated (e.g. severe renal impairment, hyperkalaemia, etc.). However, not all trials have demonstrated that ACE inhibitors reduce all-cause death, cardiovascular death, non-fatal MI, stroke, or HF in patients with atherosclerosis and without impaired LV function.³³¹^,³³²^,³³⁵ A meta-analysis, including 24 trials and 61 961 patients, documented that, in CCS patients without HF, renin−angiotensin system (RAS) inhibitors reduced cardiovascular events and death only when compared with placebo, but not when compared with active controls.³³⁶ Hence, ACE inhibitor therapy in CCS patients without HF or high cardiovascular risk is not generally recommended, unless required to meet BP targets.

Neprilysin is an endogenous enzyme that degrades vasoactive peptides such as bradykinin and natriuretic peptides. Pharmacological inhibition of neprilysin raises the levels of these peptides, enhancing diuresis, natriuresis, myocardial relaxation, and antiremodelling, and reducing renin and aldosterone secretion. The first in class is LCZ696, which combines valsartan and sacubitril (neprilysin inhibitor) in a single pill. In patients with HF (LVEF ≤35%) who remain symptomatic despite optimal treatment with an ACE inhibitor, a beta-blocker, and a mineralocorticoid receptor antagonist (MRA), sacubitril/valsartan is recommended as a replacement for an ACE inhibitor to further reduce the risk of HF hospitalization and death in ambulatory patients.³³⁷

Aldosterone blockade with spironolactone or eplerenone is recommended for use in post-MI patients who are already receiving therapeutic doses of an ACE inhibitor and a beta-blocker, have an LVEF ≤35%, and have either diabetes or HF.³³⁸^,³³⁹ Caution should be exercised when MRAs are used in patients with impaired renal function [estimated GFR (eGFR) <45 mL/min/1.73 m²] and in those with serum potassium levels ≥5.0 mmol/L.³⁴⁰

Recommendations for event prevention II

ACE = angiotensin-converting enzyme; ARB = angiotensin-receptor blocker; CCS = chronic coronary syndrome; HF = heart failure; LV = left ventricular; PCSK9 = proprotein convertase subtilisin-kexin type 9; STEMI = ST-elevation myocardial infarction.

a

Class of recommendation.

b

Level of evidence.

c

The treatment goals are shown in the European Society of Cardiology/European Atherosclerosis Society Guidelines for the management of dyslipidaemias.³¹⁵

3.3.5 Hormone replacement therapy

The results from large randomized trials have shown that hormone replacement therapy provides no prognostic benefit and increases the risk of CVD in women aged >60 years.³⁴⁴

3.4 Revascularization

In patients with CCS, optimal medical therapy is key for reducing symptoms, halting the progression of atherosclerosis, and preventing atherothrombotic events. Myocardial revascularization plays a central role in the management of CCS on top of medical treatment, but always as an adjunct to medical therapy without supplanting it. The two objectives of revascularization are symptom relief in patients with angina and/or improvement of prognosis.

Previous Guidelines support indications for revascularization mainly in patients with CCS who receive Guideline-recommended optimal medical therapy and continue to be symptomatic, and/or in whom revascularization may ameliorate prognosis.⁸⁸ These recommendations suggested that revascularization in patients with angina and significant stenosis was often a second-line therapy after medical therapy had been unsuccessful. However, angina is associated with impaired quality of life, reduced physical endurance, mental depression, and recurrent hospitalizations and office visits, with impaired clinical outcomes.³⁴⁵^,³⁴⁶

Revascularization by PCI or CABG may effectively relieve angina, reduce the use of antianginal drugs, and improve exercise capacity and quality of life compared with a strategy of medical therapy alone. In the 5 year follow-up of the FAME 2 (Fractional Flow Reserve versus Angiography for Multivessel Evaluation 2) trial, revascularization improved quality of life, and reduced the use of antianginal drugs and associated side effects.³⁴⁷ The ORBITA (Objective Randomised Blinded Investigation with optimal medical Therapy or Angioplasty in stable angina) study, entailing a sham procedure in the control group, found no significant improvement in exercise capacity with PCI.²⁶² The study highlights a significant placebo component to the clinical effects, and alerts us to the pitfalls of interpreting endpoints subject to bias in the absence of sham control and blinding. However, the ORBITA results cannot inform Guidelines due to the limited trial size, short-term observation time until crossover, and insufficient power to assess clinical endpoints.

Revascularization by either PCI or CABG also aims to effectively eliminate myocardial ischaemia and its adverse clinical manifestations among patients with significant coronary stenosis, and to reduce the risk of major acute cardiovascular events including MI and cardiovascular death. Numerous meta-analyses comparing a strategy of PCI with initial medical therapy among patients with CCS have found no³⁴⁸^,³⁴⁹ or a modest¹⁰⁴^,³⁵⁰^,³⁵¹ benefit, in terms of survival or MI for an invasive strategy. In this regard, previous Guidelines identified specific subgroups of patients (based on the anatomy of the coronary tree, LV function, risk factors, etc.) in whom revascularization may improve prognosis, indicating that in other groups it may not.⁸⁸

A meta-analysis by Windecker et al. reported an incremental reduction of death and MI by revascularization vs. medical therapy only in CCS patients when revascularization was performed with CABG or new-generation drug-eluting stents (DES), as opposed to balloon angioplasty, bare-metal stents, or early DES.³⁵¹ Data reported in 2018 indicate a potentially broader prognostic impact of revascularization strategies. The 5 year follow-up of the FAME 2 trial confirmed a sustained clinical benefit in patients treated with PCI specifically targeting the ischaemia-producing stenoses (i.e. FFR <0.80) plus optimal medical therapy vs. optimal medical therapy alone in terms of a significantly lower rate of urgent revascularization (hazard ratio 0.27, 95% CI 0.18–0.41), and a lower rate of spontaneous MI (hazard ratio 0.62, 95% CI 0.39–0.99).³⁴⁷ In contrast to some of the earlier meta-analyses, this signal was confirmed in a patient-level meta-analysis including 2400 subjects, all of whom underwent invasive physiological guidance, showing a significant reduction in cardiac death and MI after a median follow-up of 33 months with FFR-guided PCI vs. medical therapy (hazard ratio 0.74, 95% CI 0.56–0.989; P=0.041).³⁵² Together, these new data support a less restrictive indication for revascularization in CCS, in addition to specific anatomy [e.g. left main (LM)] or extended ischaemia (>10%), when PCI is restricted to angiographic stenoses on large vessels causing a significant intracoronary pressure gradient. Figure 9 summarizes a practical approach to the indications of revascularization in CCS according to the presence or absence of symptoms, and documentation of non-invasive ischaemia. However, the individual risk−benefit ratio should always be evaluated and revascularization considered only if its expected benefit outweighs its potential risk. Also, the aspect of shared decision-making is key, with full information given to the patient about the anticipated advantages and disadvantages of the two strategies, including the DAPT-related bleeding risks in cases of revascularization by PCI. For the discussion of the best choice between revascularization modalities–PCI or CABG–for individual patients, we refer readers to the 2018 ESC myocardial revascularization Guidelines.⁸⁸

Figure 9

$Decision tree for patients undergoing invasive coronary angiography. Decisions for revascularization by percutaneous coronary intervention or coronary artery bypass grafting are based on clinical presentation (symptoms present or absent), and prior documentation of ischaemia (present or absent). In the absence of prior documentation of ischaemia, indications for revascularization depend on invasive evaluation of stenosis severity or prognostic indications. Patients with no symptoms and ischaemia include candidates for transcatheter aortic valve implantation, valve, and other surgery. CAD = coronary artery disease; FFR = fractional flow reserve; iwFR = instantaneous wave-free ratio; LV = left ventricle; LVEF = left ventricular ejection fraction; MVD = multivessel disease.$

Decision tree for patients undergoing invasive coronary angiography. Decisions for revascularization by percutaneous coronary intervention or coronary artery bypass grafting are based on clinical presentation (symptoms present or absent), and prior documentation of ischaemia (present or absent). In the absence of prior documentation of ischaemia, indications for revascularization depend on invasive evaluation of stenosis severity or prognostic indications. Patients with no symptoms and ischaemia include candidates for transcatheter aortic valve implantation, valve, and other surgery. CAD = coronary artery disease; FFR = fractional flow reserve; iwFR = instantaneous wave-free ratio; LV = left ventricle; LVEF = left ventricular ejection fraction; MVD = multivessel disease.

4 Patients with new onset of heart failure or reduced left ventricular function

CAD is the most common cause of HF in Europe, and most of the trial evidence supporting management recommendations is based on research conducted in patients with ischaemic cardiomyopathy. The pathophysiology results in systolic dysfunction due to myocardial injury and ischaemia, and most patients with symptomatic HF have reduced ejection fraction (<40%), although patients with CCS may also have symptomatic HF and a preserved ejection fraction (≥50%). Patients with symptomatic HF should be managed clinically according to the 2016 ESC heart failure Guidelines.³⁴⁰

History should include the assessment of symptoms suggestive of HF, especially exercise intolerance and dyspnoea on exertion. All major past events related to CAD including MI and revascularization procedures are recorded, as well as all major cardiovascular comorbidity requiring treatment such as AF, hypertension, or valvular dysfunction, and non-cardiovascular comorbidity such as CKD, diabetes, anaemia, or cancer. Current medical therapy, adherence, and tolerance should be reviewed.

Physical examination should assess the nutritional status of patients, and estimate biological age and cognitive ability. Recorded physical signs include heart rate, heart rhythm, supine BP, murmurs suggestive of aortic stenosis or mitral insufficiency, signs of pulmonary congestion with basal rales or pleural effusion, signs of systemic congestion with dependant oedema, hepatomegaly, and elevated jugular venous pressure.

A routine ECG provides information on heart rate and rhythm, extrasystole, signs of ischaemia, pathological Q waves, hypertrophy, conduction abnormalities, and bundle branch block.

Imaging should include an echocardiographic examination with Doppler to evaluate evidence of ischaemic cardiomyopathy with HF with reduced ejection fraction, HF with mid-range ejection fraction, or HF with preserved ejection fraction, focal/diffuse LV or right ventricular systolic dysfunction, evidence of diastolic dysfunction, hypertrophy, chamber volumes, valvular function, and evidence of pulmonary hypertension. Chest X-ray can detect signs of pulmonary congestion, interstitial oedema, infiltration, or pleural effusion. If not known, coronary angiography (or coronary CTA) should be performed to establish the presence and extent of CAD, and evaluate the potential for revascularization.⁵²^,⁵³

Laboratory investigations should measure natriuretic peptide levels to rule-out the diagnosis of suspected HF. When present, the severity of HF can be assessed.²⁵^,⁴⁹ Renal function along with serum electrolytes should be measured routinely to detect the development of renal insufficiency, hyponatraemia, or hyperkalaemia, especially at the initiation and during up-titration of pharmacological therapy.

The management of patients with symptomatic HF requires adequate diuretic therapy, preferably with a loop diuretic, to relieve signs and symptoms of pulmonary and systemic congestion. Inhibitors of both the RAS system (ACE inhibitors, ARBs, angiotensin receptor−neprilysin inhibitor) and the adrenergic nervous system (beta-blockers) are indicated in all symptomatic patients with HF.³⁴⁰ In patients with persistent symptoms, an MRA is also indicated. Up-titration of these drugs should be gradual to avoid symptomatic systolic hypotension, renal insufficiency, or hyperkalaemia.

Patients who remain symptomatic, with LV systolic dysfunction and evidence of ventricular dysrhythmia or bundle branch block, may be eligible for a device [cardiac resynchronization therapy (CRT)/implantable cardioverter-defibrillator]. Such devices may provide symptomatic relief, reduce morbidity, and improve survival.^353–356 Patients with HF may decompensate rapidly following the onset of atrial or ventricular dysrhythmia, and should be treated according to current Guidelines. Patients with HF, and haemodynamically significant aortic stenosis or mitral insufficiency, may require percutaneous or surgical intervention.

Myocardial revascularization should be considered in eligible patients with HF based on their symptoms, coronary anatomy, and risk profile. Successful revascularization in patients with HF due to ischaemic cardiomyopathy may improve LV dysfunction and prognosis by reducing ischaemia to viable, hibernating myocardium. If available, cooperation with a multidisciplinary HF team is strongly advised.³⁴⁸^,³⁵⁷^,³⁵⁸

General recommendations for the management of patients with chronic coronary syndromes and symptomatic heart failure due to ischaemic cardiomyopathy and left ventricular systolic dysfunction

ACE inhibitor = angiotensin-converting enzyme; ARB = angiotensin receptor blocker; b.p.m. = beats per minute; CCS = chronic coronary syndromes; CRT = cardiac resynchronization therapy; HF = heart failure; LBBB = left bundle branch block; LV = left ventricular; LVEF = left ventricular ejection fraction; MI = myocardial infarction; MRA = mineralocorticoid receptor antagonist.

a

Class of recommendation.

b

Level of evidence.

5 Patients with a long-standing diagnosis of chronic coronary syndromes

In patients with a long-standing diagnosis of CCS, lifelong treatment and surveillance are required (Figure 10). The clinical course of patients with CCS may be benign over the course of time. However, patients with CCS may develop a variety of cardiovascular complications or undergo therapeutic measures, some directly related to the underlying CAD, and some having therapeutic or prognostic interactions with the underlying disease. Risk for complications may occur in an otherwise asymptomatic patient, and thus the assessment of risk status applies to symptomatic and asymptomatic patients.

Figure 10

Proposed algorithm according to patient types commonly observed at chronic coronary syndrome outpatient clinics. The frequency of follow-up may be subject to variation based on clinical judgement. ACS = acute coronary syndromes; CCS = chronic coronary syndromes; DAPT = dual antiplatelet therapy; ECG = electrocardiogram; LV = left ventricular; MI = myocardial infarction; PCI = percutaneous coronary intervention. ^aCardiologist, internist, general practitioner, or cardiovascular nurse.

Periodic assessment of the patient's individual risk may be considered (Figure 10). Scores that apply clinical parameters have been shown to predict outcomes among patients with CCS. Moreover, if the clinical parameters are complemented by biomarkers, such a risk score may be even more accurate. In 2017, a biomarker-based risk model to predict cardiovascular mortality in patients with CCS was developed and externally validated.³⁹⁸

5.1 Patients with stabilized symptoms <1 year after an acute coronary syndrome or patients with recent revascularization

After revascularization and/or after stabilized ACS (<1 year), patients should be monitored more vigilantly, because they are at greater risk for complications and because they are subject to changes in pharmacological treatment.⁴⁵ Thus, we recommend at least two visits in the first year of follow-up. In a patient who had LV systolic dysfunction before the revascularization procedure or after the ACS, a reassessment of LV function must be considered 8–12 weeks after the intervention. Cardiac function may have improved, owing to mechanisms such as recovery from myocardial stunning or hibernation, which may be reversed by revascularization.⁵²^,⁵³ Conversely, cardiac function may have deteriorated given other concomitant CVD (e.g. valvular disease, infection or inflammation, arrhythmia, etc.). In such cases, these other damaging factors need to be identified and treated. Likewise, non-invasive assessment of myocardial ischaemia may be considered after revascularization to rule-out residual ischaemia or to document the residual ischaemia as reference for subsequent assessments over time.

5.2 Patients >1 year after initial diagnosis or revascularization

To assess a patient's risk, an annual evaluation by a cardiovascular practitioner (cardiologist, general physician, or nurse) is warranted, even if the patient is asymptomatic. It is recommended that the annual evaluation should assess the patient's overall clinical status and medication compliance, as well as the risk profile (as reflected by risk scores). Laboratory tests—which include a lipid profile, renal function, a complete blood count, and possibly biomarkers—should be performed every 2 years.⁴⁵ A patient with a worsening risk score over time may warrant more intense therapy or diagnostic measures, although risk score-guided therapy has not yet been proved to ameliorate outcomes.

A 12 lead ECG should be a part of every such visit to delineate heart rate and heart rhythm, to detect changes suggestive of silent ischaemia/infarction, and to discern abnormalities in the specific electrocardiographic segments (e.g. PR, QRS, and QT intervals). It may be beneficial to assess LV function (diastolic and systolic), valvular status, and cardiac dimensions in apparently asymptomatic patients every 3–5 years.⁵²^,⁵³ In cases of unexplained reduction in systolic LV function, especially if regional, imaging of coronary artery anatomy is recommended. Likewise, it may be beneficial to assess non-invasively for silent ischaemia in an apparently asymptomatic patient every 3–5 years, preferably applying stress imaging. Coronary CTA should not be used for follow-up of patients with established CAD given its strength on morphological insight, but lack of functional information related to ischaemia. However, coronary CTA may be used for unique cases, such as delineation of patency of coronary artery bypass grafts.

The lipid profile and glycaemia status should be reassessed periodically to determine efficacy of treatment and, in patients without diabetes, to detect new development of diabetes. There is no evidence to support recommendations for the frequency of reassessment of these risk factors, but consensus suggests annual evaluation.

Elevated inflammatory markers, particularly of high-sensitivity C-reactive protein, have also been associated with an increased event risk in patients with and without CAD in multiple studies,²⁵ although the robustness of the association has been questioned because of reporting and publication bias.³⁹⁹ In addition, von Willebrand factor, interleukin-6, and N-terminal pro-B-type natriuretic peptide (NT-proBNP) have identified as been predictors of outcome.²⁵ Other readily available biomarkers shown to predict prognosis in patients with CCS include heart rate, haemoglobin, and white cell count.⁴⁰⁰ Scores based on aggregated biomarkers may have greater success than individual biomarkers. A multiple biomarker score combining high-sensitivity C-reactive protein, heat shock protein 70, and fibrin degradation products significantly improved C-statistics and the net reclassification index compared with a basic model using clinical data.⁴⁰¹ Similar results were reported for a combination of high-sensitivity cardiac troponin T, NT-proBNP, and LDL-C.³⁹⁸ In several studies, genetic risk scores have been shown to improve risk prediction above traditional risk factors in general population samples⁴⁰²^,⁴⁰³ and to predict recurrent events in populations with known CCS.^404–407 Although there is additional prognostic value in using several individual and aggregated biomarkers, there is currently no evidence that routine use leads to improved care. Nevertheless, these measurements may have a role in selected patients (e.g. when testing for haemostatic abnormalities in those with previous MI without conventional risk factors or a strong family history of CAD).

Patients with unequivocal symptoms suggestive of ACS should be expeditiously referred for evaluation, applying current Guidelines for diagnosis and management. Among patients with more equivocal symptoms, stress imaging is recommended⁴⁰⁸ and, if not available and the ECG is amenable to identification of ischaemia, exercise stress electrocardiography can be used as an alternative. In patients with severe angina and a high-risk clinical profile, direct referral for ICA is recommended, provided that ad hoc physiological assessment of haemodynamic stenosis significance is readily available in the catheterization laboratory [e.g. instantaneous wave-free ratio (iwFR) or FFR]. Likewise, ICA is recommended for patients with evidence of significant ischaemia obtained by non-invasive testing.

Recommendations for patients with a long-standing diagnosis of chronic coronary syndromes

CAD = coronary artery disease; CTA = computed tomography angiography; ECG = electrocardiogram; FFR = fractional flow reserve; iwFR = instantaneous wave-free ratio; LV = left ventricular.

a

Class of recommendation.

b

Level of evidence.

6 Angina without obstructive disease in the epicardial coronary arteries

In clinical practice, a marked discrepancy between findings regarding coronary anatomy, the presence of symptoms, and the results of non-invasive tests frequently occurs.¹³ These patients deserve attention, as angina and non-obstructive disease are associated with an increased risk of adverse clinical events.¹⁴ Low diagnostic yield of ICA can be explained by the presence of: (i) stenoses with mild or moderate angiographic severity, or diffuse coronary narrowing, with underestimated functional significance identified by ICA; (ii) disorders affecting the microcirculatory domain that escape the resolution of angiographic techniques; and (iii) dynamic stenoses of epicardial vessels caused by coronary spasm or intramyocardial bridges that are not evident during CTA or ICA. Intracoronary pressure measurements are useful in circumventing the first of these scenarios. For diagnostic workup, patients with angina and/or myocardial ischaemia showing coronary stenoses with non-ischaemic FFR or iwFR values may also be labelled as having non-obstructive epicardial disease.

The presence of clear-cut anginal symptoms and abnormal non-invasive tests in patients with non-obstructed epicardial vessels should lead to the suspicion of a non-obstructive cause of ischaemia. Quite often, and mainly as a result of persistence of symptoms, patients with angina and no obstructive disease undergo multiple diagnostic tests, including repeated coronary CTA or ICA, that contribute to increased healthcare costs.⁴⁰⁹ Because diagnostic pathways to investigate microcirculatory or vasomotor coronary disorders are often not implemented, a final diagnosis supported by objective evidence is seldom reached. Owing to this, patient dismay and depression are not rare in this clinical population.⁴¹⁰^,⁴¹¹ Of note, the use of a structured, systematic approach to explore microcirculatory and vasomotor disorders in patients with non-obstructive CAD, as delineated below, has been shown to increase diagnostic yield.⁴¹²^,⁴¹³ Furthermore, an RCT, which reported in 2018, found that in patients with non-obstructive coronary disease, tailored treatment guided by the results of intracoronary testing [coronary flow reserve (CFR), microcirculatory resistance, and acetylcholine testing] resulted in a significant reduction of anginal symptoms, compared with conventional, non-guided medical treatment.⁴¹⁴

6.1 Microvascular angina

Patients with microvascular angina typically have exercise-related angina, evidence of ischaemia in non-invasive tests, and either no stenoses or mild-to-moderate stenoses (40–60%), revealed by ICA or CTA, that are deemed functionally non-relevant.⁴¹⁵ Given the similarity of angina symptoms, a microvascular origin of angina is typically suspected, after excluding obstructive epicardial coronary stenoses, during diagnostic workup of patients with suspected myocardial ischaemia. Regional LV wall motion abnormalities rarely develop during exercise or stress in patients with microvascular angina.⁴¹²^,⁴¹⁶ Some patients may also have a mixed pattern of angina, with occasional episodes at rest, particularly associated with exposure to cold.

Secondary microvascular angina, in the absence of epicardial obstruction, may result from cardiac or systemic conditions, including those that cause LV hypertrophy (such as hypertrophic cardiomyopathy, aortic stenosis, and hypertensive heart disease) or inflammation (such as myocarditis or vasculitis).⁴¹⁷

6.1.1 Risk stratification

The presence of microcirculatory dysfunction in patients with CCS entails a worse prognosis than originally thought, probably because most recent evidence has been based on follow-up of patients in whom abnormalities in the microcirculation have been objectively documented with invasive or non-invasive techniques.^418–423

Microcirculatory dysfunction precedes the development of epicardial lesions, particularly in women,⁴¹⁹ and is associated with impaired outcomes. Among patients with diabetes undergoing diagnostic workup, those without obstructive epicardial disease but with an abnormal CFR have similarly poor long-term prognosis as those with obstructive epicardial disease.⁴²¹ In patients with non-significant coronary stenoses by FFR, the presence of abnormal CFR is associated with an excess of events in the long-term,⁴¹⁸^,⁴²²^,⁴²³ particularly when the index of microcirculatory resistance (IMR) is also abnormal.⁴²²

6.1.2 Diagnosis

The possibility of a microcirculatory origin of angina should be considered in patients with clear-cut angina, abnormal non-invasive functional tests, and coronary vessels that are either normal or have mild stenosis deemed functionally non-significant on ICA or CTA. One of the challenges in performing a comprehensive assessment of microvascular function is testing the two main mechanisms of dysfunction separately: impaired microcirculatory conductance and arteriolar dysregulation.^424–426 Yet, outlining which of these two pathways is affected is critically relevant in setting medical treatment to relieve patient symptoms.⁴¹⁴

Impaired microcirculatory conductance can be diagnosed by measuring CFR or minimal microcirculatory resistance (the inverse of conductance). CFR can be measured non-invasively with transthoracic Doppler echocardiography [by imaging left anterior descending (LAD) flow],⁴²⁷ magnetic resonance imaging (myocardial perfusion index),^428–430 or PET.⁴³¹ Microcirculatory resistance can be measured in the catheterization laboratory by combining intracoronary pressure with thermodilution-based data (to calculate the IMR) or Doppler flow velocity (to calculate hyperaemic microvascular resistance or HMR).⁴³²^,⁴³³ Both intracoronary thermodilution and Doppler allow the calculation of CFR. For decision-making purposes, values of IMR ≥25 units or CFR <2.0 are indicative of abnormal microcirculatory function.⁴¹⁴ Both CFR and IMR are typically measured while using intravenous vasodilators, such as adenosine or regadenoson.

In contrast, the diagnosis of arteriolar dysregulation requires the assessment of endothelial function in the coronary microcirculation by selective intracoronary acetylcholine infusion (see section 6.5). In the presence of dysfunctional vascular endothelium or abnormal function of smooth muscle cells, acetylcholine (an endothelium-dependent vasodilator that also acts directly on smooth muscle cells) triggers paradoxical arteriolar vasoconstriction.⁴³⁴ Thus, in patients with microvascular angina and arteriolar dysregulation, acetylcholine challenge is likely to trigger microvascular spasm. This arteriolar response to acetylcholine causes anginal symptoms with or without concomitant ischaemic ECG changes, and a decrease in coronary blood flow velocity if concomitant Doppler measurements are performed. Peripheral pulse tonometry during reactive hyperaemia may also reveal abnormal systemic endothelial function in patients with angina and non-obstructive CAD.⁴³⁵

6.1.3 Treatment

Treatment of microvascular angina should address the dominant mechanism of microcirculatory dysfunction. In patients with abnormal CFR <2.0 or IMR ≥25 units, and a negative acetylcholine provocation test, beta-blockers, ACE inhibitors, and statins, along with lifestyle changes and weight loss, are indicated.⁴³⁶^,⁴³⁷ Patients developing ECG changes and angina in response to acetylcholine testing but without severe epicardial vasoconstriction (all suggestive of microvascular spasm) may be treated like vasospastic angina patients. The effectiveness of a tailored treatment strategy was investigated in the CorMiCa trial, which randomized 151 patients to a stratified medical treatment (based on the results of CFR, IMR, and acetylcholine testing) vs. a standard-care group (including a sham interventional diagnostic procedure). At 1 year, there was a significant difference in angina scores favouring patients assigned to the stratified medical treatment arm.⁴¹⁴

Investigations in patients with suspected coronary microvascular angina

CFR = coronary flow reserve; CMR = cardiac magnetic resonance; ECG = electrocardiogram; FFR = fractional flow reserve; iwFR = instantaneous wave-free ratio; LAD = left anterior descending; PET = positron emission tomography.

a

Class of recommendation.

b

Level of evidence.

6.2 Vasospastic angina

Vasospastic angina should be suspected in patients with anginal symptoms occurring predominantly at rest, with maintained effort tolerance. The likelihood of vasospastic angina increases when attacks follow a circadian pattern, with more episodes at night and in the early morning hours. Patients are frequently younger and have fewer cardiovascular risk factors than patients with effort angina, except for cigarette smoking.⁴⁴² Coronary vasospasm should be also suspected in patients with patent coronary stents and persistent angina.⁴⁴³^,⁴⁴⁴

6.2.1 Diagnosis

The diagnosis of vasospastic angina is based on detecting transient ischaemic ST-segment changes during an angina attack (usually at rest). Patients with Prinzmetal angina represent a special subset in whom resting angina is accompanied by transient ST-segment elevation.⁴⁴²^,⁴⁴⁵ These ECG changes correlate with proximal vessel occlusion and diffuse, distal subocclusive narrowing of epicardial vessels. As most attacks of vasospastic angina are self-limiting, documentation of these ECG changes is challenging. Ambulatory ECG monitoring, preferably with 12 lead recording, may be helpful in patients in whom vasospastic angina is suspected. The occurrence of ST-segment shifts at normal heart rate supports the likelihood of myocardial ischaemia caused by spasm. Extended Holter monitoring (for >1 week) may be required for successful documentation of transient ST-segment changes in these patients. Ambulatory ECG monitoring may also be used to assess the results of medical therapy in controlling the frequency of vasospastic events.

In patients with suspected vasospastic angina and documented ECG changes, CTA or ICA is indicated to rule-out the presence of fixed coronary stenosis. Angiographic documentation of coronary spasm requires the use of a provocation test in the catheterization laboratory. Given the low sensitivity of hyperventilation and the cold pressor test, intracoronary administration of acetylcholine or ergonovine during ICA are the preferred provocation tests.⁴⁴² Both pharmacological agents are safe, provided that they are selectively infused into the left or right coronary artery, and that triggered spasm is readily controlled with intracoronary nitrates. A low percentage of patients may develop ventricular tachycardia/ventricular fibrillation or bradyarrhythmias during the provocation test (3.2 and 2.7%, respectively), similar to that reported during spontaneous spasm attacks (7%).⁴⁴⁶ Intravenous administration of ergonovine for non-invasive tests should be discouraged due to the risk of triggering prolonged spasm in multiple vessels, which may be very difficult to manage and can be fatal.⁴⁴⁷

A provocation test for coronary spasm is considered positive when it triggers: (i) anginal symptoms, (ii) ischaemic ECG changes, and (iii) severe vasoconstriction of the epicardial vessel. Should the test fail in triggering all three components, it should be considered equivocal.⁴⁴² The development of angina in response to acetylcholine injections in the absence of angiographically evident spasm, with or without accompanying ST-segment changes, may indicate microvascular spasm and is seen frequently in patients presenting with microvascular angina.⁴⁴⁵

6.2.2 Treatment

In patients with epicardial or microcirculatory vasomotor disorders, CCBs and long-acting nitrates constitute the treatment of choice, in addition to the control of cardiovascular risk factors and lifestyle changes.⁴³⁷^,⁴⁴⁵ Nifedipine has been shown to be effective in reducing coronary spasm associated with stent implantation.⁴⁴⁴

Recommendations for investigations in patients with suspected vasospastic angina

CTA = computed tomography angiography; ECG = electrocardiogram.

a

Class of recommendation.

b

Level of evidence.

7 Screening for coronary artery disease in asymptomatic subjects

In an effort to lower the high burden of coronary deaths in asymptomatic adults, numerous measurements of risk factors and risk markers, as well as stress tests, are often performed as screening investigations. The 2016 European Guidelines on CVD prevention in clinical practice have focused on these issues in detail.¹⁵ These recommendations have been adapted for the purpose of these Guidelines.

In general, the use of risk-estimation systems such as SCORE is recommended (see also Figure 6). Subjects with a family history of premature CAD should be screened for familial hypercholesterolaemia. Coronary calcium score, ankle−brachial index, and carotid ultrasound for plaque detection may provide useful information about the atherosclerotic risk in selected patients, but routine use of biomarkers or other imaging tests for CAD are not recommended. The new biomarkers have incremental predictive value over classical ones,⁴⁴⁸ but the net reclassification improvement is still only modest (7–18%) compared, for example, with the coronary calcium score, which has a net reclassification improvement of 66%.⁴⁴⁹

Only subjects at high event risk should be considered for further non-invasive or invasive testing. There are no data on how to manage asymptomatic subjects who receive testing and have a positive test result beyond the recommendations listed in these Guidelines. However, the principles of risk stratification, as described above for symptomatic patients, also apply to these individuals.⁴⁵⁰ It is important to remember that data demonstrating improved prognosis following appropriate management based on new biomarkers are still lacking.

It is important to note that patients with cancer and undergoing cancer treatment, or chronic inflammatory diseases such as inflammatory bowel diseases, rheumatoid arthritis, and systemic lupus erythematosus, may deserve more intensive risk screening, counselling, and management.^451–454

Persons whose occupations involve public safety (e.g. airline pilots, or lorry or bus drivers), or who are professional or high-profile athletes, commonly undergo periodic testing for the assessment of exercise capacity and evaluation of possible heart disease, including CAD. Although there are insufficient data to justify this approach, these evaluations may be done for medicolegal reasons. The threshold for performing an imaging test in such persons may be lower than in the average patient. Otherwise, the same considerations as discussed above for other asymptomatic persons apply to these individuals.

Recommendations for screening for coronary artery disease in asymptomatic subjects

ABI = ankle−brachial index; CAD = coronary artery disease; CKD = chronic kidney disease; CTA = computed tomography angiography; CVD = cardiovascular disease; ECG = electrocardiogram; IMT = intima−media thickness; SCORE = Systematic COronary Risk Evaluation.

a

Class of recommendation.

b

Level of evidence.

c

Reclassifies patients better into low- or high-risk groups.

8 Chronic coronary syndromes in specific circumstances

8.1 Cardiovascular comorbidities

8.1.1 Hypertension

Hypertension is the most prevalent cardiovascular risk factor and is closely associated with CCS. Thresholds for the definition of hypertension are provided in Table 10. BP lowering can significantly reduce major cardiovascular risk, including CHD. Meta-analysis suggests that for every 10 mmHg reduction in systolic BP, CAD can be reduced by 17%.⁴⁶³ More intensive BP targets (office BP <130 mmHg) have been associated with favourable outcomes and are endorsed by the 2018 ESC/ESH Guidelines for the management of arterial hypertension.⁴⁶⁴ It is recommended treat hypertensive patients with CCS are treated to office targets of 130/80 mmHg, because an increased systolic BP of ≥140 mmHg and diastolic BP of ≥80 mmHg, but also a systolic BP of <120 mmHg and diastolic BP of <70 mmHg, are associated with increased risk⁴⁶⁵^,⁴⁶⁶ (Table 10). Whether the J-curve phenomenon exists in patients with revascularized CAD remains uncertain. In hypertensive patients with CHD, beta-blockers and RAS blockers may improve post-MI outcomes.⁴⁶⁷ In patients with symptomatic angina, beta-blockers and calcium antagonists are the preferred components of the drug-treatment strategy. The combination of ACE inhibitors and ARBs is not recommended for the treatment of hypertension because of increased renal adverse events without beneficially influencing outcome.⁴⁶⁸^,⁴⁶⁹

Table 10

Blood pressure thresholds for the definition of hypertension with different types of blood pressure measurement^470–472

Category	Systolic BP (mmHg)		Diastolic BP (mmHg)
Office BP	≥140	and/or	≥90
≥80 years of age	≥160	and/or	≥90
Ambulatory BP
Daytime (or awake)	≥135	and/or	≥85
Night-time (or asleep)	≥120	and/or	≥70
24 h	≥130	and/or	≥80
Home BP	≥135	and/or	≥85

Category	Systolic BP (mmHg)		Diastolic BP (mmHg)
Office BP	≥140	and/or	≥90
≥80 years of age	≥160	and/or	≥90
Ambulatory BP
Daytime (or awake)	≥135	and/or	≥85
Night-time (or asleep)	≥120	and/or	≥70
24 h	≥130	and/or	≥80
Home BP	≥135	and/or	≥85

BP = blood pressure.

Table 10

Blood pressure thresholds for the definition of hypertension with different types of blood pressure measurement^470–472

Category	Systolic BP (mmHg)		Diastolic BP (mmHg)
Office BP	≥140	and/or	≥90
≥80 years of age	≥160	and/or	≥90
Ambulatory BP
Daytime (or awake)	≥135	and/or	≥85
Night-time (or asleep)	≥120	and/or	≥70
24 h	≥130	and/or	≥80
Home BP	≥135	and/or	≥85

Category	Systolic BP (mmHg)		Diastolic BP (mmHg)
Office BP	≥140	and/or	≥90
≥80 years of age	≥160	and/or	≥90
Ambulatory BP
Daytime (or awake)	≥135	and/or	≥85
Night-time (or asleep)	≥120	and/or	≥70
24 h	≥130	and/or	≥80
Home BP	≥135	and/or	≥85

BP = blood pressure.

Recommendations for hypertension treatment in chronic coronary syndromes

ACE = angiotensin converting enzyme; ARB = angiotensin receptor blocker; BP = blood pressure; CCB = calcium channel blocker; RAS = renin−angiotensin system.

a

Class of recommendation.

b

Level of evidence.

8.1.2 Valvular heart disease (including planned transcatheter aortic valve implantation)

Coronary angiography for the assessment of CAD is recommended before valve surgery or when percutaneous valvular intervention is planned, to determine if revascularization is required. Coronary CTA may be considered in patients with low risk for CAD, or in patients in whom conventional ICA is technically not feasible or associated with increased risk. The combination of PCI and transcatheter aortic valve implantation appears feasible and safe, but more data are needed before definite recommendations can be provided.⁴⁷³^,⁴⁷⁴ The routine use of stress testing to detect CAD associated with severe symptomatic valvular disease is not recommended because of low diagnostic value and potential risk. Symptom-limited stress testing in patients with valvular heart disease appears safe, and may be useful to unmask symptoms in asymptomatic patients or in patients with equivocal symptoms.⁴⁷⁵

Recommendations for valvular disease in chronic coronary syndromes⁴⁷⁶

CAD = coronary artery disease; CTA = computed tomography angiography; CVD = cardiovascular disease; ICA = invasive coronary angiography; LV = left ventricular; PCI = percutaneous coronary intervention.

a

Class of recommendation.

b

Level of evidence.

8.1.3 After heart transplantation

The follow-up and assessment of long-term heart transplant survivors requires specific know-how. Transplant CAD is largely an immunological phenomenon, and remains a significant cause of morbidity and mortality.⁴⁷⁷ ICA is recommended for the assessment of transplant CAD and should be performed annually for 5 years after transplantation. If there are no significant abnormalities, angiograms can be performed biannually thereafter. Intravascular ultrasound examinations may be useful in assessing cardiac allograft vasculopathy and plaque stability.⁴⁷⁸ Treatment options for CAD in transplant recipients include pharmacotherapy and revascularization. PCI in the transplanted heart has become an established therapy.⁴⁷⁹

8.2 Non-cardiovascular comorbidities

8.2.1 Cancer

Occurrence of CAD in patients with active cancer is increasing⁴⁵¹^,⁴⁵² as a side effect of cancer therapy (i.e. radiotherapy to the thorax/mediastinum, cardiotoxic chemotherapy, or immunotherapies) or a result of extended cancer therapies in elderly individuals. CAD in patients with active cancer is associated with challenges for clinicians as treatment decisions should be the subject of individualized discussions based on life expectancy, additional comorbidities such as thrombocytopenia, increased thrombosis and bleeding propensity, and potential interactions between drugs used in CCS management and antineoplastic drugs. In cancer patients with increased frailty, the least invasive revascularization procedures are recommended. For further information, see the ESC position paper on cancer treatments and cardiovascular toxicity.⁴⁸⁰

Recommendations for active cancer in chronic coronary syndromes

CCS = chronic coronary syndromes.

a

Class of recommendation.

b

Level of evidence.

8.2.2 Diabetes mellitus

Diabetes mellitus confers about a two-fold increased risk for CAD⁴⁸¹ and, consequently, control of risk factors is recommended for the prevention of CVD. Systolic BP in patients with diabetes should be targeted to ≤130 mmHg, if tolerated, but not <120 mmHg, and diastolic BP to <80 mmHg, but not <70 mmHg.⁴⁸² Initial antihypertension treatment should consist of a combination of a RAS blocker with a CCB or thiazide/thiazide-like diuretic. ACE inhibitors reduce albuminuria, and the appearance or progression of diabetic nephropathy, more effectively than other drug classes.⁴⁸² Patients with diabetes and CAD are considered to be at very high risk; consequently, LDL-C should be lowered to <1.8 mmol/L (<70 mg/dL) or reduced by ≥50% if the baseline LCL-C is between 1.8 and 3.5 mmol/L (70 and 135 mg/dL).¹⁵ For the majority of patients with diabetes and CAD, a target glycated HbA1c level of <7% (<53 mmol/L) is recommended.⁴⁸³^,⁴⁸⁴ Large safety studies on new glucose-lowering drugs, namely sodium-glucose co-transporter-2 and glucagon-like peptide-1 receptor agonists, have demonstrated significant reductions in cardiovascular events. Indications for their clinical use are described in the 2019 ESC/European Association for the Study of Diabetes Guidelines on diabetes mellitus, pre-diabetes, and cardiovascular diseases.¹⁶

A 12 lead ECG is recommended as part of the routine assessment for screening for conduction abnormalities, LV hypertrophy, and arrhythmias. The high prevalence of significant CAD and prohibitively high cardiovascular mortality may suggest the usefulness of routine screening for CAD (with functional imaging testing or coronary CTA) in asymptomatic patients with diabetes, but no data have shown an improvement in outcomes so far. Routine use of CTA in asymptomatic patients with diabetes is therefore not recommended.

Recommendations for diabetes mellitus in chronic coronary syndromes

ACE = angiotensin-converting enzyme; AF = atrial fibrillation; BP = blood pressure; CAD = coronary artery disease; CCS = chronic coronary syndromes; CTA = computed tomography angiography; CVD = cardiovascular disease; ECG = electrocardiogram; HbA1c = glycated haemoglobin; LDL-C = low-density lipoprotein cholesterol; MI = myocardial infarction.

a

Class of recommendation.

b

Level of evidence.

c

Treatment algorithm is available in the 2019 European Society of Cardiology/European Association for the Study of Diabetes Guidelines on diabetes mellitus, pre-diabetes, and cardiovascular diseases.¹⁶

8.2.3 Chronic kidney disease

CAD is highly prevalent in patients with CKD and a growing number of patients undergoing PCI have concomitant CKD.⁴⁹³ There is a linear increase in the risk of cardiovascular mortality with decreasing GFR.⁴⁹⁴ Medical treatment for risk-factor control (lipids, BP, and glucose) can improve outcomes. Special attention during the workup for CKD patients with suspected obstructive CAD should be paid to the fact that angina is less common and silent ischaemia more common.⁴⁹⁵ Additionally, non-invasive stress testing shows reduced accuracy in patients with CKD.⁴⁹⁶ The use of an iodinated contrast agent should be minimized to prevent further deterioration of renal function. Decisions regarding diagnostic and treatment modalities should be made accordingly. Interestingly, patients with CKD are less likely to receive invasive management for treatment of CAD compared with those without, although benefits of invasive management have been reported.⁴⁹⁷ Revascularization options in patients with CKD include CABG and PCI. Meta-analyses suggest that CABG is associated with higher short-term risk of death, stroke, and repeat revascularization, whereas PCI with a new-generation DES is associated with a higher long-term risk of repeat revascularization.⁴⁹⁸^,⁴⁹⁹ Data on patients on haemodialysis are very limited, making generalizable treatment recommendations difficult.

Recommendations for chronic kidney disease in chronic coronary syndromes

CKD = chronic coronary disease; CCS = chronic coronary syndromes.

a

Class of recommendation.

b

Level of evidence.

8.2.4 Elderly

Ageing predisposes patients to a high incidence and prevalence of CAD, in both men and women. Elderly patients (age >75 years) have the greatest mortality and morbidity risk attributable to CCS, which is enriched by the high prevalence of comorbidities (e.g. hypertension, diabetes mellitus, CKD, etc.).⁵⁰⁵ Although the prevalence of elderly patients with CAD is increasing, this population is usually undertreated, underdiagnosed, and under-represented in clinical trials. Elderly patients often present with atypical symptoms, which may delay proper diagnosis. The treatment of CCS in the elderly 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. It is recommended that radial access is used whenever possible to reduce access-site complications, when choosing an invasive strategy for patient management.⁵⁰⁶^,⁵⁰⁷ 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 elderly patients.⁵⁰⁸^,⁵⁰⁹

Recommendations for elderly patients with chronic coronary syndromes

DES = drug-eluting stents.

a

Class of recommendation.

b

Level of evidence.

8.3 Sex

Making up ≤30% of study populations, women are widely under-represented in cardiovascular studies.⁵¹⁰ This recruitment bias causes an evidence gap, as sex-based randomized controlled studies are lacking, and most data are extracted from meta-analyses and post hoc analyses of trials in ACS patients. Differences in symptom presentation, the accuracy of diagnostic tests for CAD, and other factors that lead to differential triage, evaluation, or early treatment of women with myocardial ischaemia compared with men could contribute to their worse outcomes.^511–514 Whether there are true sex-related differences in mortality after myocardial ischaemia, or whether they owing to older age or a higher prevalence of coexisting diseases in women, remains incompletely understood. It has become evident that sex-related mortality differences are particularly apparent in younger patients, typically those aged <60 years.⁵¹¹^,⁵¹²^,⁵¹⁵ The reasons for this age-dependent disparity in mortality remain unclear. Women tend to be treated less aggressively than men.⁵¹⁵ However, patient characteristics and treatments do not entirely account for sex differences in outcomes, even after PCI.⁵¹² It is therefore recommended that women who present with signs suggestive of cardiac ischaemia undergo careful investigation, as clinical symptoms might be atypical. The diagnostic accuracy of the exercise ECG is even lower in women than in men, which is in part related to functional impairment, precluding some women from achieving an adequate workload. Stress echocardiography with exercise or dobutamine stress is an accurate, non-invasive technique for the detection of obstructive CAD and risk among women with suspected CCS.⁵¹⁶ Both women and men have experienced improvements in mortality when new-generation DES were used.^517–519 The mortality reductions were similar among women and men leaving sex disparities in outcomes unchanged.⁵¹² Women have higher complication rates following CABG and may also have higher mortality risk,⁵²⁰^,⁵²¹ especially in elderly patients. Hormone replacement therapy in post-menopausal women does not reduce the risk of ischaemic myocardial disease (see section 3.3.5), and is therefore not recommended for primary and secondary prevention.³⁴⁴^,⁵²²^,⁵²³

Recommendation for sex issues and chronic coronary syndromes

a

Class of recommendation.

b

Level of evidence.

8.4 Patients with refractory angina

Refractory angina refers to long-lasting symptoms (for ≥3 months) due to established reversible ischaemia in the presence of obstructive CAD, which cannot be controlled by escalating medical therapy with the use of second- and third-line pharmacological agents, bypass grafting, or stenting including PCI of chronic total coronary occlusion. Incidence is growing with more advanced CAD, multiple comorbidities, and ageing of the population. The quality of life of patients with refractory angina is poor, with frequent hospitalization and a high level of resource utilization. The number of potential treatment options is increasing, but the level of evidence in support of their safety and efficacy varies from non-existent (in the case of transmyocardial laser application) to promising. RCTs with endpoints such as the severity and frequency of angina, as well as quality of life, are obviously needed, along with safety metrics. To confirm treatment efficacy, trials with a sham-controlled design are desirable, a significant placebo effect being part of the therapeutic effect. Patients with refractory angina are best treated in dedicated ‘angina clinics’ by multidisciplinary teams experienced in selecting the most suitable therapeutic approach in the individual patient based on an accurate diagnosis of the mechanisms of the pain syndrome. Once conventional anti-ischaemic targets have been exhausted (through an increase in nutrient blood flow delivery and/or reduction in oxygen consumption), 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 (Table 11).

Table 11

Potential treatment options for refractory angina and summary of trial data

Therapy	Type of therapy	RCT	Type of control group	Number of patients enrolled
External counterpulsation	Enhanced external counterpulsation	MUST⁵²⁴	Sham	139
Extracorporeal shockwave	Low-energy extracorporeal shockwave therapy	Not available	Not available	—
Coronary sinus constriction	Reducer device	COSIRA⁵²⁵	Sham	104
Neuromodulation	Spinal cord stimulation	STARTSTIM⁵²⁶	Not available	68
	Transcutaneous electrical neural stimulation	Not available	Not available	—
	Subcutaneous electrical neural stimulation	Not available	Not available	—
	Sympathectomy	Denby et al.⁵²⁷	Placebo	65
Gene therapy	Adenovirus fibroblast growth factor 5	Not available	Not available	—
Autologous cell therapy	Mononuclear bone marrow-derived haematopoietic progenitor cells	RENEW⁵²⁸	Placebo	112

Therapy	Type of therapy	RCT	Type of control group	Number of patients enrolled
External counterpulsation	Enhanced external counterpulsation	MUST⁵²⁴	Sham	139
Extracorporeal shockwave	Low-energy extracorporeal shockwave therapy	Not available	Not available	—
Coronary sinus constriction	Reducer device	COSIRA⁵²⁵	Sham	104
Neuromodulation	Spinal cord stimulation	STARTSTIM⁵²⁶	Not available	68
	Transcutaneous electrical neural stimulation	Not available	Not available	—
	Subcutaneous electrical neural stimulation	Not available	Not available	—
	Sympathectomy	Denby et al.⁵²⁷	Placebo	65
Gene therapy	Adenovirus fibroblast growth factor 5	Not available	Not available	—
Autologous cell therapy	Mononuclear bone marrow-derived haematopoietic progenitor cells	RENEW⁵²⁸	Placebo	112

RCT = randomized clinical trial.

Table 11

Potential treatment options for refractory angina and summary of trial data

Therapy	Type of therapy	RCT	Type of control group	Number of patients enrolled
External counterpulsation	Enhanced external counterpulsation	MUST⁵²⁴	Sham	139
Extracorporeal shockwave	Low-energy extracorporeal shockwave therapy	Not available	Not available	—
Coronary sinus constriction	Reducer device	COSIRA⁵²⁵	Sham	104
Neuromodulation	Spinal cord stimulation	STARTSTIM⁵²⁶	Not available	68
	Transcutaneous electrical neural stimulation	Not available	Not available	—
	Subcutaneous electrical neural stimulation	Not available	Not available	—
	Sympathectomy	Denby et al.⁵²⁷	Placebo	65
Gene therapy	Adenovirus fibroblast growth factor 5	Not available	Not available	—
Autologous cell therapy	Mononuclear bone marrow-derived haematopoietic progenitor cells	RENEW⁵²⁸	Placebo	112

Therapy	Type of therapy	RCT	Type of control group	Number of patients enrolled
External counterpulsation	Enhanced external counterpulsation	MUST⁵²⁴	Sham	139
Extracorporeal shockwave	Low-energy extracorporeal shockwave therapy	Not available	Not available	—
Coronary sinus constriction	Reducer device	COSIRA⁵²⁵	Sham	104
Neuromodulation	Spinal cord stimulation	STARTSTIM⁵²⁶	Not available	68
	Transcutaneous electrical neural stimulation	Not available	Not available	—
	Subcutaneous electrical neural stimulation	Not available	Not available	—
	Sympathectomy	Denby et al.⁵²⁷	Placebo	65
Gene therapy	Adenovirus fibroblast growth factor 5	Not available	Not available	—
Autologous cell therapy	Mononuclear bone marrow-derived haematopoietic progenitor cells	RENEW⁵²⁸	Placebo	112

RCT = randomized clinical trial.

Both the STARTSTIM and RENEW (Efficacy and Safety of Targeted Intramyocardial Delivery of Auto CD34+ Stem Cells for Improving Exercise Capacity in Subjects With Refractory Angina) trials were underpowered due to premature study termination. Of note, a patient-level pooled analysis of 304 patients included in three double-blind, cell therapy, placebo-controlled trials, among which was the RENEW trial, showed that active treatment with autologous haematopoietic cells had significant effects on exercise time and angina frequency.⁵²⁸

Based on positive results from two RCTs in small groups of patients, both enhanced external counterpulsation and the coronary sinus reducer device represent alternative options in patients with refractory angina, which is resistant after having exhausted all options for medical therapy and mechanical revascularization. Controlled coronary sinus narrowing with the implantation of a large stainless-steel device increases coronary sinus pressure, leading to improved perfusion in the LAD territory.

Total reported experience with all novel therapeutic options remains limited, both regarding the number of treated patients and the duration of follow-up. Larger RCTs are required to define the role of each treatment modality for specific subgroups, to decrease non-responder rates and ascertain benefit beyond potential placebo effects.

Recommendations for treatment options for refractory angina

a

Class of recommendation.

b

Level of evidence.

9 Key messages

Careful evaluation of patient history, including the characterization of anginal symptoms, and evaluation of risk factors and manifestations of CVD, as well as proper physical examination and basic testing, are crucial for the diagnosis and management of CCS.
Unless obstructive CAD can be excluded based on clinical evaluation alone, either non-invasive functional imaging or anatomical imaging using coronary CTA may be used as the initial test to rule-out or establish the diagnosis of CCS.
Selection of the initial non-invasive diagnostic test is based on the PTP, the test’s performance in ruling-in or ruling-out obstructive CAD, patient characteristics, local expertise, and the availability of the test.
For revascularization decisions, both anatomy and functional evaluation are to be considered. Either non-invasive or invasive functional evaluation is required for the assessment of myocardial ischaemia associated with angiographic stenosis, unless very high grade (>90% diameter stenosis).
Assessment of risk serves to identify CCS patients at high event risk who are projected to derive prognostic benefit from revascularization. Risk stratification includes the assessment of LV function.
Patients at high event risk should undergo invasive investigation for consideration of revascularization, even if they have mild or no symptoms.
Implementation of healthy lifestyle behaviours decreases the risk of subsequent cardiovascular events and mortality, and is additional to appropriate secondary prevention therapy. Clinicians should advise on and encourage necessary lifestyle changes in every clinical encounter.
Cognitive behavioural interventions such as supporting patients to set realistic goals, self-monitor, plan how to implement changes and deal with difficult situations, set environmental cues, and engage social support are effective interventions for behaviour change.
Multidisciplinary teams can provide patients with support to make healthy lifestyle changes, and address challenging aspects of behaviour and risk.
Anti-ischaemic treatment must be adapted to the individual patient based on comorbidities, co-administered therapies, expected tolerance and adherence, and patient preferences. The choice of anti-ischaemic drugs to treat CCS should be adapted to the patient’s heart rate, BP, and LV function.
Beta-blockers and/or CCBs remain the first-line drugs in patients with CCS. Beta-blockers are recommended in patients with LV dysfunction or HF with reduced ejection fraction.
Long-acting nitrates provoke tolerance with loss of efficacy. This requires prescription of a daily nitrate-free or nitrate-low interval of ∼10–14 h.
Antithrombotic therapy is a key part of secondary prevention in patients with CCS and warrants careful consideration. Patients with a previous MI, who are at high risk of ischaemic events and low risk of fatal bleeding, should be considered for long-term DAPT with aspirin and either a P2Y₁₂ inhibitor or very low-dose rivaroxaban, unless they have an indication for an OAC such as AF.
Statins are recommended in all patients with CCS. ACE inhibitors (or ARBs) are recommended in the presence of HF, diabetes, or hypertension and should be considered in high-risk patients.
Proton pump inhibitors are recommended in patients receiving aspirin or combination antithrombotic therapy who are at high risk of gastrointestinal bleeding.
Efforts should be made to explain to patients the importance of evidence-based prescriptions to increase adherence to treatment, and repeated therapeutic education is essential in every clinical encounter.
Patients with a long-standing diagnosis of CCS should undergo periodic visits to assess potential changes in risk status, adherence to treatment targets, and the development of comorbidities. Repeat stress imaging or ICA with functional testing is recommended in the presence of worsening symptoms and/or increased risk status.
Assessment of myocardial and valvular function and dimensions, as well as a functional test to rule-out significant myocardial silent ischaemia, may be contemplated every 3–5 years in asymptomatic patients with a long-standing diagnosis of CCS.
An assessment of coronary vasomotor function should be considered in patients with non-significant epicardial CAD and objective evidence of ischaemia.

10 Gaps in the evidence

10.1 Diagnosis and assessment

More information on the effects of various risk factors, biomarkers, and comorbidities on the PTP of obstructive CAD is needed. Adequately powered RCTs are needed to compare the effectiveness of different diagnostic strategies, and to evaluate how to best integrate diagnostic tests in patient care in terms of clinical outcomes and the use of healthcare resources.

10.2 Assessment of risk

Studies should address whether an initial invasive strategy, in addition to optimal medical therapy in patients with CCS and inducible ischaemia by non-invasive testing, improves outcomes. Larger trials are needed to verify the utility of systematic assessment of biomarkers in patients with suspected obstructive CAD.

10.3 Lifestyle management

Research regarding the most effective methods to support healthy lifestyle behaviours in brief or very brief clinical encounters, and sustain medication and lifestyle behaviour adherence over time, is needed. The cardiovascular effects of newer e-cigarettes over the long-term remain unknown, as does their effectiveness in smoking cessation.

The relative benefits of high-intensity interval training vs. moderate-intensity exercise in patients with CCS should be further evaluated. The benefits of decreasing sedentary behaviour, and the most appropriate ‘dose’ and type of physical activity in patients with CCS, are unknown, as are the effectiveness and cost-effectiveness of increasing cardiac rehabilitation participation among patients with CCS.

10.4 Pharmacological management

The need for and duration of beta-blocker therapy following MI to maintain a protective effect on cardiac events in the absence of LV systolic dysfunction are unknown.

In patients with CCS and without a previous MI, it remains to be determined whether current anti-ischaemic drugs improve prognosis.

Whether the initial use of second-line anti-ischaemic therapy (i.e. long-acting nitrates, ranolazine, nicorandil, ivabradine, or trimetazidine) alone or in combination with a first-line drug (i.e. beta-blocker or CCB) is superior to the combination of a beta-blocker with a CCB to control anginal symptoms and myocardial ischaemia in patients with CCS remains to be proven.

The efficacy and safety of aspirin or an alternative antithrombotic therapy in patients with a mild extent of atherosclerotic disease, such as that discovered by coronary CTA, requires further assessment, including the effect on cancer rates as well as cardiovascular events. The optimal long-term antithrombotic therapy, and strategies for individualizing this, in patients at high risk of ischaemic events is uncertain. Consequently, clinical studies comparing the efficacy and safety of aspirin + P2Y₁₂ inhibitor with aspirin + factor Xa inhibitor are warranted to determine which subgroups may be preferentially treated with one or other strategy. The potential clinical benefit of ticagrelor monotherapy, while stopping aspirin, remains unproved at present.

The role of biomarkers in stratifying patients' risk of ischaemic events and bleeding requires clarification, including the role of growth differentiation factor-15 in guiding the risk of bleeding with DAPT. It is uncertain what effect novel lipid-lowering strategies will have on the net clinical benefit of DAPT, with similar implications of other strategies such as intensive BP lowering and, potentially in the future, selective anti-inflammatory therapies.

10.5 Revascularization

Further studies, including RCTs, are needed to assess the value of functional vs. anatomical guidance for CABG. The concept of complete revascularization and its effect on prognosis needs to be re-evaluated by prospective comparisons of functional vs. anatomical guidance for stenting on the one hand, and bypass on the other. Of note, none of the RCTs comparing PCI with CABG to date have used combined anatomical and functional guidance for PCI, a strategy that is suggested to significantly improve outcomes of PCI (Syntax II registry).

10.6 Heart failure and left ventricular dysfunction

Most of the evidence from RCTs supporting the recommendations for the use of drugs and devices in patients with chronic heart failure is based on cohorts with stable ischaemic heart disease and reduced LV function. However, patients with CCS requiring acute or chronic mechanical support are largely excluded from clinical trials, and the optimal management of such patients with drugs and devices during episodes of acute decompensation has not been adequately addressed.

10.7 Patients with long-standing diagnosis of chronic coronary syndromes

The incremental value of using risk scores to serially evaluate patients' risks, and more importantly to adjust the intensity of treatment, remains to be determined.

The optimal time intervals for serial visits remain to be determined.

10.8 Angina without obstructive coronary artery disease

Development of safe and efficacious novel pharmacological agents for this indication remains an unmet need.

10.9 Screening in asymptomatic subjects

Further studies on biomarkers and imaging tests for screening of CAD in asymptomatic subjects are needed. Furthermore, there are limited data on how to manage asymptomatic subjects who receive testing and have a positive test result, as evidence demonstrating improved prognosis following appropriate management is still lacking.

10.10 Comorbidities

The role of PCI in patients with aortic stenosis remains undetermined with respect to the indication for coronary revascularization and timing vs. valve intervention. Further information is needed on how to adapt cardiovascular therapies in patients with chronic inflammatory diseases.

10.11 Patients with refractory angina

Larger RCTs and registries are required to define the role of additional treatment modalities for specific subgroups, to decrease non-responder rates and ascertain benefit beyond potential placebo effects.

11 ‘What to do’ and ‘what not to do’ messages from the Guidelines

ACE = angiotensin-converting enzyme; ACS = acute coronary syndromes; AF = atrial fibrillation; ARB = angiotensin receptor blocker; b.i.d. = bis in die (twice a day); BP = blood pressure; CHA₂DS₂-VASc = Cardiac failure, Hypertension, Age ≥75 [Doubled], Diabetes, Stroke [Doubled] – Vascular disease, Age 65–74 and Sex category [Female]; CAD = coronary artery disease; CCB = calcium channel blocker; CCS = chronic coronary syndromes; CKD = chronic kidney disease; CMR = cardiac magnetic resonance; CRT = cardiac resynchronization therapy; CTA = computed tomography angiography; CVD = cardiovascular disease; DAPT = dual antiplatelet therapy; DES = drug-eluting stent; ECG = electrocardiogram; FFR = fractional flow reserve; GPs = general practitioners; HbA1C = glycated haemoglobin; HF = heart failure; ICA = invasive coronary angiography; IMT = intima−media thickness; iwFR = instantaneous wave-free ratio (instant flow reserve); LBBB = left bundle branch block; LDL-C = low-density lipoprotein cholesterol; LV = left ventricular; LVEF = left ventricular ejection fraction; MI = myocardial infarction; MRA = mineralocorticoid receptor antagonist; NOAC = non-vitamin K antagonist oral anticoagulant; OAC = oral anticoagulant; o.d. = omni die (once a day); PCI = percutaneous coronary intervention; PCSK9 = proprotein convertase subtilisin-kexin type 9; RAS = renin−angiotensin system; VKA = vitamin K antagonist.

a

Class of recommendation.

b

Level of evidence.

12 Supplementary data

Supplementary Data with additional Supplementary Tables and Figures complementing the full text—as well as section 3 on patients with angina and/or dyspnoea, and suspected coronary artery disease—are available on the European Heart Journal website and via the ESC website at www.escardio.org/guidelines.

13 Appendix

Author/Task Force Member affiliations:

Stephan Achenbach, Department of Cardiology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany; Stefan Agewall, Department of Medicine, Clinical Science, Oslo, Norway; Emanuele Barbato, Advanced Biomedical Sciences, University Federico II, Naples, Italy; Jeroen J. Bax, Cardiology, Leiden University Medical Center, Leiden, Netherlands; Davide Capodanno, CardioThoracic-Vascular and Transplant Department, A.O.U. ‘Policlinico-Vittorio Emanuele’, University of Catania, Catania, Italy; Thomas Cuisset, Cardiology, CHU Timone, Marseille, France; Christi Deaton, Public Health and Primary Care, University of Cambridge School of Clinical Medicine, Cambridge, United Kingdom; Kenneth Dickstein, Cardiology, Stavanger University Hospital, University of Bergen, Stavanger, Norway; Thor Edvardsen, Cardiology, Oslo University Hospital, Oslo, Norway; Javier Escaned, Interventional Cardiology Unit, Hospital Clinico San Carlos, Madrid, Spain; Christian Funck-Brentano, Department of Clinical Pharmacology, Sorbonne Université, AP-HP, ICAN and INSERM CIC Paris-Est, Paris, France; Bernard J. Gersh, Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN, United States of America; Martine Gilard, Cardiology, Brest University, Brest, France; David Hasdai, Cardiology, Rabin Medical Center Petah Tikva, Israel; Robert Hatala, Department of Cardiology and Angiology, Slovak Cardiovascular Institute, Slovak Medical University, Bratislava, Slovakia; Felix Mahfoud, Internal Medicine III, Saarland University, Homburg, Germany; Josep Masip, Cardiology Department /Intensive Care Department, Hospital CIMA-Sanitas/Consorci Sanitari Integral/University of Barcelona, Barcelona, Spain; Claudio Muneretto, Cardiovascular Surgery, University of Brescia Medical School, Brescia, Italy; Eva Prescott, Department of Cardiology, Bispebjerg University Hospital, Copenhagen, Denmark; Antti Saraste, Heart Center, Turku University Hospital, Turku, Finland; Robert F. Storey, Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, United Kingdom; Pavel Svitil, Cardiologic Practice, Practice of General Cardiology, Jihlava, Czech Republic; Marco Valgimigli, Inselspital, University of Bern, Bern, Switzerland.

ESC Committee for Practice Guidelines (CPG): Stephan Windecker (Chairperson) (Switzerland), Victor Aboyans (France), Colin Baigent (United Kingdom), Jean-Philippe Collet (France), Veronica Dean (France), Victoria Delgado (Netherlands), Donna Fitzsimons (United Kingdom), Christopher P. Gale (United Kingdom), Diederick E. Grobbee (Netherlands), Sigrun Halvorsen (Norway), Gerhard Hindricks (Germany), Bernard Iung (France), Peter Jüni (Canada), Hugo A. Katus (Germany), Ulf Landmesser (Germany), Christophe Leclercq (France), Maddalena Lettino (Italy), Basil S. Lewis (Israel), Bela Merkely (Hungary), Christian Mueller (Switzerland), Steffen Petersen (United Kingdom), Anna Sonia Petronio (Italy), Dimitrios J. Richter (Greece), Marco Roffi (Switzerland), Evgeny Shlyakhto (Russian Federation), Iain A. Simpson (United Kingdom), Miguel Sousa-Uva (Portugal), Rhian M. Touyz (United Kingdom).

ESC National Cardiac Societies actively involved in the review process of the 2019 ESC Guidelines for the diagnosis and management of chronic coronary syndromes.

Algeria: Algerian Society of Cardiology, Salim Benkhedda; Austria: Austrian Society of Cardiology, Bernhard Metzler; Belarus: Belorussian Scientific Society of Cardiologists, Volha Sujayeva; Belgium: Belgian Society of Cardiology, Bernard Cosyns; Bosnia and Herzegovina: Association of Cardiologists of Bosnia and Herzegovina, Zumreta Kusljugic; Bulgaria: Bulgarian Society of Cardiology, Vasil Velchev; Cyprus: Cyprus Society of Cardiology, Georgios Panayi; Czech Republic: Czech Society of Cardiology, Petr Kala; Denmark: Danish Society of Cardiology, Sune Ammentorp Haahr-Pedersen; Egypt: Egyptian Society of Cardiology, Hamza Kabil; Estonia: Estonian Society of Cardiology, Tiia Ainla; Finland: Finnish Cardiac Society, Tomi Kaukonen; France: French Society of Cardiology, Guillaume Cayla; Georgia: Georgian Society of Cardiology, Zurab Pagava; Germany: German Cardiac Society, Jochen Woehrle; Greece: Hellenic Society of Cardiology, John Kanakakis; Hungary: Hungarian Society of Cardiology, Kálmán Tóth; Iceland: Icelandic Society of Cardiology, Thorarinn Gudnason; Ireland: Irish Cardiac Society, Aaron Peace; Israel: Israel Heart Society, Doron Aronson; Italy: Italian Federation of Cardiology, Carmine Riccio; Kosovo (Republic of): Kosovo Society of Cardiology, Shpend Elezi; Kyrgyzstan: Kyrgyz Society of Cardiology, Erkin Mirrakhimov; Latvia: Latvian Society of Cardiology, Silvija Hansone; Lebanon: Lebanese Society of Cardiology, Antoine Sarkis; Lithuania: Lithuanian Society of Cardiology, Ruta Babarskiene; Luxembourg: Luxembourg Society of Cardiology, Jean Beissel; Malta: Maltese Cardiac Society, Andrew J. Cassar Maempel; Moldova (Republic of): Moldavian Society of Cardiology, Valeriu Revenco; Netherlands: Netherlands Society of Cardiology, G.J. de Grooth; North Macedonia: Macedonian FYR Society of Cardiology, Hristo Pejkov; Norway: Norwegian Society of Cardiology, Vibeke Juliebø; Poland: Polish Cardiac Society, Piotr Lipiec; Portugal: Portuguese Society of Cardiology, José Santos; Romania: Romanian Society of Cardiology, Ovidiu Chioncel; Russian Federation: Russian Society of Cardiology, Dmitry Duplyakov; San Marino: San Marino Society of Cardiology, Luca Bertelli; Serbia: Cardiology Society of Serbia, Ana Djordjevic Dikic; Slovakia: Slovak Society of Cardiology, Martin Studenčan; Slovenia: Slovenian Society of Cardiology, Matjaz Bunc; Spain: Spanish Society of Cardiology, Fernando Alfonso; Sweden: Swedish Society of Cardiology, Magnus Bäck; Switzerland: Swiss Society of Cardiology, Michael Zellweger; Tunisia: Tunisian Society of Cardiology and Cardio-Vascular Surgery, Faouzi Addad; Turkey: Turkish Society of Cardiology, Aylin Yildirir; Ukraine: Ukrainian Association of Cardiology, Yuriy Sirenko; United Kingdom of Great Britain and Northern Ireland: British Cardiovascular Society, Brian Clapp.

The disclosure forms of all experts involved in the development of these Guidelines are available on the ESC website www.escardio.org/guidelines

Author/Task Force Member Affiliations: listed in the Appendix.

ESC Committee for Practice Guidelines (CPG) and National Cardiac Societies document reviewers: listed in the Appendix.

ESC entities having participated in the development of this document:

Associations: Acute Cardiovascular Care Association (ACCA), Association of Cardiovascular Nursing & Allied Professions (ACNAP), European Association of Cardiovascular Imaging (EACVI), European Association of Preventive Cardiology (EAPC), European Association of Percutaneous Cardiovascular Interventions (EAPCI), European Heart Rhythm Association (EHRA), Heart Failure Association (HFA).

Councils: Council for Cardiology Practice.

Working Groups: Atherosclerosis and Vascular Biology, Cardiovascular Pharmacotherapy, Cardiovascular Surgery, Coronary Pathophysiology and Microcirculation, Thrombosis.

The content of these ESC Guidelines has been published for personal and educational use only. No commercial use is authorized. No part of the ESC Guidelines may be translated or reproduced in any form without written permission from the ESC. Permission can be obtained upon submission of a written request to Oxford University Press, the publisher of the European Heart Journal and the party authorized to handle such permissions on behalf of the ESC (journals.permissions@oxfordjournals.org).

Disclaimer. The ESC Guidelines represent the views of the ESC and were produced after careful consideration of the scientific and medical knowledge, and the evidence available at the time of their publication. The ESC is not responsible in the event of any contradiction, discrepancy, and/or ambiguity between the ESC Guidelines and any other official recommendations or guidelines issued by the relevant public health authorities, in particular in relation to good use of healthcare or therapeutic strategies. Health professionals are encouraged to take the ESC Guidelines fully into account when exercising their clinical judgment, as well as in the determination and the implementation of preventive, diagnostic, or therapeutic medical strategies; however, the ESC Guidelines do not override, in any way whatsoever, the individual responsibility of health professionals to make appropriate and accurate decisions in consideration of each patient’s health condition and in consultation with that patient and, where appropriate and/or necessary, the patient’s caregiver. Nor do the ESC Guidelines exempt health professionals from taking into full and careful consideration the relevant official updated recommendations or guidelines issued by the competent public health authorities, in order to manage each patient’s case in light of the scientifically accepted data pursuant to their respective ethical and professional obligations. It is also the health professional’s responsibility to verify the applicable rules and regulations relating to drugs and medical devices at the time of prescription.

14 References

1

Williams

RP

,

Manou-Stathopoulou

V

,

Redwood

SR

,

Marber

MS.

‘Warm-up Angina’: harnessing the benefits of exercise and myocardial ischaemia

.

Heart

2014

;

100

:

106

–

114

.

2

Diamond

GA.

A clinically relevant classification of chest discomfort

.

J Am Coll Cardiol

1983

;

1

:

574

–

575

.

3

Genders

TS

,

Steyerberg

EW

,

Hunink

MG

,

Nieman

K

,

Galema

TW

,

Mollet

NR

,

de Feyter

PJ

,

Krestin

GP

,

Alkadhi

H

,

Leschka

S

,

Desbiolles

L

,

Meijs

MF

,

Cramer

MJ

,

Knuuti

J

,

Kajander

S

,

Bogaert

J

,

Goetschalckx

K

,

Cademartiri

F

,

Maffei

E

,

Martini

C

,

Seitun

S

,

Aldrovandi

A

,

Wildermuth

S

,

Stinn

B

,

Fornaro

J

,

Feuchtner

G

,

De Zordo

T

,

Auer

T

,

Plank

F

,

Friedrich

G

,

Pugliese

F

,

Petersen

SE

,

Davies

LC

,

Schoepf

UJ

,

Rowe

GW

,

van Mieghem

CA

,

van Driessche

L

,

Sinitsyn

V

,

Gopalan

D

,

Nikolaou

K

,

Bamberg

F

,

Cury

RC

,

Battle

J

,

Maurovich-Horvat

P

,

Bartykowszki

A

,

Merkely

B

,

Becker

D

,

Hadamitzky

M

,

Hausleiter

J

,

Dewey

M

,

Zimmermann

E

,

Laule

M.

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

.

BMJ

2012

;

344

:

e3485

.

4

Douglas

PS

,

Hoffmann

U

,

Patel

MR

,

Mark

DB

,

Al-Khalidi

HR

,

Cavanaugh

B

,

Cole

J

,

Dolor

RJ

,

Fordyce

CB

,

Huang

M

,

Khan

MA

,

Kosinski

AS

,

Krucoff

MW

,

Malhotra

V

,

Picard

MH

,

Udelson

JE

,

Velazquez

EJ

,

Yow

E

,

Cooper

LS

,

Lee

KL

; PROMISE Investigators.

Outcomes of anatomical versus functional testing for coronary artery disease

.

N Engl J Med

2015

;

372

:

1291

–

1300

.

5

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

–

2391

.

6

SCOT-HEART investigators,

Newby

DE

,

Adamson

PD

,

Berry

C

,

Boon

NA

,

Dweck

MR

,

Flather

M

,

Forbes

J

,

Hunter

A

,

Lewis

S

,

MacLean

S

,

Mills

NL

,

Norrie

J

,

Roditi

G

,

Shah

ASV

,

Timmis

AD

,

van Beek

EJR

,

Williams

MC.

Coronary CT angiography and 5-year risk of myocardial infarction

.

N Engl J Med

2018

;

379

:

924

–

933

.

7

Reeh

J

,

Therming

CB

,

Heitmann

M

,

Hojberg

S

,

Sorum

C

,

Bech

J

,

Husum

D

,

Dominguez

H

,

Sehestedt

T

,

Hermann

T

,

Hansen

KW

,

Simonsen

L

,

Galatius

S

,

Prescott

E.

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

.

Eur Heart J

2018

;

40

:

1426

–

1435

.

8

Cheng

VY

,

Berman

DS

,

Rozanski

A

,

Dunning

AM

,

Achenbach

S

,

Al-Mallah

M

,

Budoff

MJ

,

Cademartiri

F

,

Callister

TQ

,

Chang

HJ

,

Chinnaiyan

K

,

Chow

BJ

,

Delago

A

,

Gomez

M

,

Hadamitzky

M

,

Hausleiter

J

,

Karlsberg

RP

,

Kaufmann

P

,

Lin

FY

,

Maffei

E

,

Raff

GL

,

Villines

TC

,

Shaw

LJ

,

Min

JK.

Performance of the traditional age, sex, and angina typicality-based approach for estimating pretest probability of angiographically significant coronary artery disease in patients undergoing coronary computed tomographic angiography: results from the multinational coronary CT angiography evaluation for clinical outcomes: an international multicenter registry (CONFIRM)

.

Circulation

2011

;

124

:

2423

–

2432

, 2421–2428.

9

Campeau

L.

Letter: Grading of angina pectoris

.

Circulation

1976

;

54

:

522

–

523

.

10

Bosner

S

,

Haasenritter

J

,

Becker

A

,

Karatolios

K

,

Vaucher

P

,

Gencer

B

,

Herzig

L

,

Heinzel-Gutenbrunner

M

,

Schaefer

JR

,

Abu Hani

M

,

Keller

H

,

Sonnichsen

AC

,

Baum

E

,

Donner-Banzhoff

N.

Ruling out coronary artery disease in primary care: development and validation of a simple prediction rule

.

CMAJ

2010

;

182

:

1295

–

1300

.

11

Roffi

M

,

Patrono

C

,

Collet

JP

,

Mueller

C

,

Valgimigli

M

,

Andreotti

F

,

Bax

JJ

,

Borger

MA

,

Brotons

C

,

Chew

DP

,

Gencer

B

,

Hasenfuss

G

,

Kjeldsen

K

,

Lancellotti

P

,

Landmesser

U

,

Mehilli

J

,

Mukherjee

D

,

Storey

RF

,

Windecker

S.

2015 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: Task Force for the Management of Acute Coronary Syndromes in Patients Presenting without Persistent ST-Segment Elevation of the

European Society of Cardiology (ESC). Eur Heart J

2016

;

37

:

267

–

315

.

12

Ibanez

B

,

James

S

,

Agewall

S

,

Antunes

MJ

,

Bucciarelli-Ducci

C

,

Bueno

H

,

Caforio

ALP

,

Crea

F

,

Goudevenos

JA

,

Halvorsen

S

,

Hindricks

G

,

Kastrati

A

,

Lenzen

MJ

,

Prescott

E

,

Roffi

M

,

Valgimigli

M

,

Varenhorst

C

,

Vranckx

P

,

Widimsky

P.

2017 ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: The Task Force for the management of acute myocardial infarction in patients presenting with ST-segment elevation of the

European Society of Cardiology (ESC). Eur Heart J

2018

;

39

:

119

–

177

.

13

Patel

MR

,

Peterson

ED

,

Dai

D

,

Brennan

JM

,

Redberg

RF

,

Anderson

HV

,

Brindis

RG

,

Douglas

PS.

Low diagnostic yield of elective coronary angiography

.

N Engl J Med

2010

;

362

:

886

–

895

.

14

Jespersen

L

,

Hvelplund

A

,

Abildstrom

SZ

,

Pedersen

F

,

Galatius

S

,

Madsen

JK

,

Jorgensen

E

,

Kelbaek

H

,

Prescott

E.

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

–

744

.

15

Piepoli

MF

,

Hoes

AW

,

Agewall

S

,

Albus

C

,

Brotons

C

,

Catapano

AL

,

Cooney

MT

,

Corra

U

,

Cosyns

B

,

Deaton

C

,

Graham

I

,

Hall

MS

,

Hobbs

FDR

,

Lochen

ML

,

Lollgen

H

,

Marques-Vidal

P

,

Perk

J

,

Prescott

E

,

Redon

J

,

Richter

DJ

,

Sattar

N

,

Smulders

Y

,

Tiberi

M

,

van der Worp

HB

,

van Dis

I

,

Verschuren

WMM

,

Binno

S.

2016 European Guidelines on cardiovascular disease prevention in clinical practice: The Sixth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of 10 societies and by invited experts)Developed with the special contribution of the European Association for Cardiovascular Prevention & Rehabilitation (EACPR)

.

Eur Heart J

2016

;

37

:

2315

–

2381

.

16

2019 ESC/EASD Guidelines on diabetes, pre-diabetes, and cardiovascular diseases. Eur Hear J

2019

:In press.

17

Catapano

AL

,

Graham

I

,

De Backer

G

,

Wiklund

O

,

Chapman

MJ

,

Drexel

H

,

Hoes

AW

,

Jennings

CS

,

Landmesser

U

,

Pedersen

TR

,

Reiner

Z

,

Riccardi

G

,

Taskinen

MR

,

Tokgozoglu

L

,

Verschuren

WMM

,

Vlachopoulos

C

,

Wood

DA

,

Zamorano

JL

,

Cooney

MT.

2016 ESC/EAS Guidelines for the management of dyslipidaemias

.

Eur Heart J

2016

;

37

:

2999

–

3058

.

18

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

.

19

Nitsch

D

,

Grams

M

,

Sang

Y

,

Black

C

,

Cirillo

M

,

Djurdjev

O

,

Iseki

K

,

Jassal

SK

,

Kimm

H

,

Kronenberg

F

,

Oien

CM

,

Levey

AS

,

Levin

A

,

Woodward

M

,

Hemmelgarn

BR

; Chronic Kidney Disease Prognosis Consortium.

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

.

BMJ

2013

;

346

:

f324

.

20

Lopes

NH

,

da Silva Paulitsch

F

,

Pereira

A

,

Garzillo

CL

,

Ferreira

JF

,

Stolf

N

,

Hueb

W.

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

.

J Thorac Cardiovasc Surg

2009

;

137

:

1443

–

1449

.

21

Omland

T

,

Pfeffer

MA

,

Solomon

SD

,

de Lemos

JA

,

Røsjø

H

,

Šaltytė Benth

J

,

Maggioni

A

,

Domanski

MJ

,

Rouleau

JL

,

Sabatine

MS

,

Braunwald

E

,

PEACE

Investigators.

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

–

1249

.

22

Omland

T

,

de Lemos

JA

,

Sabatine

MS

,

Christophi

CA

,

Rice

MM

,

Jablonski

KA

,

Tjora

S

,

Domanski

MJ

,

Gersh

BJ

,

Rouleau

JL

,

Pfeffer

MA

,

Braunwald

E

, Prevention of Events with Angiotensin Converting Enzyme Inhibition (PEACE) Trial Investigators.

A sensitive cardiac troponin T assay in stable coronary artery disease

.

N Engl J Med

2009

;

361

:

2538

–

2547

.

23

Everett

BM

,

Brooks

MM

,

Vlachos

HE

,

Chaitman

BR

,

Frye

RL

,

Bhatt

DL

BARI 2D Study Group.

Troponin and cardiac events in stable ischemic heart disease and diabetes

.

N Engl J Med

2015

;

373

:

610

–

620

.

24

de Lemos

JA

,

Drazner

MH

,

Omland

T

,

Ayers

CR

,

Khera

A

,

Rohatgi

A

,

Hashim

I

,

Berry

JD

,

Das

SR

,

Morrow

DA

,

McGuire

DK.

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

.

JAMA

2010

;

304

:

2503

–

2512

.

25

van Holten

TC

,

Waanders

LF

,

de Groot

PG

,

Vissers

J

,

Hoefer

IE

,

Pasterkamp

G

,

Prins

MW

,

Roest

M.

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

.

PLoS One

2013

;

8

:

e62080

.

26

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

–

137

.

27

Laufer

EM

,

Mingels

AM

,

Winkens

MH

,

Joosen

IA

,

Schellings

MW

,

Leiner

T

,

Wildberger

JE

,

Narula

J

,

Van Dieijen-Visser

MP

,

Hofstra

L.

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

.

Arterioscler Thromb Vasc Biol

2010

;

30

:

1269

–

1275

.

28

Reichlin

T

,

Hochholzer

W

,

Bassetti

S

,

Steuer

S

,

Stelzig

C

,

Hartwiger

S

,

Biedert

S

,

Schaub

N

,

Buerge

C

,

Potocki

M

,

Noveanu

M

,

Breidthardt

T

,

Twerenbold

R

,

Winkler

K

,

Bingisser

R

,

Mueller

C.

Early diagnosis of myocardial infarction with sensitive cardiac troponin assays

.

N Engl J Med

2009

;

361

:

858

–

867

.

29

Keller

T

,

Zeller

T

,

Peetz

D

,

Tzikas

S

,

Roth

A

,

Czyz

E

,

Bickel

C

,

Baldus

S

,

Warnholtz

A

,

Frohlich

M

,

Sinning

CR

,

Eleftheriadis

MS

,

Wild

PS

,

Schnabel

RB

,

Lubos

E

,

Jachmann

N

,

Genth-Zotz

S

,

Post

F

,

Nicaud

V

,

Tiret

L

,

Lackner

KJ

,

Munzel

TF

,

Blankenberg

S.

Sensitive troponin I assay in early diagnosis of acute myocardial infarction

.

N Engl J Med

2009

;

361

:

868

–

877

.

30

da Silveira

AD

,

Ribeiro

RA

,

Rossini

AP

,

Stella

SF

,

Ritta

HA

,

Stein

R

,

Polanczyk

CA.

Association of anemia with clinical outcomes in stable coronary artery disease

.

Coron Artery Dis

2008

;

19

:

21

–

26

.

31

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

.

32

Shlipak

MG

,

Matsushita

K

,

Arnlov

J

,

Inker

LA

,

Katz

R

,

Polkinghorne

KR

,

Rothenbacher

D

,

Sarnak

MJ

,

Astor

BC

,

Coresh

J

,

Levey

AS

,

Gansevoort

RT

,

Prognosis Consortium

CKD

.

Cystatin C versus creatinine in determining risk based on kidney function

.

N Engl J Med

2013

;

369

:

932

–

943

.

33

Silverman

MG

,

Ference

BA

,

Im

K

,

Wiviott

SD

,

Giugliano

RP

,

Grundy

SM

,

Braunwald

E

,

Sabatine

MS.

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

.

JAMA

2016

;

316

:

1289

–

1297

.

34

Cholesterol Treatment Trialists’ (CTT) Collaboration,

Fulcher

J

,

O'Connell

R

,

Voysey

M

,

Emberson

J

,

Blackwell

L

,

Mihaylova

B

,

Simes

J

,

Collins

R

,

Kirby

A

,

Colhoun

H

,

Braunwald

E

,

La Rosa

J

,

Pedersen

TR

,

Tonkin

A

,

Davis

B

,

Sleight

P

,

Franzosi

MG

,

Baigent

C

,

Keech

A.

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

–

1405

.

35

Bartnik

M

,

Ryden

L

,

Malmberg

K

,

Ohrvik

J

,

Pyorala

K

,

Standl

E

,

Ferrari

R

,

Simoons

M

,

Soler-Soler

J

; Euro Heart Survey Investigators.

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

–

77

.

36

Cohn

PF

,

Fox

KM

,

Daly

C.

Silent myocardial ischemia

.

Circulation

2003

;

108

:

1263

–

1277

.

37

Androulakis

A

,

Aznaouridis

KA

,

Aggeli

CJ

,

Roussakis

GN

,

Michaelides

AP

,

Kartalis

AN

,

Stougiannos

PN

,

Dilaveris

PE

,

Misovoulos

PI

,

Stefanadis

CI

,

Kallikazaros

IE.

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

–

1911

.

38

Guo

Y

,

Zhang

L

,

Wang

C

,

Zhao

Y

,

Chen

W

,

Gao

M

,

Zhu

P

,

Yang

T

,

Wang

Y.

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

–

198

.

39

Nucifora

G

,

Schuijf

JD

,

van Werkhoven

JM

,

Trines

SA

,

Kajander

S

,

Tops

LF

,

Turta

O

,

Jukema

JW

,

Schreur

JH

,

Heijenbrok

MW

,

Gaemperli

O

,

Kaufmann

PA

,

Knuuti

J

,

van der Wall

EE

,

Schalij

MJ

,

Bax

JJ.

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

–

785

.

40

Pradhan

R

,

Chaudhary

A

,

Donato

AA.

Predictive accuracy of ST depression during rapid atrial fibrillation on the presence of obstructive coronary artery disease

.

Am J Emerg Med

2012

;

30

:

1042

–

1047

.

41

Forslund

L

,

Hjemdahl

P

,

Held

C

,

Bjorkander

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

–

587

.

42

Davies

RF

,

Goldberg

AD

,

Forman

S

,

Pepine

CJ

,

Knatterud

GL

,

Geller

N

,

Sopko

G

,

Pratt

C

,

Deanfield

J

,

Conti

CR.

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

–

2043

.

43

Stone

PH

,

Chaitman

BR

,

Forman

S

,

Andrews

TC

,

Bittner

V

,

Bourassa

MG

,

Davies

RF

,

Deanfield

JE

,

Frishman

W

,

Goldberg

AD

,

MacCallum

G

,

Ouyang

P

,

Pepine

CJ

,

Pratt

CM

,

Sharaf

B

,

Steingart

R

,

Knatterud

GL

,

Sopko

G

,

Conti

CR.

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

–

1401

.

44

Daly

C

,

Norrie

J

,

Murdoch

DL

,

Ford

I

,

Dargie

HJ

,

Fox

K

; TIBET (Total Ischaemic Burden European Trial) study group.

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

.

Eur Heart J

2003

;

24

:

532

–

540

.

45

Daly

CA

,

De Stavola

B

,

Sendon

JL

,

Tavazzi

L

,

Boersma

E

,

Clemens

F

,

Danchin

N

,

Delahaye

F

,

Gitt

A

,

Julian

D

,

Mulcahy

D

,

Ruzyllo

W

,

Thygesen

K

,

Verheugt

F

,

Fox

KM

; Euro Heart Survey Investigators.

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

.

BMJ

2006

;

332

:

262

–

267

.

46

Cerqueira

MD

,

Weissman

NJ

,

Dilsizian

V

,

Jacobs

AK

,

Kaul

S

,

Laskey

WK

,

Pennell

DJ

,

Rumberger

JA

,

Ryan

T

,

Verani

MS

; American Heart Association Writing Group on Myocardial Segmentation and Registration for Cardiac Imaging.

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

–

542

.

47

Eek

C

,

Grenne

B

,

Brunvand

H

,

Aakhus

S

,

Endresen

K

,

Hol

PK

,

Smith

HJ

,

Smiseth

OA

,

Edvardsen

T

,

Skulstad

H.

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

–

194

.

48

Smedsrud

MK

,

Sarvari

S

,

Haugaa

KH

,

Gjesdal

O

,

Orn

S

,

Aaberge

L

,

Smiseth

OA

,

Edvardsen

T.

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

.

J Am Coll Cardiol

2012

;

60

:

1086

–

1093

.

49

Smedsrud

MK

,

Gravning

J

,

Omland

T

,

Eek

C

,

Morkrid

L

,

Skulstad

H

,

Aaberge

L

,

Bendz

B

,

Kjekshus

J

,

Edvardsen

T.

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

–

973

.

50

Biering-Sorensen

T

,

Hoffmann

S

,

Mogelvang

R

,

Zeeberg Iversen

A

,

Galatius

S

,

Fritz-Hansen

T

,

Bech

J

,

Jensen

JS.

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

.

51

Shaw

LJ

,

Bugiardini

R

,

Merz

CN.

Women and ischemic heart disease: evolving knowledge

.

J Am Coll Cardiol

2009

;

54

:

1561

–

1575

.

52

Nagueh

SF

,

Smiseth

OA

,

Appleton

CP

,

Byrd

BF III

,

Dokainish

H

,

Edvardsen

T

,

Flachskampf

FA

,

Gillebert

TC

,

Klein

AL

,

Lancellotti

P

,

Marino

P

,

Oh

JK

,

Alexandru Popescu

B

,

Waggoner

AD.

Recommendations for the evaluation of left ventricular diastolic function by echocardiography: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging

.

Eur Heart J Cardiovasc Imaging

2016

;

17

:

1321

–

1360

.

53

Steeds

RP

,

Garbi

M

,

Cardim

N

,

Kasprzak

JD

,

Sade

E

,

Nihoyannopoulos

P

,

Popescu

BA

,

Stefanidis

A

,

Cosyns

B

,

Monaghan

M

,

Aakhus

S

,

Edvardsen

T

,

Flachskampf

F

,

Galiuto

L

,

Athanassopoulos

G

,

Lancellotti

P

; 2014–2016 EACVI Scientific Documents Committee.

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

–

1204

.

54

Senior

R

,

Becher

H

,

Monaghan

M

,

Agati

L

,

Zamorano

J

,

Vanoverschelde

JL

,

Nihoyannopoulos

P

,

Edvardsen

T

,

Lancellotti

P

; EACVI Scientific Documents Committee for 2014–16 and 2016–18.

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

.

Eur Heart J Cardiovasc Imaging

2017

;

18

:

1205

–

1205af

.

55

Greenwood

JP

,

Ripley

DP

,

Berry

C

,

McCann

GP

,

Plein

S

,

Bucciarelli-Ducci

C

,

Dall'Armellina

E

,

Prasad

A

,

Bijsterveld

P

,

Foley

JR

,

Mangion

K

,

Sculpher

M

,

Walker

S

,

Everett

CC

,

Cairns

DA

,

Sharples

LD

,

Brown

JM

; CE-MARC 2 Investigators.

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

–

1060

.

56

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

–

894

.

57

Kim

RJ

,

Wu

E

,

Rafael

A

,

Chen

EL

,

Parker

MA

,

Simonetti

O

,

Klocke

FJ

,

Bonow

RO

,

Judd

RM.

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

.

N Engl J Med

2000

;

343

:

1445

–

1453

.

58

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

–

189

.

59

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

–

1358

.

60

Montalescot

G

,

Sechtem

U

,

Achenbach

S

,

Andreotti

F

,

Arden

C

,

Budaj

A

,

Bugiardini

R

,

Crea

F

,

Cuisset

T

,

Di Mario

C

,

Ferreira

JR

,

Gersh

BJ

,

Gitt

AK

,

Hulot

JS

,

Marx

N

,

Opie

LH

,

Pfisterer

M

,

Prescott

E

,

Ruschitzka

F

,

Sabate

M

,

Senior

R

,

Taggart

DP

,

van der Wall

EE

,

Vrints

CJ.

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

.

61

Genders

TS

,

Steyerberg

EW

,

Alkadhi

H

,

Leschka

S

,

Desbiolles

L

,

Nieman

K

,

Galema

TW

,

Meijboom

WB

,

Mollet

NR

,

de Feyter

PJ

,

Cademartiri

F

,

Maffei

E

,

Dewey

M

,

Zimmermann

E

,

Laule

M

,

Pugliese

F

,

Barbagallo

R

,

Sinitsyn

V

,

Bogaert

J

,

Goetschalckx

K

,

Schoepf

UJ

,

Rowe

GW

,

Schuijf

JD

,

Bax

JJ

,

de Graaf

FR

,

Knuuti

J

,

Kajander

S

,

van Mieghem

CA

,

Meijs

MF

,

Cramer

MJ

,

Gopalan

D

,

Feuchtner

G

,

Friedrich

G

,

Krestin

GP

,

Hunink

MG

, CAD Consortium.

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

.

Eur Heart J

2011

;

32

:

1316

–

1330

.

62

Foldyna

B

,

Udelson

JE

,

Karady

J

,

Banerji

D

,

Lu

MT

,

Mayrhofer

T

,

Bittner

DO

,

Meyersohn

NM

,

Emami

H

,

Genders

TSS

,

Fordyce

CB

,

Ferencik

M

,

Douglas

PS

,

Hoffmann

U.

Pretest probability for patients with suspected obstructive coronary artery disease: re-evaluating Diamond-Forrester for the contemporary era and clinical implications: insights from the PROMISE trial

.

Eur Heart J Cardiovasc Imaging

2018

;

20

:

574

–

581

.

63

Adamson

PD

,

Newby

DE

,

Hill

CL

,

Coles

A

,

Douglas

PS

,

Fordyce

CB.

Comparison of international guidelines for assessment of suspected stable angina: insights from the PROMISE and SCOT-HEART

.

JACC Cardiovasc Imaging

2018

;

11

:

1301

–

1310

.

64

Juarez-Orozco

LE

,

Saraste

A

,

Capodanno

D

,

Prescott

E

,

Ballo

H

,

Bax

JJ

,

Wijns

W

,

Knuuti

J.

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

.

Eur Heart J Cardiovasc Imaging

2019

;doi: 10.1093/ehjci/jez054.

65

Versteylen

MO

,

Joosen

IA

,

Shaw

LJ

,

Narula

J

,

Hofstra

L.

Comparison of Framingham, PROCAM, SCORE, and Diamond Forrester to predict coronary atherosclerosis and cardiovascular events

.

J Nucl Cardiol

2011

;

18

:

904

–

911

.

66

Fordyce

CB

,

Douglas

PS

,

Roberts

RS

,

Hoffmann

U

,

Al-Khalidi

HR

,

Patel

MR

,

Granger

CB

,

Kostis

J

,

Mark

DB

,

Lee

KL

,

Udelson

JE

; Prospective Multicenter Imaging Study for Evaluation of Chest Pain (PROMISE) Investigators.

Identification of patients with stable chest pain deriving minimal value from noninvasive testing: the PROMISE minimal-risk tool, a secondary analysis of a randomized clinical trial

.

JAMA Cardiol

2017

;

2

:

400

–

408

.

67

Jensen

JM

,

Voss

M

,

Hansen

VB

,

Andersen

LK

,

Johansen

PB

,

Munkholm

H

,

Norgaard

BL.

Risk stratification of patients suspected of coronary artery disease: comparison of five different models

.

Atherosclerosis

2012

;

220

:

557

–

562

.

68

Sharma

A

,

Sekaran

NK

,

Coles

A

,

Pagidipati

NJ

,

Hoffmann

U

,

Mark

DB

,

Lee

KL

,

Al-Khalidi

HR

,

Lu

MT

,

Pellikka

PA

,

Trong

QA

,

Douglas

PS.

Impact of diabetes mellitus on the evaluation of stable chest pain patients: insights from the PROMISE (Prospective Multicenter Imaging Study for Evaluation of Chest Pain) trial

.

J Am Heart Assoc

2017

;

6

:

e007019

.

69

Budoff

MJ

,

Mayrhofer

T

,

Ferencik

M

,

Bittner

D

,

Lee

KL

,

Lu

MT

,

Coles

A

,

Jang

J

,

Krishnam

M

,

Douglas

PS

,

Hoffmann

U

; PROMISE Investigators.

Prognostic value of coronary artery calcium in the PROMISE study (Prospective Multicenter Imaging Study for Evaluation of Chest Pain)

.

Circulation

2017

;

136

:

1993

–

2005

.

70

Villines

TC

,

Hulten

EA

,

Shaw

LJ

,

Goyal

M

,

Dunning

A

,

Achenbach

S

,

Al-Mallah

M

,

Berman

DS

,

Budoff

MJ

,

Cademartiri

F

,

Callister

TQ

,

Chang

HJ

,

Cheng

VY

,

Chinnaiyan

K

,

Chow

BJ

,

Delago

A

,

Hadamitzky

M

,

Hausleiter

J

,

Kaufmann

P

,

Lin

FY

,

Maffei

E

,

Raff

GL

,

Min

JK

; CONFIRM Registry Investigators.

Prevalence and severity of coronary artery disease and adverse events among symptomatic patients with coronary artery calcification scores of zero undergoing coronary computed tomography angiography: results from the CONFIRM (Coronary CT Angiography Evaluation for Clinical Outcomes: An International Multicenter) registry

.

J Am Coll Cardiol

2011

;

58

:

2533

–

2540

.

71

De Bruyne

B

,

Pijls

NH

,

Kalesan

B

,

Barbato

E

,

Tonino

PA

,

Piroth

Z

,

Jagic

N

,

Mobius-Winkler

S

,

Rioufol

G

,

Witt

N

,

Kala

P

,

MacCarthy

P

,

Engstrom

T

,

Oldroyd

KG

,

Mavromatis

K

,

Manoharan

G

,

Verlee

P

,

Frobert

O

,

Curzen

N

,

Johnson

JB

,

Juni

P

,

Fearon

WF

; FAME 2 Trial Investigators.

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

.

N Engl J Med

2012

;

367

:

991

–

1001

.

72

Tonino

PA

,

De Bruyne

B

,

Pijls

NH

,

Siebert

U

,

Ikeno

F

,

van

t

,

Veer

M

,

Klauss

V

,

Manoharan

G

,

Engstrom

T

,

Oldroyd

KG

,

Ver Lee

PN

,

MacCarthy

PA

,

Fearon

WF

,

FAME

Study Investigators.

Fractional flow reserve versus angiography for guiding percutaneous coronary intervention

.

N Engl J Med

2009

;

360

:

213

–

224

.

73

Knuuti

J

,

Ballo

H

,

Juarez-Orozco

LE

,

Saraste

A

,

Kolh

P

,

Rutjes

AWS

,

Juni

P

,

Windecker

S

,

Bax

JJ

,

Wijns

W.

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

–

3330

.

74

Tonino

PA

,

Fearon

WF

,

De Bruyne

B

,

Oldroyd

KG

,

Leesar

MA

,

Ver Lee

PN

,

Maccarthy

PA

,

Van't Veer

M

,

Pijls

NH.

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

–

2821

.

75

Hoffmann

U

,

Ferencik

M

,

Udelson

JE

,

Picard

MH

,

Truong

QA

,

Patel

MR

,

Huang

M

,

Pencina

M

,

Mark

DB

,

Heitner

JF

,

Fordyce

CB

,

Pellikka

PA

,

Tardif

JC

,

Budoff

M

,

Nahhas

G

,

Chow

B

,

Kosinski

AS

,

Lee

KL

,

Douglas

PS

; PROMISE Investigators.

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

–

2332

.

76

Siontis

GC

,

Mavridis

D

,

Greenwood

JP

,

Coles

B

,

Nikolakopoulou

A

,

Juni

P

,

Salanti

G

,

Windecker

S.

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

.

77

Collet

C

,

Onuma

Y

,

Andreini

D

,

Sonck

J

,

Pompilio

G

,

Mushtaq

S

,

La Meir

M

,

Miyazaki

Y

,

de Mey

J

,

Gaemperli

O

,

Ouda

A

,

Maureira

JP

,

Mandry

D

,

Camenzind

E

,

Macron

L

,

Doenst

T

,

Teichgraber

U

,

Sigusch

H

,

Asano

T

,

Katagiri

Y

,

Morel

MA

,

Lindeboom

W

,

Pontone

G

,

Luscher

TF

,

Bartorelli

AL

,

Serruys

PW.

Coronary computed tomography angiography for heart team decision-making in multivessel coronary artery disease

.

Eur Heart J

2018

;

39

:

3689

–

3698

.

78

Lubbers

M

,

Dedic

A

,

Coenen

A

,

Galema

T

,

Akkerhuis

J

,

Bruning

T

,

Krenning

B

,

Musters

P

,

Ouhlous

M

,

Liem

A

,

Niezen

A

,

Hunink

M

,

de Feijter

P

,

Nieman

K.

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

–

1243

.

79

Zacharias

K

,

Ahmed

A

,

Shah

BN

,

Gurunathan

S

,

Young

G

,

Acosta

D

,

Senior

R.

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

.

80

Williams

MC

,

Hunter

A

,

Shah

ASV

,

Assi

V

,

Lewis

S

,

Smith

J

,

Berry

C

,

Boon

NA

,

Clark

E

,

Flather

M

,

Forbes

J

,

McLean

S

,

Roditi

G

,

van Beek

EJR

,

Timmis

AD

,

Newby

DE

; SCOT-HEART Investigators.

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

.

J Am Coll Cardiol

2016

;

67

:

1759

–

1768

.

81

Jorgensen

ME

,

Andersson

C

,

Norgaard

BL

,

Abdulla

J

,

Shreibati

JB

,

Torp-Pedersen

C

,

Gislason

GH

,

Shaw

RE

,

Hlatky

MA.

Functional testing or coronary computed tomography angiography in patients with stable coronary artery disease

.

J Am Coll Cardiol

2017

;

69

:

1761

–

1770

.

82

Roifman

I

,

Wijeysundera

HC

,

Austin

PC

,

Rezai

MR

,

Wright

GA

,

Tu

JV.

Comparison of anatomic and clinical outcomes in patients undergoing alternative initial noninvasive testing strategies for the diagnosis of stable coronary artery disease

.

J Am Heart Assoc

2017

;

6

:

e005462

.

83

Shaw

LJ

,

Mieres

JH

,

Hendel

RH

,

Boden

WE

,

Gulati

M

,

Veledar

E

,

Hachamovitch

R

,

Arrighi

JA

,

Merz

CN

,

Gibbons

RJ

,

Wenger

NK

,

Heller

GV

; WOMEN Trial Investigators.

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

–

1249

.

84

Steurer

J

,

Fischer

JE

,

Bachmann

LM

,

Koller

M

,

ter Riet

G.

Communicating accuracy of tests to general practitioners: a controlled study

.

BMJ

2002

;

324

:

824

–

826

.

85

Gueret

P

,

Deux

JF

,

Bonello

L

,

Sarran

A

,

Tron

C

,

Christiaens

L

,

Dacher

JN

,

Bertrand

D

,

Leborgne

L

,

Renard

C

,

Caussin

C

,

Cluzel

P

,

Helft

G

,

Crochet

D

,

Vernhet-Kovacsik

H

,

Chabbert

V

,

Ferrari

E

,

Gilard

M

,

Willoteaux

S

,

Furber

A

,

Barone-Rochette

G

,

Jankowski

A

,

Douek

P

,

Mousseaux

E

,

Sirol

M

,

Niarra

R

,

Chatellier

G

,

Laissy

JP.

Diagnostic performance of computed tomography coronary angiography (from the prospective national multicenter multivendor EVASCAN study)

.

Am J Cardiol

2013

;

111

:

471

–

478

.

86

Karthikeyan

G

,

Guzic Salobir

B

,

Jug

B

,

Devasenapathy

N

,

Alexanderson

E

,

Vitola

J

,

Kraft

O

,

Ozkan

E

,

Sharma

S

,

Purohit

G

,

Dolenc Novak

M

,

Meave

A

,

Trevethan

S

,

Cerci

R

,

Zier

S

,

Gotthardtova

L

,

Jonszta

T

,

Altin

T

,

Soydal

C

,

Patel

C

,

Gulati

G

,

Paez

D

,

Dondi

M

,

Kashyap

R.

Functional compared to anatomical imaging in the initial evaluation of patients with suspected coronary artery disease: an international, multi-center, randomized controlled trial (IAEA-SPECT/CTA study)

.

J Nucl Cardiol

2017

;

24

:

507

–

517

.

87

Knuuti

J

,

Bengel

F

,

Bax

JJ

,

Kaufmann

PA

,

Le Guludec

D

,

Perrone Filardi

P

,

Marcassa

C

,

Ajmone Marsan

N

,

Achenbach

S

,

Kitsiou

A

,

Flotats

A

,

Eeckhout

E

,

Minn

H

,

Hesse

B.

Risks and benefits of cardiac imaging: an analysis of risks related to imaging for coronary artery disease

.

Eur Heart J

2014

;

35

:

633

–

638

.

88

Neumann

FJ

,

Sousa-Uva

M

,

Ahlsson

A

,

Alfonso

F

,

Banning

AP

,

Benedetto

U

,

Byrne

RA

,

Collet

JP

,

Falk

V

,

Head

SJ

,

Juni

P

,

Kastrati

A

,

Koller

A

,

Kristensen

SD

,

Niebauer

J

,

Richter

DJ

,

Seferovic

PM

,

Sibbing

D

,

Stefanini

GG

,

Windecker

S

,

Yadav

R

,

Zembala

MO.

2018 ESC/EACTS Guidelines on myocardial revascularization

.

Eur Heart J

2019

;

40

:

87

–

165

.

89

Escaned

J

,

Echavarria-Pinto

M

,

Garcia-Garcia

HM

,

van de Hoef

TP

,

de Vries

T

,

Kaul

P

,

Raveendran

G

,

Altman

JD

,

Kurz

HI

,

Brechtken

J

,

Tulli

M

,

Von Birgelen

C

,

Schneider

JE

,

Khashaba

AA

,

Jeremias

A

,

Baucum

J

,

Moreno

R

,

Meuwissen

M

,

Mishkel

G

,

van Geuns

RJ

,

Levite

H

,

Lopez-Palop

R

,

Mayhew

M

,

Serruys

PW

,

Samady

H

,

Piek

JJ

,

Lerman

A

; ADVISE II Study Group.

Prospective assessment of the diagnostic accuracy of instantaneous wave-free ratio to assess coronary stenosis relevance: results of ADVISE II international, multicenter study (ADenosine Vasodilator Independent Stenosis Evaluation II)

.

JACC Cardiovasc Interv

2015

;

8

:

824

–

833

.

90

Toth

G

,

Hamilos

M

,

Pyxaras

S

,

Mangiacapra

F

,

Nelis

O

,

De Vroey

F

,

Di Serafino

L

,

Muller

O

,

Van Mieghem

C

,

Wyffels

E

,

Heyndrickx

GR

,

Bartunek

J

,

Vanderheyden

M

,

Barbato

E

,

Wijns

W

,

De Bruyne

B.

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

.

Eur Heart J

2014

;

35

:

2831

–

2838

.

91

Jeremias

A

,

Maehara

A

,

Genereux

P

,

Asrress

KN

,

Berry

C

,

De Bruyne

B

,

Davies

JE

,

Escaned

J

,

Fearon

WF

,

Gould

KL

,

Johnson

NP

,

Kirtane

AJ

,

Koo

BK

,

Marques

KM

,

Nijjer

S

,

Oldroyd

KG

,

Petraco

R

,

Piek

JJ

,

Pijls

NH

,

Redwood

S

,

Siebes

M

,

Spaan

JAE

,

van 't Veer

M

,

Mintz

GS

,

Stone

GW.

Multicenter core laboratory comparison of the instantaneous wave-free ratio and resting Pd/Pa with fractional flow reserve: the RESOLVE study

.

J Am Coll Cardiol

2014

;

63

:

1253

–

1261

.

92

Van Belle

E

,

Rioufol

G

,

Pouillot

C

,

Cuisset

T

,

Bougrini

K

,

Teiger

E

,

Champagne

S

,

Belle

L

,

Barreau

D

,

Hanssen

M

,

Besnard

C

,

Dauphin

R

,

Dallongeville

J

,

El Hahi

Y

,

Sideris

G

,

Bretelle

C

,

Lhoest

N

,

Barnay

P

,

Leborgne

L

,

Dupouy

P

; Investigators of the Registre Français de la FFR–R3F.

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

–

185

.

93

Curzen

N

,

Rana

O

,

Nicholas

Z

,

Golledge

P

,

Zaman

A

,

Oldroyd

K

,

Hanratty

C

,

Banning

A

,

Wheatcroft

S

,

Hobson

A

,

Chitkara

K

,

Hildick-Smith

D

,

McKenzie

D

,

Calver

A

,

Dimitrov

BD

,

Corbett

S.

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

–

255

.

94

Mason

PJ

,

Shah

B

,

Tamis-Holland

JE

,

Bittl

JA

,

Cohen

MG

,

Safirstein

J

,

Drachman

DE

,

Valle

JA

,

Rhodes

D

,

Gilchrist

IC

; American Heart Association Interventional Cardiovascular Care Committee of the Council on Clinical Cardiology; Council on Cardiovascular and Stroke Nursing; Council on Peripheral Vascular Disease; Council on Genomic and Precision Medicine.

An update on radial artery access and best practices for transradial coronary angiography and intervention in acute coronary syndrome: a scientific statement from the American Heart Association

.

Circ Cardiovasc Interv

2018

;

11

:

e000035

.

95

Arora

N

,

Matheny

ME

,

Sepke

C

,

Resnic

FS.

A propensity analysis of the risk of vascular complications after cardiac catheterization procedures with the use of vascular closure devices

.

Am Heart J

2007

;

153

:

606

–

611

.

96

Noto

TJ

Jr,

Johnson

LW

,

Krone

R

,

Weaver

WF

,

Clark

DA

,

Kramer

JR

Jr,

Vetrovec

GW.

Cardiac catheterization 1990: a report of the Registry of the Society for Cardiac Angiography and Interventions (SCA&I)

.

Cathet Cardiovasc Diagn

1991

;

24

:

75

–

83

.

97

Abidov

A

,

Rozanski

A

,

Hachamovitch

R

,

Hayes

SW

,

Aboul-Enein

F

,

Cohen

I

,

Friedman

JD

,

Germano

G

,

Berman

DS.

Prognostic significance of dyspnea in patients referred for cardiac stress testing

.

N Engl J Med

2005

;

353

:

1889

–

1898

.

98

Gupta

S

,

Rohatgi

A

,

Ayers

CR

,

Willis

BL

,

Haskell

WL

,

Khera

A

,

Drazner

MH

,

de Lemos

JA

,

Berry

JD.

Cardiorespiratory fitness and classification of risk of cardiovascular disease mortality

.

Circulation

2011

;

123

:

1377

–

1383

.

99

Gulati

M

,

Black

HR

,

Shaw

LJ

,

Arnsdorf

MF

,

Merz

CN

,

Lauer

MS

,

Marwick

TH

,

Pandey

DK

,

Wicklund

RH

,

Thisted

RA.

The prognostic value of a nomogram for exercise capacity in women

.

N Engl J Med

2005

;

353

:

468

–

475

.

100

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

.

101

Emond

M

,

Mock

MB

,

Davis

KB

,

Fisher

LD

,

Holmes

DR

Jr,

Chaitman

BR

,

Kaiser

GC

,

Alderman

E

,

Killip

T

III.

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

.

Circulation

1994

;

90

:

2645

–

2657

.

102

Mark

DB

,

Shaw

L

,

Harrell

FE

Jr,

Hlatky

MA

,

Lee

KL

,

Bengtson

JR

,

McCants

CB

,

Califf

RM

,

Pryor

DB.

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

.

N Engl J Med

1991

;

325

:

849

–

853

.

103

Shaw

LJ

,

Berman

DS

,

Picard

MH

,

Friedrich

MG

,

Kwong

RY

,

Stone

GW

,

Senior

R

,

Min

JK

,

Hachamovitch

R

,

Scherrer-Crosbie

M

,

Mieres

JH

,

Marwick

TH

,

Phillips

LM

,

Chaudhry

FA

,

Pellikka

PA

,

Slomka

P

,

Arai

AE

,

Iskandrian

AE

,

Bateman

TM

,

Heller

GV

,

Miller

TD

,

Nagel

E

,

Goyal

A

,

Borges-Neto

S

,

Boden

WE

,

Reynolds

HR

,

Hochman

JS

,

Maron

DJ

,

Douglas

PS

; National Institutes of Health/National Heart, Lung, and Blood Institute-Sponsored ISCHEMIA Trial Investigators.

Comparative definitions for moderate-severe ischemia in stress nuclear, echocardiography, and magnetic resonance imaging

.

JACC Cardiovasc Imaging

2014

;

7

:

593

–

604

.

104

Johnson

NP

,

Toth

GG

,

Lai

D

,

Zhu

H

,

Acar

G

,

Agostoni

P

,

Appelman

Y

,

Arslan

F

,

Barbato

E

,

Chen

SL

,

Di Serafino

L

,

Dominguez-Franco

AJ

,

Dupouy

P

,

Esen

AM

,

Esen

OB

,

Hamilos

M

,

Iwasaki

K

,

Jensen

LO

,

Jimenez-Navarro

MF

,

Katritsis

DG

,

Kocaman

SA

,

Koo

BK

,

Lopez-Palop

R

,

Lorin

JD

,

Miller

LH

,

Muller

O

,

Nam

CW

,

Oud

N

,

Puymirat

E

,

Rieber

J

,

Rioufol

G

,

Rodes-Cabau

J

,

Sedlis

SP

,

Takeishi

Y

,

Tonino

PA

,

Van Belle

E

,

Verna

E

,

Werner

GS

,

Fearon

WF

,

Pijls

NH

,

De Bruyne

B

,

Gould

KL.

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

.

J Am Coll Cardiol

2014

;

64

:

1641

–

1654

.

105

Smulders

MW

,

Jaarsma

C

,

Nelemans

PJ

,

Bekkers

S

,

Bucerius

J

,

Leiner

T

,

Crijns

H

,

Wildberger

JE

,

Schalla

S.

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

–

987

.

106

Hachamovitch

R

,

Rozanski

A

,

Shaw

LJ

,

Stone

GW

,

Thomson

LE

,

Friedman

JD

,

Hayes

SW

,

Cohen

I

,

Germano

G

,

Berman

DS.

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

–

1024

.

107

Barbato

E

,

Toth

GG

,

Johnson

NP

,

Pijls

NH

,

Fearon

WF

,

Tonino

PA

,

Curzen

N

,

Piroth

Z

,

Rioufol

G

,

Juni

P

,

De Bruyne

B.

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

.

J Am Coll Cardiol

2016

;

68

:

2247

–

2255

.

108

Maaniitty

T

,

Stenstrom

I

,

Bax

JJ

,

Uusitalo

V

,

Ukkonen

H

,

Kajander

S

,

Maki

M

,

Saraste

A

,

Knuuti

J.

Prognostic value of coronary CT angiography with selective PET perfusion imaging in coronary artery disease

.

JACC Cardiovasc Imaging

2017

;

10

:

1361

–

1370

.

109

Pazhenkottil

AP

,

Nkoulou

RN

,

Ghadri

JR

,

Herzog

BA

,

Buechel

RR

,

Kuest

SM

,

Wolfrum

M

,

Fiechter

M

,

Husmann

L

,

Gaemperli

O

,

Kaufmann

PA.

Prognostic value of cardiac hybrid imaging integrating single-photon emission computed tomography with coronary computed tomography angiography

.

Eur Heart J

2011

;

32

:

1465

–

1471

.

110

Stanton

T

,

Leano

R

,

Marwick

TH.

Prediction of all-cause mortality from global longitudinal speckle strain: comparison with ejection fraction and wall motion scoring

.

Circ Cardiovasc Imaging

2009

;

2

:

356

–

364

.

111

Haugaa

KH

,

Grenne

BL

,

Eek

CH

,

Ersboll

M

,

Valeur

N

,

Svendsen

JH

,

Florian

A

,

Sjoli

B

,

Brunvand

H

,

Kober

L

,

Voigt

JU

,

Desmet

W

,

Smiseth

OA

,

Edvardsen

T.

Strain echocardiography improves risk prediction of ventricular arrhythmias after myocardial infarction

.

JACC Cardiovasc Imaging

2013

;

6

:

841

–

850

.

112

Ng

ACT

,

Prihadi

EA

,

Antoni

ML

,

Bertini

M

,

Ewe

SH

,

Ajmone Marsan

N

,

Leung

DY

,

Delgado

V

,

Bax

JJ.

Left ventricular global longitudinal strain is predictive of all-cause mortality independent of aortic stenosis severity and ejection fraction

.

Eur Heart J Cardiovasc Imaging

2018

;

19

:

859

–

867

.

113

Kalam

K

,

Otahal

P

,

Marwick

TH.

Prognostic implications of global LV dysfunction: a systematic review and meta-analysis of global longitudinal strain and ejection fraction

.

Heart

2014

;

100

:

1673

–

1680

.

114

Scharrenbroich

J

,

Hamada

S

,

Keszei

A

,

Schroder

J

,

Napp

A

,

Almalla

M

,

Becker

M

,

Altiok

E.

Use of two-dimensional speckle tracking echocardiography to predict cardiac events: comparison of patients with acute myocardial infarction and chronic coronary artery disease

.

Clin Cardiol

2018

;

41

:

111

–

118

.

115

Park

SJ

,

Ahn

JM

,

Kang

SJ

,

Yoon

SH

,

Koo

BK

,

Lee

JY

,

Kim

WJ

,

Park

DW

,

Lee

SW

,

Kim

YH

,

Lee

CW

,

Park

SW.

Intravascular ultrasound-derived minimal lumen area criteria for functionally significant left main coronary artery stenosis

.

JACC Cardiovasc Interv

2014

;

7

:

868

–

874

.

116

D'Ascenzo

F

,

Barbero

U

,

Cerrato

E

,

Lipinski

MJ

,

Omede

P

,

Montefusco

A

,

Taha

S

,

Naganuma

T

,

Reith

S

,

Voros

S

,

Latib

A

,

Gonzalo

N

,

Quadri

G

,

Colombo

A

,

Biondi-Zoccai

G

,

Escaned

J

,

Moretti

C

,

Gaita

F.

Accuracy of intravascular ultrasound and optical coherence tomography in identifying functionally significant coronary stenosis according to vessel diameter: a meta-analysis of 2,581 patients and 2,807 lesions

.

Am Heart J

2015

;

169

:

663

–

673

.

117

Maron

DJ

,

Boden

WE

,

O'Rourke

RA

,

Hartigan

PM

,

Calfas

KJ

,

Mancini

GB

,

Spertus

JA

,

Dada

M

,

Kostuk

WJ

,

Knudtson

M

,

Harris

CL

,

Sedlis

SP

,

Zoble

RG

,

Title

LM

,

Gosselin

G

,

Nawaz

S

,

Gau

GT

,

Blaustein

AS

,

Bates

ER

,

Shaw

LJ

,

Berman

DS

,

Chaitman

BR

,

Weintraub

WS

,

Teo

KK

,

COURAGE

Trial Research Group.

Intensive multifactorial intervention for stable coronary artery disease: optimal medical therapy in the COURAGE (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation) trial

.

J Am Coll Cardiol

2010

;

55

:

1348

–

1358

.

118

Rotenstein

LS

,

Huckman

RS

,

Wagle

NW.

Making patients and doctors happier - the potential of patient-reported outcomes

.

N Engl J Med

2017

;

377

:

1309

–

1312

.

119

Chow

CK

,

Jolly

S

,

Rao-Melacini

P

,

Fox

KA

,

Anand

SS

,

Yusuf

S.

Association of diet, exercise, and smoking modification with risk of early cardiovascular events after acute coronary syndromes

.

Circulation

2010

;

121

:

750

–

758

.

120

Booth

JN III

,

Levitan

EB

,

Brown

TM

,

Farkouh

ME

,

Safford

MM

,

Muntner

P.

Effect of sustaining lifestyle modifications (nonsmoking, weight reduction, physical activity, and mediterranean diet) after healing of myocardial infarction, percutaneous intervention, or coronary bypass (from the REasons for Geographic and Racial Differences in Stroke Study)

.

Am J Cardiol

2014

;

113

:

1933

–

1940

.

121

Giannuzzi

P

,

Temporelli

PL

,

Marchioli

R

,

Maggioni

AP

,

Balestroni

G

,

Ceci

V

,

Chieffo

C

,

Gattone

M

,

Griffo

R

,

Schweiger

C

,

Tavazzi

L

,

Urbinati

S

,

Valagussa

F

,

Vanuzzo

D

; GOSPEL Investigators.

Global secondary prevention strategies to limit event recurrence after myocardial infarction: results of the GOSPEL study, a multicenter, randomized controlled trial from the Italian Cardiac Rehabilitation Network

.

Arch Intern Med

2008

;

168

:

2194

–

2204

.

122

Keteyian

SJ

,

Brawner

CA

,

Savage

PD

,

Ehrman

JK

,

Schairer

J

,

Divine

G

,

Aldred

H

,

Ophaug

K

,

Ades

PA.

Peak aerobic capacity predicts prognosis in patients with coronary heart disease

.

Am Heart J

2008

;

156

:

292

–

300

.

123

Wood

DA

,

Kotseva

K

,

Connolly

S

,

Jennings

C

,

Mead

A

,

Jones

J

,

Holden

A

,

De Bacquer

D

,

Collier

T

,

De Backer

G

,

Faergeman

O

;

EUROACTION Study Group. Nurse-coordinated multidisciplinary, family-based cardiovascular disease prevention programme (EUROACTION) for patients with coronary heart disease and asymptomatic individuals at high risk of cardiovascular disease: a paired, cluster-randomised controlled trial

.

Lancet

2008

;

371

:

1999

–

2012

.

124

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

.

125

Prochaska

JJ

,

Benowitz

NL.

The past, present, and future of nicotine addiction therapy

.

Annu Rev Med

2016

;

67

:

467

–

486

.

126

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

.

127

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

.

128

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

.

129

El Dib

R

,

Suzumura

EA

,

Akl

EA

,

Gomaa

H

,

Agarwal

A

,

Chang

Y

,

Prasad

M

,

Ashoorion

V

,

Heels-Ansdell

D

,

Maziak

W

,

Guyatt

G.

Electronic nicotine delivery systems and/or electronic non-nicotine delivery systems for tobacco smoking cessation or reduction: a systematic review and meta-analysis

.

BMJ Open

2017

;

7

:

e012680

.

130

Hartmann-Boyce

J

,

McRobbie

H

,

Bullen

C

,

Begh

R

,

Stead

LF

,

Hajek

P.

Electronic cigarettes for smoking cessation

.

Cochrane Database Syst Rev

2016

;

9

:

CD010216

.

131

Kalkhoran

S

,

Glantz

SA.

E-cigarettes and smoking cessation in real-world and clinical settings: a systematic review and meta-analysis

.

Lancet Respir Med

2016

;

4

:

116

–

128

.

132

Malas

M

,

van der Tempel

J

,

Schwartz

R

,

Minichiello

A

,

Lightfoot

C

,

Noormohamed

A

,

Andrews

J

,

Zawertailo

L

,

Ferrence

R.

Electronic cigarettes for smoking cessation: a systematic review

.

Nicotine Tob Res

2016

;

18

:

1926

–

1936

.

133

Hajek

P

,

Phillips-Waller

A

,

Przulj

D

,

Pesola

F

,

Myers Smith

K

,

Bisal

N

,

Li

J

,

Parrott

S

,

Sasieni

P

,

Dawkins

L

,

Ross

L

,

Goniewicz

M

,

Wu

Q

,

McRobbie

HJ.

A randomized trial of E-cigarettes versus nicotine-replacement therapy

.

N Engl J Med

2019

;

380

:

629

–

637

.

134

Freeman

AM

,

Morris

PB

,

Barnard

N

,

Esselstyn

CB

,

Ros

E

,

Agatston

A

,

Devries

S

,

O'Keefe

J

,

Miller

M

,

Ornish

D

,

Williams

K

,

Kris-Etherton

P.

Trending cardiovascular nutrition controversies

.

J Am Coll Cardiol

2017

;

69

:

1172

–

1187

.

135

Wang

X

,

Ouyang

Y

,

Liu

J

,

Zhu

M

,

Zhao

G

,

Bao

W

,

Hu

FB.

Fruit and vegetable consumption and mortality from all causes, cardiovascular disease, and cancer: systematic review and dose-response meta-analysis of prospective cohort studies

.

BMJ

2014

;

349

:

g4490

.

136

Sofi

F

,

Abbate

R

,

Gensini

GF

,

Casini

A.

Accruing evidence on benefits of adherence to the Mediterranean diet on health: an updated systematic review and meta-analysis

.

Am J Clin Nutr

2010

;

92

:

1189

–

1196

.

137

Miller

V

,

Mente

A

,

Dehghan

M

,

Rangarajan

S

,

Zhang

X

,

Swaminathan

S

,

Dagenais

G

,

Gupta

R

,

Mohan

V

,

Lear

S

,

Bangdiwala

SI

,

Schutte

AE

,

Wentzel-Viljoen

E

,

Avezum

A

,

Altuntas

Y

,

Yusoff

K

,

Ismail

N

,

Peer

N

,

Chifamba

J

,

Diaz

R

,

Rahman

O

,

Mohammadifard

N

,

Lana

F

,

Zatonska

K

,

Wielgosz

A

,

Yusufali

A

,

Iqbal

R

,

Lopez-Jaramillo

P

,

Khatib

R

,

Rosengren

A

,

Kutty

VR

,

Li

W

,

Liu

J

,

Liu

X

,

Yin

L

,

Teo

K

,

Anand

S

,

Yusuf

S

; Prospective Urban Rural Epidemiology (PURE) study investigators.

Fruit, vegetable, and legume intake, and cardiovascular disease and deaths in 18 countries (PURE): a prospective cohort study

.

Lancet

2017

;

390

:

2037

–

2049

.

138

Estruch

R

,

Ros

E

,

Salas-Salvadó

J

,

Covas

MI

,

Corella

D

,

Arós

F

,

Gómez-Gracia

E

,

Ruiz-Gutiérrez

V

,

Fiol

M

,

Lapetra

J

,

Lamuela-Raventos

RM

,

Serra-Majem

L

,

Pintó

X

,

Basora

J

,

Muñoz

MA

,

Sorlí

JV

,

Martínez

JA

,

Fitó

M

,

Gea

A

,

Hernán

MA

,

Martínez-González

MA

,

PREDIMED

Study Investigators.

Primary prevention of cardiovascular disease with a Mediterranean diet supplemented with extra-virgin olive oil or nuts

.

N Engl J Med

2018

;

378

:

e34

.

139

Wood

AM

,

Kaptoge

S

,

Butterworth

AS

,

Willeit

P

,

Warnakula

S

,

Bolton

T

,

Paige

E

,

Paul

DS

,

Sweeting

M

,

Burgess

S

,

Bell

S

,

Astle

W

,

Stevens

D

,

Koulman

A

,

Selmer

RM

,

Verschuren

WMM

,

Sato

S

,

Njolstad

I

,

Woodward

M

,

Salomaa

V

,

Nordestgaard

BG

,

Yeap

BB

,

Fletcher

A

,

Melander

O

,

Kuller

LH

,

Balkau

B

,

Marmot

M

,

Koenig

W

,

Casiglia

E

,

Cooper

C

,

Arndt

V

,

Franco

OH

,

Wennberg

P

,

Gallacher

J

,

de la Camara

AG

,

Volzke

H

,

Dahm

CC

,

Dale

CE

,

Bergmann

MM

,

Crespo

CJ

,

van der Schouw

YT

,

Kaaks

R

,

Simons

LA

,

Lagiou

P

,

Schoufour

JD

,

Boer

JMA

,

Key

TJ

,

Rodriguez

B

,

Moreno-Iribas

C

,

Davidson

KW

,

Taylor

JO

,

Sacerdote

C

,

Wallace

RB

,

Quiros

JR

,

Tumino

R

,

Blazer

DG II

,

Linneberg

A

,

Daimon

M

,

Panico

S

,

Howard

B

,

Skeie

G

,

Strandberg

T

,

Weiderpass

E

,

Nietert

PJ

,

Psaty

BM

,

Kromhout

D

,

Salamanca-Fernandez

E

,

Kiechl

S

,

Krumholz

HM

,

Grioni

S

,

Palli

D

,

Huerta

JM

,

Price

J

,

Sundstrom

J

,

Arriola

L

,

Arima

H

,

Travis

RC

,

Panagiotakos

DB

,

Karakatsani

A

,

Trichopoulou

A

,

Kuhn

T

,

Grobbee

DE

,

Barrett-Connor

E

,

van Schoor

N

,

Boeing

H

,

Overvad

K

,

Kauhanen

J

,

Wareham

N

,

Langenberg

C

,

Forouhi

N

,

Wennberg

M

,

Despres

JP

,

Cushman

M

,

Cooper

JA

,

Rodriguez

CJ

,

Sakurai

M

,

Shaw

JE

,

Knuiman

M

,

Voortman

T

,

Meisinger

C

,

Tjonneland

A

,

Brenner

H

,

Palmieri

L

,

Dallongeville

J

,

Brunner

EJ

,

Assmann

G

,

Trevisan

M

,

Gillum

RF

,

Ford

I

,

Sattar

N

,

Lazo

M

,

Thompson

SG

,

Ferrari

P

,

Leon

DA

,

Smith

GD

,

Peto

R

,

Jackson

R

,

Banks

E

,

Di Angelantonio

E

,

Danesh

J

; Emerging Risk Factors Collaboration/EPIC-CVD/UK Biobank Alcohol Study Group.

Risk thresholds for alcohol consumption: combined analysis of individual-participant data for 599 912 current drinkers in 83 prospective studies

.

Lancet

2018

;

391

:

1513

–

1523

.

140

GBD 2016 Alcohol Collaborators.

Alcohol use and burden for 195 countries and territories, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016

.

Lancet

2018

;

392

:

1015

–

1035

.

141

Yusuf

S

,

Hawken

S

,

Ounpuu

S

,

Dans

T

,

Avezum

A

,

Lanas

F

,

McQueen

M

,

Budaj

A

,

Pais

P

,

Varigos

J

,

Lisheng

L

; INTERHEART Study Investigators.

Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study

.

Lancet

2004

;

364

:

937

–

952

.

142

Piano

MR.

Alcohol's effects on the cardiovascular system

.

Alcohol Res

2017

;

38

:

219

–

241

.

143

Khan

SS

,

Ning

H

,

Wilkins

JT

,

Allen

N

,

Carnethon

M

,

Berry

JD

,

Sweis

RN

,

Lloyd-Jones

DM.

Association of body mass index with lifetime risk of cardiovascular disease and compression of morbidity

.

JAMA Cardiol

2018

;

3

:

280

–

287

.

144

Pack

QR

,

Rodriguez-Escudero

JP

,

Thomas

RJ

,

Ades

PA

,

West

CP

,

Somers

VK

,

Lopez-Jimenez

F.

The prognostic importance of weight loss in coronary artery disease: a systematic review and meta-analysis

.

Mayo Clin Proc

2014

;

89

:

1368

–

1377

.

145

Gardner

CD

,

Trepanowski

JF

,

Del Gobbo

LC

,

Hauser

ME

,

Rigdon

J

,

Ioannidis

JPA

,

Desai

M

,

King

AC.

Effect of low-fat vs low-carbohydrate diet on 12-month weight loss in overweight adults and the association with genotype pattern or insulin secretion: the DIETFITS randomized clinical trial

.

JAMA

2018

;

319

:

667

–

679

.

146

Fiuza-Luces

C

,

Garatachea

N

,

Berger

NA

,

Lucia

A.

Exercise is the real polypill

.

Physiology (Bethesda)

2013

;

28

:

330

–

358

.

147

Bruning

RS

,

Sturek

M.

Benefits of exercise training on coronary blood flow in coronary artery disease patients

.

Prog Cardiovasc Dis

2015

;

57

:

443

–

453

.

148

Cheng

W

,

Zhang

Z

,

Cheng

W

,

Yang

C

,

Diao

L

,

Liu

W.

Associations of leisure-time physical activity with cardiovascular mortality: a systematic review and meta-analysis of 44 prospective cohort studies

.

Eur J Prev Cardiol

2018

;

25

:

1864

–

1872

.

149

Lahtinen

M

,

Toukola

T

,

Junttila

MJ

,

Piira

OP

,

Lepojarvi

S

,

Kaariainen

M

,

Huikuri

HV

,

Tulppo

MP

,

Kiviniemi

AM.

Effect of changes in physical activity on risk for cardiac death in patients with coronary artery disease

.

Am J Cardiol

2018

;

121

:

143

–

148

.

150

Stewart

RAH

,

Held

C

,

Hadziosmanovic

N

,

Armstrong

PW

,

Cannon

CP

,

Granger

CB

,

Hagstrom

E

,

Hochman

JS

,

Koenig

W

,

Lonn

E

,

Nicolau

JC

,

Steg

PG

,

Vedin

O

,

Wallentin

L

,

White

HD

; STABILITY Investigators.

Physical activity and mortality in patients with stable coronary heart disease

.

J Am Coll Cardiol

2017

;

70

:

1689

–

1700

.

151

Anderson

L

,

Thompson

DR

,

Oldridge

N

,

Zwisler

AD

,

Rees

K

,

Martin

N

,

Taylor

RS.

Exercise-based cardiac rehabilitation for coronary heart disease

.

Cochrane Database Syst Rev

2016

;

1

:

CD001800

.

152

Rauch

B

,

Davos

CH

,

Doherty

P

,

Saure

D

,

Metzendorf

MI

,

Salzwedel

A

,

Voller

H

,

Jensen

K

,

Schmid

JP

; ‘Cardiac Rehabilitation Section’, European Association of Preventive Cardiology (EAPC), in cooperation with the Institute of Medical Biometry and Informatics (IMBI), Department of Medical Biometry, University of Heidelberg, Cochrane Metabolic and Endocrine Disorders Group, Institute of General Practice, Heinrich-Heine University, Düsseldorf, Germany.

The prognostic effect of cardiac rehabilitation in the era of acute revascularisation and statin therapy: A systematic review and meta-analysis of randomized and non-randomized studies - The Cardiac Rehabilitation Outcome Study (CROS)

.

Eur J Prev Cardiol

2016

;

23

:

1914

–

1939

.

153

de Vries

H

,

Kemps

HM

,

van Engen-Verheul

MM

,

Kraaijenhagen

RA

,

Peek

N.

Cardiac rehabilitation and survival in a large representative community cohort of Dutch patients

.

Eur Heart J

2015

;

36

:

1519

–

1528

.

154

Benzer

W

,

Rauch

B

,

Schmid

JP

,

Zwisler

AD

,

Dendale

P

,

Davos

CH

,

Kouidi

E

,

Simon

A

,

Abreu

A

,

Pogosova

N

,

Gaita

D

,

Miletic

B

,

Bonner

G

,

Ouarrak

T

,

McGee

H

; EuroCaReD study group.

Exercise-based cardiac rehabilitation in twelve European countries results of the European cardiac rehabilitation registry

.

Int J Cardiol

2017

;

228

:

58

–

67

.

155

Ormel

J

,

Von Korff

M

,

Burger

H

,

Scott

K

,

Demyttenaere

K

,

Huang

YQ

,

Posada-Villa

J

,

Pierre Lepine

J

,

Angermeyer

MC

,

Levinson

D

,

de Girolamo

G

,

Kawakami

N

,

Karam

E

,

Medina-Mora

ME

,

Gureje

O

,

Williams

D

,

Haro

JM

,

Bromet

EJ

,

Alonso

J

,

Kessler

R.

Mental disorders among persons with heart disease - results from World Mental Health surveys

.

Gen Hosp Psychiatry

2007

;

29

:

325

–

334

.

156

Rudisch

B

,

Nemeroff

CB.

Epidemiology of comorbid coronary artery disease and depression

.

Biol Psychiatry

2003

;

54

:

227

–

240

.

157

Baumeister

H

,

Hutter

N

,

Bengel

J.

Psychological and pharmacological interventions for depression in patients with coronary artery disease

.

Cochrane Database Syst Rev

2011

;

9

:

CD008012

.

158

Richards

SH

,

Anderson

L

,

Jenkinson

CE

,

Whalley

B

,

Rees

K

,

Davies

P

,

Bennett

P

,

Liu

Z

,

West

R

,

Thompson

DR

,

Taylor

RS.

Psychological interventions for coronary heart disease: Cochrane systematic review and meta-analysis

.

Eur J Prev Cardiol

2018

;

25

:

247

–

259

.

159

Rutledge

T

,

Redwine

LS

,

Linke

SE

,

Mills

PJ.

A meta-analysis of mental health treatments and cardiac rehabilitation for improving clinical outcomes and depression among patients with coronary heart disease

.

Psychosom Med

2013

;

75

:

335

–

349

.

160

Brook

RD

,

Newby

DE

,

Rajagopalan

S.

Air pollution and cardiometabolic disease: an update and call for clinical trials

.

Am J Hypertens

2017

;

31

:

1

–

10

.

161

Munzel

T

,

Schmidt

FP

,

Steven

S

,

Herzog

J

,

Daiber

A

,

Sorensen

M.

Environmental noise and the cardiovascular system

.

J Am Coll Cardiol

2018

;

71

:

688

–

697

.

162

Steinke

EE

,

Jaarsma

T

,

Barnason

SA

,

Byrne

M

,

Doherty

S

,

Dougherty

CM

,

Fridlund

B

,

Kautz

DD

,

Martensson

J

,

Mosack

V

,

Moser

DK

; Council on Cardiovascular and Stroke Nursing of the American Heart Association and the ESC Council on Cardiovascular Nursing and Allied Professions (CCNAP).

Sexual counselling for individuals with cardiovascular disease and their partners: a consensus document from the American Heart Association and the ESC Council on Cardiovascular Nursing and Allied Professions (CCNAP)

.

Eur Heart J

2013

;

34

:

3217

–

3235

.

163

Bispo

GS

,

de Lima Lopes

J

,

de Barros

AL.

Cardiovascular changes resulting from sexual activity and sexual dysfunction after myocardial infarction: integrative review

.

J Clin Nurs

2013

;

22

:

3522

–

3531

.

164

Levine

GN

,

Steinke

EE

,

Bakaeen

FG

,

Bozkurt

B

,

Cheitlin

MD

,

Conti

JB

,

Foster

E

,

Jaarsma

T

,

Kloner

RA

,

Lange

RA

,

Lindau

ST

,

Maron

BJ

,

Moser

DK

,

Ohman

EM

,

Seftel

AD

,

Stewart

WJ

; American Heart Association Council on Clinical Cardiology; Council on Cardiovascular Nursing; Council on Cardiovascular Surgery and Anesthesia; Council on Quality of Care and Outcomes Research.

Sexual activity and cardiovascular disease: a scientific statement from the American Heart Association

.

Circulation

2012

;

125

:

1058

–

1072

.

165

Stein

R

,

Sardinha

A

,

Araujo

CG.

Sexual activity and heart patients: a contemporary perspective

.

Can J Cardiol

2016

;

32

:

410

–

420

.

166

Steinke

EE

,

Mosack

V

,

Hill

TJ.

Change in sexual activity after a cardiac event: the role of medications, comorbidity, and psychosocial factors

.

Appl Nurs Res

2015

;

28

:

244

–

250

.

167

Chowdhury

R

,

Khan

H

,

Heydon

E

,

Shroufi

A

,

Fahimi

S

,

Moore

C

,

Stricker

B

,

Mendis

S

,

Hofman

A

,

Mant

J

,

Franco

OH.

Adherence to cardiovascular therapy: a meta-analysis of prevalence and clinical consequences

.

Eur Heart J

2013

;

34

:

2940

–

2948

.

168

Gnjidic

D

,

Bennett

A

,

Le Couteur

DG

,

Blyth

FM

,

Cumming

RG

,

Waite

L

,

Handelsman

D

,

Naganathan

V

,

Matthews

S

,

Hilmer

SN.

Ischemic heart disease, prescription of optimal medical therapy and geriatric syndromes in community-dwelling older men: a population-based study

.

Int J Cardiol

2015

;

192

:

49

–

55

.

169

Mohammed

S

,

Arabi

A

,

El-Menyar

A

,

Abdulkarim

S

,

AlJundi

A

,

Alqahtani

A

,

Arafa

S

,

Al Suwaidi

J.

Impact of polypharmacy on adherence to evidence-based medication in patients who underwent percutaneous coronary intervention

.

Curr Vasc Pharmacol

2016

;

14

:

388

–

393

.

170

Wimmer

BC

,

Cross

AJ

,

Jokanovic

N

,

Wiese

MD

,

George

J

,

Johnell

K

,

Diug

B

,

Bell

JS.

Clinical outcomes associated with medication regimen complexity in older people: a systematic review

.

J Am Geriatr Soc

2017

;

65

:

747

–

753

.

171

Nieuwlaat

R

,

Wilczynski

N

,

Navarro

T

,

Hobson

N

,

Jeffery

R

,

Keepanasseril

A

,

Agoritsas

T

,

Mistry

N

,

Iorio

A

,

Jack

S

,

Sivaramalingam

B

,

Iserman

E

,

Mustafa

RA

,

Jedraszewski

D

,

Cotoi

C

,

Haynes

RB.

Interventions for enhancing medication adherence

.

Cochrane Database Syst Rev

2014

;

11

:

CD000011

.

172

Demonceau

J

,

Ruppar

T

,

Kristanto

P

,

Hughes

DA

,

Fargher

E

,

Kardas

P

,

De Geest

S

,

Dobbels

F

,

Lewek

P

,

Urquhart

J

,

Vrijens

B

; ABC project team.

Identification and assessment of adherence-enhancing interventions in studies assessing medication adherence through electronically compiled drug dosing histories: a systematic literature review and meta-analysis

.

Drugs

2013

;

73

:

545

–

562

.

173

Acharjee

S

,

Teo

KK

,

Jacobs

AK

,

Hartigan

PM

,

Barn

K

,

Gosselin

G

,

Tanguay

JF

,

Maron

DJ

,

Kostuk

WJ

,

Chaitman

BR

,

Mancini

GB

,

Spertus

JA

,

Dada

MR

,

Bates

ER

,

Booth

DC

,

Weintraub

WS

,

O'Rourke

RA

,

Boden

WE

; COURAGE Trial Research Group.

Optimal medical therapy with or without percutaneous coronary intervention in women with stable coronary disease: a pre-specified subset analysis of the Clinical Outcomes Utilizing Revascularization and Aggressive druG Evaluation (COURAGE) trial

.

Am Heart J

2016

;

173

:

108

–

117

.

174

Koertge

J

,

Weidner

G

,

Elliott-Eller

M

,

Scherwitz

L

,

Merritt-Worden

TA

,

Marlin

R

,

Lipsenthal

L

,

Guarneri

M

,

Finkel

R

,

Saunders

DE

Jr,

McCormac

P

,

Scheer

JM

,

Collins

RE

,

Ornish

D.

Improvement in medical risk factors and quality of life in women and men with coronary artery disease in the Multicenter Lifestyle Demonstration Project

.

Am J Cardiol

2003

;

91

:

1316

–

1322

.

175

MacIntyre

CR

,

Mahimbo

A

,

Moa

AM

,

Barnes

M.

Influenza vaccine as a coronary intervention for prevention of myocardial infarction

.

Heart

2016

;

102

:

1953

–

1956

.

176

Hebsur

S

,

Vakil

E

,

Oetgen

WJ

,

Kumar

PN

,

Lazarous

DF.

Influenza and coronary artery disease: exploring a clinical association with myocardial infarction and analyzing the utility of vaccination in prevention of myocardial infarction

.

Rev Cardiovasc Med

2014

;

15

:

168

–

175

.

177

Kadoglou

NPE

,

Bracke

F

,

Simmers

T

,

Tsiodras

S

,

Parissis

J.

Influenza infection and heart failure-vaccination may change heart failure prognosis?

Heart Fail Rev

2017

;

22

:

329

–

336

.

178

Clar

C

,

Oseni

Z

,

Flowers

N

,

Keshtkar-Jahromi

M

,

Rees

K.

Influenza vaccines for preventing cardiovascular disease

.

Cochrane Database Syst Rev

2015

;

5

:

CD005050

.

179

Paules

CI

,

Subbarao

K.

Influenza vaccination and prevention of cardiovascular disease mortality - Authors' reply

.

Lancet

2018

;

391

:

427

–

428

.

180

Mohseni

H

,

Kiran

A

,

Khorshidi

R

,

Rahimi

K.

Influenza vaccination and risk of hospitalization in patients with heart failure: a self-controlled case series study

.

Eur Heart J

2017

;

38

:

326

–

333

.

181

Artinian

NT

,

Fletcher

GF

,

Mozaffarian

D

,

Kris-Etherton

P

,

Van Horn

L

,

Lichtenstein

AH

,

Kumanyika

S

,

Kraus

WE

,

Fleg

JL

,

Redeker

NS

,

Meininger

JC

,

Banks

J

,

Stuart-Shor

EM

,

Fletcher

BJ

,

Miller

TD

,

Hughes

S

,

Braun

LT

,

Kopin

LA

,

Berra

K

,

Hayman

LL

,

Ewing

LJ

,

Ades

PA

,

Durstine

JL

,

Houston-Miller

N

,

Burke

LE

; American Heart Association Prevention Committee of the Council on Cardiovascular Nursing.

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

–

441

.

182

Janssen

V

,

De Gucht

V

,

Dusseldorp

E

,

Maes

S.

Lifestyle modification programmes for patients with coronary heart disease: a systematic review and meta-analysis of randomized controlled trials

.

Eur J Prev Cardiol

2013

;

20

:

620

–

640

.

183

Aldcroft

SA

,

Taylor

NF

,

Blackstock

FC

,

O'Halloran

PD.

Psychoeducational rehabilitation for health behavior change in coronary artery disease:

a systematic review of controlled trials. J Cardiopulm Rehabil Prev

2011

;

31

:

273

–

281

.

184

Voogdt-Pruis

HR

,

Beusmans

GH

,

Gorgels

AP

,

Kester

AD

,

Van Ree

JW.

Effectiveness of nurse-delivered cardiovascular risk management in primary care: a randomised trial

.

Br J Gen Pract

2010

;

60

:

40

–

46

.

185

Caldeira

D

,

Ferreira

JJ

,

Costa

J.

Influenza vaccination and prevention of cardiovascular disease mortality

.

Lancet

2018

;

391

:

426

–

427

.

186

Caldeira

D

,

Costa

J

,

Vaz-Carneiro

A.

[

Analysis of the Cochrane Review: Influenza Vaccines for Preventing Cardiovascular Disease. Cochrane Database Syst Rev. 2015;5:CD005050]

.

Acta Med Port

2015

;

28

:

424

–

426

.

187

Udell

JA

,

Farkouh

ME

,

Solomon

SD

,

Vardeny

O.

Does influenza vaccination influence cardiovascular complications?

Expert Rev Cardiovasc Ther

2015

;

13

:

593

–

596

.

188

Camm

AJ

,

Manolis

A

,

Ambrosio

G

,

Daly

C

,

Komajda

M

,

Lopez de Sa

E

,

Lopez-Sendon

JL

,

Mugelli

A

,

Muggli

F

,

Tamargo

J.

Unresolved issues in the management of chronic stable angina

.

Int J Cardiol

2015

;

201

:

200

–

207

.

189

Ferrari

R

,

Camici

PG

,

Crea

F

,

Danchin

N

,

Fox

K

,

Maggioni

AP

,

Manolis

AJ

,

Marzilli

M

,

Rosano

GMC

,

Lopez-Sendon

JL.

Expert consensus document: A ‘diamond’ approach to personalized treatment of angina

.

Nat Rev Cardiol

2018

;

15

:

120

–

132

.

190

Ambrosio

G

,

Mugelli

A

,

Lopez-Sendon

J

,

Tamargo

J

,

Camm

J.

Management of stable angina: A commentary on the European Society of Cardiology guidelines

.

Eur J Prev Cardiol

2016

;

23

:

1401

–

1412

.

191

Thadani

U.

Management of stable angina - current guidelines: a critical appraisal

.

Cardiovasc Drugs Ther

2016

;

30

:

419

–

426

.

192

Husted

SE

,

Ohman

EM.

Pharmacological and emerging therapies in the treatment of chronic angina

.

Lancet

2015

;

386

:

691

–

701

.

193

National Institute for Health and Care Excellence (NICE). Stable angina: management. Clinical guideline [CG126]. https://www.nice.org.uk/guidance/cg126 (

28 March 2019

).

194

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

–

436

.

195

Rousan

TA

,

Mathew

ST

,

Thadani

U.

Drug therapy for stable angina pectoris

.

Drugs

2017

;

77

:

265

–

284

.

196

Pehrsson

SK

,

Ringqvist

I

,

Ekdahl

S

,

Karlson

BW

,

Ulvenstam

G

,

Persson

S.

Monotherapy with amlodipine or atenolol versus their combination in stable angina pectoris

.

Clin Cardiol

2000

;

23

:

763

–

770

.

197

Emanuelsson

H

,

Egstrup

K

,

Nikus

K

,

Ellstrom

J

,

Glud

T

,

Pater

C

,

Scheibel

M

,

Tisell

A

,

Totterman

KJ

,

Forsby

M.

Antianginal efficacy of the combination of felodipine-metoprolol 10/100 mg compared with each drug alone in patients with stable effort-induced angina pectoris: a multicenter parallel group study. The TRAFFIC Study Group

.

Am Heart J

1999

;

137

:

854

–

862

.

198

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

–

848

.

199

Wight

LJ

,

VandenBurg

MJ

,

Potter

CE

,

Freeth

CJ.

A large scale comparative study in general practice with nitroglycerin spray and tablet formulations in elderly patients with angina pectoris

.

Eur J Clin Pharmacol

1992

;

42

:

341

–

342

.

200

Heidenreich

PA

,

McDonald

KM

,

Hastie

T

,

Fadel

B

,

Hagan

V

,

Lee

BK

,

Hlatky

MA.

Meta-analysis of trials comparing beta-blockers, calcium antagonists, and nitrates for stable angina

.

JAMA

1999

;

281

:

1927

–

1936

.

201

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

.

202

Ferratini

M.

Risk of rebound phenomenon during nitrate withdrawal

.

Int J Cardiol

1994

;

45

:

89

–

96

.

203

Diaz

A

,

Bourassa

MG

,

Guertin

MC

,

Tardif

JC.

Long-term prognostic value of resting heart rate in patients with suspected or proven coronary artery disease

.

Eur Heart J

2005

;

26

:

967

–

974

.

204

Jouven

X

,

Empana

JP

,

Schwartz

PJ

,

Desnos

M

,

Courbon

D

,

Ducimetiere

P.

Heart-rate profile during exercise as a predictor of sudden death

.

N Engl J Med

2005

;

352

:

1951

–

1958

.

205

Shu de

F

,

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

–

341

.

206

Fox

KM

,

Mulcahy

D

,

Findlay

I

,

Ford

I

,

Dargie

HJ.

The Total Ischaemic Burden European Trial (TIBET). Effects of atenolol, nifedipine SR and their combination on the exercise test and the total ischaemic burden in 608 patients with stable angina. The TIBET Study Group

.

Eur Heart J

1996

;

17

:

96

–

103

.

207

Wallace

WA

,

Wellington

KL

,

Chess

MA

,

Liang

CS.

Comparison of nifedipine gastrointestinal therapeutic system and atenolol on antianginal efficacies and exercise hemodynamic responses in stable angina pectoris

.

Am J Cardiol

1994

;

73

:

23

–

28

.

208

Kawanishi

DT

,

Reid

CL

,

Morrison

EC

,

Rahimtoola

SH.

Response of angina and ischemia to long-term treatment in patients with chronic stable angina: a double-blind randomized individualized dosing trial of nifedipine, propranolol and their combination

.

J Am Coll Cardiol

1992

;

19

:

409

–

417

.

209

Bangalore

S

,

Bhatt

DL

,

Steg

PG

,

Weber

MA

,

Boden

WE

,

Hamm

CW

,

Montalescot

G

,

Hsu

A

,

Fox

KA

,

Lincoff

AM.

beta-blockers and cardiovascular events in patients with and without myocardial infarction: post hoc analysis from the CHARISMA trial

.

Circ Cardiovasc Qual Outcomes

2014

;

7

:

872

–

881

.

210

Andersson

C

,

Shilane

D

,

Go

AS

,

Chang

TI

,

Kazi

D

,

Solomon

MD

,

Boothroyd

DB

,

Hlatky

MA.

β-blocker therapy and cardiac events among patients with newly diagnosed coronary heart disease

.

J Am Coll Cardiol

2014

;

64

:

247

–

252

.

211

Poole-Wilson

PA

,

Swedberg

K

,

Cleland

JG

,

Di Lenarda

A

,

Hanrath

P

,

Komajda

M

,

Lubsen

J

,

Lutiger

B

,

Metra

M

,

Remme

WJ

,

Torp-Pedersen

C

,

Scherhag

A

,

Skene

A

; Carvedilol Or Metoprolol European Trial Investigators.

Comparison of carvedilol and metoprolol on clinical outcomes in patients with chronic heart failure in the Carvedilol Or Metoprolol European Trial (COMET): randomised controlled trial

.

Lancet

2003

;

362

:

7

–

13

.

212

Leizorovicz

A

,

Lechat

P

,

Cucherat

M

,

Bugnard

F.

Bisoprolol for the treatment of chronic heart failure: a meta-analysis on individual data of two placebo-controlled studies--CIBIS and CIBIS II. Cardiac Insufficiency Bisoprolol Study

.

Am Heart J

2002

;

143

:

301

–

307

.

213

Freemantle

N

,

Cleland

J

,

Young

P

,

Mason

J

,

Harrison

J.

beta Blockade after myocardial infarction: systematic review and meta regression analysis

.

BMJ

1999

;

318

:

1730

–

1737

.

214

Packer

M

,

Bristow

MR

,

Cohn

JN

,

Colucci

WS

,

Fowler

MB

,

Gilbert

EM

,

Shusterman

NH.

The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. U.S. Carvedilol Heart Failure Study Group

.

N Engl J Med

1996

;

334

:

1349

–

1355

.

215

Hwang

D

,

Lee

JM

,

Kim

HK

,

Choi

KH

,

Rhee

TM

,

Park

J

,

Park

TK

,

Yang

JH

,

Song

YB

,

Choi

JH

,

Hahn

JY

,

Choi

SH

,

Koo

BK

,

Kim

YJ

,

Chae

SC

,

Cho

MC

,

Kim

CJ

,

Gwon

HC

,

Jeong

MH

,

Kim

HS

;

KAMIR Investigators. Prognostic impact of beta-blocker dose after acute myocardial infarction

.

Circ J

2019

;

83

:

410

–

417

.

216

Dahl Aarvik

M

,

Sandven

I

,

Dondo

TB

,

Gale

CP

,

Ruddox

V

,

Munkhaugen

J

,

Atar

D

,

Otterstad

JE.

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

.

217

Bangalore

S

,

Steg

G

,

Deedwania

P

,

Crowley

K

,

Eagle

KA

,

Goto

S

,

Ohman

EM

,

Cannon

CP

,

Smith

SC

,

Zeymer

U

,

Hoffman

EB

,

Messerli

FH

,

Bhatt

DL

;

REACH Registry Investigators. β-Blocker use and clinical outcomes in stable outpatients with and without coronary artery disease

.

JAMA

2012

;

308

:

1340

–

1349

.

218

Motivala

AA

,

Parikh

V

,

Roe

M

,

Dai

D

,

Abbott

JD

,

Prasad

A

,

Mukherjee

D.

Predictors, trends, and outcomes (among older patients ≥65 years of age) associated with beta-blocker use in patients with stable angina undergoing elective percutaneous coronary intervention: insights From the NCDR registry

.

JACC Cardiovasc Interv

2016

;

9

:

1639

–

1648

.

219

Zhang

H

,

Yuan

X

,

Zhang

H

,

Chen

S

,

Zhao

Y

,

Hua

K

,

Rao

C

,

Wang

W

,

Sun

H

,

Hu

S

,

Zheng

Z.

Efficacy of long-term beta-blocker therapy for secondary prevention of long-term outcomes after coronary artery bypass grafting surgery

.

Circulation

2015

;

131

:

2194

–

2201

.

220

Puymirat

E

,

Riant

E

,

Aissaoui

N

,

Soria

A

,

Ducrocq

G

,

Coste

P

,

Cottin

Y

,

Aupetit

JF

,

Bonnefoy

E

,

Blanchard

D

,

Cattan

S

,

Steg

G

,

Schiele

F

,

Ferrières

J

,

Juillière

Y

,

Simon

T

,

Danchin

N.

β blockers and mortality after myocardial infarction in patients without heart failure: multicentre prospective cohort study

.

BMJ

2016

;

354

:

i4801

.

221

Bangalore

S

,

Makani

H

,

Radford

M

,

Thakur

K

,

Toklu

B

,

Katz

SD

,

DiNicolantonio

JJ

,

Devereaux

PJ

,

Alexander

KP

,

Wetterslev

J

,

Messerli

FH.

Clinical outcomes with beta-blockers for myocardial infarction: a meta-analysis of randomized trials

.

Am J Med

2014

;

127

:

939

–

953

.

222

Hong

J

,

Barry

AR.

Long-term beta-blocker therapy after myocardial infarction in the reperfusion era: a systematic review

.

Pharmacotherapy

2018

;

38

:

546

–

554

.

223

Tsujimoto

T

,

Kajio

H

,

Shapiro

MF

,

Sugiyama

T.

Risk of all-cause mortality in diabetic patients taking beta-blockers

.

Mayo Clin Proc

2018

;

93

:

409

–

418

.

224

Sorbets

E

,

Steg

PG

,

Young

R

,

Danchin

N

,

Greenlaw

N

,

Ford

I

,

Tendera

M

,

Ferrari

R

,

Merkely

B

,

Parkhomenko

A

,

Reid

C

,

Tardif

JC

,

Fox

KM.

β-blockers, calcium antagonists, and mortality in stable coronary artery disease: an international cohort study

.

Eur Heart J

2018

:

40

;

1399

–

1407

.

225

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

.

226

Pascual

I

,

Moris

C

,

Avanzas

P.

Beta-blockers and calcium channel blockers: first line agents

.

Cardiovasc Drugs Ther

2016

;

30

:

357

–

365

.

227

Cooper-DeHoff

RM

,

Chang

SW

,

Pepine

CJ.

Calcium antagonists in the treatment of coronary artery disease

.

Curr Opin Pharmacol

2013

;

13

:

301

–

308

.

228

Padala

SK

,

Lavelle

MP

,

Sidhu

MS

,

Cabral

KP

,

Morrone

D

,

Boden

WE

,

Toth

PP.

Antianginal therapy for stable ischemic heart disease: a contemporary review

.

J Cardiovasc Pharmacol Ther

2017

;

22

:

499

–

510

.

229

Rehnqvist

N

,

Hjemdahl

P

,

Billing

E

,

Bjorkander

I

,

Eriksson

SV

,

Forslund

L

,

Held

C

,

Nasman

P

,

Wallen

NH.

Effects of metoprolol vs verapamil in patients with stable angina pectoris. The Angina Prognosis Study in Stockholm (APSIS)

.

Eur Heart J

1996

;

17

:

76

–

81

.

230

Pepine

CJ

,

Handberg

EM

,

Cooper-DeHoff

RM

,

Marks

RG

,

Kowey

P

,

Messerli

FH

,

Mancia

G

,

Cangiano

JL

,

Garcia-Barreto

D

,

Keltai

M

,

Erdine

S

,

Bristol

HA

,

Kolb

HR

,

Bakris

GL

,

Cohen

JD

,

Parmley

WW

;

INVEST Investigators. A calcium antagonist vs a non-calcium antagonist hypertension treatment strategy for patients with coronary artery disease. The International Verapamil-Trandolapril Study (INVEST): a randomized controlled trial

.

JAMA

2003

;

290

:

2805

–

2816

.

231

Ried

LD

,

Tueth

MJ

,

Handberg

E

,

Kupfer

S

,

Pepine

CJ

;

INVEST Study Group. A Study of Antihypertensive Drugs and Depressive Symptoms (SADD-Sx) in patients treated with a calcium antagonist versus an atenolol hypertension treatment strategy in the International Verapamil SR-Trandolapril Study (INVEST

).

Psychosom Med

2005

;

67

:

398

–

406

.

232

Poole-Wilson

PA

,

Lubsen

J

,

Kirwan

BA

,

van Dalen

FJ

,

Wagener

G

,

Danchin

N

,

Just

H

,

Fox

KA

,

Pocock

SJ

,

Clayton

TC

,

Motro

M

,

Parker

JD

,

Bourassa

MG

,

Dart

AM

,

Hildebrandt

P

,

Hjalmarson

A

,

Kragten

JA

,

Molhoek

GP

,

Otterstad

JE

,

Seabra-Gomes

R

,

Soler-Soler

J

,

Weber

S

, Coronary disease Trial Investigating Outcome with Nifedipine gastrointestinal therapeutic system investigators.

Effect of long-acting nifedipine on mortality and cardiovascular morbidity in patients with stable angina requiring treatment (ACTION trial): randomised controlled trial

.

Lancet

2004

;

364

:

849

–

857

.

233

Nissen

SE

,

Tuzcu

EM

,

Libby

P

,

Thompson

PD

,

Ghali

M

,

Garza

D

,

Berman

L

,

Shi

H

,

Buebendorf

E

,

Topol

EJ

;

CAMELOT Investigators. Effect of antihypertensive agents on cardiovascular events in patients with coronary disease and normal blood pressure: the CAMELOT study: a randomized controlled trial

.

JAMA

2004

;

292

:

2217

–

2225

.

234

Frishman

WH

,

Glasser

S

,

Stone

P

,

Deedwania

PC

,

Johnson

M

,

Fakouhi

TD.

Comparison of controlled-onset, extended-release verapamil with amlodipine and amlodipine plus atenolol on exercise performance and ambulatory ischemia in patients with chronic stable angina pectoris

.

Am J Cardiol

1999

;

83

:

507

–

514

.

235

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

–

2536

.

236

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

.

237

Tardif

JC

,

Ponikowski

P

,

Kahan

T

; ASSOCIATE Study Investigators.

Efficacy of the I(f) current inhibitor ivabradine in patients with chronic stable angina receiving beta-blocker therapy: a 4-month, randomized, placebo-controlled trial

.

Eur Heart J

2009

;

30

:

540

–

548

.

238

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

–

816

.

239

Fox

K

,

Ford

I

,

Steg

PG

,

Tardif

JC

,

Tendera

M

,

Ferrari

R

; SIGNIFY Investigators.

Ivabradine in stable coronary artery disease without clinical heart failure

.

N Engl J Med

2014

;

371

:

1091

–

1099

.

240

European Medicines Agency. European Medicines Agency recommends measures to reduce risk of heart problems with Corlentor/Procoralan (ivabradine). https://www.ema.europa.eu/en/news/european-medicines-agency-recommends-measures-reduce-risk-heart-problems-corlentorprocoralan (28 March 2019).

241

Doring

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

:

S74

–

S81

.

242

Di Somma

S

,

Liguori

V

,

Petitto

M

,

Carotenuto

A

,

Bokor

D

,

de Divitiis

O

,

de Divitiis

M.

A double-blind comparison of nicorandil and metoprolol in stable effort angina pectoris

.

Cardiovasc Drugs Ther

1993

;

7

:

119

–

123

.

243

Zhu

WL

,

Shan

YD

,

Guo

JX

,

Wei

JP

,

Yang

XC

,

Li

TD

,

Jia

SQ

,

He

Q

,

Chen

JZ

,

Wu

ZG

,

Li

ZQ

,

You

K.

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

–

833

.

244

Jiang

J

,

Li

Y

,

Zhou

Y

,

Li

X

,

Li

H

,

Tang

B

,

Dai

X

,

Ma

T

,

Li

L

,

Huo

Y.

Oral nicorandil reduces ischemic attacks in patients with stable angina: a prospective, multicenter, open-label, randomized, controlled study

.

Int J Cardiol

2016

;

224

:

183

–

187

.

245

Medicines & Healthcare products Regulatory Agency (MHRA). Public Assessment Report. UKPAR. Nicorandil 10 mg Tablets. Nicorandil 20 mg Tablets. http://www.mhra.gov.uk/home/groups/par/documents/websiteresources/con786861.pdf (28 March 2019).

246

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

–

1275

.

247

Morrow

DA

,

Scirica

BM

,

Karwatowska-Prokopczuk

E

,

Murphy

SA

,

Budaj

A

,

Varshavsky

S

,

Wolff

AA

,

Skene

A

,

McCabe

CH

,

Braunwald

E

;

MERLIN-TIMI 36 Trial Investigators. Effects of ranolazine on recurrent cardiovascular events in patients with non-ST-elevation acute coronary syndromes: the MERLIN-TIMI 36 randomized trial

.

JAMA

2007

;

297

:

1775

–

1783

.

248

Wilson

SR

,

Scirica

BM

,

Braunwald

E

,

Murphy

SA

,

Karwatowska-Prokopczuk

E

,

Buros

JL

,

Chaitman

BR

,

Morrow

DA.

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

–

1516

.

249

Kosiborod

M

,

Arnold

SV

,

Spertus

JA

,

McGuire

DK

,

Li

Y

,

Yue

P

,

Ben-Yehuda

O

,

Katz

A

,

Jones

PG

,

Olmsted

A

,

Belardinelli

L

,

Chaitman

BR.

Evaluation of ranolazine in patients with type 2 diabetes mellitus and chronic stable angina: results from the TERISA randomized clinical trial (Type 2 Diabetes Evaluation of Ranolazine in Subjects With Chronic Stable Angina

).

J Am Coll Cardiol

2013

;

61

:

2038

–

2045

.

250

Alexander

KP

,

Weisz

G

,

Prather

K

,

James

S

,

Mark

DB

,

Anstrom

KJ

,

Davidson-Ray

L

,

Witkowski

A

,

Mulkay

AJ

,

Osmukhina

A

,

Farzaneh-Far

R

,

Ben-Yehuda

O

,

Stone

GW

,

Ohman

EM.

Effects of ranolazine on angina and quality of life after percutaneous coronary intervention with incomplete revascularization: results from the Ranolazine for Incomplete Vessel Revascularization (RIVER-PCI) Trial

.

Circulation

2016

;

133

:

39

–

47

.

251

Weisz

G

,

Genereux

P

,

Iniguez

A

,

Zurakowski

A

,

Shechter

M

,

Alexander

KP

,

Dressler

O

,

Osmukhina

A

,

James

S

,

Ohman

EM

,

Ben-Yehuda

O

,

Farzaneh-Far

R

,

Stone

GW

;

RIVER-PCI investigators. Ranolazine in patients with incomplete revascularisation after percutaneous coronary intervention (RIVER-PCI): a multicentre, randomised, double-blind, placebo-controlled trial

.

Lancet

2016

;

387

:

136

–

145

.

252

McCarthy

CP

,

Mullins

KV

,

Kerins

DM.

The role of trimetazidine in cardiovascular disease: beyond an anti-anginal agent

.

Eur Heart J Cardiovasc Pharmacother

2016

;

2

:

266

–

272

.

253

European Medicines Agency. Questions and answers on the review of medicines containing trimetazidine (20 mg tablets, 35 mg modified release tablet and 20 mg/ml oral solution). https://www.ema.europa.eu/en/documents/referral/questions-answers-review-medicines-containing-trimetazidine-20-mg-tablets-35-mg-modified-release/ml-oral-solution_en.pdf (28 March 2019).

254

European Medicines Agency. Assessment Report for trimetazidine containing medicinal products. https://www.ema.europa.eu/en/documents/referral/trimetazidine-article-31-referral-assessment-report_en.pdf (28 March 2019).

255

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

–

785

.

256

Noman

A

,

Ang

DS

,

Ogston

S

,

Lang

CC

,

Struthers

AD.

Effect of high-dose allopurinol on exercise in patients with chronic stable angina: a randomised, placebo controlled crossover trial

.

Lancet

2010

;

375

:

2161

–

2167

.

257

Singh

JA

,

Yu

S.

Allopurinol reduces the risk of myocardial infarction (MI) in the elderly: a study of Medicare claims

.

Arthritis Res Ther

2016

;

18

:

209

.

258

Okafor

ON

,

Farrington

K

,

Gorog

DA.

Allopurinol as a therapeutic option in cardiovascular disease

.

Pharmacol Ther

2017

;

172

:

139

–

150

.

259

Kolloch

R

,

Legler

UF

,

Champion

A

,

Cooper-Dehoff

RM

,

Handberg

E

,

Zhou

Q

,

Pepine

CJ.

Impact of resting heart rate on outcomes in hypertensive patients with coronary artery disease: findings from the INternational VErapamil-SR/trandolapril STudy (INVEST

).

Eur Heart J

2008

;

29

:

1327

–

1334

.

260

Tuunanen

H

,

Engblom

E

,

Naum

A

,

Nagren

K

,

Scheinin

M

,

Hesse

B

,

Juhani Airaksinen

KE

,

Nuutila

P

,

Iozzo

P

,

Ukkonen

H

,

Opie

LH

,

Knuuti

J.

Trimetazidine, a metabolic modulator, has cardiac and extracardiac benefits in idiopathic dilated cardiomyopathy

.

Circulation

2008

;

118

:

1250

–

1258

.

261

Ho

JE

,

Bittner

V

,

Demicco

DA

,

Breazna

A

,

Deedwania

PC

,

Waters

DD.

Usefulness of heart rate at rest as a predictor of mortality, hospitalization for heart failure, myocardial infarction, and stroke in patients with stable coronary heart disease (Data from the Treating to New Targets [TNT] trial)

.

Am J Cardiol

2010

;

105

:

905

–

911

.

262

Al-Lamee

R

,

Thompson

D

,

Dehbi

HM

,

Sen

S

,

Tang

K

,

Davies

J

,

Keeble

T

,

Mielewczik

M

,

Kaprielian

R

,

Malik

IS

,

Nijjer

SS

,

Petraco

R

,

Cook

C

,

Ahmad

Y

,

Howard

J

,

Baker

C

,

Sharp

A

,

Gerber

R

,

Talwar

S

,

Assomull

R

,

Mayet

J

,

Wensel

R

,

Collier

D

,

Shun-Shin

M

,

Thom

SA

,

Davies

JE

,

Francis

DP

;

ORBITA investigators. Percutaneous coronary intervention in stable angina (ORBITA): a double-blind, randomised controlled trial

.

Lancet

2018

;

391

:

31

–

40

.

263

Nossaman

VE

,

Nossaman

BD

,

Kadowitz

PJ.

Nitrates and nitrites in the treatment of ischemic cardiac disease

.

Cardiol Rev

2010

;

18

:

190

–

197

.

264

Davies

RF

,

Habibi

H

,

Klinke

WP

,

Dessain

P

,

Nadeau

C

,

Phaneuf

DC

,

Lepage

S

,

Raman

S

,

Herbert

M

,

Foris

K

,

Linden

W

,

Buttars

JA

; Canadian Amlodipine/atenolol In Silent Ischemia Study (CASIS).

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

–

625

.

265

Salazar

CA

,

Basilio Flores

JE

,

Veramendi Espinoza

LE

,

Mejia Dolores

JW

,

Rey Rodriguez

DE

,

Loza Munarriz

C.

Ranolazine for stable angina pectoris

.

Cochrane Database Syst Rev

2017

;

2

:

CD011747

.

266

Badran

HM

,

Ibrahim

WA

,

Faheem

N

,

Yassin

R

,

Alashkar

T

,

Yacoub

M.

Provocation of left ventricular outflow tract obstruction using nitrate inhalation in hypertrophic cardiomyopathy: relation to electromechanical delay

.

Glob Cardiol Sci Pract

2015

;

2015

:

15

.

267

Webb

DJ

,

Muirhead

GJ

,

Wulff

M

,

Sutton

JA

,

Levi

R

,

Dinsmore

WW.

Sildenafil citrate potentiates the hypotensive effects of nitric oxide donor drugs in male patients with stable angina

.

J Am Coll Cardiol

2000

;

36

:

25

–

31

.

268

CURRENT-OASIS 7 Investigators,

Mehta

SR

,

Bassand

JP

,

Chrolavicius

S

,

Diaz

R

,

Eikelboom

JW

,

Fox

KA

,

Granger

CB

,

Jolly

S

,

Joyner

CD

,

Rupprecht

HJ

,

Widimsky

P

,

Afzal

R

,

Pogue

J

,

Yusuf

S.

Dose comparisons of clopidogrel and aspirin in acute coronary syndromes

.

N Engl J Med

2010

;

363

:

930

–

942

.

269

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

.

270

Antithrombotic Trialists' (ATT) Collaboration,

Baigent

C

,

Blackwell

L

,

Collins

R

,

Emberson

J

,

Godwin

J

,

Peto

R

,

Buring

J

,

Hennekens

C

,

Kearney

P

,

Meade

T

,

Patrono

C

,

Roncaglioni

MC

,

Zanchetti

A.

Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials

.

Lancet

2009

;

373

:

1849

–

1860

.

271

Aradi

D

,

Storey

RF

,

Komócsi

A

,

Trenk

D

,

Gulba

D

,

Kiss

RG

,

Husted

S

,

Bonello

L

,

Sibbing

D

,

Collet

JP

,

Huber

K

;

Working Group on Thrombosis of the European Society of Cardiology. Expert position paper on the role of platelet function testing in patients undergoing percutaneous coronary intervention

.

Eur Heart J

2014

;

35

:

209

–

215

.

272

Coxib and traditional NSAID Trialists' (CNT) Collaboration,

Bhala

N

,

Emberson

J

,

Merhi

A

,

Abramson

S

,

Arber

N

,

Baron

JA

,

Bombardier

C

,

Cannon

C

,

Farkouh

ME

,

FitzGerald

GA

,

Goss

P

,

Halls

H

,

Hawk

E

,

Hawkey

C

,

Hennekens

C

,

Hochberg

M

,

Holland

LE

,

Kearney

PM

,

Laine

L

,

Lanas

A

,

Lance

P

,

Laupacis

A

,

Oates

J

,

Patrono

C

,

Schnitzer

TJ

,

Solomon

S

,

Tugwell

P

,

Wilson

K

,

Wittes

J

,

Baigent

C.

Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomised trials

.

Lancet

2013

;

382

:

769

–

779

.

273

CAPRIE Steering Committee.

A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE

).

Lancet

1996

;

348

:

1329

–

1339

.

274

Hiatt

WR

,

Fowkes

FG

,

Heizer

G

,

Berger

JS

,

Baumgartner

I

,

Held

P

,

Katona

BG

,

Mahaffey

KW

,

Norgren

L

,

Jones

WS

,

Blomster

J

,

Millegard

M

,

Reist

C

,

Patel

MR

;

EUCLID Trial Steering Committee and Investigators. Ticagrelor versus clopidogrel in symptomatic peripheral artery disease

.

N Engl J Med

2017

;

376

:

32

–

40

.

275

Agewall

S

,

Cattaneo

M

,

Collet

JP

,

Andreotti

F

,

Lip

GY

,

Verheugt

FW

,

Huber

K

,

Grove

EL

,

Morais

J

,

Husted

S

,

Wassmann

S

,

Rosano

G

,

Atar

D

,

Pathak

A

,

Kjeldsen

K

,

Storey

RF

; ESC Working Group on Cardiovascular Pharmacology and Drug Therapy and ESC Working Group on Thrombosis.

Expert position paper on the use of proton pump inhibitors in patients with cardiovascular disease and antithrombotic therapy

.

Eur Heart J

2013

;

34

:

1708

–

1713

, 1713a–1713b.

276

Wiviott

SD

,

Braunwald

E

,

McCabe

CH

,

Montalescot

G

,

Ruzyllo

W

,

Gottlieb

S

,

Neumann

FJ

,

Ardissino

D

,

De Servi

S

,

Murphy

SA

,

Riesmeyer

J

,

Weerakkody

G

,

Gibson

CM

,

Antman

EM

;

TRITON-TIMI 38 Investigators. Prasugrel versus clopidogrel in patients with acute coronary syndromes

.

N Engl J Med

2007

;

357

:

2001

–

2015

.

277

Roe

MT

,

Armstrong

PW

,

Fox

KA

,

White

HD

,

Prabhakaran

D

,

Goodman

SG

,

Cornel

JH

,

Bhatt

DL

,

Clemmensen

P

,

Martinez

F

,

Ardissino

D

,

Nicolau

JC

,

Boden

WE

,

Gurbel

PA

,

Ruzyllo

W

,

Dalby

AJ

,

McGuire

DK

,

Leiva-Pons

JL

,

Parkhomenko

A

,

Gottlieb

S

,

Topacio

GO

,

Hamm

C

,

Pavlides

G

,

Goudev

AR

,

Oto

A

,

Tseng

CD

,

Merkely

B

,

Gasparovic

V

,

Corbalan

R

,

Cinteza

M

,

McLendon

RC

,

Winters

KJ

,

Brown

EB

,

Lokhnygina

Y

,

Aylward

PE

,

Huber

K

,

Hochman

JS

,

Ohman

EM

;

TRILOGY ACS Investigators. Prasugrel versus clopidogrel for acute coronary syndromes without revascularization

.

N Engl J Med

2012

;

367

:

1297

–

1309

.

278

Gurbel

PA

,

Bliden

KP

,

Butler

K

,

Tantry

US

,

Gesheff

T

,

Wei

C

,

Teng

R

,

Antonino

MJ

,

Patil

SB

,

Karunakaran

A

,

Kereiakes

DJ

,

Parris

C

,

Purdy

D

,

Wilson

V

,

Ledley

GS

,

Storey

RF.

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

–

2585

.

279

Storey

RF

,

Angiolillo

DJ

,

Patil

SB

,

Desai

B

,

Ecob

R

,

Husted

S

,

Emanuelsson

H

,

Cannon

CP

,

Becker

RC

,

Wallentin

L.

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

–

1462

.

280

Storey

RF

,

Bliden

KP

,

Ecob

R

,

Karunakaran

A

,

Butler

K

,

Wei

C

,

Tantry

U

,

Gurbel

PA.

Earlier recovery of platelet function after discontinuation of treatment with ticagrelor compared with clopidogrel in patients with high antiplatelet responses

.

J Thromb Haemost

2011

;

9

:

1730

–

1737

.

281

Vranckx

P

,

Valgimigli

M

,

Windecker

S

,

Steg

PG

,

Hamm

C

,

Juni

P

,

Garcia-Garcia

HM

,

van Es

GA

,

Serruys

PW.

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

–

1245

.

282

Wallentin

L

,

Becker

RC

,

Budaj

A

,

Cannon

CP

,

Emanuelsson

H

,

Held

C

,

Horrow

J

,

Husted

S

,

James

S

,

Katus

H

,

Mahaffey

KW

,

Scirica

BM

,

Skene

A

,

Steg

PG

,

Storey

RF

,

Harrington

RA

;

PLATO Investigators, Freij A, Thorsén M. Ticagrelor versus clopidogrel in patients with acute coronary syndromes

.

N Engl J Med

2009

;

361

:

1045

–

1057

.

283

Wallentin

L

,

Lindholm

D

,

Siegbahn

A

,

Wernroth

L

,

Becker

RC

,

Cannon

CP

,

Cornel

JH

,

Himmelmann

A

,

Giannitsis

E

,

Harrington

RA

,

Held

C

,

Husted

S

,

Katus

HA

,

Mahaffey

KW

,

Steg

PG

,

Storey

RF

,

James

SK

; PLATO study group.

Biomarkers in relation to the effects of ticagrelor in comparison with clopidogrel in non-ST-elevation acute coronary syndrome patients managed with or without in-hospital revascularization: a substudy from the Prospective Randomized Platelet Inhibition and Patient Outcomes (PLATO) trial

.

Circulation

2014

;

129

:

293

–

303

.

284

Valgimigli

M

,

Bueno

H

,

Byrne

RA

,

Collet

JP

,

Costa

F

,

Jeppsson

A

,

Juni

P

,

Kastrati

A

,

Kolh

P

,

Mauri

L

,

Montalescot

G

,

Neumann

FJ

,

Petricevic

M

,

Roffi

M

,

Steg

PG

,

Windecker

S

,

Zamorano

JL

,

Levine

GN.

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

–

260

.

285

Storey

RF

,

Angiolillo

DJ

,

Bonaca

MP

,

Thomas

MR

,

Judge

HM

,

Rollini

F

,

Franchi

F

,

Ahsan

AJ

,

Bhatt

DL

,

Kuder

JF

,

Steg

PG

,

Cohen

M

,

Muthusamy

R

,

Braunwald

E

,

Sabatine

MS.

Platelet inhibition with ticagrelor 60 mg versus 90 mg twice daily in the PEGASUS-TIMI 54 trial

.

J Am Coll Cardiol

2016

;

67

:

1145

–

1154

.

286

Storey

RF

,

Bliden

KP

,

Patil

SB

,

Karunakaran

A

,

Ecob

R

,

Butler

K

,

Teng

R

,

Wei

C

,

Tantry

US

,

Gurbel

PA

; ONSET/OFFSET Investigators.

Incidence of dyspnea and assessment of cardiac and pulmonary function in patients with stable coronary artery disease receiving ticagrelor, clopidogrel, or placebo in the ONSET/OFFSET study

.

J Am Coll Cardiol

2010

;

56

:

185

–

193

.

287

Storey

RF

,

Becker

RC

,

Harrington

RA

,

Husted

S

,

James

SK

,

Cools

F

,

Steg

PG

,

Khurmi

NS

,

Emanuelsson

H

,

Cooper

A

,

Cairns

R

,

Cannon

CP

,

Wallentin

L.

Characterization of dyspnoea in PLATO study patients treated with ticagrelor or clopidogrel and its association with clinical outcomes

.

Eur Heart J

2011

;

32

:

2945

–

2953

.

288

Orme

RC

,

Parker

WAE

,

Thomas

MR

,

Judge

HM

,

Baster

K

,

Sumaya

W

,

Morgan

KP

,

McMellon

HC

,

Richardson

JD

,

Grech

ED

,

Wheeldon

NM

,

Hall

IR

,

Iqbal

J

,

Barmby

D

,

Gunn

JP

,

Storey

RF.

Study of two dose regimens of ticagrelor compared with clopidogrel in patients undergoing percutaneous coronary intervention for stable coronary artery disease (STEEL-PCI

).

Circulation

2018

;

138

:

1290

–

1300

.

289

Mauri

L

,

Kereiakes

DJ

,

Yeh

RW

,

Driscoll-Shempp

P

,

Cutlip

DE

,

Steg

PG

,

Normand

SL

,

Braunwald

E

,

Wiviott

SD

,

Cohen

DJ

,

Holmes

DR

Jr,

Krucoff

MW

,

Hermiller

J

,

Dauerman

HL

,

Simon

DI

,

Kandzari

DE

,

Garratt

KN

,

Lee

DP

,

Pow

TK

,

Ver Lee

P

,

Rinaldi

MJ

,

Massaro

JM

;

DAPT Study Investigators. Twelve or 30 months of dual antiplatelet therapy after drug-eluting stents

.

N Engl J Med

2014

;

371

:

2155

–

2166

.

290

Yeh

RW

,

Kereiakes

DJ

,

Steg

PG

,

Windecker

S

,

Rinaldi

MJ

,

Gershlick

AH

,

Cutlip

DE

,

Cohen

DJ

,

Tanguay

JF

,

Jacobs

A

,

Wiviott

SD

,

Massaro

JM

,

Iancu

AC

,

Mauri

L

;

DAPT Study Investigators. Benefits and risks of extended duration dual antiplatelet therapy after PCI in patients with and without acute myocardial infarction

.

J Am Coll Cardiol

2015

;

65

:

2211

–

2221

.

291

Bhatt

DL

,

Bonaca

MP

,

Bansilal

S

,

Angiolillo

DJ

,

Cohen

M

,

Storey

RF

,

Im

K

,

Murphy

SA

,

Held

P

,

Braunwald

E

,

Sabatine

MS

,

Steg

PG.

Reduction in ischemic events with ticagrelor in diabetic patients with prior myocardial infarction in PEGASUS-TIMI 54

.

J Am Coll Cardiol

2016

;

67

:

2732

–

2740

.

292

Bansilal

S

,

Bonaca

MP

,

Cornel

JH

,

Storey

RF

,

Bhatt

DL

,

Steg

PG

,

Im

K

,

Murphy

SA

,

Angiolillo

DJ

,

Kiss

RG

,

Parkhomenko

AN

,

Lopez-Sendon

J

,

Isaza

D

,

Goudev

A

,

Kontny

F

,

Held

P

,

Jensen

EC

,

Braunwald

E

,

Sabatine

MS

,

Oude Ophuis

AJ.

Ticagrelor for secondary prevention of atherothrombotic events in patients with multivessel coronary disease

.

J Am Coll Cardiol

2018

;

71

:

489

–

496

.

293

Bonaca

MP

,

Bhatt

DL

,

Storey

RF

,

Steg

PG

,

Cohen

M

,

Kuder

J

,

Goodrich

E

,

Nicolau

JC

,

Parkhomenko

A

,

Lopez-Sendon

J

,

Dellborg

M

,

Dalby

A

,

Spinar

J

,

Aylward

P

,

Corbalan

R

,

Abola

MTB

,

Jensen

EC

,

Held

P

,

Braunwald

E

,

Sabatine

MS.

Ticagrelor for prevention of ischemic events after myocardial infarction in patients with peripheral artery disease

.

J Am Coll Cardiol

2016

;

67

:

2719

–

2728

.

294

Alexander

JH

,

Lopes

RD

,

James

S

,

Kilaru

R

,

He

Y

,

Mohan

P

,

Bhatt

DL

,

Goodman

S

,

Verheugt

FW

,

Flather

M

,

Huber

K

,

Liaw

D

,

Husted

SE

,

Lopez-Sendon

J

,

De Caterina

R

,

Jansky

P

,

Darius

H

,

Vinereanu

D

,

Cornel

JH

,

Cools

F

,

Atar

D

,

Leiva-Pons

JL

,

Keltai

M

,

Ogawa

H

,

Pais

P

,

Parkhomenko

A

,

Ruzyllo

W

,

Diaz

R

,

White

H

,

Ruda

M

,

Geraldes

M

,

Lawrence

J

,

Harrington

RA

,

Wallentin

L

;

APPRAISE-2 Investigators. Apixaban with antiplatelet therapy after acute coronary syndrome

.

N Engl J Med

2011

;

365

:

699

–

708

.

295

Hurlen

M

,

Abdelnoor

M

,

Smith

P

,

Erikssen

J

,

Arnesen

H.

Warfarin, aspirin, or both after myocardial infarction

.

N Engl J Med

2002

;

347

:

969

–

974

.

296

Mega

JL

,

Braunwald

E

,

Wiviott

SD

,

Bassand

JP

,

Bhatt

DL

,

Bode

C

,

Burton

P

,

Cohen

M

,

Cook-Bruns

N

,

Fox

KA

,

Goto

S

,

Murphy

SA

,

Plotnikov

AN

,

Schneider

D

,

Sun

X

,

Verheugt

FW

,

Gibson

CM

;

ATLAS ACS 2–TIMI 51 Investigators. Rivaroxaban in patients with a recent acute coronary syndrome

.

N Engl J Med

2012

;

366

:

9

–

19

.

297

Eikelboom

JW

,

Connolly

SJ

,

Bosch

J

,

Dagenais

GR

,

Hart

RG

,

Shestakovska

O

,

Diaz

R

,

Alings

M

,

Lonn

EM

,

Anand

SS

,

Widimsky

P

,

Hori

M

,

Avezum

A

,

Piegas

LS

,

Branch

KRH

,

Probstfield

J

,

Bhatt

DL

,

Zhu

J

,

Liang

Y

,

Maggioni

AP

,

Lopez-Jaramillo

P

,

O'Donnell

M

,

Kakkar

AK

,

Fox

KAA

,

Parkhomenko

AN

,

Ertl

G

,

Stork

S

,

Keltai

M

,

Ryden

L

,

Pogosova

N

,

Dans

AL

,

Lanas

F

,

Commerford

PJ

,

Torp-Pedersen

C

,

Guzik

TJ

,

Verhamme

PB

,

Vinereanu

D

,

Kim

JH

,

Tonkin

AM

,

Lewis

BS

,

Felix

C

,

Yusoff

K

,

Steg

PG

,

Metsarinne

KP

,

Cook Bruns

N

,

Misselwitz

F

,

Chen

E

,

Leong

D

,

Yusuf

S

;

COMPASS Investigators. Rivaroxaban with or without aspirin in stable cardiovascular disease

.

N Engl J Med

2017

;

377

:

1319

–

1330

.

298

Ohman

EM

,

Roe

MT

,

Steg

PG

,

James

SK

,

Povsic

TJ

,

White

J

,

Rockhold

F

,

Plotnikov

A

,

Mundl

H

,

Strony

J

,

Sun

X

,

Husted

S

,

Tendera

M

,

Montalescot

G

,

Bahit

MC

,

Ardissino

D

,

Bueno

H

,

Claeys

MJ

,

Nicolau

JC

,

Cornel

JH

,

Goto

S

,

Kiss

RG

,

Guray

U

,

Park

DW

,

Bode

C

,

Welsh

RC

,

Gibson

CM.

Clinically significant bleeding with low-dose rivaroxaban versus aspirin, in addition to P2Y12 inhibition, in acute coronary syndromes (GEMINI-ACS-1): a double-blind, multicentre, randomised trial

.

Lancet

2017

;

389

:

1799

–

1808

.

299

Kirchhof

P

,

Benussi

S

,

Kotecha

D

,

Ahlsson

A

,

Atar

D

,

Casadei

B

,

Castella

M

,

Diener

HC

,

Heidbuchel

H

,

Hendriks

J

,

Hindricks

G

,

Manolis

AS

,

Oldgren

J

,

Popescu

BA

,

Schotten

U

,

Van Putte

B

,

Vardas

P.

2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS

.

Eur Heart J

2016

;

37

:

2893

–

2962

.

300

Lip

GYH

,

Collet

JP

,

Haude

M

,

Byrne

R

,

Chung

EH

,

Fauchier

L

,

Halvorsen

S

,

Lau

D

,

Lopez-Cabanillas

N

,

Lettino

M

,

Marin

F

,

Obel

I

,

Rubboli

A

,

Storey

RF

,

Valgimigli

M

,

Huber

K.

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

–

193

.

301

Lopes

RD

,

Heizer

G

,

Aronson

R

,

Vora

AN

,

Massaro

T

,

Mehran

R

,

Goodman

SG

,

Windecker

S

,

Darius

H

,

Li

J

,

Averkov

O

,

Bahit

MC

,

Berwanger

O

,

Budaj

A

,

Hijazi

Z

,

Parkhomenko

A

,

Sinnaeve

P

,

Storey

RF

,

Thiele

H

,

Vinereanu

D

,

Granger

CB

,

Alexander

JH

;

AUGUSTUS Investigators. Antithrombotic therapy after acute coronary syndrome or PCI in atrial fibrillation

.

N Engl J Med

2019

;

380

:

1509

–

1524

.

302

Sousa-Uva

M

,

Storey

R

,

Huber

K

,

Falk

V

,

Leite-Moreira

AF

,

Amour

J

,

Al-Attar

N

,

Ascione

R

,

Taggart

D

,

Collet

JP

;

ESC Working Group on Cardiovascular Surgery and ESC Working Group on Thrombosis. Expert position paper on the management of antiplatelet therapy in patients undergoing coronary artery bypass graft surgery

.

Eur Heart J

2014

;

35

:

1510

–

1514

.

303

Saw

J

,

Wong

GC

,

Mayo

J

,

Bernstein

V

,

Mancini

GB

,

Ye

J

,

Skarsgard

P

,

Starovoytov

A

,

Cairns

J.

Ticagrelor and aspirin for the prevention of cardiovascular events after coronary artery bypass graft surgery

.

Heart

2016

;

102

:

763

–

769

.

304

Zhao

Q

,

Zhu

Y

,

Xu

Z

,

Cheng

Z

,

Mei

J

,

Chen

X

,

Wang

X.

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

–

1686

.

305

Connolly

SJ

,

Eikelboom

JW

,

Bosch

J

,

Dagenais

G

,

Dyal

L

,

Lanas

F

,

Metsarinne

K

,

O'Donnell

M

,

Dans

AL

,

Ha

JW

,

Parkhomenko

AN

,

Avezum

AA

,

Lonn

E

,

Lisheng

L

,

Torp-Pedersen

C

,

Widimsky

P

,

Maggioni

AP

,

Felix

C

,

Keltai

K

,

Hori

M

,

Yusoff

K

,

Guzik

TJ

,

Bhatt

DL

,

Branch

KRH

,

Cook Bruns

N

,

Berkowitz

SD

,

Anand

SS

,

Varigos

JD

,

Fox

KAA

,

Yusuf

S

;

COMPASS investigators. Rivaroxaban with or without aspirin in patients with stable coronary artery disease: an international, randomised, double-blind, placebo-controlled trial

.

Lancet

2018

;

391

:

205

–

218

.

306

Anand

SS

,

Caron

F

,

Eikelboom

JW

,

Bosch

J

,

Dyal

L

,

Aboyans

V

,

Abola

MT

,

Branch

KRH

,

Keltai

K

,

Bhatt

DL

,

Verhamme

P

,

Fox

KAA

,

Cook-Bruns

N

,

Lanius

V

,

Connolly

SJ

,

Yusuf

S.

Major adverse limb events and mortality in patients with peripheral artery disease: the COMPASS trial

.

J Am Coll Cardiol

2018

;

71

:

2306

–

2315

.

307

Bonaca

MP

,

Bhatt

DL

,

Cohen

M

,

Steg

PG

,

Storey

RF

,

Jensen

EC

,

Magnani

G

,

Bansilal

S

,

Fish

MP

,

Im

K

,

Bengtsson

O

,

Oude Ophuis

T

,

Budaj

A

,

Theroux

P

,

Ruda

M

,

Hamm

C

,

Goto

S

,

Spinar

J

,

Nicolau

JC

,

Kiss

RG

,

Murphy

SA

,

Wiviott

SD

,

Held

P

,

Braunwald

E

,

Sabatine

MS

;

PEGASUS-TIMI 54 Steering Committee and Investigators. Long-term use of ticagrelor in patients with prior myocardial infarction

.

N Engl J Med

2015

;

372

:

1791

–

1800

.

308

Cannon

CP

,

Bhatt

DL

,

Oldgren

J

,

Lip

GYH

,

Ellis

SG

,

Kimura

T

,

Maeng

M

,

Merkely

B

,

Zeymer

U

,

Gropper

S

,

Nordaby

M

,

Kleine

E

,

Harper

R

,

Manassie

J

,

Januzzi

JL

,

Ten Berg

JM

,

Steg

PG

,

Hohnloser

SH

;

RE-DUAL PCI Steering Committee and Investigators. Dual antithrombotic therapy with dabigatran after PCI in atrial fibrillation

.

N Engl J Med

2017

;

377

:

1513

–

1524

.

309

Dewilde

WJ

,

Oirbans

T

,

Verheugt

FW

,

Kelder

JC

,

De Smet

BJ

,

Herrman

JP

,

Adriaenssens

T

,

Vrolix

M

,

Heestermans

AA

,

Vis

MM

,

Tijsen

JG

,

van 't Hof

AW

,

ten Berg

JM

; WOEST study investigators.

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

–

1115

.

310

Gibson

CM

,

Mehran

R

,

Bode

C

,

Halperin

J

,

Verheugt

FW

,

Wildgoose

P

,

Birmingham

M

,

Ianus

J

,

Burton

P

,

van Eickels

M

,

Korjian

S

,

Daaboul

Y

,

Lip

GY

,

Cohen

M

,

Husted

S

,

Peterson

ED

,

Fox

KA.

Prevention of bleeding in patients with atrial fibrillation undergoing PCI

.

N Engl J Med

2016

;

375

:

2423

–

2434

.

311

Giugliano

RP

,

Ruff

CT

,

Braunwald

E

,

Murphy

SA

,

Wiviott

SD

,

Halperin

JL

,

Waldo

AL

,

Ezekowitz

MD

,

Weitz

JI

,

Spinar

J

,

Ruzyllo

W

,

Ruda

M

,

Koretsune

Y

,

Betcher

J

,

Shi

M

,

Grip

LT

,

Patel

SP

,

Patel

I

,

Hanyok

JJ

,

Mercuri

M

,

Antman

EM

;

ENGAGE AF-TIMI 48 Investigators. Edoxaban versus warfarin in patients with atrial fibrillation

.

N Engl J Med

2013

;

369

:

2093

–

2104

.

312

Steensig

K

,

Olesen

KKW

,

Thim

T

,

Nielsen

JC

,

Jensen

SE

,

Jensen

LO

,

Kristensen

SD

,

Botker

HE

,

Lip

GYH

,

Maeng

M.

Should the presence or extent of coronary artery disease be quantified in the CHA2DS2-VASc score in atrial fibrillation? A report from the Western Denmark Heart Registry

.

Thromb Haemost

2018

;

118

:

2162

–

2170

.

313

Garratt

KN

,

Weaver

WD

,

Jenkins

RG

,

Pow

TK

,

Mauri

L

,

Kereiakes

DJ

,

Winters

KJ

,

Christen

T

,

Allocco

DJ

,

Lee

DP.

Prasugrel plus aspirin beyond 12 months is associated with improved outcomes after TAXUS Liberte paclitaxel-eluting coronary stent placement

.

Circulation

2015

;

131

:

62

–

73

.

314

Bonaca

MP

,

Bhatt

DL

,

Steg

PG

,

Storey

RF

,

Cohen

M

,

Im

K

,

Oude Ophuis

T

,

Budaj

A

,

Goto

S

,

Lopez-Sendon

J

,

Diaz

R

,

Dalby

A

,

Van de Werf

F

,

Ardissino

D

,

Montalescot

G

,

Aylward

P

,

Magnani

G

,

Jensen

EC

,

Held

P

,

Braunwald

E

,

Sabatine

MS.

Ischaemic risk and efficacy of ticagrelor in relation to time from P2Y12 inhibitor withdrawal in patients with prior myocardial infarction: insights from PEGASUS-TIMI 54

.

Eur Heart J

2016

;

37

:

1133

–

1142

.

315

Mach F, Baigent C, Catapano AL, Koskinas KC, Casula M, Badimon L, Chapman MJ, De Backer GG, Delgado V, Ference BA, Graham IM, Halliday A, Landmesser U, Mihaylova B, Pedersen TR, Riccardi G, Richter DJ, Sabatine MS, Taskinen M-R, Tokgozoglu L, Wiklund O. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J 2020;41:111–188.

316

Giugliano

RP

,

Cannon

CP

,

Blazing

MA

,

Nicolau

JC

,

Corbalan

R

,

Spinar

J

,

Park

JG

,

White

JA

,

Bohula

EA

,

Braunwald

E

; IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial) Investigators.

Benefit of adding ezetimibe to statin therapy on cardiovascular outcomes and safety in patients with versus without diabetes mellitus: results from IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial)

.

Circulation

2018

;

137

:

1571

–

1582

.

317

Cannon

CP

,

Blazing

MA

,

Giugliano

RP

,

McCagg

A

,

White

JA

,

Theroux

P

,

Darius

H

,

Lewis

BS

,

Ophuis

TO

,

Jukema

JW

,

De Ferrari

GM

,

Ruzyllo

W

,

De Lucca

P

,

Im

K

,

Bohula

EA

,

Reist

C

,

Wiviott

SD

,

Tershakovec

AM

,

Musliner

TA

,

Braunwald

E

,

Califf

RM

;

IMPROVE-IT Investigators. Ezetimibe added to statin therapy after acute coronary syndromes

.

N Engl J Med

2015

;

372

:

2387

–

2397

.

318

Lloyd-Jones

DM

,

Morris

PB

,

Ballantyne

CM

,

Birtcher

KK

,

Daly

DD

Jr,

DePalma

SM

,

Minissian

MB

,

Orringer

CE

,

Smith

SC

Jr.

2017 focused update of the 2016 ACC expert consensus decision pathway on the role of non-statin therapies for LDL-cholesterol lowering in the management of atherosclerotic cardiovascular disease risk: a report of the American College of Cardiology Task Force on Expert Consensus Decision Pathways

.

J Am Coll Cardiol

2017

;

70

:

1785

–

1822

.

319

Rosenson

RS

,

Baker

S

,

Banach

M

,

Borow

KM

,

Braun

LT

,

Bruckert

E

,

Brunham

LR

,

Catapano

AL

,

Elam

MB

,

Mancini

GBJ

,

Moriarty

PM

,

Morris

PB

,

Muntner

P

,

Ray

KK

,

Stroes

ES

,

Taylor

BA

,

Taylor

VH

,

Watts

GF

,

Thompson

PD.

Optimizing cholesterol treatment in patients with muscle complaints

.

J Am Coll Cardiol

2017

;

70

:

1290

–

1301

.

320

Sabatine

MS

,

Giugliano

RP

,

Keech

AC

,

Honarpour

N

,

Wiviott

SD

,

Murphy

SA

,

Kuder

JF

,

Wang

H

,

Liu

T

,

Wasserman

SM

,

Sever

PS

,

Pedersen

TR

;

FOURIER Steering Committee and Investigators. Evolocumab and clinical outcomes in patients with cardiovascular disease

.

N Engl J Med

2017

;

376

:

1713

–

1722

.

321

Ray

KK

,

Ginsberg

HN

,

Davidson

MH

,

Pordy

R

,

Bessac

L

,

Minini

P

,

Eckel

RH

,

Cannon

CP.

Reductions in atherogenic lipids and major cardiovascular events: a pooled analysis of 10 ODYSSEY trials comparing alirocumab with control

.

Circulation

2016

;

134

:

1931

–

1943

.

322

Robinson

JG

,

Farnier

M

,

Krempf

M

,

Bergeron

J

,

Luc

G

,

Averna

M

,

Stroes

ES

,

Langslet

G

,

Raal

FJ

,

El Shahawy

M

,

Koren

MJ

,

Lepor

NE

,

Lorenzato

C

,

Pordy

R

,

Chaudhari

U

,

Kastelein

JJ

;

ODYSSEY LONG TERM Investigators. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events

.

N Engl J Med

2015

;

372

:

1489

–

1499

.

323

Schwartz

GG

,

Steg

PG

,

Szarek

M

,

Bhatt

DL

,

Bittner

VA

,

Diaz

R

,

Edelberg

JM

,

Goodman

SG

,

Hanotin

C

,

Harrington

RA

,

Jukema

JW

,

Lecorps

G

,

Mahaffey

KW

,

Moryusef

A

,

Pordy

R

,

Quintero

K

,

Roe

MT

,

Sasiela

WJ

,

Tamby

JF

,

Tricoci

P

,

White

HD

,

Zeiher

AM

; ODYSSEY OUTCOMES Committees and Investigators.

Alirocumab and cardiovascular outcomes after acute coronary syndrome

.

N Engl J Med

2018

;

379

:

2097

–

2107

.

324

Schmidt

AF

,

Pearce

LS

,

Wilkins

JT

,

Overington

JP

,

Hingorani

AD

,

Casas

JP.

PCSK9 monoclonal antibodies for the primary and secondary prevention of cardiovascular disease

.

Cochrane Database Syst Rev

2017

;

4

:

CD011748

.

325

Robinson

JG

,

Rosenson

RS

,

Farnier

M

,

Chaudhari

U

,

Sasiela

WJ

,

Merlet

L

,

Miller

K

,

Kastelein

JJ.

Safety of very low low-density lipoprotein cholesterol levels with alirocumab: pooled data from randomized trials

.

J Am Coll Cardiol

2017

;

69

:

471

–

482

.

326

Arbel

R

,

Hammerman

A

,

Triki

N

,

Greenberg

D.

PCSK9 inhibitors may improve cardiovascular outcomes-Can we afford them?

Int J Cardiol

2016

;

220

:

242

–

245

.

327

Zhai

C

,

Cong

H

,

Liu

Y

,

Zhang

Y

,

Liu

X

,

Zhang

H

,

Ren

Z.

Effect of high-dose statin pretreatment on the incidence of periprocedural myocardial infarction in patients undergoing percutaneous coronary intervention: grading the evidence through a cumulative meta-analysis

.

Clin Cardiol

2015

;

38

:

668

–

678

.

328

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

.

329

Pfeffer

MA

,

Braunwald

E

,

Moye

LA

,

Basta

L

,

Brown

EJ

Jr,

Cuddy

TE

,

Davis

BR

,

Geltman

EM

,

Goldman

S

,

Flaker

GC

,

Klein

M

,

Lamas

GA

,

Packer

M

,

Rouleau

J

,

Rouleau

JL

,

Rutherford

J

,

Wertheimer

JH

,

Hawkins

M

; SAVE Investigators.

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

–

677

.

330

Flather

MD

,

Yusuf

S

,

Kober

L

,

Pfeffer

M

,

Hall

A

,

Murray

G

,

Torp-Pedersen

C

,

Ball

S

,

Pogue

J

,

Moye

L

,

Braunwald

E.

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

–

1581

.

331

Heart Outcomes Prevention Evaluation Study

Investigators

,

Yusuf

S

,

Sleight

P

,

Pogue

J

,

Bosch

J

,

Davies

R

,

Dagenais

G.

Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients

.

N Engl J Med

2000

;

342

:

145

–

153

.

332

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

–

788

.

333

Dagenais

GR

,

Pogue

J

,

Fox

K

,

Simoons

ML

,

Yusuf

S.

Angiotensin-converting-enzyme inhibitors in stable vascular disease without left ventricular systolic dysfunction or heart failure: a combined analysis of three trials

.

Lancet

2006

;

368

:

581

–

588

.

334

Patel

A

ADVANCE Collaborative Group

MacMahon

S

,

Chalmers

J

,

Neal

B

,

Woodward

M

,

Billot

L

,

Harrap

S

,

Poulter

N

,

Marre

M

,

Cooper

M

,

Glasziou

P

,

Grobbee

DE

,

Hamet

P

,

Heller

S

,

Liu

LS

,

Mancia

G

,

Mogensen

CE

,

Pan

CY

,

Rodgers

A

,

Williams

B.

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

–

840

.

335

Braunwald

E

,

Domanski

MJ

,

Fowler

SE

,

Geller

NL

,

Gersh

BJ

,

Hsia

J

,

Pfeffer

MA

,

Rice

MM

,

Rosenberg

YD

,

Rouleau

JL

;

PEACE Trial Investigators. Angiotensin-converting-enzyme inhibition in stable coronary artery disease

.

N Engl J Med

2004

;

351

:

2058

–

2068

.

336

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

.

337

McMurray

JJ

,

Packer

M

,

Desai

AS

,

Gong

J

,

Lefkowitz

MP

,

Rizkala

AR

,

Rouleau

JL

,

Shi

VC

,

Solomon

SD

,

Swedberg

K

,

Zile

MR

; PARADIGM-HF Investigators and Committees.

Angiotensin-neprilysin inhibition versus enalapril in heart failure

.

N Engl J Med

2014

;

371

:

993

–

1004

.

338

Pitt

B

,

Zannad

F

,

Remme

WJ

,

Cody

R

,

Castaigne

A

,

Perez

A

,

Palensky

J

,

Wittes

J.

The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators

.

N Engl J Med

1999

;

341

:

709

–

717

.

339

Rossignol

P

,

Girerd

N

,

Bakris

G

,

Vardeny

O

,

Claggett

B

,

McMurray

JJV

,

Swedberg

K

,

Krum

H

,

van Veldhuisen

DJ

,

Shi

H

,

Spanyers

S

,

Vincent

J

,

Fay

R

,

Lamiral

Z

,

Solomon

SD

,

Zannad

F

,

Pitt

B.

Impact of eplerenone on cardiovascular outcomes in heart failure patients with hypokalaemia

.

Eur J Heart Fail

2017

;

19

:

792

–

799

.

340

Ponikowski

P

,

Voors

AA

,

Anker

SD

,

Bueno

H

,

Cleland

JGF

,

Coats

AJS

,

Falk

V

,

Gonzalez-Juanatey

JR

,

Harjola

VP

,

Jankowska

EA

,

Jessup

M

,

Linde

C

,

Nihoyannopoulos

P

,

Parissis

JT

,

Pieske

B

,

Riley

JP

,

Rosano

GMC

,

Ruilope

LM

,

Ruschitzka

F

,

Rutten

FH

,

van der Meer

P.

2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC)Developed with the special contribution of the Heart Failure Association (HFA) of the ESC

.

Eur Heart J

2016

;

37

:

2129

–

2200

.

341

Baigent

C

,

Keech

A

,

Kearney

PM

,

Blackwell

L

,

Buck

G

,

Pollicino

C

,

Kirby

A

,

Sourjina

T

,

Peto

R

,

Collins

R

,

Simes

R

, Cholesterol Treatment Trialists' (CTT) Collaborators.

Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins

.

Lancet

2005

;

366

:

1267

–

1278

.

342

Cholesterol Treatment Trialists’ (CTT) Collaboration,

Baigent

C

,

Blackwell

L

,

Emberson

J

,

Holland

LE

,

Reith

C

,

Bhala

N

,

Peto

R

,

Barnes

EH

,

Keech

A

,

Simes

J

,

Collins

R.

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

–

1681

.

343

Kernis

SJ

,

Harjai

KJ

,

Stone

GW

,

Grines

LL

,

Boura

JA

,

O'Neill

WW

,

Grines

CL.

Does beta-blocker therapy improve clinical outcomes of acute myocardial infarction after successful primary angioplasty?

J Am Coll Cardiol

2004

;

43

:

1773

–

1779

.

344

Manson

JE

,

Hsia

J

,

Johnson

KC

,

Rossouw

JE

,

Assaf

AR

,

Lasser

NL

,

Trevisan

M

,

Black

HR

,

Heckbert

SR

,

Detrano

R

,

Strickland

OL

,

Wong

ND

,

Crouse

JR

,

Stein

E

,

Cushman

M

; Women's Health Initiative Investigators.

Estrogen plus progestin and the risk of coronary heart disease

.

N Engl J Med

2003

;

349

:

523

–

534

.

345

Spertus

JA

,

Salisbury

AC

,

Jones

PG

,

Conaway

DG

,

Thompson

RC.

Predictors of quality-of-life benefit after percutaneous coronary intervention

.

Circulation

2004

;

110

:

3789

–

3794

.

346

Steg

PG

,

Greenlaw

N

,

Tendera

M

,

Tardif

JC

,

Ferrari

R

,

Al-Zaibag

M

,

Dorian

P

,

Hu

D

,

Shalnova

S

,

Sokn

FJ

,

Ford

I

,

Fox

KM

; Prospective Observational Longitudinal Registry of Patients With Stable Coronary Artery Disease (CLARIFY) Investigators.

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

–

1659

.

347

Xaplanteris

P

,

Fournier

S

,

Pijls

NHJ

,

Fearon

WF

,

Barbato

E

,

Tonino

PAL

,

Engstrom

T

,

Kaab

S

,

Dambrink

JH

,

Rioufol

G

,

Toth

GG

,

Piroth

Z

,

Witt

N

,

Frobert

O

,

Kala

P

,

Linke

A

,

Jagic

N

,

Mates

M

,

Mavromatis

K

,

Samady

H

,

Irimpen

A

,

Oldroyd

K

,

Campo

G

,

Rothenbuhler

M

,

Juni

P

,

De Bruyne

B

;

FAME 2 Investigators. Five-year outcomes with PCI guided by fractional flow reserve

.

N Engl J Med

2018

;

379

:

250

–

259

.

348

Trikalinos

TA

,

Alsheikh-Ali

AA

,

Tatsioni

A

,

Nallamothu

BK

,

Kent

DM.

Percutaneous coronary interventions for non-acute coronary artery disease: a quantitative 20-year synopsis and a network meta-analysis

.

Lancet

2009

;

373

:

911

–

918

.

349

Stergiopoulos

K

,

Brown

DL.

Initial coronary stent implantation with medical therapy vs medical therapy alone for stable coronary artery disease: meta-analysis of randomized controlled trials

.

Arch Intern Med

2012

;

172

:

312

–

319

.

350

Bangalore

S

,

Pursnani

S

,

Kumar

S

,

Bagos

PG.

Percutaneous coronary intervention versus optimal medical therapy for prevention of spontaneous myocardial infarction in subjects with stable ischemic heart disease

.

Circulation

2013

;

127

:

769

–

781

.

351

Windecker

S

,

Stortecky

S

,

Stefanini

GG

,

da Costa

BR

,

Rutjes

AW

,

Di Nisio

M

,

Silletta

MG

,

Maione

A

,

Alfonso

F

,

Clemmensen

PM

,

Collet

JP

,

Cremer

J

,

Falk

V

,

Filippatos

G

,

Hamm

C

,

Head

S

,

Kappetein

AP

,

Kastrati

A

,

Knuuti

J

,

Landmesser

U

,

Laufer

G

,

Neumann

FJ

,

Richter

D

,

Schauerte

P

,

Sousa Uva

M

,

Taggart

DP

,

Torracca

L

,

Valgimigli

M

,

Wijns

W

,

Witkowski

A

,

Kolh

P

,

Juni

P.

Revascularisation versus medical treatment in patients with stable coronary artery disease: network meta-analysis

.

BMJ

2014

;

348

:

g3859

.

352

Zimmermann

FM

,

Omerovic

E

,

Fournier

S

,

Kelbaek

H

,

Johnson

NP

,

Rothenbuhler

M

,

Xaplanteris

P

,

Abdel-Wahab

M

,

Barbato

E

,

Hofsten

DE

,

Tonino

PAL

,

Boxma-de Klerk

BM

,

Fearon

WF

,

Kober

L

,

Smits

PC

,

De Bruyne

B

,

Pijls

NHJ

,

Juni

P

,

Engstrom

T.

Fractional flow reserve-guided percutaneous coronary intervention vs. medical therapy for patients with stable coronary lesions: meta-analysis of individual patient data

.

Eur Heart J

2019

;

40

:

180

–

186

.

353

Gage

RM

,

Burns

KV

,

Bank

AJ.

Echocardiographic and clinical response to cardiac resynchronization therapy in heart failure patients with and without previous right ventricular pacing

.

Eur J Heart Fail

2014

;

16

:

1199

–

1205

.

354

Moss

AJ

,

Zareba

W

,

Hall

WJ

,

Klein

H

,

Wilber

DJ

,

Cannom

DS

,

Daubert

JP

,

Higgins

SL

,

Brown

MW

,

Andrews

ML

; Multicenter Automatic Defibrillator Implantation Trial II Investigators.

Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction

.

N Engl J Med

2002

;

346

:

877

–

883

.

355

Cleland

JG

,

Daubert

JC

,

Erdmann

E

,

Freemantle

N

,

Gras

D

,

Kappenberger

L

,

Tavazzi

L

; Cardiac Resynchronization-Heart Failure (CARE-HF) Study Investigators.

The effect of cardiac resynchronization on morbidity and mortality in heart failure

.

N Engl J Med

2005

;

352

:

1539

–

1549

.

356

Daubert

C

,

Gold

MR

,

Abraham

WT

,

Ghio

S

,

Hassager

C

,

Goode

G

,

Szili-Torok

T

,

Linde

C

; REVERSE Study Group.

Prevention of disease progression by cardiac resynchronization therapy in patients with asymptomatic or mildly symptomatic left ventricular dysfunction: insights from the European cohort of the REVERSE (Resynchronization Reverses Remodeling in Systolic Left Ventricular Dysfunction) trial

.

J Am Coll Cardiol

2009

;

54

:

1837

–

1846

.

357

Velazquez

EJ

,

Lee

KL

,

Deja

MA

,

Jain

A

,

Sopko

G

,

Marchenko

A

,

Ali

IS

,

Pohost

G

,

Gradinac

S

,

Abraham

WT

,

Yii

M

,

Prabhakaran

D

,

Szwed

H

,

Ferrazzi

P

,

Petrie

MC

,

O'Connor

CM

,

Panchavinnin

P

,

She

L

,

Bonow

RO

,

Rankin

GR

,

Jones

RH

,

Rouleau

JL

; STICH Investigators.

Coronary-artery bypass surgery in patients with left ventricular dysfunction

.

N Engl J Med

2011

;

364

:

1607

–

1616

.

358

Petrie

MC

,

Jhund

PS

,

She

L

,

Adlbrecht

C

,

Doenst

T

,

Panza

JA

,

Hill

JA

,

Lee

KL

,

Rouleau

JL

,

Prior

DL

,

Ali

IS

,

Maddury

J

,

Golba

KS

,

White

HD

,

Carson

P

,

Chrzanowski

L

,

Romanov

A

,

Miller

AB

,

Velazquez

EJ

; STICH Trial Investigators.

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

–

1324

.

359

Faris

RF

,

Flather

M

,

Purcell

H

,

Poole-Wilson

PA

,

Coats

AJ.

Diuretics for heart failure

.

Cochrane Database Syst Rev

2012

;

1

:

CD003838

.

360

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

–

158

.

361

Hjalmarson

A

,

Goldstein

S

,

Fagerberg

B

,

Wedel

H

,

Waagstein

F

,

Kjekshus

J

,

Wikstrand

J

,

El Allaf

D

,

Vitovec

J

,

Aldershvile

J

,

Halinen

M

,

Dietz

R

,

Neuhaus

KL

,

Janosi

A

,

Thorgeirsson

G

,

Dunselman

PH

,

Gullestad

L

,

Kuch

J

,

Herlitz

J

,

Rickenbacher

P

,

Ball

S

,

Gottlieb

S

,

Deedwania

P.

Effects of controlled-release metoprolol on total mortality, hospitalizations, and well-being in patients with heart failure: the Metoprolol CR/XL Randomized Intervention Trial in congestive heart failure (MERIT-HF). MERIT-HF Study Group

.

JAMA

2000

;

283

:

1295

–

1302

.

362

Packer

M

,

Coats

AJ

,

Fowler

MB

,

Katus

HA

,

Krum

H

,

Mohacsi

P

,

Rouleau

JL

,

Tendera

M

,

Castaigne

A

,

Roecker

EB

,

Schultz

MK

,

DeMets

DL

; Carvedilol Prospective Randomized Cumulative Survival Study Group.

Effect of carvedilol on survival in severe chronic heart failure

.

N Engl J Med

2001

;

344

:

1651

–

1658

.

363

MERIT-HF Study

Group.

Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF

).

Lancet

1999

;

353

:

2001

–

2007

.

364

Packer

M

,

Fowler

MB

,

Roecker

EB

,

Coats

AJ

,

Katus

HA

,

Krum

H

,

Mohacsi

P

,

Rouleau

JL

,

Tendera

M

,

Staiger

C

,

Holcslaw

TL

,

Amann-Zalan

I

,

DeMets

DL

; Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) Study Group.

Effect of carvedilol on the morbidity of patients with severe chronic heart failure: results of the carvedilol prospective randomized cumulative survival (COPERNICUS) study

.

Circulation

2002

;

106

:

2194

–

2199

.

365

CIBIS-II Investigators and Committees.

The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial

.

Lancet

1999

;

353

:

9

–

13

.

366

Flather

MD

,

Shibata

MC

,

Coats

AJ

,

Van Veldhuisen

DJ

,

Parkhomenko

A

,

Borbola

J

,

Cohen-Solal

A

,

Dumitrascu

D

,

Ferrari

R

,

Lechat

P

,

Soler-Soler

J

,

Tavazzi

L

,

Spinarova

L

,

Toman

J

,

Bohm

M

,

Anker

SD

,

Thompson

SG

,

Poole-Wilson

PA

; SENIORS Investigators.

Randomized trial to determine the effect of nebivolol on mortality and cardiovascular hospital admission in elderly patients with heart failure (SENIORS

).

Eur Heart J

2005

;

26

:

215

–

225

.

367

Dargie

HJ.

Effect of carvedilol on outcome after myocardial infarction in patients with left-ventricular dysfunction: the CAPRICORN randomised trial

.

Lancet

2001

;

357

:

1385

–

1390

.

368

SOLVD Investigators,

Yusuf

S

,

Pitt

B

,

Davis

CE

,

Hood

WB

Jr,

Cohn

JN.

Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions

.

N Engl J Med

1992

;

327

:

685

–

691

.

369

Granger

CB

,

McMurray

JJ

,

Yusuf

S

,

Held

P

,

Michelson

EL

,

Olofsson

B

,

Ostergren

J

,

Pfeffer

MA

,

Swedberg

K

; CHARM Investigators and Committees.

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

–

776

.

370

Zannad

F

,

McMurray

JJ

,

Krum

H

,

van Veldhuisen

DJ

,

Swedberg

K

,

Shi

H

,

Vincent

J

,

Pocock

SJ

,

Pitt

B

; EMPHASIS-HF Study Group.

Eplerenone in patients with systolic heart failure and mild symptoms

.

N Engl J Med

2011

;

364

:

11

–

21

.

371

Taylor

AL

,

Ziesche

S

,

Yancy

C

,

Carson

P

,

D'Agostino

R

Jr,

Ferdinand

K

,

Taylor

M

,

Adams

K

,

Sabolinski

M

,

Worcel

M

,

Cohn

JN

; African-American Heart Failure Trial Investigators.

Combination of isosorbide dinitrate and hydralazine in blacks with heart failure

.

N Engl J Med

2004

;

351

:

2049

–

2057

.

372

Swedberg

K

,

Komajda

M

,

Bohm

M

,

Borer

JS

,

Ford

I

,

Dubost-Brama

A

,

Lerebours

G

,

Tavazzi

L

;

SHIFT Investigators. Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study

.

Lancet

2010

;

376

:

875

–

885

.

373

Fox

K

,

Ford

I

,

Steg

PG

,

Tendera

M

,

Robertson

M

,

Ferrari

R

; BEAUTIFUL Investigators.

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

–

2345

.

374

Packer

M

,

O'Connor

CM

,

Ghali

JK

,

Pressler

ML

,

Carson

PE

,

Belkin

RN

,

Miller

AB

,

Neuberg

GW

,

Frid

D

,

Wertheimer

JH

,

Cropp

AB

,

DeMets

DL.

Effect of amlodipine on morbidity and mortality in severe chronic heart failure. Prospective Randomized Amlodipine Survival Evaluation Study Group

.

N Engl J Med

1996

;

335

:

1107

–

1114

.

375

Wijeysundera

HC

,

Hansen

MS

,

Stanton

E

,

Cropp

AS

,

Hall

C

,

Dhalla

NS

,

Ghali

J

,

Rouleau

JL

; PRAISE II Investigators

. Neurohormones and oxidative stress in nonischemic cardiomyopathy: relationship to survival and the effect of treatment with amlodipine

.

Am Heart J

2003

;

146

:

291

–

297

.

376

Desai

AS

,

Fang

JC

,

Maisel

WH

,

Baughman

KL.

Implantable defibrillators for the prevention of mortality in patients with nonischemic cardiomyopathy: a meta-analysis of randomized controlled trials

.

JAMA

2004

;

292

:

2874

–

2879

.

377

Kadish

A

,

Dyer

A

,

Daubert

JP

,

Quigg

R

,

Estes

NA

,

Anderson

KP

,

Calkins

H

,

Hoch

D

,

Goldberger

J

,

Shalaby

A

,

Sanders

WE

,

Schaechter

A

,

Levine

JH

; Defibrillators in Non-Ischemic Cardiomyopathy Treatment Evaluation (DEFINITE) Investigators

. Prophylactic defibrillator implantation in patients with nonischemic dilated cardiomyopathy

.

N Engl J Med

2004

;

350

:

2151

–

2158

.

378

Hohnloser

SH

,

Kuck

KH

,

Dorian

P

,

Roberts

RS

,

Hampton

JR

,

Hatala

R

,

Fain

E

,

Gent

M

,

Connolly

SJ

; DINAMIT Investigators.

Prophylactic use of an implantable cardioverter-defibrillator after acute myocardial infarction

.

N Engl J Med

2004

;

351

:

2481

–

2488

.

379

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

–

1583

.

380

Connolly

SJ

,

Hallstrom

AP

,

Cappato

R

,

Schron

EB

,

Kuck

KH

,

Zipes

DP

,

Greene

HL

,

Boczor

S

,

Domanski

M

,

Follmann

D

,

Gent

M

,

Roberts

RS.

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

–

2078

.

381

Connolly

SJ

,

Gent

M

,

Roberts

RS

,

Dorian

P

,

Roy

D

,

Sheldon

RS

,

Mitchell

LB

,

Green

MS

,

Klein

GJ

,

O'Brien

B.

Canadian implantable defibrillator study (CIDS) : a randomized trial of the implantable cardioverter defibrillator against amiodarone

.

Circulation

2000

;

101

:

1297

–

1302

.

382

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

–

754

.

383

Linde

C

,

Abraham

WT

,

Gold

MR

,

St John Sutton

M

,

Ghio

S

,

Daubert

C

; REVERSE (REsynchronization reVErses Remodeling in Systolic left vEntricular dysfunction) Study Group.

Randomized trial of cardiac resynchronization in mildly symptomatic heart failure patients and in asymptomatic patients with left ventricular dysfunction and previous heart failure symptoms

.

J Am Coll Cardiol

2008

;

52

:

1834

–

1843

.

384

Linde

C

,

Gold

MR

,

Abraham

WT

,

St John Sutton

M

,

Ghio

S

,

Cerkvenik

J

,

Daubert

C

; REsynchronization reVErses Remodeling in Systolic left vEntricular dysfunction Study Group.

Long-term impact of cardiac resynchronization therapy in mild heart failure: 5-year results from the REsynchronization reVErses Remodeling in Systolic left vEntricular dysfunction (REVERSE) study

.

Eur Heart J

2013

;

34

:

2592

–

2599

.

385

Cazeau

S

,

Leclercq

C

,

Lavergne

T

,

Walker

S

,

Varma

C

,

Linde

C

,

Garrigue

S

,

Kappenberger

L

,

Haywood

GA

,

Santini

M

,

Bailleul

C

,

Daubert

JC

;

Multisite Stimulation in Cardiomyopathies (MUSTIC) Study Investigators. Effects of multisite biventricular pacing in patients with heart failure and intraventricular conduction delay

.

N Engl J Med

2001

;

344

:

873

–

880

.

386

Cleland

JG

,

Daubert

JC

,

Erdmann

E

,

Freemantle

N

,

Gras

D

,

Kappenberger

L

,

Tavazzi

L.

Longer-term effects of cardiac resynchronization therapy on mortality in heart failure [the CArdiac REsynchronization-Heart Failure (CARE-HF) trial extension phase]

.

Eur Heart J

2006

;

27

:

1928

–

1932

.

387

Cleland

JG

,

Freemantle

N

,

Erdmann

E

,

Gras

D

,

Kappenberger

L

,

Tavazzi

L

,

Daubert

JC.

Long-term mortality with cardiac resynchronization therapy in the Cardiac Resynchronization-Heart Failure (CARE-HF) trial

.

Eur J Heart Fail

2012

;

14

:

628

–

634

.

388

Bristow

MR

,

Saxon

LA

,

Boehmer

J

,

Krueger

S

,

Kass

DA

,

De Marco

T

,

Carson

P

,

DiCarlo

L

,

DeMets

D

,

White

BG

,

DeVries

DW

,

Feldman

AM

; Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) Investigators.

Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure

.

N Engl J Med

2004

;

350

:

2140

–

2150

.

389

Cleland

JG

,

Abraham

WT

,

Linde

C

,

Gold

MR

,

Young

JB

,

Claude Daubert

J

,

Sherfesee

L

,

Wells

GA

,

Tang

AS.

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

–

3556

.

390

Tang

AS

,

Wells

GA

,

Talajic

M

,

Arnold

MO

,

Sheldon

R

,

Connolly

S

,

Hohnloser

SH

,

Nichol

G

,

Birnie

DH

,

Sapp

JL

,

Yee

R

,

Healey

JS

,

Rouleau

JL

; Resynchronization-Defibrillation for Ambulatory Heart Failure Trial Investigators.

Cardiac-resynchronization therapy for mild-to-moderate heart failure

.

N Engl J Med

2010

;

363

:

2385

–

2395

.

391

Moss

AJ

,

Hall

WJ

,

Cannom

DS

,

Klein

H

,

Brown

MW

,

Daubert

JP

,

Estes

NA III

,

Foster

E

,

Greenberg

H

,

Higgins

SL

,

Pfeffer

MA

,

Solomon

SD

,

Wilber

D

,

Zareba

W

; MADIT-CRT Trial Investigators.

Cardiac-resynchronization therapy for the prevention of heart-failure events

.

N Engl J Med

2009

;

361

:

1329

–

1338

.

392

Goldenberg

I

,

Kutyifa

V

,

Klein

HU

,

Cannom

DS

,

Brown

MW

,

Dan

A

,

Daubert

JP

,

Estes

NA III

,

Foster

E

,

Greenberg

H

,

Kautzner

J

,

Klempfner

R

,

Kuniss

M

,

Merkely

B

,

Pfeffer

MA

,

Quesada

A

,

Viskin

S

,

McNitt

S

,

Polonsky

B

,

Ghanem

A

,

Solomon

SD

,

Wilber

D

,

Zareba

W

,

Moss

AJ.

Survival with cardiac-resynchronization therapy in mild heart failure

.

N Engl J Med

2014

;

370

:

1694

–

1701

.

393

Phillips

CO

,

Wright

SM

,

Kern

DE

,

Singa

RM

,

Shepperd

S

,

Rubin

HR.

Comprehensive discharge planning with postdischarge support for older patients with congestive heart failure: a meta-analysis

.

JAMA

2004

;

291

:

1358

–

1367

.

394

Stewart

S

,

Vandenbroek

AJ

,

Pearson

S

,

Horowitz

JD.

Prolonged beneficial effects of a home-based intervention on unplanned readmissions and mortality among patients with congestive heart failure

.

Arch Intern Med

1999

;

159

:

257

–

261

.

395

McAlister

FA

,

Stewart

S

,

Ferrua

S

,

McMurray

JJ.

Multidisciplinary strategies for the management of heart failure patients at high risk for admission: a systematic review of randomized trials

.

J Am Coll Cardiol

2004

;

44

:

810

–

819

.

396

Feltner

C

,

Jones

CD

,

Cene

CW

,

Zheng

ZJ

,

Sueta

CA

,

Coker-Schwimmer

EJ

,

Arvanitis

M

,

Lohr

KN

,

Middleton

JC

,

Jonas

DE.

Transitional care interventions to prevent readmissions for persons with heart failure: a systematic review and meta-analysis

.

Ann Intern Med

2014

;

160

:

774

–

784

.

397

Pursnani

S

,

Korley

F

,

Gopaul

R

,

Kanade

P

,

Chandra

N

,

Shaw

RE

,

Bangalore

S.

Percutaneous coronary intervention versus optimal medical therapy in stable coronary artery disease: a systematic review and meta-analysis of randomized clinical trials

.

Circ Cardiovasc Interv

2012

;

5

:

476

–

490

.

398

Lindholm

D

,

Lindback

J

,

Armstrong

PW

,

Budaj

A

,

Cannon

CP

,

Granger

CB

,

Hagstrom

E

,

Held

C

,

Koenig

W

,

Ostlund

O

,

Stewart

RAH

,

Soffer

J

,

White

HD

,

de Winter

RJ

,

Steg

PG

,

Siegbahn

A

,

Kleber

ME

,

Dressel

A

,

Grammer

TB

,

Marz

W

,

Wallentin

L.

Biomarker-based risk model to predict cardiovascular mortality in patients with stable coronary disease

.

J Am Coll Cardiol

2017

;

70

:

813

–

826

.

399

Hemingway

H

,

Philipson

P

,

Chen

R

,

Fitzpatrick

NK

,

Damant

J

,

Shipley

M

,

Abrams

KR

,

Moreno

S

,

McAllister

KS

,

Palmer

S

,

Kaski

JC

,

Timmis

AD

,

Hingorani

AD.

Evaluating the quality of research into a single prognostic biomarker: a systematic review and meta-analysis of 83 studies of C-reactive protein in stable coronary artery disease

.

PLoS Med

2010

;

7

:

e1000286

.

400

Rapsomaniki

E

,

Shah

A

,

Perel

P

,

Denaxas

S

,

George

J

,

Nicholas

O

,

Udumyan

R

,

Feder

GS

,

Hingorani

AD

,

Timmis

A

,

Smeeth

L

,

Hemingway

H.

Prognostic models for stable coronary artery disease based on electronic health record cohort of 102 023 patients

.

Eur Heart J

2014

;

35

:

844

–

852

.

401

Eapen

DJ

,

Manocha

P

,

Patel

RS

,

Hammadah

M

,

Veledar

E

,

Wassel

C

,

Nanjundappa

RA

,

Sikora

S

,

Malayter

D

,

Wilson

PW

,

Sperling

L

,

Quyyumi

AA

,

Epstein

SE.

Aggregate risk score based on markers of inflammation, cell stress, and coagulation is an independent predictor of adverse cardiovascular outcomes

.

J Am Coll Cardiol

2013

;

62

:

329

–

337

.

402

Inouye

M

,

Abraham

G

,

Nelson

CP

,

Wood

AM

,

Sweeting

MJ

,

Dudbridge

F

,

Lai

FY

,

Kaptoge

S

,

Brozynska

M

,

Wang

T

,

Ye

S

,

Webb

TR

,

Rutter

MK

,

Tzoulaki

I

,

Patel

RS

,

Loos

RJF

,

Keavney

B

,

Hemingway

H

,

Thompson

J

,

Watkins

H

,

Deloukas

P

,

Di Angelantonio

E

,

Butterworth

AS

,

Danesh

J

,

Samani

NJ

; UK Biobank CardioMetabolic Consortium CHD Working Group.

Genomic risk prediction of coronary artery disease in 480,000 adults: implications for primary prevention

.

J Am Coll Cardiol

2018

;

72

:

1883

–

1893

.

403

Tada

H

,

Melander

O

,

Louie

JZ

,

Catanese

JJ

,

Rowland

CM

,

Devlin

JJ

,

Kathiresan

S

,

Shiffman

D.

Risk prediction by genetic risk scores for coronary heart disease is independent of self-reported family history

.

Eur Heart J

2016

;

37

:

561

–

567

.

404

Pereira

A

,

Mendonca

MI

,

Sousa

AC

,

Borges

S

,

Freitas

S

,

Henriques

E

,

Rodrigues

M

,

Freitas

AI

,

Guerra

G

,

Ornelas

I

,

Pereira

D

,

Brehm

A

,

Palma Dos Reis

R.

Genetic risk score and cardiovascular mortality in a southern european population with coronary artery disease

.

Int J Clin Pract

2017

;

71

:

e12956

.

405

Christiansen

MK

,

Nyegaard

M

,

Larsen

SB

,

Grove

EL

,

Wurtz

M

,

Neergaard-Petersen

S

,

Hvas

AM

,

Jensen

HK

,

Kristensen

SD.

A genetic risk score predicts cardiovascular events in patients with stable coronary artery disease

.

Int J Cardiol

2017

;

241

:

411

–

416

.

406

Vaara

S

,

Tikkanen

E

,

Parkkonen

O

,

Lokki

ML

,

Ripatti

S

,

Perola

M

,

Nieminen

MS

,

Sinisalo

J.

Genetic risk scores predict recurrence of acute coronary syndrome

.

Circ Cardiovasc Genet

2016

;

9

:

172

–

178

.

407

Mega

JL

,

Stitziel

NO

,

Smith

JG

,

Chasman

DI

,

Caulfield

M

,

Devlin

JJ

,

Nordio

F

,

Hyde

C

,

Cannon

CP

,

Sacks

F

,

Poulter

N

,

Sever

P

,

Ridker

PM

,

Braunwald

E

,

Melander

O

,

Kathiresan

S

,

Sabatine

MS.

Genetic risk, coronary heart disease events, and the clinical benefit of statin therapy: an analysis of primary and secondary prevention trials

.

Lancet

2015

;

385

:

2264

–

2271

.

408

Harb

SC

,

Marwick

TH.

Prognostic value of stress imaging after revascularization: a systematic review of stress echocardiography and stress nuclear imaging

.

Am Heart J

2014

;

167

:

77

–

85

.

409

Bugiardini

R

,

Bairey Merz

CN.

Angina with "normal" coronary arteries: a changing philosophy

.

JAMA

2005

;

293

:

477

–

484

.

410

Vermeltfoort

IA

,

Raijmakers

PG

,

Odekerken

DA

,

Kuijper

AF

,

Zwijnenburg

A

,

Teule

GJ.

Association between anxiety disorder and the extent of ischemia observed in cardiac syndrome X

.

J Nucl Cardiol

2009

;

16

:

405

–

410

.

411

Asbury

EA

,

Creed

F

,

Collins

P.

Distinct psychosocial differences between women with coronary heart disease and cardiac syndrome X

.

Eur Heart J

2004

;

25

:

1695

–

1701

.

412

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

–

1453

.

413

Lee

BK

,

Lim

HS

,

Fearon

WF

,

Yong

AS

,

Yamada

R

,

Tanaka

S

,

Lee

DP

,

Yeung

AC

,

Tremmel

JA.

Invasive evaluation of patients with angina in the absence of obstructive coronary artery disease

.

Circulation

2015

;

131

:

1054

–

1060

.

414

Ford

TJ

,

Stanley

B

,

Good

R

,

Rocchiccioli

P

,

McEntegart

M

,

Watkins

S

,

Eteiba

H

,

Shaukat

A

,

Lindsay

M

,

Robertson

K

,

Hood

S

,

McGeoch

R

,

McDade

R

,

Yii

E

,

Sidik

N

,

McCartney

P

,

Corcoran

D

,

Collison

D

,

Rush

C

,

McConnachie

A

,

Touyz

RM

,

Oldroyd

KG

,

Berry

C.

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

.

J Am Coll Cardiol

2018

;

72

:

2841

–

2855

.

415

Ong

P

,

Camici

PG

,

Beltrame

JF

,

Crea

F

,

Shimokawa

H

,

Sechtem

U

,

Kaski

JC

,

Bairey Merz

CN

; Coronary Vasomotion Disorders International Study Group (COVADIS).

International standardization of diagnostic criteria for microvascular angina

.

Int J Cardiol

2018

;

250

:

16

–

20

.

416

Mygind

ND

,

Michelsen

MM

,

Pena

A

,

Frestad

D

,

Dose

N

,

Aziz

A

,

Faber

R

,

Host

N

,

Gustafsson

I

,

Hansen

PR

,

Hansen

HS

,

Bairey Merz

CN

,

Kastrup

J

,

Prescott

E.

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

.

417

Crea

F

,

Camici

PG

,

Bairey Merz

CN.

Coronary microvascular dysfunction: an update

.

Eur Heart J

2014

;

35

:

1101

–

1111

.

418

van de Hoef

TP

,

van Lavieren

MA

,

Damman

P

,

Delewi

R

,

Piek

MA

,

Chamuleau

SA

,

Voskuil

M

,

Henriques

JP

,

Koch

KT

,

de Winter

RJ

,

Spaan

JA

,

Siebes

M

,

Tijssen

JG

,

Meuwissen

M

,

Piek

JJ.

Physiological basis and long-term clinical outcome of discordance between fractional flow reserve and coronary flow velocity reserve in coronary stenoses of intermediate severity

.

Circ Cardiovasc Interv

2014

;

7

:

301

–

311

.

419

Pepine

CJ

,

Anderson

RD

,

Sharaf

BL

,

Reis

SE

,

Smith

KM

,

Handberg

EM

,

Johnson

BD

,

Sopko

G

,

Bairey Merz

CN.

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

–

2832

.

420

Taqueti

VR

,

Everett

BM

,

Murthy

VL

,

Gaber

M

,

Foster

CR

,

Hainer

J

,

Blankstein

R

,

Dorbala

S

,

Di Carli

MF.

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

.

Circulation

2015

;

131

:

528

–

535

.

421

Murthy

VL

,

Naya

M

,

Foster

CR

,

Gaber

M

,

Hainer

J

,

Klein

J

,

Dorbala

S

,

Blankstein

R

,

Di Carli

MF.

Association between coronary vascular dysfunction and cardiac mortality in patients with and without diabetes mellitus

.

Circulation

2012

;

126

:

1858

–

1868

.

422

Lee

JM

,

Jung

JH

,

Hwang

D

,

Park

J

,

Fan

Y

,

Na

SH

,

Doh

JH

,

Nam

CW

,

Shin

ES

,

Koo

BK.

Coronary flow reserve and microcirculatory resistance in patients with intermediate coronary stenosis

.

J Am Coll Cardiol

2016

;

67

:

1158

–

1169

.

423

Lee

JM

,

Choi

KH

,

Hwang

D

,

Park

J

,

Jung

JH

,

Kim

HY

,

Jung

HW

,

Cho

YK

,

Yoon

HJ

,

Song

YB

,

Hahn

JY

,

Doh

JH

,

Nam

CW

,

Shin

ES

,

Hur

SH

,

Koo

BK.

Prognostic implication of thermodilution coronary flow reserve in patients undergoing fractional flow reserve measurement

.

JACC Cardiovasc Interv

2018

;

11

:

1423

–

1433

.

424

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

–

463

.

425

Mejia-Renteria

H

,

van der Hoeven

N

,

van de Hoef

TP

,

Heemelaar

J

,

Ryan

N

,

Lerman

A

,

van Royen

N

,

Escaned

J

. Targeting the dominant mechanism of coronary microvascular dysfunction with intracoronary physiology tests

.

Int J Cardiovasc Imaging

2017

;

33

:

1041

–

1059

.

426

Leung

M

,

Juergens

CP

,

Lo

ST

,

Leung

DY.

Evaluation of coronary microvascular function by left ventricular contractile reserve with low-dose dobutamine echocardiography

.

EuroIntervention

2014

;

9

:

1202

–

1209

.

427

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

–

631

.

428

Liu

A

,

Wijesurendra

RS

,

Liu

JM

,

Forfar

JC

,

Channon

KM

,

Jerosch-Herold

M

,

Piechnik

SK

,

Neubauer

S

,

Kharbanda

RK

,

Ferreira

VM.

Diagnosis of microvascular angina using cardiac magnetic resonance

.

J Am Coll Cardiol

2018

;

71

:

969

–

979

.

429

Vermeltfoort

IA

,

Bondarenko

O

,

Raijmakers

PG

,

Odekerken

DA

,

Kuijper

AF

,

Zwijnenburg

A

,

van der Vis-Melsen

MJ

,

Twisk

JW

,

Beek

AM

,

Teule

GJ

,

van Rossum

AC.

Is subendocardial ischaemia present in patients with chest pain and normal coronary angiograms? A cardiovascular MR study. Eur Heart J

2007

;

28

:

1554

–

1558

.

430

Shufelt

CL

,

Thomson

LE

,

Goykhman

P

,

Agarwal

M

,

Mehta

PK

,

Sedlak

T

,

Li

N

,

Gill

E

,

Samuels

B

,

Azabal

B

,

Kar

S

,

Kothawade

K

,

Minissian

M

,

Slomka

P

,

Berman

DS

,

Bairey Merz

CN.

Cardiac magnetic resonance imaging myocardial perfusion reserve index assessment in women with microvascular coronary dysfunction and reference controls

.

Cardiovasc Diagn Ther

2013

;

3

:

153

–

160

.

431

Taqueti

VR

,

Hachamovitch

R

,

Murthy

VL

,

Naya

M

,

Foster

CR

,

Hainer

J

,

Dorbala

S

,

Blankstein

R

,

Carli MF

Di

.

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

.

432

Echavarria-Pinto

M

,

Escaned

J

,

Macias

E

,

Medina

M

,

Gonzalo

N

,

Petraco

R

,

Sen

S

,

Jimenez-Quevedo

P

,

Hernandez

R

,

Mila

R

,

Ibanez

B

,

Nunez-Gil

IJ

,

Fernandez

C

,

Alfonso

F

,

Banuelos

C

,

Garcia

E

,

Davies

J

,

Fernandez-Ortiz

A

,

Macaya

C.

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

–

2566

.

433

Nolte

F

,

van de Hoef

TP

,

Meuwissen

M

,

Voskuil

M

,

Chamuleau

SA

,

Henriques

JP

,

Verberne

HJ

,

van Eck-Smit

BL

,

Koch

KT

,

de Winter

RJ

,

Spaan

JA

,

Tijssen

JG

,

Siebes

M

,

Piek

JJ.

Increased hyperaemic coronary microvascular resistance adds to the presence of myocardial ischaemia

.

EuroIntervention

2014

;

9

:

1423

–

1431

.

434

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

–

3181

.

435

Matsuzawa

Y

,

Sugiyama

S

,

Sugamura

K

,

Nozaki

T

,

Ohba

K

,

Konishi

M

,

Matsubara

J

,

Sumida

H

,

Kaikita

K

,

Kojima

S

,

Nagayoshi

Y

,

Yamamuro

M

,

Izumiya

Y

,

Iwashita

S

,

Matsui

K

,

Jinnouchi

H

,

Kimura

K

,

Umemura

S

,

Ogawa

H.

Digital assessment of endothelial function and ischemic heart disease in women

.

J Am Coll Cardiol

2010

;

55

:

1688

–

1696

.

436

Pauly

DF

,

Johnson

BD

,

Anderson

RD

,

Handberg

EM

,

Smith

KM

,

Cooper-DeHoff

RM

,

Sopko

G

,

Sharaf

BM

,

Kelsey

SF

,

Merz

CN

,

Pepine

CJ.

In women with symptoms of cardiac ischemia, nonobstructive coronary arteries, and microvascular dysfunction, angiotensin-converting enzyme inhibition is associated with improved microvascular function: a double-blind randomized study from the National Heart, Lung and Blood Institute Women's Ischemia Syndrome Evaluation (WISE)

.

Am Heart J

2011

;

162

:

678

–

684

.

437

Ong

P

,

Athanasiadis

A

,

Sechtem

U.

Pharmacotherapy for coronary microvascular dysfunction

.

Eur Heart J Cardiovasc Pharmacother

2015

;

1

:

65

–

71

.

438

Ong

P

,

Athanasiadis

A

,

Borgulya

G

,

Vokshi

I

,

Bastiaenen

R

,

Kubik

S

,

Hill

S

,

Schaufele

T

,

Mahrholdt

H

,

Kaski

JC

,

Sechtem

U.

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

–

1730

.

439

Schoenenberger

AW

,

Adler

E

,

Gujer

S

,

Jamshidi

P

,

Kobza

R

,

Stuck

AE

,

Resink

TJ

,

Erne

P.

Prognostic value of an abnormal response to acetylcholine in patients with angina and non-obstructive coronary artery disease: long-term follow-up of the Heart Quest cohort

.

Int J Cardiol

2016

;

221

:

539

–

545

.

440

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

–

2358

.

441

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

.

442

Beltrame

JF

,

Crea

F

,

Kaski

JC

,

Ogawa

H

,

Ong

P

,

Sechtem

U

,

Shimokawa

H

,

Bairey Merz

CN

; Coronary Vasomotion Disorders International Study Group (COVADIS).

International standardization of diagnostic criteria for vasospastic angina

.

Eur Heart J

2017

;

38

:

2565

–

2568

.

443

Ong

P

,

Athanasiadis

A

,

Perne

A

,

Mahrholdt

H

,

Schaufele

T

,

Hill

S

,

Sechtem

U.

Coronary vasomotor abnormalities in patients with stable angina after successful stent implantation but without in-stent restenosis

.

Clin Res Cardiol

2014

;

103

:

11

–

19

.

444

Tsuburaya

R

,

Takahashi

J

,

Nakamura

A

,

Nozaki

E

,

Sugi

M

,

Yamamoto

Y

,

Hiramoto

T

,

Horiguchi

S

,

Inoue

K

,

Goto

T

,

Kato

A

,

Shinozaki

T

,

Ishida

E

,

Miyata

S

,

Yasuda

S

,

Shimokawa

H

;

NOVEL Investigators. Beneficial effects of long-acting nifedipine on coronary vasomotion abnormalities after drug-eluting stent implantation: the NOVEL study

.

Eur Heart J

2016

;

37

:

2713

–

2721

.

445

JCS Joint Working Group.

Guidelines for diagnosis and treatment of patients with vasospastic angina (Coronary Spastic Angina) (JCS 2013)

.

Circ J

2014

;

78

:

2779

–

2801

.

446

Takagi

Y

,

Yasuda

S

,

Takahashi

J

,

Tsunoda

R

,

Ogata

Y

,

Seki

A

,

Sumiyoshi

T

,

Matsui

M

,

Goto

T

,

Tanabe

Y

,

Sueda

S

,

Sato

T

,

Ogawa

S

,

Kubo

N

,

Momomura

S

,

Ogawa

H

,

Shimokawa

H

; Japanese Coronary Spasm Association.

Clinical implications of provocation tests for coronary artery spasm: safety, arrhythmic complications, and prognostic impact: multicentre registry study of the Japanese Coronary Spasm Association

.

Eur Heart J

2013

;

34

:

258

–

267

.

447

Buxton

A

,

Goldberg

S

,

Hirshfeld

JW

,

Wilson

J

,

Mann

T

,

Williams

DO

,

Overlie

P

,

Oliva

P.

Refractory ergonovine-induced coronary vasospasm: importance of intracoronary nitroglycerin

.

Am J Cardiol

1980

;

46

:

329

–

334

.

448

Laaksonen

R

,

Ekroos

K

,

Sysi-Aho

M

,

Hilvo

M

,

Vihervaara

T

,

Kauhanen

D

,

Suoniemi

M

,

Hurme

R

,

Marz

W

,

Scharnagl

H

,

Stojakovic

T

,

Vlachopoulou

E

,

Lokki

ML

,

Nieminen

MS

,

Klingenberg

R

,

Matter

CM

,

Hornemann

T

,

Juni

P

,

Rodondi

N

,

Raber

L

,

Windecker

S

,

Gencer

B

,

Pedersen

ER

,

Tell

GS

,

Nygard

O

,

Mach

F

,

Sinisalo

J

,

Luscher

TF.

Plasma ceramides predict cardiovascular death in patients with stable coronary artery disease and acute coronary syndromes beyond LDL-cholesterol

.

Eur Heart J

2016

;

37

:

1967

–

1976

.

449

Yeboah

J

,

McClelland

RL

,

Polonsky

TS

,

Burke

GL

,

Sibley

CT

,

O'Leary

D

,

Carr

JJ

,

Goff

DC

,

Greenland

P

,

Herrington

DM.

Comparison of novel risk markers for improvement in cardiovascular risk assessment in intermediate-risk individuals

.

JAMA

2012

;

308

:

788

–

795

.

450

Zellweger

MJ

,

Hachamovitch

R

,

Kang

X

,

Hayes

SW

,

Friedman

JD

,

Germano

G

,

Berman

DS.

Threshold, incidence, and predictors of prognostically high-risk silent ischemia in asymptomatic patients without prior diagnosis of coronary artery disease

.

J Nucl Cardiol

2009

;

16

:

193

–

200

.

451

Dahlén

T

,

Edgren

G

,

Lambe

M

,

Höglund

M

,

Björkholm

M

,

Sandin

F

,

Själander

A

,

Richter

J

,

Olsson-Strömberg

U

,

Ohm

L

,

Bäck

M

,

Stenke

L

; Swedish CML Group and the Swedish CML Register Group.

Cardiovascular events associated with use of tyrosine kinase inhibitors in chronic myeloid leukemia: a population-based cohort study

.

Ann Intern Med

2016

;

165

:

161

–

166

.

452

Darby

S

,

McGale

P

,

Peto

R

,

Granath

F

,

Hall

P

,

Ekbom

A.

Mortality from cardiovascular disease more than 10 years after radiotherapy for breast cancer: nationwide cohort study of 90 000 Swedish women

.

BMJ

2003

;

326

:

256

–

257

.

453

Hooning

MJ

,

Botma

A

,

Aleman

BM

,

Baaijens

MH

,

Bartelink

H

,

Klijn

JG

,

Taylor

CW

,

van Leeuwen

FE.

Long-term risk of cardiovascular disease in 10-year survivors of breast cancer

.

J Natl Cancer Inst

2007

;

99

:

365

–

375

.

454

Peters

MJ

,

Symmons

DP

,

McCarey

D

,

Dijkmans

BA

,

Nicola

P

,

Kvien

TK

,

McInnes

IB

,

Haentzschel

H

,

Gonzalez-Gay

MA

,

Provan

S

,

Semb

A

,

Sidiropoulos

P

,

Kitas

G

,

Smulders

YM

,

Soubrier

M

,

Szekanecz

Z

,

Sattar

N

,

Nurmohamed

MT.

EULAR evidence-based recommendations for cardiovascular risk management in patients with rheumatoid arthritis and other forms of inflammatory arthritis

.

Ann Rheum Dis

2010

;

69

:

325

–

331

.

455

Scientific Steering Committee on behalf of the Simon Broome Register Group.

Risk of fatal coronary heart disease in familial hypercholesterolaemia

.

BMJ

1991

;

303

:

893

–

896

.

456

Nordestgaard

BG

,

Chapman

MJ

,

Humphries

SE

,

Ginsberg

HN

,

Masana

L

,

Descamps

OS

,

Wiklund

O

,

Hegele

RA

,

Raal

FJ

,

Defesche

JC

,

Wiegman

A

,

Santos

RD

,

Watts

GF

,

Parhofer

KG

,

Hovingh

GK

,

Kovanen

PT

,

Boileau

C

,

Averna

M

,

Boren

J

,

Bruckert

E

,

Catapano

AL

,

Kuivenhoven

JA

,

Pajukanta

P

,

Ray

K

,

Stalenhoef

AF

,

Stroes

E

,

Taskinen

MR

,

Tybjaerg-Hansen

A;

European Atherosclerosis Society Consensus Panel.

Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: consensus statement of the European Atherosclerosis Society

.

Eur Heart J

2013

;

34

:

3478

–

3490a

.

457

Zeb

I

,

Budoff

M.

Coronary artery calcium screening: does it perform better than other cardiovascular risk stratification tools?

Int J Mol Sci

2015

;

16

:

6606

–

6620

.

458

Gupta

A

,

Kesavabhotla

K

,

Baradaran

H

,

Kamel

H

,

Pandya

A

,

Giambrone

AE

,

Wright

D

,

Pain

KJ

,

Mtui

EE

,

Suri

JS

,

Sanelli

PC

,

Mushlin

AI.

Plaque echolucency and stroke risk in asymptomatic carotid stenosis: a systematic review and meta-analysis

.

Stroke

2015

;

46

:

91

–

97

.

459

Ankle Brachial Index Collaboration,

Fowkes

FG

,

Murray

GD

,

Butcher

I

,

Heald

CL

,

Lee

RJ

,

Chambless

LE

,

Folsom

AR

,

Hirsch

AT

,

Dramaix

M

,

deBacker

G

,

Wautrecht

JC

,

Kornitzer

M

,

Newman

AB

,

Cushman

M

,

Sutton-Tyrrell

K

,

Fowkes

FG

,

Lee

AJ

,

Price

JF

,

d'Agostino

RB

,

Murabito

JM

,

Norman

PE

,

Jamrozik

K

,

Curb

JD

,

Masaki

KH

,

Rodriguez

BL

,

Dekker

JM

,

Bouter

LM

,

Heine

RJ

,

Nijpels

G

,

Stehouwer

CD

,

Ferrucci

L

,

McDermott

MM

,

Stoffers

HE

,

Hooi

JD

,

Knottnerus

JA

,

Ogren

M

,

Hedblad

B

,

Witteman

JC

,

Breteler

MM

,

Hunink

MG

,

Hofman

A

,

Criqui

MH

,

Langer

RD

,

Fronek

A

,

Hiatt

WR

,

Hamman

R

,

Resnick

HE

,

Guralnik

J

,

McDermott

MM.

Ankle brachial index combined with Framingham Risk Score to predict cardiovascular events and mortality: a meta-analysis

.

JAMA

2008

;

300

:

197

–

208

.

460

Den Ruijter

HM

,

Peters

SA

,

Anderson

TJ

,

Britton

AR

,

Dekker

JM

,

Eijkemans

MJ

,

Engstrom

G

,

Evans

GW

,

de Graaf

J

,

Grobbee

DE

,

Hedblad

B

,

Hofman

A

,

Holewijn

S

,

Ikeda

A

,

Kavousi

M

,

Kitagawa

K

,

Kitamura

A

,

Koffijberg

H

,

Lonn

EM

,

Lorenz

MW

,

Mathiesen

EB

,

Nijpels

G

,

Okazaki

S

,

O'Leary

DH

,

Polak

JF

,

Price

JF

,

Robertson

C

,

Rembold

CM

,

Rosvall

M

,

Rundek

T

,

Salonen

JT

,

Sitzer

M

,

Stehouwer

CD

,

Witteman

JC

,

Moons

KG

,

Bots

ML.

Common carotid intima-media thickness measurements in cardiovascular risk prediction: a meta-analysis

.

JAMA

2012

;

308

:

796

–

803

.

461

Ioannidis

JP

,

Tzoulaki

I.

Minimal and null predictive effects for the most popular blood biomarkers of cardiovascular disease

.

Circ Res

2012

;

110

:

658

–

662

.

462

Wurtz

P

,

Havulinna

AS

,

Soininen

P

,

Tynkkynen

T

,

Prieto-Merino

D

,

Tillin

T

,

Ghorbani

A

,

Artati

A

,

Wang

Q

,

Tiainen

M

,

Kangas

AJ

,

Kettunen

J

,

Kaikkonen

J

,

Mikkila

V

,

Jula

A

,

Kahonen

M

,

Lehtimaki

T

,

Lawlor

DA

,

Gaunt

TR

,

Hughes

AD

,

Sattar

N

,

Illig

T

,

Adamski

J

,

Wang

TJ

,

Perola

M

,

Ripatti

S

,

Vasan

RS

,

Raitakari

OT

,

Gerszten

RE

,

Casas

JP

,

Chaturvedi

N

,

Ala-Korpela

M

,

Salomaa

V.

Metabolite profiling and cardiovascular event risk: a prospective study of 3 population-based cohorts

.

Circulation

2015

;

131

:

774

–

785

.

463

Ettehad

D

,

Emdin

CA

,

Kiran

A

,

Anderson

SG

,

Callender

T

,

Emberson

J

,

Chalmers

J

,

Rodgers

A

,

Rahimi

K.

Blood pressure lowering for prevention of cardiovascular disease and death: a systematic review and meta-analysis

.

Lancet

2016

;

387

:

957

–

967

.

464

Williams

B

,

Mancia

G

,

Spiering

W

,

Agabiti Rosei

E

,

Azizi

M

,

Burnier

M

,

Clement

DL

,

Coca

A

,

de Simone

G

,

Dominiczak

A

,

Kahan

T

,

Mahfoud

F

,

Redon

J

,

Ruilope

L

,

Zanchetti

A

,

Kerins

M

,

Kjeldsen

SE

,

Kreutz

R

,

Laurent

S

,

Lip

GYH

,

McManus

R

,

Narkiewicz

K

,

Ruschitzka

F

,

Schmieder

RE

,

Shlyakhto

E

,

Tsioufis

C

,

Aboyans

V

,

Desormais

I.

2018 ESC/ESH Guidelines for the management of arterial hypertension

.

Eur Heart J

2018

;

39

:3021

–

3104

.

465

Vidal-Petiot

E

,

Ford

I

,

Greenlaw

N

,

Ferrari

R

,

Fox

KM

,

Tardif

JC

,

Tendera

M

,

Tavazzi

L

,

Bhatt

DL

,

Steg

PG

; CLARIFY Investigators.

Cardiovascular event rates and mortality according to achieved systolic and diastolic blood pressure in patients with stable coronary artery disease: an international cohort study

.

Lancet

2016

;

388

:

2142

–

2152

.

466

Bohm

M

,

Schumacher

H

,

Teo

KK

,

Lonn

EM

,

Mahfoud

F

,

Mann

JFE

,

Mancia

G

,

Redon

J

,

Schmieder

RE

,

Sliwa

K

,

Weber

MA

,

Williams

B

,

Yusuf

S.

Achieved blood pressure and cardiovascular outcomes in high-risk patients: results from ONTARGET and TRANSCEND trials

.

Lancet

2017

;

389

:

2226

–

2237

.

467

Law

MR

,

Morris

JK

,

Wald

NJ.

Use of blood pressure lowering drugs in the prevention of cardiovascular disease: meta-analysis of 147 randomised trials in the context of expectations from prospective epidemiological studies

.

BMJ

2009

;

338

:

b1665

.

468

Fried

LF

,

Emanuele

N

,

Zhang

JH

,

Brophy

M

,

Conner

TA

,

Duckworth

W

,

Leehey

DJ

,

McCullough

PA

,

O'Connor

T

,

Palevsky

PM

,

Reilly

RF

,

Seliger

SL

,

Warren

SR

,

Watnick

S

,

Peduzzi

P

,

Guarino

P

, VA NEPHRON-D Investigators.

Combined angiotensin inhibition for the treatment of diabetic nephropathy

.

N Engl J Med

2013

;

369

:

1892

–

1903

.

469

ONTARGET Investigators,

Yusuf

S

,

Teo

KK

,

Pogue

J

,

Dyal

L

,

Copland

I

,

Schumacher

H

,

Dagenais

G

,

Sleight

P

,

Anderson

C.

Telmisartan, ramipril, or both in patients at high risk for vascular events

.

N Engl J Med

2008

;

358

:

1547

–

1559

.

470

Thomopoulos

C

,

Parati

G

,

Zanchetti

A.

Effects of blood pressure lowering on outcome incidence in hypertension. 1. Overview, meta-analyses, and meta-regression analyses of randomized trials

.

J Hypertens

2014

;

32

:

2285

–

2295

.

471

Williamson

JD

,

Supiano

MA

,

Applegate

WB

,

Berlowitz

DR

,

Campbell

RC

,

Chertow

GM

,

Fine

LJ

,

Haley

WE

,

Hawfield

AT

,

Ix

JH

,

Kitzman

DW

,

Kostis

JB

,

Krousel-Wood

MA

,

Launer

LJ

,

Oparil

S

,

Rodriguez

CJ

,

Roumie

CL

,

Shorr

RI

,

Sink

KM

,

Wadley

VG

,

Whelton

PK

,

Whittle

J

,

Woolard

NF

,

Wright

JT

Jr,

Pajewski

NM

; SPRINT Research Group.

Intensive vs standard blood pressure control and cardiovascular disease outcomes in adults aged ≥75 years: a randomized clinical trial

.

JAMA

2016

;

315

:

2673

–

2682

.

472

Odden

MC

,

McClure

LA

,

Sawaya

BP

,

White

CL

,

Peralta

CA

,

Field

TS

,

Hart

RG

,

Benavente

OR

,

Pergola

PE.

Achieved blood pressure and outcomes in the secondary prevention of small subcortical strokes trial

.

Hypertension

2016

;

67

:

63

–

69

.

473

Witberg

G

,

Regev

E

,

Chen

S

,

Assali

A

,

Barbash

IM

,

Planer

D

,

Vaknin-Assa

H

,

Guetta

V

,

Vukasinovic

V

,

Orvin

K

,

Danenberg

HD

,

Segev

A

,

Kornowski

R.

The prognostic effects of coronary disease severity and completeness of revascularization on mortality in patients undergoing transcatheter aortic valve replacement

.

JACC Cardiovasc Interv

2017

;

10

:

1428

–

1435

.

474

Chakravarty

T

,

Sharma

R

,

Abramowitz

Y

,

Kapadia

S

,

Latib

A

,

Jilaihawi

H

,

Poddar

KL

,

Giustino

G

,

Ribeiro

HB

,

Tchetche

D

,

Monteil

B

,

Testa

L

,

Tarantini

G

,

Facchin

M

,

Lefevre

T

,

Lindman

BR

,

Hariri

B

,

Patel

J

,

Takahashi

N

,

Matar

G

,

Mirocha

J

,

Cheng

W

,

Tuzcu

ME

,

Sievert

H

,

Rodes-Cabau

J

,

Colombo

A

,

Finkelstein

A

,

Fajadet

J

,

Makkar

RR.

Outcomes in patients with transcatheter aortic valve replacement and left main stenting: the TAVR-LM registry

.

J Am Coll Cardiol

2016

;

67

:

951

–

960

.

475

Rafique

AM

,

Biner

S

,

Ray

I

,

Forrester

JS

,

Tolstrup

K

,

Siegel

RJ.

Meta-analysis of prognostic value of stress testing in patients with asymptomatic severe aortic stenosis

.

Am J Cardiol

2009

;

104

:

972

–

977

.

476

Baumgartner

H

,

Falk

V

,

Bax

JJ

,

De Bonis

M

,

Hamm

C

,

Holm

PJ

,

Iung

B

,

Lancellotti

P

,

Lansac

E

,

Rodriguez Munoz

D

,

Rosenhek

R

,

Sjogren

J

,

Tornos Mas

P

,

Vahanian

A

,

Walther

T

,

Wendler

O

,

Windecker

S

,

Zamorano

JL.

2017 ESC/EACTS Guidelines for the management of valvular heart disease

.

Eur Heart J

2017

;

38

:2739

–

2791

.

477

Zimmer

RJ

,

Lee

MS.

Transplant coronary artery disease

.

JACC Cardiovasc Interv

2010

;

3

:

367

–

377

.

478

Okada

K

,

Fearon

WF

,

Luikart

H

,

Kitahara

H

,

Otagiri

K

,

Tanaka

S

,

Kimura

T

,

Yock

PG

,

Fitzgerald

PJ

,

Yeung

AC

,

Valantine

HA

,

Khush

KK

,

Honda

Y.

Attenuated-signal plaque progression predicts long-term mortality after heart transplantation: IVUS assessment of cardiac allograft vasculopathy

.

J Am Coll Cardiol

2016

;

68

:

382

–

392

.

479

Luc

JGY

,

Choi

JH

,

Rizvi

SA

,

Phan

K

,

Moncho Escriva

E

,

Patel

S

,

Reeves

GR

,

Boyle

AJ

,

Entwistle

JW

,

Morris

RJ

,

Massey

HT

,

Tchantchaleishvili

V.

Percutaneous coronary intervention versus coronary artery bypass grafting in heart transplant recipients with coronary allograft vasculopathy: a systematic review and meta-analysis of 1,520 patients

.

Ann Cardiothorac Surg

2018

;

7

:

19

–

30

.

480

Zamorano

JL

,

Lancellotti

P

,

Rodriguez Munoz

D

,

Aboyans

V

,

Asteggiano

R

,

Galderisi

M

,

Habib

G

,

Lenihan

DJ

,

Lip

GYH

,

Lyon

AR

,

Lopez Fernandez

T

,

Mohty

D

,

Piepoli

MF

,

Tamargo

J

,

Torbicki

A

,

Suter

TM.

2016 ESC Position Paper on cancer treatments and cardiovascular toxicity developed under the auspices of the ESC Committee for Practice Guidelines: The Task Force for cancer treatments and cardiovascular toxicity of the European Society of Cardiology (ESC)

.

Eur Heart J

2016

;

37

:2768

–

2801

.

481

Emerging Risk Factors Collaboration,

Sarwar

N

,

Gao

P

,

Seshasai

SR

,

Gobin

R

,

Kaptoge

S

,

Di Angelantonio

E

,

Ingelsson

E

,

Lawlor

DA

,

Selvin

E

,

Stampfer

M

,

Stehouwer

CD

,

Lewington

S

,

Pennells

L

,

Thompson

A

,

Sattar

N

,

White

IR

,

Ray

KK

,

Danesh

J.

Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies

.

Lancet

2010

;

375

:

2215

–

2222

.

482

Thomopoulos

C

,

Parati

G

,

Zanchetti

A.

Effects of blood-pressure-lowering treatment on outcome incidence in hypertension: 10 - Should blood pressure management differ in hypertensive patients with and without diabetes mellitus? Overview and meta-analyses of randomized trials

.

J Hypertens

2017

;

35

:

922

–

944

.

483

Shepherd

J

,

Barter

P

,

Carmena

R

,

Deedwania

P

,

Fruchart

JC

,

Haffner

S

,

Hsia

J

,

Breazna

A

,

LaRosa

J

,

Grundy

S

,

Waters

D.

Effect of lowering LDL cholesterol substantially below currently recommended levels in patients with coronary heart disease and diabetes: the Treating to New Targets (TNT) study

.

Diabetes Care

2006

;

29

:

1220

–

1226

.

484

ADVANCE Collaborative Group,

Patel

A

,

MacMahon

S

,

Chalmers

J

,

Neal

B

,

Billot

L

,

Woodward

M

,

Marre

M

,

Cooper

M

,

Glasziou

P

,

Grobbee

D

,

Hamet

P

,

Harrap

S

,

Heller

S

,

Liu

L

,

Mancia

G

,

Mogensen

CE

,

Pan

C

,

Poulter

N

,

Rodgers

A

,

Williams

B

,

Bompoint

S

,

de Galan

BE

,

Joshi

R

,

Travert

F

.

Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes

.

N Engl J Med

2008

;

358

:

2560

–

2572

.

485

Zinman

B

,

Wanner

C

,

Lachin

JM

,

Fitchett

D

,

Bluhmki

E

,

Hantel

S

,

Mattheus

M

,

Devins

T

,

Johansen

OE

,

Woerle

HJ

,

Broedl

UC

,

Inzucchi

SE

; EMPA-REG OUTCOME Investigators.

Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes

.

N Engl J Med

2015

;

373

:

2117

–

2128

.

486

Neal

B

,

Perkovic

V

,

Matthews

DR

,

Mahaffey

KW

,

Fulcher

G

,

Meininger

G

,

Erondu

N

,

Desai

M

,

Shaw

W

,

Vercruysse

F

,

Yee

J

,

Deng

H

,

de Zeeuw

D

; CANVAS-R Trial Collaborative Group.

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

–

393

.

487

Neal

B

,

Perkovic

V

,

Mahaffey

KW

,

de Zeeuw

D

,

Fulcher

G

,

Erondu

N

,

Shaw

W

,

Law

G

,

Desai

M

,

Matthews

DR

; CANVAS Program Collaborative Group.

Canagliflozin and cardiovascular and renal events in type 2 diabetes

.

N Engl J Med

2017

;

377

:

644

–

657

.

488

Marso

SP

,

Daniels

GH

,

Brown-Frandsen

K

,

Kristensen

P

,

Mann

JF

,

Nauck

MA

,

Nissen

SE

,

Pocock

S

,

Poulter

NR

,

Ravn

LS

,

Steinberg

WM

,

Stockner

M

,

Zinman

B

,

Bergenstal

RM

,

Buse

JB

; LEADER Steering Committee; LEADER Trial Investigators.

Liraglutide and cardiovascular outcomes in type 2 diabetes

.

N Engl J Med

2016

;

375

:

311

–

322

.

489

Marso

SP

,

Bain

SC

,

Consoli

A

,

Eliaschewitz

FG

,

Jodar

E

,

Leiter

LA

,

Lingvay

I

,

Rosenstock

J

,

Seufert

J

,

Warren

ML

,

Woo

V

,

Hansen

O

,

Holst

AG

,

Pettersson

J

,

Vilsboll

T

; SUSTAIN-6 Investigators.

Semaglutide and cardiovascular outcomes in patients with type 2 diabetes

.

N Engl J Med

2016

;

375

:

1834

–

1844

.

490

Hernandez

AF

,

Green

JB

,

Janmohamed

S

,

D'Agostino

RB

Sr,

Granger

CB

,

Jones

NP

,

Leiter

LA

,

Rosenberg

AE

,

Sigmon

KN

,

Somerville

MC

,

Thorpe

KM

,

McMurray

JJV

,

Del Prato

S

; Harmony Outcomes committees and investigators.

Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial

.

Lancet

2018

;

392

:

1519

–

1529

.

491

Kang

SH

,

Park

GM

,

Lee

SW

,

Yun

SC

,

Kim

YH

,

Cho

YR

,

Park

HW

,

Suh

J

,

Yang

DH

,

Kang

JW

,

Lim

TH

,

Jung

CH

,

Koh

EH

,

Lee

WJ

,

Kim

MS

,

Lee

KU

,

Park

JY.

Long-term prognostic value of coronary CT angiography in asymptomatic type 2 diabetes mellitus

.

JACC Cardiovasc Imaging

2016

;

9

:

1292

–

1300

.

492

Clerc

OF

,

Fuchs

TA

,

Stehli

J

,

Benz

DC

,

Grani

C

,

Messerli

M

,

Giannopoulos

AA

,

Buechel

RR

,

Luscher

TF

,

Pazhenkottil

AP

,

Kaufmann

PA

,

Gaemperli

O.

Non-invasive screening for coronary artery disease in asymptomatic diabetic patients: a systematic review and meta-analysis of randomised controlled trials

.

Eur Heart J Cardiovasc Imaging

2018

;

19

:

838

–

846

.

493

Lee

JM

,

Kang

J

,

Lee

E

,

Hwang

D

,

Rhee

TM

,

Park

J

,

Kim

HL

,

Lee

SE

,

Han

JK

,

Yang

HM

,

Park

KW

,

Na

SH

,

Kang

HJ

,

Koo

BK

,

Kim

HS.

Chronic kidney disease in the second-generation drug-eluting stent era: pooled analysis of the Korean Multicenter Drug-Eluting Stent Registry

.

JACC Cardiovasc Interv

2016

;

9

:

2097

–

2109

.

494

Fox

CS

,

Matsushita

K

,

Woodward

M

,

Bilo

HJ

,

Chalmers

J

,

Heerspink

HJ

,

Lee

BJ

,

Perkins

RM

,

Rossing

P

,

Sairenchi

T

,

Tonelli

M

,

Vassalotti

JA

,

Yamagishi

K

,

Coresh

J

,

de Jong

PE

,

Wen

CP

,

Nelson

RG

; Chronic Kidney Disease Prognosis Consortium.

Associations of kidney disease measures with mortality and end-stage renal disease in individuals with and without diabetes: a meta-analysis

.

Lancet

2012

;

380

:

1662

–

1673

.

495

Schmidt

A

,

Stefenelli

T

,

Schuster

E

,

Mayer

G.

Informational contribution of noninvasive screening tests for coronary artery disease in patients on chronic renal replacement therapy

.

Am J Kidney Dis

2001

;

37

:

56

–

63

.

496

Bangalore

S.

Stress testing in patients with chronic kidney disease: the need for ancillary markers for effective risk stratification and prognosis

.

J Nucl Cardiol

2016

;

23

:

570

–

574

.

497

Smilowitz

NR

,

Gupta

N

,

Guo

Y

,

Mauricio

R

,

Bangalore

S.

Management and outcomes of acute myocardial infarction in patients with chronic kidney disease

.

Int J Cardiol

2017

;

227

:

1

–

7

.

498

Bangalore

S

,

Guo

Y

,

Samadashvili

Z

,

Blecker

S

,

Xu

J

,

Hannan

EL.

Revascularization in patients with multivessel coronary artery disease and chronic kidney disease: everolimus-eluting stents versus coronary artery bypass graft surgery

.

J Am Coll Cardiol

2015

;

66

:

1209

–

1220

.

499

Wang

Y

,

Zhu

S

,

Gao

P

,

Zhang

Q.

Comparison of coronary artery bypass grafting and drug-eluting stents in patients with chronic kidney disease and multivessel disease: a meta-analysis

.

Eur J Intern Med

2017

;

43

:

28

–

35

.

500

Palmer

SC

,

Navaneethan

SD

,

Craig

JC

,

Johnson

DW

,

Perkovic

V

,

Hegbrant

J

,

Strippoli

GF.

HMG CoA reductase inhibitors (statins) for people with chronic kidney disease not requiring dialysis

.

Cochrane Database Syst Rev

2014

;

5

:

CD007784

.

501

Lv

J

,

Ehteshami

P

,

Sarnak

MJ

,

Tighiouart

H

,

Jun

M

,

Ninomiya

T

,

Foote

C

,

Rodgers

A

,

Zhang

H

,

Wang

H

,

Strippoli

GF

,

Perkovic

V.

Effects of intensive blood pressure lowering on the progression of chronic kidney disease: a systematic review and meta-analysis

.

CMAJ

2013

;

185

:

949

–

957

.

502

Klag

MJ

,

Whelton

PK

,

Randall

BL

,

Neaton

JD

,

Brancati

FL

,

Ford

CE

,

Shulman

NB

,

Stamler

J.

Blood pressure and end-stage renal disease in men

.

N Engl J Med

1996

;

334

:

13

–

18

.

503

Marenzi

G

,

Assanelli

E

,

Campodonico

J

,

Lauri

G

,

Marana

I

,

De Metrio

M

,

Moltrasio

M

,

Grazi

M

,

Rubino

M

,

Veglia

F

,

Fabbiocchi

F

,

Bartorelli

AL.

Contrast volume during primary percutaneous coronary intervention and subsequent contrast-induced nephropathy and mortality

.

Ann Intern Med

2009

;

150

:

170

–

177

.

504

Laskey

WK

,

Jenkins

C

,

Selzer

F

,

Marroquin

OC

,

Wilensky

RL

,

Glaser

R

,

Cohen

HA

,

Holmes

DR

Jr; NHLBI Dynamic Registry Investigators.

Volume-to-creatinine clearance ratio: a pharmacokinetically based risk factor for prediction of early creatinine increase after percutaneous coronary intervention

.

J Am Coll Cardiol

2007

;

50

:

584

–

590

.

505

Malkin

CJ

,

Prakash

R

,

Chew

DP.

The impact of increased age on outcome from a strategy of early invasive management and revascularisation in patients with acute coronary syndromes: retrospective analysis study from the ACACIA registry

.

BMJ Open

2012

;

2

:

e000540

.

506

Vranckx

P

,

Frigoli

E

,

Rothenbuhler

M

,

Tomassini

F

,

Garducci

S

,

Ando

G

,

Picchi

A

,

Sganzerla

P

,

Paggi

A

,

Ugo

F

,

Ausiello

A

,

Sardella

G

,

Franco

N

,

Nazzaro

M

,

de Cesare

N

,

Tosi

P

,

Falcone

C

,

Vigna

C

,

Mazzarotto

P

,

Di Lorenzo

E

,

Moretti

C

,

Campo

G

,

Penzo

C

,

Pasquetto

G

,

Heg

D

,

Juni

P

,

Windecker

S

,

Valgimigli

M

; MATRIX Investigators.

Radial versus femoral access in patients with acute coronary syndromes with or without ST-segment elevation

.

Eur Heart J

2017

;

38

:

1069

–

1080

.

507

Cantor

WJ

,

Mehta

SR

,

Yuan

F

,

Dzavik

V

,

Worthley

M

,

Niemela

K

,

Valentin

V

,

Fung

A

,

Cheema

AN

,

Widimsky

P

,

Natarajan

M

,

Jedrzejowski

B

,

Jolly

SS.

Radial versus femoral access for elderly patients with acute coronary syndrome undergoing coronary angiography and intervention: insights from the RIVAL trial

.

Am Heart J

2015

;

170

:

880

–

886

.

508

Varenne

O

,

Cook

S

,

Sideris

G

,

Kedev

S

,

Cuisset

T

,

Carrie

D

,

Hovasse

T

,

Garot

P

,

El Mahmoud

R

,

Spaulding

C

,

Helft

G

,

Diaz Fernandez

JF

,

Brugaletta

S

,

Pinar-Bermudez

E

,

Mauri Ferre

J

,

Commeau

P

,

Teiger

E

,

Bogaerts

K

,

Sabate

M

,

Morice

MC

,

Sinnaeve

PR

; SENIOR investigators.

Drug-eluting stents in elderly patients with coronary artery disease (SENIOR): a randomised single-blind trial

.

Lancet

2018

;

391

:

41

–

50

.

509

Urban

P

,

Meredith

IT

,

Abizaid

A

,

Pocock

SJ

,

Carrie

D

,

Naber

C

,

Lipiecki

J

,

Richardt

G

,

Iniguez

A

,

Brunel

P

,

Valdes-Chavarri

M

,

Garot

P

,

Talwar

S

,

Berland

J

,

Abdellaoui

M

,

Eberli

F

,

Oldroyd

K

,

Zambahari

R

,

Gregson

J

,

Greene

S

,

Stoll

HP

,

Morice

MC

; LEADERS FREE Investigators.

Polymer-free drug-coated coronary stents in patients at high bleeding risk

.

N Engl J Med

2015

;

373

:

2038

–

2047

.

510

Kim

ES

,

Carrigan

TP

,

Menon

V.

Enrollment of women in National Heart, Lung, and Blood Institute-funded cardiovascular randomized controlled trials fails to meet current federal mandates for inclusion

.

J Am Coll Cardiol

2008

;

52

:

672

–

673

.

511

Ricci

B

,

Cenko

E

,

Vasiljevic

Z

,

Stankovic

G

,

Kedev

S

,

Kalpak

O

,

Vavlukis

M

,

Zdravkovic

M

,

Hinic

S

,

Milicic

D

,

Manfrini

O

,

Badimon

L

,

Bugiardini

R.

Acute coronary syndrome: the risk to young women

.

J Am Heart Assoc

2017

;

6

:

e007519

.

512

Cenko

E

,

Yoon

J

,

Kedev

S

,

Stankovic

G

,

Vasiljevic

Z

,

Krljanac

G

,

Kalpak

O

,

Ricci

B

,

Milicic

D

,

Manfrini

O

,

van der Schaar

M

,

Badimon

L

,

Bugiardini

R.

Sex differences in outcomes after STEMI: effect modification by treatment strategy and age

.

JAMA Intern Med

2018

;

178

:

632

–

639

.

513

Khan

NA

,

Daskalopoulou

SS

,

Karp

I

,

Eisenberg

MJ

,

Pelletier

R

,

Tsadok

MA

,

Dasgupta

K

,

Norris

CM

,

Pilote

L

; GENESIS PRAXY Team.

Sex differences in acute coronary syndrome symptom presentation in young patients

.

JAMA Intern Med

2013

;

173

:

1863

–

1871

.

514

Oertelt-Prigione

S

,

Seeland

U

,

Kendel

F

,

Rucke

M

,

Floel

A

,

Gaissmaier

W

,

Heim

C

,

Schnabel

R

,

Stangl

V

,

Regitz-Zagrosek

V.

Cardiovascular risk factor distribution and subjective risk estimation in urban women--the BEFRI study: a randomized cross-sectional study

.

BMC Med

2015

;

13

:

52

.

515

Davis

M

,

Diamond

J

,

Montgomery

D

,

Krishnan

S

,

Eagle

K

,

Jackson

E.

Acute coronary syndrome in young women under 55 years of age: clinical characteristics, treatment, and outcomes

.

Clin Res Cardiol

2015

;

104

:

648

–

655

.

516

Aggeli

C

,

Polytarchou

K

,

Felekos

I

,

Zisimos

K

,

Venieri

E

,

Verveniotis

A

,

Varvarousis

D

,

Toutouzas

K

,

Tsiamis

E

,

Tousoulis

D.

Effect of gender on the prognostic value of dobutamine stress myocardial contrast echocardiography

.

Hellenic J Cardiol

2017

;

58

:

419

–

424

.

517

Morice

MC

,

Mikhail

GW

,

Mauri i Ferre

F

,

Modena

MG

,

Strasser

RH

,

Grinfeld

L

,

Sudhir

K

,

Stuteville

M

,

Papeleu

P

,

Li

D

,

Rutledge

D

,

Windecker

S.

SPIRIT Women, evaluation of the safety and efficacy of the XIENCE V everolimus-eluting stent system in female patients: referral time for coronary intervention and 2-year clinical outcomes

.

EuroIntervention

2012

;

8

:

325

–

335

.

518

Duvernoy

CS

,

Smith

DE

,

Manohar

P

,

Schaefer

A

,

Kline-Rogers

E

,

Share

D

,

McNamara

R

,

Gurm

HS

,

Moscucci

M.

Gender differences in adverse outcomes after contemporary percutaneous coronary intervention: an analysis from the Blue Cross Blue Shield of Michigan Cardiovascular Consortium (BMC2) percutaneous coronary intervention registry

.

Am Heart J

2010

;

159

:

677

–

683 e671

.

519

Giustino

G

,

Baber

U

,

Salianski

O

,

Sartori

S

,

Stone

GW

,

Leon

MB

,

Aquino

M

,

Stefanini

GG

,

Steg

PG

,

Windecker

S

,

M

OD

,

Wijns

W

,

Serruys

PW

,

Valgimigli

M

,

Morice

MC

,

Camenzind

E

,

Weisz

G

,

Smits

PC

,

Kandzari

D

,

Von Birgelen

C

,

Dangas

GD

,

Cha

JY

,

Galatius

S

,

Jeger

RV

,

Kimura

T

,

Mikhail

GW

,

Itchhaporia

D

,

Mehta

L

,

Ortega

R

,

Kim

HS

,

Kastrati

A

,

Genereux

P

,

Chieffo

A

,

Mehran

R.

Safety and efficacy of new-generation drug-eluting stents in women at high risk for atherothrombosis: from the Women in Innovation and Drug-Eluting Stents collaborative patient-level pooled analysis

.

Circ Cardiovasc Interv

2016

;

9

:

e002995

.

520

Filardo

G

,

Hamman

BL

,

Pollock

BD

,

da Graca

B

,

Sass

DM

,

Phan

TK

,

Edgerton

J

,

Prince

SL

,

Ring

WS

.

Excess short-term mortality in women after isolated coronary artery bypass graft surgery

.

Open Heart

2016

;

3

:

e000386

.

521

Arif

R

,

Farag

M

,

Gertner

V

,

Szabo

G

,

Weymann

A

,

Veres

G

,

Ruhparwar

A

,

Bekeredjian

R

,

Bruckner

T

,

Karck

M

,

Kallenbach

K

,

Beller

CJ.

Female gender and differences in outcome after isolated coronary artery bypass graft surgery: does age play a role?

PLoS One

2016

;

11

:

e0145371

.

522

Banks

E

,

Canfell

K.

Invited commentary: hormone therapy risks and benefits--the Women's Health Initiative findings and the postmenopausal estrogen timing hypothesis

.

Am J Epidemiol

2009

;

170

:

24

–

28

.

523

Clarkson

TB

,

Melendez

GC

,

Appt

SE.

Timing hypothesis for postmenopausal hormone therapy: its origin, current status, and future

.

Menopause

2013

;

20

:

342

–

353

.

524

Arora

RR

,

Chou

TM

,

Jain

D

,

Fleishman

B

,

Crawford

L

,

McKiernan

T

,

Nesto

R

,

Ferrans

CE

,

Keller

S.

Effects of enhanced external counterpulsation on Health-Related Quality of Life continue 12 months after treatment: a substudy of the Multicenter Study of Enhanced External Counterpulsation

.

J Investig Med

2002

;

50

:

25

–

32

.

525

Verheye

S

,

Jolicoeur

EM

,

Behan

MW

,

Pettersson

T

,

Sainsbury

P

,

Hill

J

,

Vrolix

M

,

Agostoni

P

,

Engstrom

T

,

Labinaz

M

,

de Silva

R

,

Schwartz

M

,

Meyten

N

,

Uren

NG

,

Doucet

S

,

Tanguay

JF

,

Lindsay

S

,

Henry

TD

,

White

CJ

,

Edelman

ER

,

Banai

S.

Efficacy of a device to narrow the coronary sinus in refractory angina

.

N Engl J Med

2015

;

372

:

519

–

527

.

526

Zipes

DP

,

Svorkdal

N

,

Berman

D

,

Boortz-Marx

R

,

Henry

T

,

Lerman

A

,

Ross

E

,

Turner

M

,

Irwin

C.

Spinal cord stimulation therapy for patients with refractory angina who are not candidates for revascularization

.

Neuromodulation

2012

;

15

:

550

–

558

; discussion 558–559.

527

Denby

C

,

Groves

DG

,

Eleuteri

A

,

Tsang

HK

,

Leach

A

,

Hammond

C

,

Bridson

JD

,

Fisher

M

,

Elt

M

,

Laflin

R

,

Fisher

AC.

Temporary sympathectomy in chronic refractory angina: a randomised, double-blind, placebo-controlled trial

.

Br J Pain

2015

;

9

:

142

–

148

.

528

Henry

TD

,

Losordo

DW

,

Traverse

JH

,

Schatz

RA

,

Jolicoeur

EM

,

Schaer

GL

,

Clare

R

,

Chiswell

K

,

White

CJ

,

Fortuin

FD

,

Kereiakes

DJ

,

Zeiher

AM

,

Sherman

W

,

Hunt

AS

,

Povsic

TJ.

Autologous CD34+ cell therapy improves exercise capacity, angina frequency and reduces mortality in no-option refractory angina: a patient-level pooled analysis of randomized double-blinded trials

.

Eur Heart J

2018

;

39

:

2208

–

2216

.

529

Briones

E

,

Lacalle

JR

,

Marin-Leon

I

,

Rueda

JR.

Transmyocardial laser revascularization versus medical therapy for refractory angina

.

Cochrane Database Syst Rev

2015

;

2

:

CD003712

.