Update on cardiovascular prevention in clinical practice: A position paper of the European Association of Preventive Cardiology of the European Society of Cardiology*

Abstract

European guidelines on cardiovascular prevention in clinical practice were first published in 1994 and have been regularly updated, most recently in 2016, by the Sixth European Joint Task Force. Given the amount of new information that has become available since then, components from the task force and experts from the European Association of Preventive Cardiology of the European Society of Cardiology were invited to provide a summary and critical review of the most important new studies and evidence since the latest guidelines were published. The structure of the document follows that of the previous document and has six parts: Introduction (epidemiology and cost effectiveness); Cardiovascular risk; How to intervene at the population level; How to intervene at the individual level; Disease-specific interventions; and Settings: where to intervene? In fact, in keeping with the guidelines, greater emphasis has been put on a population-based approach and on disease-specific interventions, avoiding re-interpretation of information already and previously considered. Finally, the presence of several gaps in the knowledge is highlighted.

Guidelines, blood pressure, clinical settings, diabetes, healthy lifestyle, lipids, nutrition, physical activity, population, prevention, primary care, psychosocial factors, rehabilitation, risk assessment, risk management, smoking, stakeholder

Introduction

The 2016 European guidelines on cardiovascular disease (CVD) prevention represented an evidence-based consensus of the Sixth European Joint Task Force involving 10 professional societies, in which the evidence and knowledge gaps in managing CVD prevention were revised. In addition, the guidelines provided tools for healthcare professionals to promote population-based strategies and integrate these into national or regional prevention frameworks and to translate these into locally delivered healthcare services, in line with the recommendations of the World Health Organization (WHO) global status report on non-communicable diseases 2010.¹

For the present document, components from the Sixth European Joint Task Force and experts from the European Association of Preventive Cardiology (EAPC) of the European Society of Cardiology (ESC) were invited to provide a summary and critical review of the most important new studies and evidence since the 2016 guidelines were published.

The structure of the document follows that of the previous document and has six parts: Introduction (epidemiology and cost effectiveness); Cardiovascular risk; How to intervene at the population level; How to intervene at the individual level; Disease-specific interventions; and Settings: where to intervene?

In keeping with the 2016 guidelines, greater emphasis has been put on a population-based approach and on disease-specific interventions. Finally, the presence of several gaps in the knowledge is highlighted.

Epidemiology

According to the latest (2017) European data from the ESC atlas, CVD accounts for 45% of all deaths in Europe and 37% of all deaths in the European Union (EU) and thus remains one of the most common disorders.² There were approximately 83.5 million people living with CVD in ESC member countries in 2015. The prevalence was driven predominantly by peripheral vascular disease (∼35.7 million), followed by ischaemic heart disease (IHD) (∼29.4 million), other CVDs such as pericardial disease, valvular heart disease (∼13.3 million), atrial fibrillation (AF) (∼9.5 million) and stroke (∼7.5 million). Moreover, the economic status with the differences in gross domestic product in each country plays a critical role. Age-standardised prevalent cases of CVD per 100,000 people in high and middle-income countries were 5093 and 6570 for women compared with 6563 and 8358 for men. IHD was less prevalent in high-income compared with middle-income countries in women (1212 vs. 2212) and men (2267 vs. 3788). Stroke prevalence showed similar inequality between high and middle-income countries in women (448 vs. 843) and men (497 vs. 863). This reflects not only population growth and ageing, because age-standardised data for men and women show consistent declines in CVD prevalence across high-income ESC member countries during the last 25 years. Instead, half of the middle-income countries recorded an increase in disease prevalence, with the inequalities in disease burden being further emphasised by a greater than two-fold excess of disability-adjusted life years lost to IHD in middle-income compared with high-income ESC member countries: in women and men, there were a mean of 1004 and 2407 age-standardised disability-adjusted life years per 100,000 people lost during 2015 in high-income member countries compared with 2715 and 5977 in middle-income member countries.

Similarly for incidence, out of more than 11 million new cases of CVD in the 47 ESC member countries in 2015, larger increases were observed in middle-income countries in both women and men (by 17% and 26%, respectively) versus high-income countries (by 11% and 22%, respectively).

A higher prevalence of CVD risk factors, such as obesity, diabetes mellitus (DM), age-standardised raised blood pressure (BP), and smoking in middle-income countries is likely to have contributed to the higher cardiovascular mortality.² For example, the average prevalence of age-standardised raised BP in women and men was 18.3% and 27.3% in high-income ESC member countries and 23.5% and 30.3% in middle-income countries.

This presents the middle-income member countries of the ESC with a clear economic imperative to develop policies to protect their populations against the development and progression of CVD. Prevalence statistics are not always closely associated with gross domestic product. Thus, the commitment to the cause of tackling CVD is not simply a question of resources but also requires sound health policies that are backed up by implementation strategies.

Cost effectiveness

How to reduce CVD costs is an increasingly pressing question for low and middle-income countries. In primary prevention, across all age ranges, targeted case finding using a prior estimate of CVD risk is more efficient than universal case finding in healthy adults, which supports the implementation of validated risk scores.³ A small case-based training programme for general practitioners in the Stockholm County, aimed to implement evidence-based care of patients at very high risk of coronary death, was associated with decreased mortality and showed long-term cost-effectiveness.⁴

In a non-European country (India) a microsimulation model of myocardial infarction (MI) and stroke has demonstrated the efficacy and the cost-effectiveness of expanding national insurance to cover primary prevention, secondary prevention and tertiary treatment for CVD.⁵

Cardiovascular risk

Risk stratification and scores

Non-traditional CVD risk factors

Non-traditional risk factors are considered potentially useful if: (a) they improve risk classification; (b) there was no evidence of substantial publication bias; and (c) their measurement is likely to be cost-effective. Consequently, socioeconomic status, family history, (central) obesity, coronary artery calcium (CAC) scoring, carotid plaque, abnormal ankle–brachial index (ABI) have been considered potentially useful risk modifiers of the Systematic COronary Risk Evaluation (SCORE).¹ In 2018, the US Preventive Services Task Force updated its 2009 and 2013 recommendations by providing a novel evidence report and systematic review.⁶ They concluded that ABI, CAC scoring and high-sensitivity C-reactive protein can improve discrimination and reclassification with respect to conventional risk scores, but that such improvements were generally small and that the literature was insufficient to draw firm conclusions on their added value.⁶

The 2019 American College of Cardiology (ACC)/American Heart Association (AHA) guideline on the primary prevention of CVD, which considers 10-year risk estimation, takes a relatively liberal position, in that many ‘risk enhancing factors’ are recommended (class IIa) to guide decision-making in borderline (5% to <7.5%) and intermediate (7.5% to <20%) risk groups.⁷ These include, among others, family history, ethnicity, metabolic syndrome criteria, renal function, high-sensitivity C-reactive protein, lipoprotein(a), apolipoprotein B, ABI, history of pregnancy-associated conditions or premature menopause and chronic inflammatory disease. The US guideline apparently fails to account for the substantial level of publication bias in this field⁸ and does not make explicit that a favourable profile of these ‘risk enhancers’ would lower an individual’s risk considerably. A separate class IIa recommendation was issued regarding the use of CAC in some patients at borderline and all patients at intermediate risk. This approach seems more aggressive than the 2016 ESC guideline, which only has a class IIb recommendation to consider CAC around decisional thresholds.¹ Taken together, relatively little new evidence has emerged regarding the added value of many suggested biomarkers and other risk modifiers. Key questions regarding evidence, cost-effectiveness and potential harm of the larger-scale use of CAC for refinement of risk stratification remain.

Future interest in the wider use of cardiac biomarkers (i.e. natriuretic peptide and cardiac troponin blood concentration) is rising due to emerging promising data^9,10 but further work is needed.

Which risk score?

There is debate about the optimum algorithm for CVD risk estimation. Although the SCORE risk engine is generally recommended in the current ESC guideline, the use of any risk score is encouraged, if such risk score was developed in a methodologically sound manner and is optimally calibrated for use in particular countries or geographical regions,¹¹ such as Q-RISK/JBS3 of people in the United Kingdom.¹²

However, the need for a revaluation with recalibration of the current risk scores has been underlined. A head-to-head comparison of four algorithms (Framingham risk score, SCORE, pooled cohort equations and Reynolds risk score) recommended by primary prevention guidelines have shown wide differences in clinical performances. These differences were reduced after ‘recalibration’, using the risk factor profile and CVD incidence of target populations. It was estimated that to prevent one CVD event, it would be necessary to initiate statin therapy in 44–51 such individuals using original algorithms, in contrast to 37–39 individuals with recalibrated algorithms.¹¹

Furthermore, two other important issues regarding risk assessment are subject to current debate.

First, the question of whether risk stratification for people with previous CVD events may be appropriate remains unanswered. Risk among such persons is heterogeneous and with the introduction of very costly interventions (such as proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors), further risk stratification in secondary prevention may become necessary. Some models have already been developed and suggest that predictors of risk may be quite different from primary prevention.^13,14

A second interesting development is to adopt a lifetime perspective on CVD risk assessment. Although this was already touched on in the 2016 ESC guideline, and is also part of the 2019 US guideline,⁷ there is no consensus as to which level of lifetime risk and at which particular age this risk is calculated should trigger treatment recommendations. An extension of this lifetime risk perspective is to calculate lifetime benefit from the initiation of cardiovascular preventive drugs. This perspective may be more intuitive to patients facing a decision whether or not to start preventive drug treatment. Models have been developed to calculate (disease-free) life-years gained for both for populations of people with and without DM.^15,16 For the time being, such alternative perspectives primarily facilitate communication with patients about treatment decisions, but if further studies validate this approach, life-time (disease-free) gained could become a more central criterion in formal treatment recommendations and in supporting the importance of even a moderate reduction in cardiovascular risk.

Other risk markers

Genetics and epigenetics

There has been a significant increase in the number of epidemiological studies investigating cardiovascular risk factors and outcomes in relation to DNA methylation, histone modifications, RNA-based mechanisms but many gaps remain in our understanding of the underlying cause and biological implications. An association between coronary artery disease (CAD) presence and characteristics and selected circulating transcriptional and epigenetic-sensitive biomarkers linked to the cholesterol pathway has been observed.¹⁷

A polygenic risk score derived from up to 57 common DNA sequence variants previously associated with CAD¹⁸ has allowed us to identify individuals with a greater burden of subclinical atherosclerosis and who would derive a greater relative and absolute benefit from statin therapy to prevent a first CAD event.¹⁹

It is noteworthy that there is still no evidence of cost-effectiveness of the application of cardiovascular genetic risk score testing in clinical practice, such as targeting statin therapy in individuals at low to moderate cardiovascular risk.²⁰

Psychosocial

The EUROASPIRE IV survey²¹ confirmed the high prevalence of symptoms of depression and anxiety in patients with CAD (22.4% and 26.3%, respectively). Both symptoms were more prevalent in women than men (30.6% vs. 19.8% and 39.4% vs. 22.1%, respectively), and were associated with lower educational level and a more sedentary lifestyle. Furthermore, depression was associated with current smoking, central obesity and DM.

The ESC position paper on depression and CAD²² confirmed the relevance of depressive symptoms for CAD incidence and prognosis, and summarised pathophysiological mechanisms such as poor and sedentary lifestyles, neurohumoral activation, inflammation and endothelial dysfunction, that promote coronary atherosclerosis and microvascular remodelling. Thus, depression may trigger more intensive efforts to detect and manage risk factors. Whether treating depression per se improves outlook remains unclear.

With respect to the ESC guideline regarding the clinical interview,¹ a validation study has shown only moderate to fair correlations of the screening items with established psychometric questionnaires.²³ Hence, refinement of the screening items is required.

As adverse experiences in childhood and adolescence, such as psychological, physical, or sexual abuse in the child and substance abuse of family members, are associated with worse cardiometabolic outcomes in adults, a position statement of the AHA²⁴ recommended the development of early interventions to ameliorate these harmful exposures.

In the recent update on the QRISK score (https://qrisk.org/three) having severe mental illnesses (i.e. schizophrenia, bipolar disorder and moderate/severe depression) leads to meaningful risk reclassification.²⁵

Imaging methods

In patients with intermediate or borderline cardiovascular risk, CAC measurement based on computed tomography (CT) can reclassify risk upward (particularly if the score is ≥100 Agatston units or ≥75th age/sex/race percentile) or downward (if CAC is zero and it is now a IIa recommendation in the ACC/AHA guidelines) in risk stratification.⁷

However, while the amount of CAC roughly correlates with the total amount of atherosclerosis present in the coronary arteries, it correlates poorly with the degree of luminal narrowing. Furthermore, it does not provide direct information about the total plaque burden or stenosis severity and can be absent in middle-aged patients with soft non-calcified plaque.

In the randomised open-label, SCOT-HEART trial²⁶ in patients with stable chest pain, the use of CT coronary angiography on top of standard of care (with consequent changes in treatment) reduced the rate of death from CAD or non-fatal MI (hazard ratio (HR) 0.59, 95% confidence interval (CI) 0.41–0.84; P = 0.004), compared with standard care alone. This difference was driven primarily by a lower rate of non-fatal MI. The reductions in coronary events were the same irrespective of symptoms, independent of baseline statin use or cardiovascular risk score. These findings suggest that using a cardiovascular risk score both over and undertreats individuals, and that CT coronary angiography appears to be associated with better reductions in coronary events irrespective of the risk score. The reasons for the benefits of CT coronary angiography might be related to better targeted secondary prevention, closer adherence to lifestyle modifications and preventive therapies and coronary revascularisation in those with prognostically significant disease.

Currently, the use of CT coronary angiography as a risk stratification tool in asymptomatic individuals is not supported by data as no prospective, randomised intervention studies have been performed.

Clinical conditions affecting cardiovascular risk

Diabetes mellitus

One group that can benefit from earlier identification are individuals with undiagnosed DM. Screening for DM in individuals identified as high risk by validated DM risk scores applied to electronic primary care data is feasible and can result in more intensive treatment of CVD risk factors and reduction in CVD risk.^27,28 Patients who lost 5% body weight or greater at one year after diagnosis of DM had a 48% lower 10-year adjusted hazard of CVD incidence compared to maintained weight.²⁷ Weight loss can also result in remission of DM as shown in the DIRECT trial in primary care randomly assigning people with overweight/obesity and type 2 DM diagnosed in the last 6 years to a diet replacement programme or usual care. In the intervention group, 24% achieved a weight loss of 15 kg or greater, 46% had DM remission compared to 0% and 4% of the usual care group at one year. The amount of weight loss was associated with DM remission, as 86% of those who lost 15 kg or greater achieved remission in the first year compared to 34% of those with 5–10 kg weight loss.²⁹

While most guidelines prioritise the use of intensive risk factor management in people with type 2 DM above the age of 40 years, as do the 2016 ESC CVD prevention guidelines,¹ recent research has better highlighted the importance of age of onset as a predictor of life years lost from DM. There is now clear evidence that younger onset type 2 DM leads to considerably greater losses and excess CVD outcomes, such that those developing type 2 under the age of 20 years can lose well over a decade in life years whereas there may be negligible loss of life when DM develops after the age of 80 years.³⁰ These findings should help to focus better on CVD risk factor management in those developing DM under the age of 40 years, although caution with the use of statins and some antihypertensive agents remains important for women of childbearing age. Similarly, recent evidence suggests that age of onset also matters to those with type 1 DM because it is associated with greater loss of life expectancy.³¹ There is some evidence that people with type 1 DM have greater excess and absolute risks for CAD and heart failure (HF) than those with type 2 DM,³² and thus there may be longer-term benefits from more aggressive use of statins and BP control.

Chronic kidney disease

Chronic kidney disease is a recognised as a marker for future CVD events. In the recent update on the QRISK score (https://qrisk.org/three) having chronic kidney disease (stage 3, 4, 5) leads to meaningful risk reclassification.²⁵

Influenza

An association between acute respiratory infections, especially those occurring at times of peak influenza virus circulation and acute MI has been reported by observational studies.^33,34

A self-controlled case series design to evaluate the association between laboratory-confirmed influenza infection and hospitalisation for MI showed that the incidence of admissions for MI was six times as high during the 7 days after laboratory confirmation of influenza infection versus control interval (20.0 admissions per week vs. 3.3 admissions per week). The incidence ratio point estimates were highest for older adults, for patients with influenza B infection and for patients who had their first MI.³⁵

The recommendation on influenza vaccination on secondary prevention in patients with CVD is supported by new evidence. A Cochrane review of eight randomised clinical trials (RCTs) in 12,029 patients with CVD³⁶ reported a significant reduction in cardiovascular mortality among patients vaccinated against influenza (relative risk (RR) 0.44, 95% CI 0.26–0.76).

Strong evidence of the effectiveness of influenza vaccination in primary prevention of CVD is still lacking.

Periodontitis

Most published studies have found a positive association between periodontitis and CVD.³⁷ A cross-sectional analysis of a cohort of 60,174 participants³⁸ showed that periodontitis was independently associated with atherosclerotic CVD (odds ratio (OR) 1.59, 95% CI 1.39–1.81). A nationwide cohort of 17,691 patients who received a hospital diagnosis of periodontitis within a 15-year period and matched them with 83,003 controls from the general population found an increased risk of cardiovascular death (OR 2.02, 95% CI 1.87–2.18) and for all-cause mortality (OR 2.70, 95% CI 2.60–2.81).³⁹ A meta-analysis of observational studies including 22 observational studies including 129,630 participants showed that patients with periodontitis have an increased risk of MI (OR 2.02, 95% CI 1.59–2.57).⁴⁰

A systematic review to investigate the effects of periodontal therapy in preventing the occurrence of, and management or recurrence of, CVD in patients with chronic periodontitis⁴¹ found very low quality evidence that was insufficient to support or refute whether periodontal therapy can prevent the recurrence of CVD in the long term in patients with chronic periodontitis. No evidence on primary prevention was found.

Cancer

Several systemic reviews and meta-analyses are available on the benefit of exercise training programmes in attenuating the reductions in exercise tolerance⁴² and in improving outcomes.⁴³

Regarding the early detection of cardiac injury, exercise cardiac magnetic resonance imaging has been shown to be a more sensitive marker of cardiotoxicity than the current standard of care tools to assess resting left ventricular ejection fraction in breast cancer patients.⁴⁴ Also, the use of biomarkers has emerged as a valuable tool for the early identification and monitoring of cardiotoxicity. In particular, cardiac troponin and B-type natriuretic peptide (BNP) elevation during chemotherapy allows the identification of patients more prone to develop myocardial dysfunction and cardiac events.⁴⁵

Autoimmune disease

The assessment of risk factor profile is warranted in adults with inflammatory autoimmune disorders. The current guideline¹ draws attention to increased CVD risk in autoimmune disease, particularly rheumatoid arthritis (RA), but potentially all autoimmune diseases are associated with systemic inflammation increased risk: e.g. there is emerging evidence that connective tissue disease and, to a somewhat lesser degree, inflammatory bowel disease are associated with increased cardiovascular risk.⁴⁶

In 2017, the European League Against Rheumatism (EULAR) updated its CVD risk management guideline,⁴⁷ but this is now being updated again. The evidence supporting increased CVD risk has strengthened, and is related to both traditional and non-traditional risk factors, the latter including inflammatory activity, clinical disease phenotype and serum antibody profile. Based on recent evidence, EULAR has widened their recommendation for CVD risk management to all types of inflammatory joint disease, although the evidence remains strongest for RA. Their recommendation is to use CVD risk prediction models in these patients and multiply risk estimates by 1.5, even though this multiplication factor is uncertain and critically depends on disease phenotype and activity.

That noted, RA was associated with a higher independent HR for CVD outcomes in QRISK3 of approximately 1.2 to 1.3, but this may be because oral steroids were also a strong independent risk factor for incident CVD, suggesting (although not providing evidence) that some of the risk previously associated with CVD in RA may have been mediated by steroids, or else steroids may reflect disease severity.²⁵

Sleep apnoea

Epidemiological research indicates that obstructive sleep apnoea (OSA) is associated with increases in the incidence and progression of CAD, HF, stroke and AF.⁴⁸ Central sleep apnoea associated with Cheyne–Stokes respiration (CSA-CSR) predicts incident HF and AF; among patients with HF, CSA-CSR strongly predicts mortality. Thus, OSA and CSA-CSR are potentially modifiable risk factors for CVD. Treatment of OSA is generally reserved for those individuals with an apnoea–hypopnea index (the number of apnoeas and hypopnoeas observed per hour) of 5 or greater in patients with either signs/symptoms of sleep apnoea or associated medical conditions (including hypertension, HF, CAD, significant arrhythmias and other forms of CVD). Alternatively, an apnoea–hypopnea index of 15 or greater is treated as OSA, even in the absence of signs, symptoms or associated medical conditions.⁴⁹

Treatment of OSA with continuous positive airway pressure (CPAP) may improve patient-reported outcomes such as sleepiness, quality of life and mood, but evidence on the primary prevention of CVD with CPAP is limited to small studies, with surrogate endpoints, combined endpoints and observational data.⁴⁸ Furthermore, adherence to CPAP seems a critical issue, and a potential role for oral appliances (mandibular advancement devices) has been put forward.⁵⁰

Erectile dysfunction

Erectile dysfunction (ED) is often associated with CAD.⁵¹ The third Princeton Consensus Conference⁵² recommends assessing cardiovascular risk in all patients with ED and CVD to estimate the risk of mortality and morbidity associated with sexual activity, and advocates lifestyle changes:⁵³ these measures are likely to reduce cardiovascular risk and improve erectile function. Notably ED features as a new independent risk factor for CVD in QRISK3.²⁵

Migraine

Migraine headache, especially migraine with aura, has been linked to cerebral hypoperfusion, systemic vasculopathy, endothelial dysfunction and a hypercoagulable state: these factors may increase the risk of various adverse cardiovascular and cerebrovascular events.⁵⁴ A meta-analysis of 16 cohort studies, which included 394,942 migraineurs and 757,465 non-migraineurs has shown that migraine was associated with a higher risk of major adverse cardiovascular and cerebrovascular events (adjusted HR 1.42, P<0.001), driven by a higher risk of stroke and MI. There was no difference in the risk of all-cause mortality.⁵⁵

Other relevant groups

The young

A large body of data suggests that younger adults (i.e. <40 years of age) tend to develop an increasingly unhealthy cardiovascular risk profile, especially in terms of an increased prevalence of being overweight or obese, increasing rates of DM, substance abuse and electronic cigarette (e-cig) smoking over the past two decades.⁵⁶

Obesity has been identified as the major risk factor to address for the successful prevention of CVD and associated mortality. Substance abuse such as opioids, cocaine and anabolic steroids has increased among young adults in the past decades, that is likely to carry adverse risks of future cardiovascular events, particularly among those from a low socioeconomic background.⁵⁶

In young adults, very high levels of circulating low-density lipoprotein (LDL) cholesterol are often attributable to familial hypercholesterolemia. By the use of the modified Dutch Lipid Clinic Network criteria, which are based on non-genetic data, familial hypercholesterolemia is predicted to affect approximately one in 130–250 individuals worldwide; however, this condition is thought to be severely underdiagnosed in most countries.⁵⁷

The continuous relationship between BP and the risk of events has been shown at all ages and in all ethnic groups. Diastolic BP appears to be a better predictor of events than systolic BP in younger (<50 years) versus older patients. Diastolic BP tends to decline from midlife as a consequence of arterial stiffening; consequently, systolic BP assumes even greater importance as a risk factor from midlife.⁵⁸

Masked hypertension is associated with higher cardiovascular risk⁵⁹ and is more common in younger people than in older people, associated with male sex, smoking habit and higher levels of alcohol consumption, anxiety, physical and job stress.⁵⁸

On the other hand, physical activity (PA) ‘per se’ in young athletes plays a hypotensive role with respect to normal control.^60,61

The presence of organ damage in younger hypertensive patients with grade 1 hypertension classified as low risk according to the SCORE system provides unequivocal evidence of hypertension-mediated damage and indicates a clear need for BP-lowering treatment.⁵⁸ The recent ESC guidelines recommend that in younger patients with hypertension treated with BP-lowering medication, office BP should be reduced to 130/80 mmHg or less if treatment is well tolerated.⁵⁸

Further studies are warranted to improve our understanding of the magnitude of the problem of CVD in young adults and to elucidate treatable risk factors that underlie the observed increasing rates of CVDs in this population.

Ageing

Management of cardiovascular risk factors in the elderly (>65 years of age) should be followed with caution and common sense, adverse effects should be monitored closely and treatment should be reconsidered periodically. Moreover, individuals older than 75 years are biologically a very heterogeneous group, with frequent frailty, comorbid conditions and multiple concomitant drugs. All these, as well as personal preferences, must be taken into account in treatment decisions.

A prospective cohort study of subjects aged 80 years and older⁶² found that cardiovascular risk factors were not associated with mortality (such as body mass index (BMI), levels of total cholesterol and LDL-cholesterol, current or prior smoking habit), while the presence of frailty was a strong risk factor for all-cause mortality (HR 2.5, 95% CI 1.9–3.2) and for cardiovascular mortality (HR 2.2, 95% CI 1.4–3.4). The optimal target BP may be higher among older treated hypertensive patients than among middle-aged patients. In addition, among frail or multimorbid older individuals, a relatively low BP may be associated with worse outcomes, and antihypertensive treatment may cause more harm than benefit.⁶³

Care should be individualised in older adults with diabetes, and glycaemic targets suggested by guidelines are considered too tight for frail older individuals.⁶⁴ Management of DM in older adults should be adjusted for frailty status, with the intention of reducing complications and improving quality of life.⁶⁵

The decision to initiate primary prevention with statins in people older than 75 years of age cannot be based directly on RCT evidence.⁶⁶

A meta-analysis of data from all large statin trials to compare the effects of statin therapy at different ages showed significant reductions in major vascular events irrespective of age, but there is less direct evidence of benefit among patients older than 75 years who do not already have evidence of occlusive vascular disease.⁶⁷ Thus, limited evidence is available on therapy for primary prevention of CVDs in very elderly and frail individuals.

Women

It is generally held that women are at lower risk of CVD than men, but this is misleading. Ultimately, more women than men die of CVD in Europe, but at an older age. Inspection of the SCORE charts suggests that risk is deferred by about 10 years. The ESC guideline¹ emphasises the increased risk of the development of sustained hypertension and/or DM in women who have had obstetric complications including pre-eclampsia, pregnancy-related hypertension and gestational DM. The degree to which CVD risk is elevated independently of these risk factors was less certain. Moreover, pregnancy complications, such as pre-eclampsia, also increase the cardiovascular risk of the offspring and not only of the mother.⁶⁸

Lifestyle (before conception) of the future mother and father can (by epigenetic mechanisms) influence the possibility to have a healthy child.⁶⁹

Although the evidence has been strengthened and now extends to miscarriage and stillbirth,⁷⁰ it remains unclear if obstetric conditions predict CVD independently of classic risk factors. Awareness of the risk of, in particular, future hypertension and DM remains as relevant as before for women with the aforementioned pregnancy-related disorders.

As for non-obstetric conditions, few new data on the association of polycystic ovary syndrome have emerged. Premature menopause, particularly if associated with early oophorectomy, remains an important risk factor.⁷⁰

Gender disparities in CVD prevention are age dependent, as shown by an analysis of the Treatment of cardiovascular Risk in Primary care using Electronic Decision suppOrt (TORPEDO) study.⁷¹ Women attending primary healthcare services in Australia were less likely than men to have risk factors measured and recorded such that absolute CVD risk can be assessed. For those with, or at high risk of, CVD, the prescription of appropriate preventive medications was more frequent in older women but less frequent in younger women, compared with their male counterparts.⁷¹

Although the percentage of women smokers is lower than men, a recent meta-analysis of 75 cohort studies (approximately 2.4 million individuals) showed a 25% greater risk of CAD in women smokers compared with male smokers (RR 1.25, 95% CI, 1.12–1.39).⁷²

Ethnicity

Cardiovascular risk varies considerably according to ethnicity.¹ In the recent update on the QRISK score ethnicity (Indian, Pakistani, Bangladeshi, Chinese, black African, black Caribbean, other ethnic group) leads to meaningful risk reclassification.²⁵

How to intervene at the population level

Healthy diet

Governmental restrictions and mandates

Providing a growing global population with healthy diets from sustainable food systems is an immediate challenge. Although global food production of calories has kept pace with population growth, more than 820 million people worldwide have insufficient food and many more consume low quality diets that cause micronutrient deficiencies and contribute to a substantial rise in the incidence of diet-related obesity and diet-related non-communicable diseases, including CAD, stroke and DM. Unhealthy diets pose a greater risk to morbidity and mortality than do unsafe sex and alcohol, drug and tobacco use combined.^73,74

It is predicted that the current generation of children may have a shorter life expectancy than their parents due to the high prevalence of obesity and its health consequences. According to UNICEF and WHO, in Europe 800,000 children suffer from obesity, due to children’s exposure to unhealthy food marketing.⁷⁵

A global transformation of the food system is urgently needed.⁷³ Dietary changes from current diets to healthy diets are likely to benefit human health substantially, averting about 10.8–11.6 million deaths per year, a reduction of 19.0–23.6%.

Healthy diets have an appropriate caloric intake and consist of a diversity of plant-based foods (including plant protein, i.e. peas, lentils), low amounts of animal source foods, unsaturated rather than saturated fats and small amounts of refined grains, highly processed foods and added sugars.⁷³

A reduction in the intake of sugars and sweeteners and progressive elimination of industrially produced trans-fats is recommended.¹

On 24 April 2019, the EU Commission adopted a regulation setting a maximum limit of trans-fat in industrially produced trans-fats of 2 g per 100 g of fat.⁷⁶ This regulation is in line with the Danish regulation and corresponds to what the European Heart Network and other organisations called for. However, the 2-year transition period to 1 April 2021 is considered too long.

Evidence-based recommendations on the control of the marketing of foods and calorie-rich beverages to children which requires governments to protect children’s health have been set up.⁷⁷ In June 2019, the European Commission’s science and knowledge service updated the document on ‘Health Promotion and Disease Prevention’ and highlighted the need for policy recommendations to reduce the intake of sugars, with a special focus on recommendations for children. These recommendation included the provision of information to consumers, to make healthy choices more available and to implement financial (dis)incentives such as taxes on products with high amounts of sugars.⁷⁸

Labelling and information

Independently and coherently formulated criteria for nutrient profiles, nutrition claims and front-of-pack logos (e.g. traffic lights, healthy choices, keyholes and Nutriscore) have been promoted.⁷⁹ In particular, since 2017, the logo Nutriscore has been implemented comprising negative components (energy, sugar, saturated fat, salt) as well as positive components (vegetables, fruits, nuts, fibre and protein) leading to an end score from A ‘best nutritional quality’ to E for the ‘least good nutritional quality’.⁸⁰ This logo has been introduced in France and recently in Belgium.⁸¹ Countries such as Spain and Portugal are considering this logo. The European consumer organisation (BEUC) supports this system, while the European Heart Network continues to recommend the traffic light system. In The Netherlands a survey into the consumer understanding of different logos will be conducted.

Physical activity promotion

PA promotion should be integrated into the settings in which people live, work and play, to increase participation. There are multiple policy opportunities across different sectors: schools, business and industry, community recreation, fitness and parks, faith-based settings, healthcare, mass media, public health and sports.⁸²

A population-based policy approach can contribute to reducing inequalities by age, sex and socioeconomic status, geographical location and domains of PA, targeting those less active in PA and should be interconnected with policy actions focused on individually centred intervention. WHO indicates four strategic objectives to create: (a) active societies; (b) active environments; (c) active people; and (d) active systems. Each objective is an important effective component of a population-based response to increasing PA and reducing sedentary behaviour, and is achievable through 20 policy actions.⁸³

Community-wide campaign

Community-wide campaigns that use intensive contact with the majority of the target population over time can increase PA across the population.⁸⁴ It should involve educational, recreational, worksite, primary care and faith-based settings, offering convenient locations for reaching different target groups with different strategies. Multicomponent kindergarden and school interventions are effective in promoting increased school-based PA.^82,83

Environment and policy level

Longer occupational sitting times are significantly associated with higher mortality, while higher levels of PA are associated with a reduced risk of cancer and cardiovascular death.⁸⁵ Strong evidence shows that point of decision prompts the encouragemrnt of individuals to make an active choice and can increase the use of stairs.^84,86 Moderate evidence shows that: (a) built environment characteristics and infrastructure that support pedestrian or bicycling transport positively affect PA levels among children, adults and older adults; (b) readily usable and safe walking and cycling infrastructure and related built environment features are also associated with greater amounts of recreational PA among children and adults; (c) access to indoor (gym or fitness centres) or outdoor facilities (parks, trails and other green spaces) are associated with greater PA among children and adults. To decrease sedentary behaviours, moderate evidence suggests that school-based interventions targeting a reduction in television viewing and other screen-time activities, and worksite interventions including modifications to the workstation can have a positive impact.^84,86

Smoking bans

Tobacco consumption has been confirmed to be the leading cause of preventable death worldwide.⁸⁷ The risk is also high in never smokers, but who are exposed to exposed to second hand smoke; in Greece these individuals exhibited a two-fold elevated 10-year CVD risk.⁸⁸

Despite several population-based anti-smoking policies, 28% of the total population across Europe is still smoking.⁸⁹

Only high-income European countries have shown accelerated decreases in consumption since the action plan by the WHO Framework Convention on Tobacco Control (FCTC) on global cigarette consumption was ratified by 181 countries. In contrast, low and middle-income countries showed increased consumption.⁹⁰ The difference in effect between the countries might be because low and middle-income countries have limited resources to regulate the tobacco industry. This should motivate stronger implementation of established tobacco control policies and more forceful responses to the activities of the tobacco industry.⁹⁰ There is very strong scientific evidence on the measures that successfully reduce and prevent tobacco use. The most effective strategy is to increase the price of tobacco products.⁸⁷ In addition, there are smoke-free legislation and policies, marketing restrictions, advertising bans and hard-hitting media campaigns, and access to smoking cessation services.⁹¹ These measures should be regulated through robust legislation and rigorous enforcement, and have resulted in substantial prevalence declines of tobacco use in high-income countries.⁹² A sign towards the opposite direction has been given in Austria: the smoking ban which was scheduled to begin in May 2018 in all bars and restaurants was recently overturned by lawmakers from a new ruling coalition in the government.⁹³

Air pollution

Exposure to PM_2.5 has been linked to premature mortality, in 70% of the cases due to cardiovascular causes.^{94,  95} Even brief exposures to polluted air are associated with MI, stroke, arrhythmias, AF and hospitalisation for exacerbation of HF in susceptible individuals.⁹⁶ There is equally strong evidence suggesting that chronic and persistent exposure to air pollution increases the progression of atherosclerotic lesions and has adverse effects on BP regulation, peripheral thrombosis, endothelial function and insulin sensitivity. In addition to individual susceptibility factors, vulnerability to ambient air pollution is also moderated by environmental factors, such as the built environment, noise, ambient temperature, neighborhood green spaces and proximity to major roadways or co-exposure to other pollutants and toxins.^97,98

How to intervene at the individual level

Behaviour

In addition to face-to-face communication, media-based (e.g. telephone, internet, mass media) interventions have gained increased attention for CVD prevention. A RCT on telephone coaching for behaviour change in patients after acute coronary syndrome (ACS) has shown significant though modest effects on BMI, waist circumference, PA and daily intake of vegetables.⁹⁹ A RCT showed the effectiveness of a Web-based health behaviour change support system and group lifestyle counselling on body weight loss in overweight and obese subjects.¹⁰⁰

A systematic review on internet-delivered interventions in patients with CAD has shown that personalised, concrete support for behaviour change may have favourable outcomes; however, a considerable heterogeneity between studies with respect to the design and quality hinder sound conclusions.¹⁰¹

Adherence

Cardiovascular fixed-dose combination pills, or polypills, may help address the widespread lack of access and adherence to proved medicines. Adherence benefits from switching to a polypill resulted in risk factor changes that were at least as good as usual care across a wide variety of treatment patterns, including equally potent or more potent regimens.¹⁰²

In addition to face-to-face interventions, there were increasing efforts to evaluate the effects of mobile phone-based interventions. With respect to CVD primary prevention, a Cochrane systematic review and meta-analysis¹⁰³ concluded that there is low quality and inconclusive evidence that mobile phone-based interventions might improve medication adherence and/or have favourable effects on outcomes such as BP or LDL-cholesterol.¹⁰³

With respect to secondary prevention, a Cochrane systematic review¹⁰⁴ evaluated mobile phone text messaging for patients after acute cardiac events. Due to the heterogeneity of methods, populations and outcomes, the authors were unable to perform a meta-analysis. Although the authors found favourable effects on medication adherence in six out of seven trials, they concluded that there is insufficient evidence to draw conclusions on the effectiveness of mobile phone-based interventions in CVD secondary prevention.¹⁰⁴ Similar conclusions were derived by a systematic review and meta-synthesis of quantitative and qualitative data on mobile applications for CVD patients.¹⁰⁵ Patients with implanted devices (such as implantable cardioverter defibrillator or cardiac resynchronisation systems) showed little interest in receiving dedicated information on the overall management of their disease, underlying the insufficient awareness of patients towards the key role of self-control health status and the promotion of a healthy lifestyle.¹⁰⁶

Physical activity and sedentary behaviour

PA is associated with beneficial health outcomes. There is an inverse dose–response relationship between moderate–vigorous aerobic PA and all-cause and cardiovascular mortality and incident CVD: CAD, ischaemic stroke and HF.¹⁰⁷ Benefits start to accumulate from moving to being inactive to perform PA at a lower amount, and increases with the higher amount of PA.¹⁰⁸ In healthy adults 150 to 300 minutes a week of moderate intensity PA or 75 to 150 minutes of vigorous intensity PA or an equivalent combination thereof (a volume of 500–1000 metabolic equivalent minutes per week), reduces the risk of all causes of mortality.¹⁰⁹ Higher volumes of PA through higher intensity, greater frequency or longer duration contribute to risk reduction, but greater increases in PA are required to obtain a modest gain in benefit. PA amounts up to three to five times the recommendation shows no evidence in mortality risk.¹⁰⁷ There is now evidence that bouts of any duration, even less than 10 minutes, are effective and count for the daily/weekly volume target of PA.^84,110

There is moderate evidence that high intensity interval training can improve insulin sensitivity, BP and body composition similarly to aerobic continuous PA training, especially in overweight or obese adults.¹¹¹ The improvements in risk factor control are more likely to occur in adults at greater risk of CVD and DM. There are no universally accepted lengths for the high intensity period, recovery period or ratio of the two, no universally accepted relative intensity at which the high intensity component should be performed.

There is a strong evidence of a dose–response association between sedentary behaviour and all causes of mortality, CVD mortality and incident CVD and type 2 DM.⁸⁴ Individuals who sit the most and perform the least of moderate to vigorous PA have the greatest risk of mortality, while individuals who sit the least and perform the most of moderate to vigorous PA have the lowest risk.^84,112 Strong evidence for a sedentary behaviour guideline is still lacking.

The most effective interventions to increase activity are based on theories of behaviour change, teaching people skills to incorporate PA in their daily routine and attain an active lifestyle. Strong evidence demonstrates that counselling participants to set PA goals and self-monitoring their progress increases PA in the adult population.^110,113

Technologies that use computerised information or communication interface-based approaches can provide virtual coaching and deliver behavioural changes, ‘just in time’ personalised advice and support to the users. Wearable activity monitors such as pedometers and accelerometers in combination with goal-setting and other behavioural strategies provide direct PA feedback and can increase PA levels in the general and type 2 DM population.¹¹⁴ Telephone-assisted, web-based or internet-based interventions, with educational components provide effective remote guidance to individuals to increase PA. Smartphone applications increase PA in children and adolescents.^115,116

Smoking cessation: role of electronic cigarettes

E-cigarettes (electronic cigarettes) are a rapidly changing product class, and are known by many different names, including ‘e-cigs’, ‘e-hookahs’, ‘mods’ and ‘vape pens’.¹¹⁷ Most e-cigs contain nicotine whose exposure can harm the developing brain and nicotine exposure during adolescence can impact learning, memory and attention.¹¹⁷ In addition to nicotine, the aerosol that users inhale and exhale from e-cigs can potentially expose both themselves and bystanders to other harmful substances, including heavy metals, volatile organic compounds and ultrafine particles that can be inhaled deeply into the lungs.¹¹⁷ To making e-cigs more appealing to young people, some of the chemicals used to create certain flavours may also have health risks.¹¹⁷ A new type of e-cig (JUUL) has recently become increasingly popular due to its minimal exhaled aerosol, reduced odour and small size, making it easy to conceal,¹¹⁸ but with a high level of nicotine.¹¹⁹

E-cigs can be used to deliver other drugs, including marijuana: in 2016, one-third of US middle and high school students who ever used e-cigs had used marijuana in e-cigarettes.¹²⁰ It may be that e-cigs are more effective in promoting nicotine dependence than as an aid to smoking cessation.

Body weight

There is increasing evidence on the beneficial effect of body weight reduction with caloric restriction. A meta-analysis of 63 studies showed that each additional kilogram loss induced by lifestyle interventions was associated with 43% lower odds of type 2 DM.¹²¹

Caloric restriction without malnutrition leads to increased longevity and delayed onset of age-associated disorders in rhesus monkeys.¹²²

Nutrition

Fatty acids and carbohydrate intake

Novel findings have challenged the current guideline recommendation which restricts saturated fat to less than 10% of total fat.¹ The PURE study of dietary habits in 135,000 people from 18 countries around the world for 7 years observed that high carbohydrate intake was associated with a higher risk of total mortality, whereas total fat and individual types of fat were related to lower total mortality.¹²³ These findings should be considered with caution as about 85% of the fat intake in EU countries is within the highest fat quintile of PURE, in which the high carbohydrate intake may have been just a proxy for poverty, and saturated fat consumption was generally low. Finally, the negative relationship goes against the findings of multiple studies.¹

The PURE findings are only partially confirmed by other reports studying the association between saturated fats and the risk of CAD in which the importance of which nutrient saturated fats are replaced by is considered: poly unsaturated fats (–25%), monounsaturated fats (–15%) and to a lesser extent carbohydrates from whole grains (–9%) reduce CVD risk with isocaloric substitution of dietary saturated fat.^124,125 Also, the replacement of animal fats, including dairy fat, with vegetable sources of fats and polyunsaturated fatty acids may reduce the risk of CVD.^126,127 Whether the food matrix may modify the effect of dairy fat on health outcomes warrants further investigation.

Fruit and vegetables

The PURE study also observed the beneficial effect of increasing the consumption of fruit, vegetables and legumes on total and cardiovascular mortality: the maximum benefit was seen at three to four servings a day (equivalent to 375–500 g/day), with no additional benefit with higher intakes.¹²³ The benefit from some fruits, vegetables, or legumes was greater if they were eaten raw rather than cooked.¹²⁸

Meats

From both a health point of view as well as environmentally sustainable food production, a lower consumption of red meat, especially processed meat, has usually been recommended.

However, the evidence is still controversial. A meta-analysis of 24 RCTs concluded that 0.5 servings per day of red meat or more did not influence blood lipids, lipoproteins, or BP in comparison with less than 0.5 servings a day.¹²⁹ In a subsequent meta-analysis which included 36 RCTs, only when red meat was substituted with high-quality plant foods (i.e. nuts, soy, and legumes) were more favourable LDL-cholesterol concentrations (–0.2 mmol/l) observed.¹³⁰ By reducing processed meats, salt intake will also be reduced.

Functional foods

Red yeast rice (RYR) (white rice with the yeast Monascus purpureus) contains monacolin, which is chemically identical to lovastatin. Although RYR supplementation is effective in reducing LDL-cholesterol, long-term safety and possible adverse effects are not determined. Most supplements also contain other ingredients, with unknown effects and interactions.^76,131 The formulation and dosage of RYR is also variable¹³² raising concerns regarding their medical prescription.

Minerals

The relation between salt intake and CVD is debated. A U-shaped association has recently been observed in a pooled analysis, which included 133,118 individuals (63,559 with hypertension and 69,559 without hypertension), from 49 countries with estimated 24-hour urinary sodium excretion, from a single morning fasting urine sample.¹³³ This finding should be confirmed by a more rigorous methodology (e.g by 24-hour urine samples complete, preferably over several days).

Alcoholic beverages

The relation between alcohol consumption and CVD is still controversial, even though the evidence base for overall harm is increasing.

There have been multiple systematic reviews and meta-analyses of the association between consumption and aggregated CVD: most have shown that, compared with non-drinking, moderate levels of alcohol intake are associated with a lower risk of morbidity and mortality from CVD, as well as more favourable cardiovascular health profiles in general.¹³⁴ A large-scale study of 1.93 million adults without CVD at baseline showed that in the group of non-drinkers there was an increased risk of CAD, CVD and all-cause mortality.¹³⁵

There is, however, growing skepticism around this observation, with recent commentary pieces pointing out several methodological shortcomings in the evidence on which the U-shape is based.¹³⁶ In a large analysis involving 599,912 current drinkers without previous CVD from 19 high-income countries, the threshold for the lowest risk of all-cause mortality was about 100 g per week. For CVD subtypes, alcohol consumption was roughly linearly associated with a higher risk of stroke, CAD excluding MI, HF, fatal hypertensive disease and fatal aortic aneurysm. By contrast, increased alcohol consumption was log linearly associated with a lower risk of MI.¹³⁷ These data support the adoption of lower limits of alcohol consumption than are recommended in most current guidelines, for example to a maximum of one glass per portion per day for both men and women.

Lipid control

Proprotein convertase subtilisin/kexin type 9 inhibition

The FOURIER trial tested the effect of evolocumab on 27,564 patients with atherosclerotic CVD and LDL-cholesterol levels of 70 mg/dL or greater (≥1.8 mmol/L) on a background of statin therapy.¹³⁸ Following treatment with evolocumab, at 48 weeks LDL-cholesterol was reduced by 59% compared with placebo. After a median follow-up of 2.2 years, evolocumab reduced the risk of the primary endpoint (a composite of cardiovascular death, MI, stroke, hospitalisation for unstable angina, or coronary revascularisation) by 15% (P<0.001) and secondary endpoint (a composite of cardiovascular death, MI, or stroke) by 20% (P<0.001).¹³⁸ The effectiveness of evolocumab was independent of the baseline LDL-cholesterol levels.¹³⁹

The ODYSSEY OUTCOMES study assessed the effect of alirocumab in 18,924 patients with a recent ACS, having LDL-cholesterol levels of 70 mg/dL or greater (≥1.8 mmol/L) and receiving statin therapy at a high intensity dose or at the maximum tolerated dose.¹⁴⁰ At 48 weeks, alirocumab reduced LDL-cholesterol levels by 54.7%; after a median follow-up of 2.8 years, the risk of a composite primary endpoint event (death from CAD, non-fatal MI, fatal or non-fatal ischaemic stroke, or unstable angina requiring hospitalisation) was reduced by 15% (P<0.001), with a greater absolute benefit among patients with higher baseline LDL-cholesterol levels.¹⁴⁰

In both studies no increase in new-onset DM or worsening of glycaemic parameters were observed, nor was there evidence of an adverse effect on cognitive function or the risk of cancer. The results of these two trials support a clinical benefit from LDL-cholesterol lowering beyond that obtained with statin therapy in high and very high risk patients and lower LDL-cholesterol targets adopted by the 2019 ESC guidelines.⁶⁴ However, data on long term safety and total survival are still awaited.

Cost-effectiveness can be a critical issue in the context of the prescription of PCSK9 inhibitors¹⁴¹ and a selective adoption to very high-risk CVD patients to reduce the overall budgetary impact of PCSK9 inhibitor treatment has been advised.^142,143

Omega-3 fatty acids

Patients with elevated triglyceride levels are at increased risk of ischaemic events; the REDUCE-IT trial evaluated the effect of icosapent ethyl (a highly purified eicosapentaenoic acid ethyl ester, 4 g daily) in 8179 patients with established CVD under statin therapy and with high fasting triglyceride levels (135–499 mg/dL).¹⁴⁴ After a mean follow-up of 4.9 years, the risk of the primary endpoint (a composite of cardiovascular death, non-fatal MI, non-fatal stroke, coronary revascularisation, or unstable angina) was reduced by 25% and the secondary endpoint (a composite of cardiovascular death, non-fatal MI, or non-fatal stroke) by 26%.¹⁴⁴

These results should be contrasted against the background of other recent findings. A meta-analysis of 10 randomised trials involving 78,000 patients did not show that the groups that received n-3 fatty acids had a lower risk of major adverse cardiovascular events than those receiving placebo,¹⁴⁵ although most trials were not confined to subjects with raised triglyceride levels, nor did ASCEND (A Study of Cardiovascular Events in Diabetes), which tested 1 g capsules containing 840 mg of marine n-3 fatty acids daily in patients with type 2 DM.¹⁴⁶ In addition, the results of the Vitamin D and Omega-3 Trial (VITAL), a primary prevention trial involving more than 25,000 participants, did not show a lower incidence of the primary cardiovascular composite outcome of MI, stroke, or cardiovascular death in either arm.¹⁴⁷

More data are needed to clarify the benefits of this class of drugs, also in higher dosages in cardiovascular event reduction.

Diabetes mellitus

Multiple positive trials demonstrating the superiority of a novel class of DM agents for either cardiovascular or renal outcomes have emerged. In some cases, total or cardiovascular mortality was reduced, and positive results were also seen for the prevention of HF. Such positive trials come either from the sodium-glucose co-transporter-2 (SGLT2) inhibitor class (empagliflozin, dapagliflozin or canagliflozin), as recently summarised in a meta-analysis,¹⁴⁸ or the glucagon-like peptide 1 (GLP-1) receptor agonist class of drugs (liraglutide, semaglutide, albiglutide, dulglutide) likewise recently summarised for drugs.¹⁴⁹ The outcome benefits for most of the drugs in each class outweigh potential harms and side effects, and both classes cause weight loss and reductions in BP without increasing hypoglycaemia rates. Consequently, the use of such agents in those patients with existing CVD has been promoted in many guidelines, although uptake has been modest.¹⁵⁰ Notably, the prevention of HF or the prevention of meaningful renal outcomes seems to occur to broadly similar extents with SGLT2 inhibitors whether patients have existing CVD or multiple risk factors.¹⁴⁸ Thus, those patients without existing CVD but at elevated risk of HF or renal progression would stand to benefit from earlier SGLT2 inhibitor use. Such guidance fits with an increasing focus on the prevention of HF in DM. The outcome benefits of both classes seem to be largely independent of their effects on glucose levels per se. This is in keeping with the recent findings from the DAPA-HF (Dapagliflozin And Prevention of Adverse-outcomes in Heart Failure) trial: among patients with HF and a reduced ejection fraction, the risk of worsening HF or death from cardiovascular causes was lower among those who received dapagliflozin than among those who received placebo, regardless of the presence or absence of diabetes.¹⁵¹

Hypertension

The SPRINT trial introduced the ‘unobserved’ BP measurement, a method that it is recommended in the Canadian guidelines,¹⁵² but that it is difficult to apply in many healthcare facilities and produces BP levels that are lower than office measures on which many epidemiological studies and previous intervention trials have been based. Furthermore, some SPRINT participants had medication reduced to allow them to participate, which complicates interpretation. Out-of-office BP measurement is upgraded as the best method to diagnose and control hypertension. The wider use of out-of-office BP measurement with ambulatory monitoring and/or home BP measurement which are considered an option to confirm the diagnosis of hypertension, detect white coat and masked hypertension, and monitor BP control is today recommended.⁵⁸

The second recommendation includes a change in the strategy to improve BP control. Two drug combination therapies for the initial treatment of most people with hypertension, preferred in a single pill, is now recommended. Simplified drug treatment algorithms are recommended with the preferred use of an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker combined with a calcium antagonist or/and a thiazide/thiazide-like diuretic as the core treatment strategy for most patients, with beta-blockers used for specific indications. Monotherapy is recommended for patients with stage 1 hypertension with a low risk (particularly if SBP is <150 mmHg) or in very old (>80 years) or frailer patients.⁵⁸

The third recommendation corresponds to when to treat and goals to be achieved. Overall there is a less conservative treatment of BP and the newly introduced target BP ranges for treated patients identify better the recommended BP target and lower safety boundaries for treated BP, according to a patient’s age and specific comorbidities. Lower BP thresholds and treatment targets for older patients are recommended with emphasis on considerations of biological rather than chronological age (i.e. the importance of frailty, independence and the tolerability of treatment). In this regard, treatment should never be denied or withdrawn on the basis of age, provided that treatment is tolerated.⁵⁸

Guidelines also recommended drug treatment: (a) to subjects with white coat hypertension if evidence of hypertension multiorgan damage or in whom cardiovascular risk is high or very high is present; (b) to subjects in high-normal BP when their cardiovascular risk is very high due to established CVD, mainly coronary heart disease.⁵⁸

Finally, strong emphasis on the importance of evaluating treatment adherence as a major cause of poor BP control is now a key issue, as well as the key role for dieticians, nurses and pharmacists in the longer-term management of hypertension. Their role in the education, support and follow-up of treated hypertensive patients is relevant as part of the overall strategy to improve BP control.⁵⁸

Unfortunately, not all the gaps pointed out in the ESC CVD prevention guidelines are solved yet. What is still unanswered is the optimal out-of-office (home and ambulatory) BP targets, and do treatment strategies based on control of out-of-office BP provide an advantage over strategies based on conventional (office) BP control?

Antiplatelet therapy

New evidence supports the current recommendation against aspirin use in primary prevention.¹ Recent meta-analyses including, respectively, 11 and 15 trials with more than 155,000 individuals each without a history of atherosclerotic disease demonstrated that aspirin did not affect all-cause mortality or cardiovascular death or no cardiovascular death in the primary prevention setting.¹⁵³ This was further confirmed by sequential analysis, which also suggested the futility of conducting further trials to assess a benefit of aspirin on all-cause mortality.¹⁵⁴

The lack of benefit was evident even in people with DM and patients with high cardiovascular risk (i.e. 10-year risk >7.5%). The use of aspirin for primary prevention in patients with DM increases the risk of total bleeding without reducing the risk of major adverse cardiovascular outcomes.¹⁵⁵

Psychosocial factors

The current guideline¹ recommends the treatment of psychosocial risk factors via multimodal behavioural interventions, psychotherapy, medication or collaborative care, in order to counteract psychosocial stress, depression and anxiety, to facilitate behaviour change and to improve quality of life and prognosis in patients with established CVD and patients at high CVD risk, when the psychosocial risk factor worsens classic risk factors.

A recent meta-analysis on psychological interventions in addition to exercise-based cardiac rehabilitation (CR) compared to exercise-based CR alone in patients with CAD¹⁵⁶ has shown a trend towards a reduction of depressive symptoms and cardiac morbidity, but no additional impact on anxiety, quality of life and cardiovascular or total mortality.¹⁵⁶ Hence, considering the low to moderate quality and high methodological heterogeneity of available studies, there is considerable uncertainty under which conditions psychological interventions in addition to exercise-based CR exert their optimal effects.¹⁵⁶

Another meta-analysis showed the efficacy of cognitive psychotherapy for reducing psychological symptoms in patients with CVD and significant symptoms of depression and anxiety,¹⁵⁷ but there was no effect on cardiovascular events.¹⁵⁷ However, a recent trial has shown for the first time a favourable effect of antidepressant medication on long-term cardiac outcomes.¹⁵⁸ In patients with ACS and minor/major depression, the effectiveness of therapy with a selective serotonin reuptake inhibitor (SSRI, escitalopram) on depression and anxiety resulted in a significant reduction of major adverse cardiac events after 8.1 years (HR 0.68, 95% CI 0.49–0.96; P = 0.03).¹⁵⁸ Thus, treatment with SSRIs may improve subjective wellbeing and prognosis in depressed patients with CAD, but confirmation by additional trials is needed.

Disease-specific interventions

Atrial fibrillation

The focused update on cardiovascular prevention in patients with AF is mainly based on the topic of anticoagulation, because of the approval of new medications and the emergence of new strategies after ACS.

Based on the four major RCTs comparing non-vitamin K oral anticoagulants (NOACs) with warfarin (vitamin K antagonist, VKA),^159–162 there is now consistent evidence of at least non-inferiority for the combined endpoint of stroke or systemic embolism. When combined with a superior safety profile, NOACs are now recommended as first line therapy for eligible patients.

In patients with AF and ACS managed by percutaneous coronary intervention (PCI), recommended strategies need to incorporate recent evidence from PIONEER AF-PCI (an open-label, randomised, controlled, multicentre study exploring two treatment strategies of rivaroxaban and a dose-adjusted oral VKA treatment strategy in subjects with AF who undergo PCI)¹⁶³ and RE-DUAL PCI (Randomized Evaluation of Dual Antithrombotic Therapy with Dabigatran versus Triple Therapy with Warfarin in Patients with Non-valvular Atrial Fibrillation Undergoing Percutaneous Coronary Intervention),¹⁶⁴ considering rivaroxaban and dabigatran options for anticoagulants in this patient population. PIONEER AF-PCI randomly assigned patients to low-dose rivaroxaban (15 mg once daily) plus a P2Y12 inhibitor for 12 months; very low dose rivaroxaban (2.5 mg twice daily) plus dual antiplatelet therapy (DAPT) for one, 6, or 12 months; or standard therapy with a dose-adjusted VKA (once daily) plus DAPT for one, 6, or 12 months. The rates of thromboembolic events (death from cardiovascular causes, ACS, or stroke) were similar in the three groups, while significant bleeding was lower in the two rivaroxaban groups. RE-DUAL PCI randomly assigned patients to receive double therapy with dabigatran (110 mg twice daily) plus either clopidogrel or ticagrelor, double therapy with dabigatran (150 mg twice daily) plus either clopidogrel or ticagrelor, or triple therapy with warfarin plus aspirin (≤100 mg daily) and either clopidogrel or ticagrelor. With respect to the composite efficacy endpoint of thromboembolic events (MI, stroke, or systemic embolism), death, or unplanned revascularisation dabigatran-based dual therapy was non-inferior to VKA-based triple therapy. Dual therapy with dabigatran also reduced bleeding complications as compared to conventional triple therapy. Also a non-inferiority for bleeding of an edoxaban-based regimen compared with the VKA-based regimen, without significant differences in ischaemic events in patients with AF who had PCI, was observed in the ENTRUST-AF PCI (Edoxaban Treatment versus Vitamin K Antagonist in Patients with Atrial Fibrillation Undergoing Percutaneous Coronary Intervention) trial.¹⁶⁵

Taken together, these two studies seem to orient clinical practice towards an increasing use of dual therapy (consisting of a NOAC plus clopidogrel, which was the most common P2Y12 inhibitor used), even though current recommendations consider NOAC-based dual therapy in only a subset of patients at increased risk of bleeding.¹⁶⁶

Coronary artery disease

In CAD patients, secondary prevention should start as soon as possible, and physicians in general practice are the key persons to initiate and coordinate intervention and provide long-term follow-up. A systematic approach is recommended to risk assessment. Specialised prevention programmes should be delivered as CR¹⁶⁷ or other structured, physician-led prevention programmes for all patients with CVD or at high risk of CVD. The structure, length and type of programme offered differ widely by country, affected by national guidelines and standards, legislation and payment factors.

Despite significant improvements in the management of patients presenting with ACS, secondary prevention remains challenging.¹⁶⁸ The implementation of pharmacological and non-pharmacological interventions is still very poor.¹⁶⁹: Proper utilisation of and adherence to evidence-based treatment strategies and interventions have to be the priority after ACS in order to improve long-term outcomes. It is essential to identify health system-related difficulties and weaknesses in the management and support of secondary prevention post-ACS discharge.¹⁷⁰

Heart failure

Biomarkers

Plasma biomarkers are useful tools in the diagnosis and prognosis of HF. Whereas cardiac-specific biomarkers, including natriuretic peptides (atrial natriuretic peptide and BNP) and high sensitivity troponins, are widely used in clinical practice, other biomarkers have not yet proved their utility.¹⁷¹ Thus, some plasma biomarkers have the potential to provide information about specific processes (e.g. cardiac strain, interstitial/replacement fibrosis, endothelial dysfunction and pathological hypertrophic processes) that drive cardiac dysfunction in the individual HF patient¹⁷² and they could be used to improve and guide medical therapy.¹⁷³

Exercise training

A new meta-analysis¹⁷⁴ and the Cochrane meta-analysis¹⁷⁵ involved 44 studies that included 5783 people with heart failure with reduced ejection fraction (HFrEF), and had findings consistent with those of the previous (2014) version of the Cochrane review: significant reductions in overall hospital admissions, as well as in HF admissions. These findings have recently been confirmed by the CROS-HF meta-analysis and review.¹⁷⁶

Further evidence is needed to show the effects of exercise rehabilitation among traditionally less represented HF patient groups including older, women, people with heart failure with preserved ejection fraction (HFpEF) (currently under investigation) as well as the impact of and alternative delivery settings including home and using technology-based programmes.

Telemonitoring

A recent Cochrane review identified 25 relevant trials and found that telemonitoring reduced all-cause mortality by about 20% and the HF hospitalisation by about 30%.¹⁷⁷ The beneficial effects have been confirmed by the TIM-HF2 trial which demonstrated that remote telemonitoring, including home assessment of weight, BP, ECG and general health status in the context of a 24/7 support system, reduced the proportion of days lost due to unplanned cardiovascular (mainly HF) hospitalisations or death (P = 0.046).¹⁷⁸

Cerebrovascular disease

Despite advances in earlier diagnosis, reperfusive strategies and the aggressive management of risk factors, stroke remains a leading cause of death and long-term disability worldwide. Recently, the POINT study¹⁷⁹ compared short-term (3 months) DAPT based on aspirin and clopidogrel with a single antiplatelet regimen in patients with minor stroke and high-risk transient ischaemic attack, showing a reduction in recurrent stroke in the DAPT group at 90 days and a higher risk of major bleeding than aspirin alone. The HR for ischaemic events (mostly occurring in the first week after the index event) was 0.75 (95% CI 0.59–0.95), while the 90-day prevalence of major haemorrhage was 0.9% in the DAPT group versus 0.4% in the aspirin-alone group (HR 2.32, 95% CI 1.10–4.87). In this population generally considered as having a lower risk (as compared to patients with AF in whom anticoagulation is mandatory, or patients with severe extracranial carotid disease who might benefit from endarterectomy or stenting), novel evidence confirmed the difficulty of obtaining clear net benefit by adopting combination antiplatelet therapy.

Recent acquisitions are also targeted on risk reduction of future stroke and dementia in subjects with silent cerebrovascular disease (SCD), a common incidental finding on cerebral brain imaging defined as the presence of silent brain infarcts, magnetic resonance imaging white matter hyperintensities of presumed vascular origin and cerebral microbleeds. In clinical practice, magnetic resonance imaging is preferred to CT (for the diagnosis of SCD), as it allows us to detect chronic microbleeds. As in the case of the primary and secondary prevention of stroke, patients with SCD also need intensive evaluation and modification of vascular risk factors, including hypertension, DM, dyslipidaemia, cigarette smoking and physical inactivity.¹⁸⁰

Peripheral arterial disease

Patients with peripheral arterial disease (PAD) have a heightened risk of cardiovascular morbidity and mortality, being unfortunately often under-recognised and under-treated.

Exercise training combined with revascularisation procedures is the cornerstone in the treatment and prevention of progression in PAD.^181,182

Antithrombotic therapy based on combination therapies may play an important role in the prevention of death, ischaemic cardiovascular and limb events in patients with lower extremity PAD. In the COMPASS trial,¹⁸³ a low dose (2.5 mg twice a day) of NOAC rivaroxaban plus aspirin (100 mg once a day) – as compared to aspirin alone – was shown to reduce the composite endpoint of cardiovascular death, MI, or stroke (HR 0.72, 95% CI 0.57–0.90; P = 0.0047) and major adverse limb events including major amputation (HR 0.54, 95% CI 0.35–0.82; P = 0.0037) among patients with previous peripheral bypass surgery or angioplasty, limb or foot amputation, intermittent claudication, carotid or CAD with an ABI of less than 0.90. However, the rivaroxaban plus aspirin combination increased major bleeding compared with the aspirin-alone group (HR 1.61, 95% CI 1.12–2.31; P = 0.0089), which was mainly gastrointestinal. The cost-effectiveness of low-dose rivaroxaban and aspirin versus aspirin alone in people with peripheral or carotid artery disease has been assessed by in a high-income country only (Australia).¹⁸⁴

In the PEGASUS-TIMI 54 randomised trial¹⁸⁵ the addition of ticagrelor (90 mg or 60 mg twice a day) to aspirin in a subgroup of PAD patients with a history of MI (one to 3 years earlier) was associated with a reduced risk of cardiovascular and limb events at the expense of increased major bleeding. The absolute risk reduction was 4.1% (number needed to treat 25) and the 60 mg dose had particularly favourable outcomes for cardiovascular and all-cause mortality. According to novel evidence, the use of combined antithrombotic therapies could now be advocated for secondary prevention in symptomatic PAD, even though their adoption needs to be tailored according to the individual thrombotic and bleeding risk.

The pivotal role of exercise training has been highlighted in systemic reviews of RCTs in which the combination of physical intervention and lower limb revascularisation led to an increase in pain-free (mean difference range 38–408 m) and in maximal walking distances (range 82–321 m).¹⁸¹

Another meta-analysis confirmed the higher efficacy of the combination of exercise training and revascularisation in improving total walking distance, ABI and reducing the risk of future revascularisation or amputation.¹⁸²

The settings: where to intervene?

Clinical settings

The role of primary care and community services in cardiovascular prevention remains essential, both in the identification of high-risk individuals and in providing interventions. Population screening via health checks in England has shown that the proportion of individuals attending was higher among older people, those with a CVD family history and those in economically deprived areas. Data on impact are limited but have shown a small increase in disease detection, statin and anti-hypertensive prescriptions and a small decrease in modelled CVD risk.¹⁸⁶ A systematic review of 31 studies using multiple health behaviour changes in primary care to reduce cardiovascular risk in people without established CVD found a modest, statistically significant effect on individual behaviours and overall cardiovascular risk.¹⁸⁷

A meta-analysis of prospective controlled cohort studies and retrospective controlled cohort studies published since 1995 confirmed the efficacy of CR on cardiac prognosis even in the era of statin therapy and acute revascularisation.¹⁸⁸ CR after an ACS event and coronary artery bypass grafting intervention was significantly associated with reduced mortality (prospective controlled cohort studies HR 0.37, 95% CI 0.20–0.69; retrospective controlled cohort studies 0.64, 95% CI 0.49–0.840.37–0.64), but the heterogeneity of study designs and CR programmes highlight the need for defining internationally accepted standards in CR, including lifestyle changes.¹⁸⁸

eHealth

Engaging cardiovascular prevention more widely with at-risk individuals and patients could be enhanced through eHealth interventions. To improve CR uptake and delivery, eHealth (telemedicine) technology has been shown to be cost-effective in Belgium.¹⁸⁹ In a systematic review of 30 trials, telehealth as an adjunct or an alternative to rehabilitation or usual care achieved improved outcomes in recurrent cardiac events, total cholesterol, LDL and smoking.¹⁹⁰

The use of mobile apps continues to grow. A review of 10 studies (n = 607 patients) found that patients found some features appealing: behavioural tracking, self-monitoring, education, managing provider communication and flexible, customisable options. The studies found variable results in effectiveness in risk factor control and self-management.¹⁰⁵ A major challenge for eHealth interventions is their variability and the need to determine the features, components, frequency and duration of contact that are most effective for changing behaviour and decreasing CVD risk.

How to monitor preventive activities: standard of performance

The latest 2016 guidelines¹ recommend to monitor the process of CVD prevention activity delivery and outcomes to improve the implementation of quality of care in clinical practice. The development of standards of performance involves the identification of a set of measures, targeting a specific patient population observed over a particular time period. These measures should be specifically suitable for public and external reporting, providing an indication of quality. The EAPC of the ESC is undergoing a quality of care programme aiming to develop and implement an accreditation of clinical centres providing primary prevention, secondary prevention and rehabilitation, and sports cardiology, to be applied in ESC-related countries.¹⁹¹

The ACC/AHA review updated the clinical performance and quality measures for CR,¹⁹² considering the following CR performance measures:

• CR patient referral (inpatient setting): Percentage of patients hospitalised with qualifying event/diagnosis for CR in previous 12 months referred to outpatient CR programme.

• Exercise training referral for HF (inpatient setting): Percentage of patients hospitalised with primary diagnosis of HFrEF in previous 12 months, referred for exercise training, typically delivered in the setting of outpatient CR programme.

• CR patient referral (outpatient setting): Percentage of patients in outpatient setting, who in the previous 12 months had a qualifying event/diagnosis for CR and did not participate in CR programme, but are to be referred to a programme.

• Exercise training referral for HF (outpatient setting): Percentage of patients in outpatient setting, who in the previous 12 months had a new HFrEF event or exacerbation and have not participated in an exercise training programme, but are to be referred for exercise training.

• CR enrolment – claims based (outpatient provider): Percentage of patients with qualifying event/diagnosis for CR who attend at least one session in a CR programme.

• CR enrolment – registry/electronic health records based (inpatient provider): Percentage of patients with qualifying event/diagnosis for CR who attend at least one session in a CR programme.

Every cardiovascular prevention or CR programme should be formally submitted to regular audits, which should include the collection of data to meet the purpose of monitoring prevention and rehabilitation service resources.¹⁹³

Gaps in the knowledge

Unfortunately, not all the gaps pointed out in the ESC CVD prevention guidelines are solved yet.

• There is a need for a revaluation and recalibration of the current risk scores.

• Evidence, cost-effectiveness and potential harm of larger-scale use of CAC scoring for refinement of risk stratification is needed.

• The role of cardiac biomarkers (i.e. natriuretic peptide and cardiac troponin blood concentration) in risk stratification is needed.

• There is still no evidence of cost-effectiveness of the application of cardiovascular genetic risk score testing in clinical practice, such as targeting statin therapy in individuals at low to moderate cardiovascular risk.

• The use of CT coronary angiography as a risk stratification tool in asymptomatic individuals is not supported by data.

• Refinement of the screening items with established psychometric questionnaires is required.

• Strong evidence of the effectiveness of influenza vaccination in primary prevention of CVD is still lacking.

• Whether periodontal therapy can prevent the recurrence of CVD in the long term in patients with chronic periodontitis; no evidence on primary prevention was found.

• To estimate the magnitude of the problem of CVD in young adults and to elucidate treatable risk factors that underlie the observed increasing rates of CVDs in this population is required.

• The decision to initiate primary prevention with statins in people older than 75 years of age cannot be based directly on RCT evidence.

• Thus limited evidence is available on therapy for primary prevention of CVDs in very elderly and frail individuals.

• E-cigarettes may be more effective in promoting nicotine dependence than as an aid to smoking cessation.

• Evidence is required on the benefit in terms of increased longevity and delayed onset of age-associated disorders of caloric restriction without malnutrition in humans.

• The relation between alcohol consumption and CVD is still controversial, even though the evidence base for overall harm is increasing.

• The U-shaped association between salt intake and CVD is debated.

• The clinical benefit from LDL-cholesterol lowering beyond that obtained with statin therapy in high and very high risk patients has been put forward, although data on long-term safety and total survival are still awaited.

• To clarify the benefit of omega-3 fatty acids also in higher dosages in cardiovascular event reduction.

• The optimal out-of-office (home and ambulatory) BP targets, and whether treatment strategies based on control of out-of-office BP provide an advantage over strategies based on conventional (office) BP control.

• Cost-effectiveness of low-dose rivaroxaban and aspirin versus aspirin alone in people with peripheral or carotid artery disease has been assessed in a high-income country only.

• Under which conditions psychological interventions in addition to exercise-based CR exert their optimal effects.

• Treatment with SSRIs may improve subjective wellbeing and prognosis in depressed patients with CAD, but confirmation by additional trials is needed.

• The heterogeneity of study designs and CR programmes highlights the need for defining internationally accepted standards in CR, including lifestyle changes.

• Further evidence is needed to show the effects of exercise rehabilitation among traditionally less represented HF patient groups, including older, women, people with HFpEF (currently under investigation) as well as the impact and alternative delivery settings including home and using technology-based programmes.

• A major challenge for eHealth interventions is their variability, and we need to determine the features, components, frequency and duration of contacts that are most effective for changing behaviour and decreasing CVD risk.

Acknowledgement

The authors would like to thank the document reviewers: Birna Bjarnason-Wehrens, Veronique Cornelissen, Paul Dendale, Richter Dimitrios, Nicolle Kraenkel, Jari Laukkanen, Pedro Marques Vidal, Miguel Mendes, Josef Niebauer, Ann-Dorthe Olsen Zwisler, Antonio Pelliccia.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

Author notes

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For details of reviewers see the end of the paper.