Authors

• Børge G. Nordestgaard — Copenhagen University Hospital, Copenhagen, Denmark
• Francesco Cosentino — Stockholm, Sweden
• Ulf Landmesser — Berlin, Germany
• Ulrich Laufs — Leipzig, Germany

DOI

Full Text

## Preamble During 2017 several landmark studies have been published that have practical implications for atherosclerotic cardiovascular disease (ASCVD) prevention and risk factor control, such as lipids and lipoproteins, inflammation, diabetes, hypertension, and healthy lifestyle. We use the term ‘ASCVD’ where relevant to simplify the reading of this article for the non-specialist, although the exact definition as ASCVD differ slightly from study to study. However, in sections where ASCVD clearly is not the relevant endpoint (e.g. in hypertension research) we do not use ‘ASCVD’, but instead of use other words to describe endpoints. All relevant trials have been performed on a background of optimal medical therapy, such as described in the European Society of Cardiology(ESC)/European Atherosclerosis Society (EAS) guidelines on ASCVD prevention and management of dyslipidaemia for lipid-lowering. (1, 2) For example, important new evidence for additional risk reduction relates to lipid-lowering [proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition, (3) cholesteryl ester transfer protein (CETP) inhibition (4)] to the reduction of systemic inflammation (interleukin-1β inhibition (5)) and to anti-thrombotic therapy (low-dose factor Xa antagonism (6)). Since these novel treatments have not yet been tested in combination and because of the practical and economic limitations, an important challenge for the years to come is patient selection. Also, the benefit to risk dimension of any new therapeutic agent needs to be considered. This review article is intended to provide the practicing physician with the information needed to identify patients in secondary prevention that may benefit the most from additional novel treatments (**Figure 1**), and at the same time give a comprehensive update of novel insights relevant both to primary and secondary prevention of ASCVD. Use and accessibility of novel treatments will depend critically on whether patients live in high income, upper middle-income or lower middle-income countries, as levels of cardiovascular risk factors, cardiovascular mortality rates, and thus the prevention potential differ between such countries. (7) Figure 1. A 2017 optimally treated patient with coronary heart disease on statin, aspirin, angiotensin-converting enzyme inhibitor, and beta-blocker. Do new trials suggest that we should add additional drugs or lifestyle modification, and what in whom? PCSK9, proprotein convertase subtilisin/kexin type 9; LDL-C, low-density lipoprotein cholesterol; ACE, angiotensin converting enzyme. This Figure has been reprinted with permission of Oxford University Press on behalf of European Society of Cardiology. This Figure has been reprinted with permission of Oxford University Press on behalf of European Society of Cardiology. ## Lifestyle Observational epidemiology in the field of lifestyle is difficult to trust due to the high-risk of confounding (a third factor influences both disease risk and lifestyle) and reverse causation (diseases will change a person’s lifestyle), and therefore only randomized intervention trials and genetic Mendelian randomizations studies can be trusted. However, each of these study designs have limitations. (8–10) Importantly, as randomized intervention trials are very difficult to conduct for lifestyle factors, we often are left with observational and genetic studies in this field. Below is what we choose to highlight for 2017. The concept of ‘metabolically healthy obesity’, namely that in the absence of metabolic dysfunction, individuals with excess adiposity are not at greater cardiovascular risk, has been controversial. A recent pan-European case-cohort study nested within the European Prospective Investigation into Cancer and Nutrition study (EPIC-CVD), observed higher cardiovascular risk with increasing general and central adiposity. (11) Other cohort studies have challenged this concept reporting an excess of cardiovascular risk in metabolically healthy obese as compared to normal weight individuals. (12–15) These results highlight the importance of population-wide prevention of obesity with lifestyle intervention targeting eating behaviour and physical activity. Importantly however, steady and sustained weight loss is preferable as in patients with coronary heart disease the highest vs. lowest variation in body weight was associated with 64% more coronary and 124% more mortality events. (16) Coffee consumption is observationally associated with reduced all-cause, cardiovascular and other cause-specific mortality. (17–19) However, both reverse causation and confounding by other lifestyle factors may bias such results. Interestingly therefore, Mendelian randomization studies free of confounding found no causal effect of coffee intake on all-cause or cardiovascular mortality, or on cardiovascular disease. (19) Likewise, in Mendelian randomization studies milk intake appears not to influence risk of hypertension or cardiovascular disease. (20, 21) Alcohol intake: novel findings include that acute beer alcohol consumption during the Munich Octoberfest was associated with cardiac arrhythmias and sinus tachycardia. (22) Large UK and USA cohorts found moderate alcohol intake associated with less of most cardiovascular disease endpoints while heavy and binge drinking or alcohol abuse were associated with more cardiovascular disease or deaths. (23–25) A Mendelian randomization study of genotypes associated with higher education suggested that low education is causally associated with ASCVD events. (26) Using UK-Biobank participants, it was observed that the association between physical activity and mortality was strongest in those with lowest strength and lowest cardiorespiratory fitness, suggesting that these subgroups would benefit the most from more physical activity (27); preventing or delaying cardiovascular disease or diabetes seemed to delay cognitive decline and possibly dementia. (28) Adherence to a healthy lifestyle consisting of non-smoking, light to moderate alcohol intake, high physical activity, fruit and vegetables intake, and normal body weight was associated with a substantially lower burden of ASCVD in Chinese, (29) like previously observed in Europeans. Interestingly, in Spain skipping breakfast was associated with more non-coronary and generalized atherosclerosis, independent of other cardiovascular risk factors. (30) Importantly however, lifestyle can be difficult to change, even for patients with acute coronary syndrome and/or revascularization. (31) Further, in the PURE study covering all major parts of the World and recruiting 135 335 individuals between 2003 and 2013 with follow-up until 2017, higher intake of fruit, vegetables, and legumes was associated with lower non-cardiovascular and total mortality, with a non-significant trend for cardiovascular mortality. (32) The findings also included that as little as three servings per day consisting of only 375 g per day were associated with similar benefit. This indicate that optimal health benefits may be achieved with a more modest consumption of fruit, vegetables, and legumes than that recommended in high-income Europe and the USA, an approach that is more likely to be affordable in low-income and middle-income countries. In contrast to popular opinion, higher fat intake was not associated with ASCVD or death. Finally, air pollution, noise, and other environmental stressors, depending on where a person choose to live, may influence cardiovascular health and mortality. (33, 34) For example, long-term exposure to road traffic noise and ambient air pollution were associated adversely with cardiovascular biochemical risk factors (35) and self-reported hypertension. (36) Worldwide ambient air pollution with aerodynamic diameter 2.6 mmol/L (100 mg/dL)] treated with intense statin therapy, were randomized to evolocumab or placebo (3): LDL cholesterol was reduced 59% to 0.8 mmol/L (30 mg/dL), ASCVD events 15% (absolute risk reduction 1.5%), and myocardial infarction was reduced 27% (absolute risk reduction 1.2%). Moreover, a pre-specified secondary analysis of FOURIER suggested reduced ASCVD at achieved LDL cholesterol 50 000 men aged 65–74 to screening or not for abdominal aortic aneurism, peripheral arterial disease, and hypertension; those diagnosed in the screening group were offered relevant follow-up and treatment including surgery and antihypertensive medication, which was associated with a 7% reduced all-cause mortality (absolute risk reduction 0.6%) primarily linked to initiation of pharmacological therapy. (133) Importantly, mortality related to abdominal aortic aneurism may differ from country to country, and can be influenced by rate of surgical repair and aneurysm diameter at repair. (134) A low ankle-brachial index help identify patients with abdominal aortic aneurism and peripheral arterial disease and predict ASCVD events, although to a lesser extent than increased coronary artery calcification. (135) Arterial thrombosis depends on atherosclerotic plaque vulnerability, which likely differs in individuals taking statins or not due to reduced lipid-driven plaque inflammation in those on statins. (136) Interestingly, new data support that a chronically affected haematopoietic system potentially drive low-grade inflammation in patients with atherosclerosis. (137) For venous thromboembolism, meta-analyses of observational studies found a 27% reduced risk of recurrent venous thromboembolism associated with statin use, (138) in accordance with findings in the randomized JUPITER trial. (139) Finally, in patients with venous thromboembolism in equipoise for continued anticoagulation, the risk of a recurrent event was reduced approximately 70% by rivaroxaban compared with aspirin, without a significant increase in bleeding rates; (140) this confirms previous studies with other novel oral anticoagulants. ## Guidelines and consensus statements Despite evidence-based recommendation for widespread use of statins in both primary and secondary prevention of ASCVD, (1, 2) statin compliance is a major problem worldwide, (141, 142) partly due to negative press (143, 144) and in consequence discontinuation of statin use and increased risk of myocardial infarction and cardiovascular mortality. (143–146) In support, in the ASCOT-LLA trial muscle-related adverse events were similar in those receiving atorvastatin and placebo during blinding, however, after un-blinding and follow-up for an additional 2.3 years muscle-related adverse events were now 41% higher in those who knew they were receiving atorvastatin. (147) Therefore, any patient claiming statin intolerance including muscle symptoms needs careful counselling with his or her physician, including better diagnostics of statin intolerance and advice on how to continue statin therapy despite perceived side effects. (141, 142, 148) Various updates of major guidelines for prevention of cardiovascular disease has occurred lately, (1, 149–154) and despite use of the same scientific evidence to guide lifestyle changes and medical intervention advise tend to differ between guidelines. For example, the ACC/AHA guidelines compared with the ESC/EAS guidelines placed higher priority for assigning statins in primary prevention to those who later developed ASCVD (155); this difference was mainly explained by the fact that the American guidelines assigned statin therapy to more individuals that the European guidelines. That said, the European guidelines is limited by using the SCORE algorithm for ASCVD risk assignment based only on ASCVD mortality in cohorts recruited many years ago, and limited to only 40–65 years old. (156, 157) Although the risk of ASCVD increases with increasing age above 65 years (156) with age as the most important ASCVD risk predictor, arguments differ with respect to how important age should be in determining statin assignment. (158, 159) Although the American ACC/AHA risk score overestimates ASCVD risk, particularly in Chinese, (160) the European ESC/EAS SCORE may in some populations overestimate risk even more. (155) Therefore, ideally risk scores for ASCVD needs to be recalibrated to each country and ethnic group before it is used to assign statin therapy. In 2017, exactly that has happened for the UK QRISK3 risk prediction algorithms for the NICE guidelines, (149) using current data from 981 general practices and 7.9 million patients aged 25–84 in England to develop new scores and another 328 practices and 2.7 million patients to validate the new score algorithms. (161) By 2017, the use of non-fasting rather than fasting lipid profiles is now recommended in many guidelines and consensus statements worldwide, (89) including in the UK, (149) Europe, (1, 2, 162) Canada, (150, 151) Brazil, (163) and in the USA. (153, 164, 165) Finally, new USA guidelines have lowered the threshold for the definition of hypertension to ≥130/80 mmHg systolic/diastolic BP (earlier 140/90 mmHg), (166) placing very large proportions of adult populations in potential need for BP-lowering medication or intensified BP-lowering in the USA. ## Conclusion 2017 has been a very exciting year for studies in ASCVD prevention, including landmark clinical trials, genetic Mendelian randomization studies, and observational prospective cohort studies. **Figure 1** illustrates some of the new concepts for additional preventive measures in secondary prevention in a patient with coronary heart disease already on statin, aspirin, ACE inhibitor, and beta-blocker. Naturally, many new concepts await confirmation by additional studies and their test in clinical practice. Importantly, considerable inter-individual variability has been noted in the response to a number of the agents discussed in this review. Therefore, for all new (and old) drugs, it is important to monitor response, particularly at a time when economic pressures oblige clinicians to use therapeutic agents in an optimal manner on a personalised basis. ## Acknowledgments Published on behalf of the European Society of Cardiology. All rights reserved. © The Author. For permissions please email: journals.permissions@oup.com

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