2021 ESC Guidelines on cardiovascular disease prevention in clinical practice: Developed by the Task Force for cardiovascular disease prevention in clinical practice with representatives of the European Society of Cardiology and 12 medical societies With the special contribution of the European Association of Preventive Cardiology (EAPC)

Classes of recommendations

Table 2

Levels of evidence

2. Introduction

Atherosclerotic cardiovascular (CV) disease (ASCVD) incidence and mortality rates are declining in many countries in Europe, but it is still a major cause of morbidity and mortality. Over the past few decades, major ASCVD risk factors have been identified. The most important way to prevent ASCVD is to promote a healthy lifestyle throughout life, especially not smoking. Effective and safe risk factor treatments have been developed, and most drugs are now generic and available at low costs. Nevertheless, the prevalence of unhealthy lifestyle is still high, and ASCVD risk factors are often poorly treated, even in patients considered to be at high (residual) CVD risk.¹ Prevention of CV events by reducing CVD risk is the topic of these guidelines.

2.1. Definition and rationale

The present guidelines have been developed to support healthcare professionals in their efforts to reduce the burden of ASCVD in both individual patients, as well as at a population level. The previous European Guidelines on CVD prevention in clinical practice were published in 2016.² Recent developments in prediction of cardiovascular disease (CVD) risk and treatment benefit, as well as novel treatments and treatment goals, necessitated new, up-to-date guidelines. The current guidelines on CVD prevention in clinical practice concentrate principally but not exclusively on the risk factors, risk classification, and prevention of ASCVD.

The current guidelines provide recommendations on ASCVD prevention to support shared decision-making by the patient and their healthcare professional based on individual patient characteristics. Special considerations have been given to differences in age, sex and gender, life expectancy, risk factor profiles, ethnic, and geographic differences. Estimating CVD risk not only in apparently healthy subjects, but also in older persons and in patients with established ASCVD or diabetes mellitus (DM), provides information for tailored intervention on an individual level. Treatment goals can be individualized in a stepwise approach. ‘Residual’ CVD risk is defined as the risk estimated after initial lifestyle changes and risk factor treatment, and is mostly used in patients with established ASCVD. For younger apparently healthy subjects, lifetime CVD risk estimates are available to support treatment decisions, replacing 10-year risk algorithms that consistently estimate low 10-year risk even in the presence of high risk factor levels. In an ageing population, treatment decisions require a specific CVD risk score that takes competing non-CVD risk into account, as well as specific low-density lipoprotein cholesterol (LDL-C) and blood pressure (BP) treatment considerations. Estimating lifetime benefit in individual patients of smoking cessation, LDL-C lowering, and BP lowering provides opportunities to communicate benefit of treatment in an easy-to-understand way. Personalized treatment decisions using CVD risk estimations and a stepwise approach to treatment is more complex than a more general one-size-fits-all prevention strategy, but reflects the diversity in patients and patient characteristics in clinical practice.

Regarding LDL-C, BP, and glycaemic control in patients with DM, goals and targets remain as recommended in recent European Society of Cardiology (ESC) Guidelines.^3–5 These prevention guidelines propose a new, stepwise approach to treatment intensification as a tool to help physicians and patients pursue these targets in a way that fits patient profile and preferences. Of note, however, new evidence and/or new consensus may have resulted in some differences with these recent domain-specific ESC Guidelines. New evidence on antithrombotic treatment regimens for ASCVD prevention is also presented. Sex-specific aspects are included.

ASCVD prevention needs an integrated, interdisciplinary approach including input from several disciplines and areas of expertise. We must work together in a patient- and family-centred way to address each of the core components of prevention and rehabilitation, including lifestyle modification, psychosocial factors, risk factor treatment, and social determinants (Central Illustration).

Figure 1

Central Illustration. ASCVD = atherosclerotic cardiovascular disease; CKD = chronic kidney disease; COPD = chronic obstructive pulmonary disease; CVD = cardiovascular disease

2.2. Development

The Task Force chairs and members were appointed by the ESC Clinical Practice Guidelines Committee (CPG). Each member of the Task Force was assigned specific writing tasks, which were reviewed by other (sub)section writers, the section coordinators, and the chairs. The text was developed over 11 months, during which the Task Force members met collectively on three occasions and corresponded intensively between meetings. The review panel consisted of experts selected by all the scientific societies that were involved in the development of these guidelines, not only the ESC.

2.3. Cost-effectiveness

The Task Force acknowledge the fact that healthcare budgets are, in many circumstances, limited and thus that certain recommendations and goals may not always be attainable. However, the current guidelines do not provide cost-effectiveness analyses. Large national and regional differences in budgets and costs associated with both interventions and diseases/events preclude valid universal cost-effectiveness analyses. However, some recommendations clearly have financial implications, either in terms of costs for individual patients and/or in terms of budget impact. Some of these recommendations pertain to diagnosis (e.g. large-scale use of expensive imaging tests such as computed tomography), others to interventions (e.g. expensive drugs, such as novel lipid-lowering or anti-diabetic drugs). For such recommendations, it is inappropriate to ‘unconditionally’ implement them without first considering cost-effectiveness in a national or regional context or, ideally, to perform formal cost-effectiveness analyses with country-specific input parameters and cost-effectiveness thresholds.

2.4. What is new?

New recommendations, and new and revised concepts, are presented in Table 3.

Table 3

What is new

ABI = ankle brachial index; AF = atrial fibrillation; ASCVD = atherosclerotic cardiovascular disease; b.i.d. = bis in die (twice a day); BP = blood pressure; CAC = coronary artery calcium; CHD = coronary heart disease; CKD = chronic kidney disease; CR = cardiac rehabilitation; CV = cardiovascular; CVD = cardiovascular disease; DM = diabetes mellitus; EBCR = exercise-based cardiac rehabilitation; ED = erectile dysfunction; FH = familial hypercholesterolaemia; GLP-1RA = glucagon-like peptide-1 receptor agonist; HF = heart failure; HFrEF = heart failure with reduced ejection fraction; HMOD = hypertension-mediated organ damage; LDL-C = low-density lipoprotein cholesterol; LEAD = lower extremity artery disease; mHealth = mobile device-based healthcare; o.d. = omni die (once a day); PA = physical activity; PCSK9 = proprotein convertase subtilisin/kexin type 9; PM = particulate matter; PUFA = polyunsaturated fatty acid; SBP = systolic blood pressure; SCORE2 = Systematic Coronary Risk Estimation 2; SCORE2-OP = Systematic Coronary Risk Estimation 2-Older Persons; SGLT2 = sodium-glucose cotransporter 2; SNRI = serotonin-noradrenaline reuptake inhibitor; SSRI = selective serotonin reuptake inhibitor; TOD = target organ damage.

New sections

Section 3

3.2.2 Sex and gender and their impact on health
3.2.3 Atherosclerotic cardiovascular disease risk classification
3.2.3.1 A stepwise approach to risk factor treatment and treatment intensification
3.2.3.2 Risk estimation in apparently healthy people
3.2.3.3 Translating atherosclerotic cardiovascular disease risk to treatment thresholds
3.2.3.4 Risk estimation and risk factor treatment in apparently healthy people 50–69 years of age
3.2.3.5 Risk estimation and risk factor treatment estimation in apparently healthy people ≥70 years of age
3.2.3.6 Risk estimation and risk factor treatment in apparently healthy people <50 years of age
3.2.3.7 Risk estimation and risk factor treatment in patients with established atherosclerotic cardiovascular disease
3.2.4 Communication of cardiovascular disease risk
3.3.1 Psychosocial factors
3.3.4 Frailty
3.3.8 Environmental exposure
3.4 Clinical conditions
3.4.2 Atrial fibrillation
3.4.3 Heart failure
3.4.5 Chronic obstructive pulmonary disease
3.4.6 Inflammatory conditions
3.4.7 Infections (human immunodeficiency virus, influenza, periodontitis)
3.4.8 Migraine
3.4.9 Sleep disorders and obstructive sleep apnoea
3.4.10 Mental disorders
3.4.11 Non-alcoholic fatty liver disease
3.4.12 Sex-specific conditions

4.10 Anti-inflammatory treatment

New /revised concepts

SCORE2 and SCORE2-OP risk charts for fatal and non-fatal (myocardial infarction, stroke) ASCVD
Estimating 10-year total CVD risk in apparently healthy people 50–69 years of age
Estimating lifetime risk in apparently healthy people <50 years of age
Estimating 10-year total CVD risk in apparently healthy people ≥70 years of age
Cut-offs of 10-year CVD risk, based on SCORE2/SCORE2-OP, to define low–moderate risk, high risk, and very high risk for apparently healthy people in different age groups (<50, 50–69, and ≥70 years)
Estimating 10-year CVD risk in patients with established CVD and/or DM
Lifetime benefit of stopping smoking, reducing LDL-C, or lowering SBP (sections 3 and 4)
A stepwise approach to attaining ultimate treatment goals (sections 3 and 4)
Communication of CVD risk and benefit of treatment to patients in an understandable way
Stepwise approach to risk factor treatment and treatment intensification

Explicitly addressing cost-effectiveness (on a loco-regional or national level) before implementing some recommendations
Non-fasting lipid measurement (section 4.6.1.1)
A stepwise approach to attaining treatment goals (sections 3 and 4)
Anti-inflammatory treatment for very-high-risk patients

Taking into consideration population level interventions to mitigate the effects of pollution on CVD health

Risk management of disease-specific CVD. This section addresses CVD prevention when certain underlying diseases are present and aims to provide guidance on how to prevent the worsening of existing, or the development of further, comorbidities that could increase the overall risk of CVD
Subsections include: 6.1 Coronary artery disease; 6.2 Heart failure; 6.3 Cerebrovascular disease; 6.4 Lower extremity artery disease; 6.5 Chronic kidney disease; 6.6 Atrial fibrillation; 6.7 Multimorbidity

New sections

Section 3

3.2.2 Sex and gender and their impact on health
3.2.3 Atherosclerotic cardiovascular disease risk classification
3.2.3.1 A stepwise approach to risk factor treatment and treatment intensification
3.2.3.2 Risk estimation in apparently healthy people
3.2.3.3 Translating atherosclerotic cardiovascular disease risk to treatment thresholds
3.2.3.4 Risk estimation and risk factor treatment in apparently healthy people 50–69 years of age
3.2.3.5 Risk estimation and risk factor treatment estimation in apparently healthy people ≥70 years of age
3.2.3.6 Risk estimation and risk factor treatment in apparently healthy people <50 years of age
3.2.3.7 Risk estimation and risk factor treatment in patients with established atherosclerotic cardiovascular disease
3.2.4 Communication of cardiovascular disease risk
3.3.1 Psychosocial factors
3.3.4 Frailty
3.3.8 Environmental exposure
3.4 Clinical conditions
3.4.2 Atrial fibrillation
3.4.3 Heart failure
3.4.5 Chronic obstructive pulmonary disease
3.4.6 Inflammatory conditions
3.4.7 Infections (human immunodeficiency virus, influenza, periodontitis)
3.4.8 Migraine
3.4.9 Sleep disorders and obstructive sleep apnoea
3.4.10 Mental disorders
3.4.11 Non-alcoholic fatty liver disease
3.4.12 Sex-specific conditions

4.10 Anti-inflammatory treatment

New /revised concepts

SCORE2 and SCORE2-OP risk charts for fatal and non-fatal (myocardial infarction, stroke) ASCVD
Estimating 10-year total CVD risk in apparently healthy people 50–69 years of age
Estimating lifetime risk in apparently healthy people <50 years of age
Estimating 10-year total CVD risk in apparently healthy people ≥70 years of age
Cut-offs of 10-year CVD risk, based on SCORE2/SCORE2-OP, to define low–moderate risk, high risk, and very high risk for apparently healthy people in different age groups (<50, 50–69, and ≥70 years)
Estimating 10-year CVD risk in patients with established CVD and/or DM
Lifetime benefit of stopping smoking, reducing LDL-C, or lowering SBP (sections 3 and 4)
A stepwise approach to attaining ultimate treatment goals (sections 3 and 4)
Communication of CVD risk and benefit of treatment to patients in an understandable way
Stepwise approach to risk factor treatment and treatment intensification

Explicitly addressing cost-effectiveness (on a loco-regional or national level) before implementing some recommendations
Non-fasting lipid measurement (section 4.6.1.1)
A stepwise approach to attaining treatment goals (sections 3 and 4)
Anti-inflammatory treatment for very-high-risk patients

Taking into consideration population level interventions to mitigate the effects of pollution on CVD health

Risk management of disease-specific CVD. This section addresses CVD prevention when certain underlying diseases are present and aims to provide guidance on how to prevent the worsening of existing, or the development of further, comorbidities that could increase the overall risk of CVD
Subsections include: 6.1 Coronary artery disease; 6.2 Heart failure; 6.3 Cerebrovascular disease; 6.4 Lower extremity artery disease; 6.5 Chronic kidney disease; 6.6 Atrial fibrillation; 6.7 Multimorbidity

ASCVD = atherosclerotic cardiovascular disease; CVD = cardiovascular disease; DM =diabetes mellitus; LDL-C = low-density lipoprotein cholesterol; SBP = systolic bloodpressure; SCORE2 = Systematic Coronary Risk Estimation 2; SCORE2-OP = Systematic Coronary Risk Estimation 2-Older Persons.

New sections

Section 3

3.2.2 Sex and gender and their impact on health
3.2.3 Atherosclerotic cardiovascular disease risk classification
3.2.3.1 A stepwise approach to risk factor treatment and treatment intensification
3.2.3.2 Risk estimation in apparently healthy people
3.2.3.3 Translating atherosclerotic cardiovascular disease risk to treatment thresholds
3.2.3.4 Risk estimation and risk factor treatment in apparently healthy people 50–69 years of age
3.2.3.5 Risk estimation and risk factor treatment estimation in apparently healthy people ≥70 years of age
3.2.3.6 Risk estimation and risk factor treatment in apparently healthy people <50 years of age
3.2.3.7 Risk estimation and risk factor treatment in patients with established atherosclerotic cardiovascular disease
3.2.4 Communication of cardiovascular disease risk
3.3.1 Psychosocial factors
3.3.4 Frailty
3.3.8 Environmental exposure
3.4 Clinical conditions
3.4.2 Atrial fibrillation
3.4.3 Heart failure
3.4.5 Chronic obstructive pulmonary disease
3.4.6 Inflammatory conditions
3.4.7 Infections (human immunodeficiency virus, influenza, periodontitis)
3.4.8 Migraine
3.4.9 Sleep disorders and obstructive sleep apnoea
3.4.10 Mental disorders
3.4.11 Non-alcoholic fatty liver disease
3.4.12 Sex-specific conditions

4.10 Anti-inflammatory treatment

New /revised concepts

SCORE2 and SCORE2-OP risk charts for fatal and non-fatal (myocardial infarction, stroke) ASCVD
Estimating 10-year total CVD risk in apparently healthy people 50–69 years of age
Estimating lifetime risk in apparently healthy people <50 years of age
Estimating 10-year total CVD risk in apparently healthy people ≥70 years of age
Cut-offs of 10-year CVD risk, based on SCORE2/SCORE2-OP, to define low–moderate risk, high risk, and very high risk for apparently healthy people in different age groups (<50, 50–69, and ≥70 years)
Estimating 10-year CVD risk in patients with established CVD and/or DM
Lifetime benefit of stopping smoking, reducing LDL-C, or lowering SBP (sections 3 and 4)
A stepwise approach to attaining ultimate treatment goals (sections 3 and 4)
Communication of CVD risk and benefit of treatment to patients in an understandable way
Stepwise approach to risk factor treatment and treatment intensification

Explicitly addressing cost-effectiveness (on a loco-regional or national level) before implementing some recommendations
Non-fasting lipid measurement (section 4.6.1.1)
A stepwise approach to attaining treatment goals (sections 3 and 4)
Anti-inflammatory treatment for very-high-risk patients

Taking into consideration population level interventions to mitigate the effects of pollution on CVD health

Risk management of disease-specific CVD. This section addresses CVD prevention when certain underlying diseases are present and aims to provide guidance on how to prevent the worsening of existing, or the development of further, comorbidities that could increase the overall risk of CVD
Subsections include: 6.1 Coronary artery disease; 6.2 Heart failure; 6.3 Cerebrovascular disease; 6.4 Lower extremity artery disease; 6.5 Chronic kidney disease; 6.6 Atrial fibrillation; 6.7 Multimorbidity

New sections

Section 3

3.2.2 Sex and gender and their impact on health
3.2.3 Atherosclerotic cardiovascular disease risk classification
3.2.3.1 A stepwise approach to risk factor treatment and treatment intensification
3.2.3.2 Risk estimation in apparently healthy people
3.2.3.3 Translating atherosclerotic cardiovascular disease risk to treatment thresholds
3.2.3.4 Risk estimation and risk factor treatment in apparently healthy people 50–69 years of age
3.2.3.5 Risk estimation and risk factor treatment estimation in apparently healthy people ≥70 years of age
3.2.3.6 Risk estimation and risk factor treatment in apparently healthy people <50 years of age
3.2.3.7 Risk estimation and risk factor treatment in patients with established atherosclerotic cardiovascular disease
3.2.4 Communication of cardiovascular disease risk
3.3.1 Psychosocial factors
3.3.4 Frailty
3.3.8 Environmental exposure
3.4 Clinical conditions
3.4.2 Atrial fibrillation
3.4.3 Heart failure
3.4.5 Chronic obstructive pulmonary disease
3.4.6 Inflammatory conditions
3.4.7 Infections (human immunodeficiency virus, influenza, periodontitis)
3.4.8 Migraine
3.4.9 Sleep disorders and obstructive sleep apnoea
3.4.10 Mental disorders
3.4.11 Non-alcoholic fatty liver disease
3.4.12 Sex-specific conditions

4.10 Anti-inflammatory treatment

New /revised concepts

SCORE2 and SCORE2-OP risk charts for fatal and non-fatal (myocardial infarction, stroke) ASCVD
Estimating 10-year total CVD risk in apparently healthy people 50–69 years of age
Estimating lifetime risk in apparently healthy people <50 years of age
Estimating 10-year total CVD risk in apparently healthy people ≥70 years of age
Cut-offs of 10-year CVD risk, based on SCORE2/SCORE2-OP, to define low–moderate risk, high risk, and very high risk for apparently healthy people in different age groups (<50, 50–69, and ≥70 years)
Estimating 10-year CVD risk in patients with established CVD and/or DM
Lifetime benefit of stopping smoking, reducing LDL-C, or lowering SBP (sections 3 and 4)
A stepwise approach to attaining ultimate treatment goals (sections 3 and 4)
Communication of CVD risk and benefit of treatment to patients in an understandable way
Stepwise approach to risk factor treatment and treatment intensification

Explicitly addressing cost-effectiveness (on a loco-regional or national level) before implementing some recommendations
Non-fasting lipid measurement (section 4.6.1.1)
A stepwise approach to attaining treatment goals (sections 3 and 4)
Anti-inflammatory treatment for very-high-risk patients

Taking into consideration population level interventions to mitigate the effects of pollution on CVD health

Risk management of disease-specific CVD. This section addresses CVD prevention when certain underlying diseases are present and aims to provide guidance on how to prevent the worsening of existing, or the development of further, comorbidities that could increase the overall risk of CVD
Subsections include: 6.1 Coronary artery disease; 6.2 Heart failure; 6.3 Cerebrovascular disease; 6.4 Lower extremity artery disease; 6.5 Chronic kidney disease; 6.6 Atrial fibrillation; 6.7 Multimorbidity

ASCVD = atherosclerotic cardiovascular disease; CVD = cardiovascular disease; DM =diabetes mellitus; LDL-C = low-density lipoprotein cholesterol; SBP = systolic bloodpressure; SCORE2 = Systematic Coronary Risk Estimation 2; SCORE2-OP = Systematic Coronary Risk Estimation 2-Older Persons.

3. Risk factors and clinical conditions

3.1. Target population for assessing cardiovascular disease risk

CVD risk assessment or screening can be done opportunistically or systematically. Opportunistic screening, which means screening without a predefined strategy, is done when a person presents for some other reason. Systematic screening can be done in the general population as part of a formal screening programme, with call and recall of patients, or in targeted subpopulations such as subjects with type 2 DM, or family history of premature CVD. Systematic screening results in improvements in risk factors, but has no effect on CVD outcomes.^6–9 Opportunistic screening for ASCVD risk factors, such as BP or lipids, is effective at increasing detection rates and is recommended, although a beneficial effect on clinical outcome is uncertain.¹⁰

Structured national programmes aiming to identify undocumented ASCVD risk factors in adults over 40 years of age without DM or ASCVD and treat them have shown better risk factor control, but there are conflicting results as to clinical outcomes.¹¹^,¹² A high-risk strategy of inviting the population predicted to be at the highest risk according to an integrated risk score would be equally effective at preventing new cases of CVD and have potential cost savings.¹³ One large trial of mobile ultrasound screening for aortic aneurysm, peripheral artery disease (PAD), and hypertension in males aged 65–74 years showed a 7% mortality reduction at 5 years.¹⁴

A common criticism of screening in general is the potential that false positive and false negative results may cause harm. However, evidence on CVD screening shows that those who participate do not report mental distress.^15–18

Systematic CVD risk assessment assessment in the general population (adult men >40 and women >50 years of age) with no known CV risk factors appears not cost-effective in reducing subsequent vascular events and premature death, at least in short-term follow-up, but does increase detection of CV risk factors. Risk assessment is not a one-time event; it should be repeated, for example, every 5 years, although there are no empirical data to guide intervals.

3.2. Risk factors and risk classification

3.2.1. Risk factors

The main causal and modifiable ASCVD risk factors are blood apolipoprotein-B-containing lipoproteins [of which low-density lipoprotein (LDL) is most abundant], high BP, cigarette smoking, and DM. Another important risk factor is adiposity, which increases CVD risk via both major conventional risk factors and other mechanisms. In addition to these, there are many other relevant risk factors, modifiers, and clinical conditions, which are addressed under risk modifiers and clinical conditions (sections 3.3 and 3.4).

Recommendations for CVD risk assessment

ASCVD = atherosclerotic cardiovascular disease; BP = blood pressure; CV = cardiovascular; CVD = cardiovascular disease; DM = diabetes mellitus; FH = familial hypercholesterolaemia.

a

Class of recommendation.

b

Level of evidence.

3.2.1.1 Cholesterol

The causal role of LDL-C, and other apo-B-containing lipoproteins, in the development of ASCVD is demonstrated beyond any doubt by genetic, observational, and interventional studies.²⁰ The key attributes of LDL-C as a risk factor for ASCVD are:

Prolonged lower LDL-C is associated with lower risk of ASCVD throughout the range studied, and the results of randomized controlled trials (RCTs) indicate that lowering LDL-C safely reduces CVD risk even at low LDL-C levels [e.g. LDL-C <1.4 mmol/L (55 mg/dL)].²⁰
The relative reduction in CVD risk is proportional to the absolute size of the change in LDL-C, irrespective of the drug(s) used to achieve such change.²¹
The absolute benefit of lowering LDL-C depends on the absolute risk of ASCVD and the absolute reduction in LDL-C, so even a small absolute reduction in LDL-C may be beneficial in a high- or very-high-risk patient.²²
Non-high-density lipoprotein cholesterol (HDL-C) encompasses all atherogenic (apo-B-containing) lipoproteins, and is calculated as: total cholesterol – HDL-C = non-HDL-C. The relationship between non-HDL-C and CV risk is at least as strong as the relationship with LDL-C. Non-HDL-C levels contain, in essence, the same information as a measurement of apo-B plasma concentration.²³^,²⁴ Non-HDL-C is used as an input in the Systemic Coronary Risk Estimation 2 (SCORE2) and SCORE2-Older Persons (SCORE2-OP) risk algorithms.

HDL-C is inversely associated with CVD risk. Very high HDL-C levels may signal an increased CVD risk. There is, however, no evidence from Mendelian randomization studies, or randomized trials of cholesteryl ester transfer protein inhibitors, that raising plasma HDL-C reduces CVD risk.^25–28 HDL-C is nonetheless a useful biomarker to refine risk estimation using the SCORE2 algorithms. The SCORE2 algorithm cannot be used for patients with a genetic lipid disorder, such as familial hypercholesterolaemia (FH). Specific LDL-C thresholds and targets are recommended irrespective of estimated CV risk for patients with FH or other rare/genetic lipid disorders.

3.2.1.2 Blood pressure

Longitudinal studies, genetic epidemiological studies, and RCTs have shown that raised BP is a major cause of both ASCVD and non-atherosclerotic CVD [particularly heart failure (HF)], accounting for 9.4 million deaths and 7% of global disability adjusted life-years.²⁹ Elevated BP is a risk factor for the development of coronary artery disease (CAD), HF, cerebrovascular disease, lower extremity arterial disease (LEAD), chronic kidney disease (CKD), and atrial fibrillation (AF). The risk of death from either CAD or stroke increases linearly from BP levels as low as 90 mmHg systolic and 75 mmHg diastolic upwards.³⁰^,³¹ The absolute benefit of reducing systolic BP (SBP) depends on absolute risk and the absolute reduction in SBP, except that lower limits of SBP are imposed by tolerability and safety considerations. Management is determined by the category of hypertension (optimal, normal, high-normal, stages 1 to 3, and isolated systolic hypertension), defined according to seated office BP, ambulatory BP monitoring (ABPM), or home BP average values (see section 4.7). Evidence suggests that lifetime BP evolution differs in women compared to men, potentially resulting in an increased CVD risk at lower BP thresholds.^32–34 The SCORE2 algorithm cannot be used for patients with secondary causes and rarer forms of hypertension, such as primary hyperaldosteronism.

3.2.1.3 Cigarette smoking

Cigarette smoking is responsible for 50% of all avoidable deaths in smokers, with half of these due to ASCVD. A lifetime smoker has a 50% probability of dying due to smoking, and on average will lose 10 years of life.³⁵ The CVD risk in smokers <50 years of age is five-fold higher than in non-smokers.³⁶ Prolonged smoking is more hazardous for women than for men.³⁷ Worldwide, after high SBP, smoking is the leading risk factor for disability adjusted life-years.³⁸ Second-hand smoke is associated with an increase in CVD risk.³⁹ Some smokeless tobacco is also associated with increased risk of CVD.⁴⁰

3.2.1.4 Diabetes mellitus

Type 1 DM, type 2 DM, and prediabetes are independent risk factors for ASCVD, increasing risk of ASCVD by about two-fold, depending on the population and therapeutic control.⁴¹ Women with type 2 DM appear to have a particularly higher risk for stroke.⁴² Patients with type 2 DM are likely to have multiple ASCVD risk factors (including dyslipidaemia and hypertension), each of which mediates an increase in risk of both ASCVD and non-ASCVD.

3.2.1.5 Adiposity

Over recent decades, body mass index (BMI)—measured as weight (in kg) divided by squared height (in m²)—has increased substantially worldwide in children, adolescents, and adults.⁴³ Mendelian randomization analyses suggest a linear relation between BMI and mortality in non-smokers and a J-shaped relation in ever-smokers.⁴⁴ All-cause mortality is lowest at a BMI of 20–25 kg/m² in apparently healthy people, with a J-shaped or U-shaped relation.⁴⁵^,⁴⁶ In HF patients, there is evidence for an obesity paradox, with lower mortality risk in patients with higher BMI. A meta-analysis concluded that both BMI and waist circumference are similarly, strongly, and continuously associated with ASCVD and type 2 DM.⁴⁷

3.2.2. Sex and gender and their impact on health

The current prevention guidelines recognize the importance of integrating sex, gender, and gender identity considerations into the risk assessment and clinical management of individuals and populations. These guidelines also acknowledge the complexity of the inter-relationship between these concepts and CV, as well as psychological, health. There is, at present, no official ESC position on the specific terminology to be used. According to the World Health Organization (WHO), sex ‘refers to the different biological and physiological characteristics of females, males, and intersex persons, such as chromosomes, hormones and reproductive organs’.⁴⁸

This is to be distinguished from gender, which ‘refers to the characteristics of women, men, girls and boys that are socially constructed. This includes norms, behaviours and roles associated with being a woman, man, girl or boy, as well as relationships with each other. As a social construct, gender varies from society to society and can change over time’.⁴⁸ The Global Health 50/50 definition further states that gender refers ‘to the socially constructed norms that impose and determine roles, relationships, and positional power for all people across their lifetime’.⁴⁹

Where evidence exists on the risk modifying effect of sex or where sex-specific clinical conditions and clinical management strategies exist, this has been included in these guidelines.⁵⁰ The influence of gender on an individual’s experience and access to healthcare is paramount.⁵⁰ The specific health concerns related to gender are thus also acknowledged in these prevention Guidelines.

Epigenetic effects of social constructs appear to condition the translation of biological sex into disease pathophysiology. Furthermore, social constructs can also be determinants of health access, healthcare utilization, disease perception, decision-making, and perhaps therapeutic response,⁵⁰ including in the field of CVD and ASCVD prevention. Research is ongoing, but gaps in evidence remain and this has also been recognized in the guidelines.

Examples of specific topics regarding physiological, pathological, and clinical differences related to sex and gender that have been studied include left ventricular (LV) ejection fraction (LVEF), adverse drug reactions, trends in ASCVD risk factors and awareness, sex disparities in the management of and outcomes after acute coronary syndromes (ACS).^51–58 Furthermore, CVD health after menopause transition, pregnancy disorders, and gynaecologic conditions have recently been reviewed.⁵⁹

3.2.3. Cardiovascular disease risk classification

The current guidelines on CVD prevention in clinical practice concentrate principally, but not exclusively, on risk and prevention of ASCVD. This includes risk factors, risk prediction, risk modifiers, as well as clinical conditions that often increase the likelihood of ASCVD.

Identifying patients who will benefit most from ASCVD risk factor treatment is central to ASCVD prevention efforts. In general, the higher the absolute CVD risk, the higher the absolute benefit of risk factor treatment, and thus the lower the number needed to treat to prevent one CVD event during a period of time.⁶⁰^,⁶¹ With this in mind, the estimation of CVD risk remains the cornerstone of these guidelines and thus appears at the forefront of the proposed management schemes, which are summarized in flowcharts.

Age is the major driver of CVD risk. Women below 50 years and men below 40 years of age are almost invariably at low 10-year CVD risk, but may have unfavourable modifiable risk factors that sharply increase their longer-term CVD risk. Conversely, men over 65 years and women over 75 years of age are almost always at high 10-year CVD risk. Only between the ages of 55 and 75 years in women and 40 and 65 years in men does the 10-year CVD risk vary around commonly used thresholds for intervention. The age categories <50, 50–69, and ≥70 years should be used with common sense and flexibility. Different age ranges may be considered for men and women and may differ according to geographic region. Uncertainty around risk estimations should also be considered.

CVD risk can also be assessed in patients with type 2 DM and in patients with established ASCVD. The populations or patient groups in whom CVD risk needs to be considered are summarized and presented in Table 4. Lifetime CVD risk estimation is available for various groups of patients, and enables estimation of lifetime benefit from preventive interventions such as smoking cessation (see section 4.5.1), lipid-lowering (see section 4.6.2.1), and BP treatment (see section 4.7.5.2). Lifetime risk and benefit estimation may be used for communication in the shared decision-making process, together with consideration of comorbidities, frailty, patient preferences for initiating (STEP 1) and intensifying (STEP 2) risk factor treatment (Figure 2).

Figure 2

Examples of a stepwise approach to risk stratification and treatment options. ASCVD = atherosclerotic cardiovascular disease; CKD = chronic kidney disease; DM = diabetes mellitus; FH = familial hypercholesterolaemia; TOD = target organ damage.

Table 4

Patient categories and associated cardiovascular disease risk.

ACR = albumin-to-creatinine ratio: (to convert mg/g to mg/mmol: divide by 10); ACS = acute coronary syndromes; ADVANCE = Action in Diabetes and Vascular disease: preterAx and diamicroN-MR Controlled Evaluation; AMI = acute myocardial infarction; ASCVD = atherosclerotic cardiovascular disease; CKD = chronic kidney disease; CTA = computed tomography angiography; CV = cardiovascular; CVD = cardiovascular disease; DIAL = Diabetes lifetime-perspective prediction; DM = diabetes mellitus; FH = familial hypercholesterolaemia; eGFR = estimated glomerular filtration rate; IMT = intima-media thickness; LIFE-CVD = LIFEtime-perspective CardioVascular Disease; N/A = not applicable; PAD = peripheral artery disease; REACH = Reduction of Atherothrombosis for Continued Health; SBP = systolic blood pressure; SCORE = Systematic Coronary Risk Estimation; SMART = Secondary Manifestations of Arterial Disease; TIA = transient ischaemic attack.

3.2.3.1 A stepwise approach to risk factor treatment and treatment intensification

As explained before, targets and goals for LDL-C, BP, and glycaemic control in DM remain as recommended in recent ESC Guidelines.^3–5 These guidelines propose a stepwise approach to treatment intensification as a tool to help physicians and patients pursue these targets in a way that fits patient profiles and preferences. This principle (outlined in Figure 2, using the example of a stepwise approach) is not conceptually novel, but rather reflects routine clinical practice, in which treatment strategies are initiated and then intensified, both as part of a shared decision-making process involving healthcare professionals and patients.

A stepwise approach starts with prevention goals for all, regardless of CVD risk. This is followed by CVD risk stratification and discussion of potential benefits of treatment with the patient. If treatment is initiated, its effect must be evaluated, and subsequent treatment intensification to reach ultimate risk factor goals must be considered in all patients, taking into account additional benefit, comorbidities, and frailty, all of which converge with patient preferences in a shared decision-making process.

In the field of DM, studies have shown benefit of a stepwise approach to treatment intensification and do not support the contention of ‘therapeutic nihilism’ occurring in either physicians or patients. In fact, it appears that attainment of treatment goals is similar, side-effects are fewer, and patient satisfaction is significantly higher with such an approach.⁶⁶^,⁶⁷ We do, however, emphasize that stopping assessment of treatment goals and/or treatment routinely after the first step is inappropriate. The evidence-based ultimate targets of treatment intensification are optimal from the perspective of CVD risk reduction and are to be considered in all patients.

3.2.3.2 Risk estimation in apparently healthy people

Apparently healthy people are those without established ASCVD, type 2 DM, or severe comorbidities. In the 2016 ESC prevention guidelines,² the Systemic Coronary Risk Estimation (SCORE) algorithm was used to estimate 10-year risk of CVD death. However, CVD morbidity (non-fatal myocardial infarction, non-fatal stroke) combined with CVD mortality better reflects the total burden of ASCVD. The updated SCORE algorithm—SCORE2—used in these guidelines (see Figure 3), estimates an individual’s 10-year risk of fatal and non-fatal CVD events (myocardial infarction, stroke) in apparently healthy people aged 40–69 years with risk factors that are untreated or have been stable for several years.⁶⁸

Systematic Coronary Risk Estimation 2 and Systematic Coronary Risk Estimation 2-Older Persons risk charts for fatal and non-fatal (myocardial infarction, stroke) cardiovascular disease.68,72 ASCVD = atherosclerotic cardiovascular disease; CV = cardiovascular; CVD = cardiovascular disease; SBP = systolic blood pressure; HDL-C = high-density lipoprotein cholesterol; SCORE2 = Systematic Coronary Risk Estimation 2; SCORE2-OP = Systematic Coronary Risk Estimation 2-Older Persons; TFYR = The Former Yugoslav Republic; UK = United Kingdom. For apparently healthy people aged 40–69 years, the SCORE2 algorithm68 is used to estimate 10-year risk of fatal and non-fatal (myocardial infarction, stroke) CVD. For apparently healthy people ≥70 years of age, the SCORE2-OP is used.72. Low-risk countries: Belgium, Denmark, France, Israel, Luxembourg, Norway, Spain, Switzerland, the Netherlands, and the UK. Moderate-risk countries: Austria, Cyprus, Finland, Germany, Greece, Iceland, Ireland, Italy, Malta, Portugal, San Marino, Slovenia, and Sweden. High-risk countries: Albania, Bosnia and Herzegovina, Croatia, Czech Republic, Estonia, Hungary, Kazakhstan, Poland, Slovakia, and Turkey. Very-high-risk countries: Algeria, Armenia, Azerbaijan, Belarus, Bulgaria, Egypt, Georgia, Kyrgyzstan, Latvia, Lebanon, Libya, Lithuania, Montenegro, Morocco, Republic of Moldova, Romania, Russian Federation, Serbia, Syria, TFYR (Macedonia), Tunisia, Ukraine, and Uzbekistan.

Figure 3

Systematic Coronary Risk Estimation 2 and Systematic Coronary Risk Estimation 2-Older Persons risk charts for fatal and non-fatal (myocardial infarction, stroke) cardiovascular disease.⁶⁸^,⁷² ASCVD = atherosclerotic cardiovascular disease; CV = cardiovascular; CVD = cardiovascular disease; SBP = systolic blood pressure; HDL-C = high-density lipoprotein cholesterol; SCORE2 = Systematic Coronary Risk Estimation 2; SCORE2-OP = Systematic Coronary Risk Estimation 2-Older Persons; TFYR = The Former Yugoslav Republic; UK = United Kingdom. For apparently healthy people aged 40–69 years, the SCORE2 algorithm⁶⁸ is used to estimate 10-year risk of fatal and non-fatal (myocardial infarction, stroke) CVD. For apparently healthy people ≥70 years of age, the SCORE2-OP is used.⁷². Low-risk countries: Belgium, Denmark, France, Israel, Luxembourg, Norway, Spain, Switzerland, the Netherlands, and the UK. Moderate-risk countries: Austria, Cyprus, Finland, Germany, Greece, Iceland, Ireland, Italy, Malta, Portugal, San Marino, Slovenia, and Sweden. High-risk countries: Albania, Bosnia and Herzegovina, Croatia, Czech Republic, Estonia, Hungary, Kazakhstan, Poland, Slovakia, and Turkey. Very-high-risk countries: Algeria, Armenia, Azerbaijan, Belarus, Bulgaria, Egypt, Georgia, Kyrgyzstan, Latvia, Lebanon, Libya, Lithuania, Montenegro, Morocco, Republic of Moldova, Romania, Russian Federation, Serbia, Syria, TFYR (Macedonia), Tunisia, Ukraine, and Uzbekistan.

Several specific considerations apply to CVD risk estimation in older people. First, the gradient of the relationship between classical risk factors, such as lipids and BP, with CVD risk attenuates with age.⁶⁹ Second, CVD-free survival dissociates from overall survival progressively with increasing age, because risk for non-CVD mortality increases (‘competing risk’).⁷⁰ For these reasons, traditional risk models that do not take into account the competing risk of non-CVD mortality, tend to overestimate the actual 10-year risk of CVD, and hence overestimate the potential benefit of treatment.⁷¹ The SCORE2-OP algorithm estimates 5-year and 10-year fatal and non-fatal CVD events (myocardial infarction, stroke) adjusted for competing risks in apparently healthy people aged ≥70 years.⁷²

SCORE2 and SCORE2-OP are calibrated to four clusters of countries (low, moderate, high, and very high CVD risk) that are grouped based on national CVD mortality rates published by the WHO (Supplementary Table 3 and Figure 4).⁷³ Low-risk countries: Belgium, Denmark, France, Israel, Luxembourg, Norway, Spain, Switzerland, the Netherlands, and the United Kingdom (UK). Moderate-risk countries: Austria, Cyprus, Finland, Germany, Greece, Iceland, Ireland, Italy, Malta, Portugal, San Marino, Slovenia, and Sweden. High-risk countries: Albania, Bosnia and Herzegovina, Croatia, Czech Republic, Estonia, Hungary, Kazakhstan, Poland, Slovakia, and Turkey. Very high-risk countries: Algeria, Armenia, Azerbaijan, Belarus, Bulgaria, Egypt, Georgia, Kyrgyzstan, Latvia, Lebanon, Libya, Lithuania, Montenegro, Morocco, Republic of Moldova, Romania, Russian Federation, Serbia, Syria, The Former Yugoslav Republic (Macedonia), Tunisia, Ukraine, and Uzbekistan. A multiplier approach has been used for converting CVD mortality rates to fatal and non-fatal CVD events.⁷⁴ The SCORE2 algorithm can be accessed in the ESC CVD Risk app (freely available from app stores) and in risk charts for the four clusters of countries (Figure 4). The SCORE2 charts do not apply to persons with documented CVD or other high-risk conditions such as DM, FH, or other genetic or rare lipid or BP disorders, CKD, and in pregnant women.

Risk regions based on World Health Organization cardiovascular mortality rates.68,72,73

Figure 4

Risk regions based on World Health Organization cardiovascular mortality rates.⁶⁸^,⁷²^,⁷³

To estimate a person’s 10-year risk of total CVD events, one must first identify the correct cluster of countries and the accompanying risk table for their sex, smoking status, and (nearest) age. Within that table, one then finds the cell nearest to the person’s BP and non-HDL-C. Risk estimates then need to be adjusted upwards as the person approaches the next age category.

3.2.3.3 Translating cardiovascular disease risk to treatment thresholds

While no risk threshold is universally applicable, the intensity of treatment should increase with increasing CVD risk. In individual cases, however, no lower threshold of total CVD risk precludes treatment of risk factors. Conversely, no high threshold for total CVD risk implies ‘mandatory’ treatment. Across the entire range of CVD risk, the decision to initiate interventions remains a matter of individual consideration and shared decision-making (see also section 4.1). In general, risk factor treatment recommendations are based on categories of CVD risk (‘low-to-moderate’, ‘high’, and ‘very high’). The cut-off risk levels for these categories are numerically different for various age groups to avoid undertreatment in the young and to avoid overtreatment in older persons. As age is a major driver of CVD risk, but lifelong risk factor treatment benefit is higher in younger people, the risk thresholds for considering treatment are lower for younger people (Table 5).

Table 5

Cardiovascular disease risk categories based on SCORE2 and SCORE2-OP in apparently healthy people according to age

<50 years

50–69 years

≥70 years^a

Low-to-moderate CVD risk: risk factor treatment generally not recommended

<2.5%

<5%

<7.5%

High CVD risk: risk factor treatment should be considered

2.5 to <7.5%

5 to <10%

7.5 to <15%

Very high CVD risk: risk factor treatment generally recommended^a

≥7.5%

≥10%

≥15%

CVD = cardiovascular disease.

a

In apparently healthy people ≥70 years old, the treatment recommendation for lipid-lowering drugs is Class IIb (‘may be considered’).

The division of the population into three distinct age groups (<50, 50–69, and ≥70 years) results in a discontinuous increase in risk thresholds for low-to-moderate, high, and very high risk. In reality, age is obviously continuous, and a sensible application of the thresholds in clinical practice would require some flexibility in handling these risk thresholds as patients move towards the next age group, or recently passed the age cut-off. Figure 5 illustrates how a continuous increase in age relates to increasing risk thresholds, and may be used as a guide for daily practice.

Figure 5

Schematic representation of increasing 10-year cardiovascular disease risk thresholds across age groups. CVD = atherosclerotic cardiovascular disease.

Risk categories do not ‘automatically’ translate into recommendations for starting drug treatment. In all age groups, consideration of risk modifiers, lifetime CVD risk, treatment benefit, comorbidities, frailty, and patient preferences may further guide treatment decisions.

Also, note that many patients can move themselves towards a lower risk category without taking drugs just by stopping smoking. Finally, note that persons ≥70 years old may be at very high risk whilst being at target SBP, and primary prevention with lipid-lowering drugs in older persons is a Class IIb (‘may consider’) recommendation; see section 4.6.

In the 50–69-year age range, a 10-year CVD mortality risk threshold of 5% estimated with the previously used SCORE algorithm corresponds, on average, to a 10-year fatal and non-fatal CVD risk threshold of 10% estimated with SCORE2, as approximately the same number of people are above the risk threshold and would qualify for treatment.⁶⁸

As the 10-year CVD risk thresholds guide treatment decisions and have an impact on healthcare costs and resources, countries or regions may decide on using higher or lower treatment thresholds.

3.2.3.4 Risk estimation and risk factor treatment in apparently healthy people 50–69 years of age

Stopping smoking, lifestyle recommendations, and SBP <160 mmHg are recommended for all (Figure 6). A 10-year CVD risk (fatal and non-fatal ASCVD events) ≥10% is generally considered ‘very high risk’, and treatment of CVD risk factors is recommended. A 10-year CVD risk of 5 to <10% is considered ‘high risk’, and treatment of risk factors should be considered, taking CVD risk modifiers, lifetime risk and treatment benefit (in low- and moderate-risk regions, Box 1), and patient preferences into account. A 10-year CVD risk <5% is considered ‘low-to-moderate risk’, and would generally not qualify for risk factor treatment unless one or several risk modifiers (see section 3.3) increase risk, or the estimated lifetime risk and treatment benefit is considered substantial.

Figure 6

Flow chart of cardiovascular disease risk and risk factor treatment in apparently healthy persons. ASCVD = atherosclerotic cardiovascular disease; CKD = chronic kidney disease; CVD = cardiovascular disease; DM = diabetes mellitus; ESC = European Society of Cardiology; FH = familial hypercholesterolaemia; LDL-C = low-density lipoprotein cholesterol; LIFE-CVD = LIFEtime-perspective CardioVascular Disease; SBP = systolic blood pressure; SCORE2 = Systematic Coronary Risk Estimation 2; SCORE2-OP = Systematic Coronary Risk Estimation 2-Older Persons. Solid lines represent default options for the majority of people. Dotted lines represent alternative choices for some, depending on the patient-specific characteristics and conditions indicated in the boxes. Ultimate treatment goals for SBP (<130 mmHg) and LDL-C (according to level of risk) according to the respective ESC Guidelines are to be pursued as indicated. The stepwise approach has to be applied as a whole: after STEP 1, considering proceeding to the intensified goals of STEP 2 is mandatory. Risk scores are available in the ESC CVD Risk Calculator app for mobile devices (https://www.escardio.org/Education/ESC-Prevention-of-CVD-Programme/Risk-assessment/esc-cvd-risk-calculation-app) and at websites such as https://www.u-prevent.com. ^aDoes not include patients with CVD, DM, CKD, or FH. ^bThe LIFE-CVD model for estimating lifetime CVD risk and treatment benefit is calibrated for low- and moderate-risk regions (see Box 1).

3.2.3.5 Risk estimation and risk factor treatment estimation in apparently healthy people ≥70 years of age

Stop smoking, lifestyle recommendations and a SBP <160 mmHg are recommended for all (Figure 6). Age is the dominant driver of CVD risk, and estimated 10-year CVD risk of almost all individuals ≥70 years exceeds conventional risk thresholds. Also, lifetime benefit of treatment in terms of time gained free of CVD is lower in older people. Therefore, the CVD risk thresholds for risk factor treatment are higher in apparently healthy people ≥70 years. A 10-year CVD risk >15% is generally considered ‘very high risk’, and treatment of ASCVD risk factors is recommended (note: the recommendation for lipid-lowering treatment in apparently healthy people ≥70 years is class IIb; ‘may be considered’; see section 4.6). A 10-year CVD risk of 7.5 to <15% is considered ‘high risk’, and treatment of risk factors should be considered taking CVD risk modifiers, frailty, lifetime treatment benefit (in low and moderate risk regions, Box 1), comorbidities, polypharmacy, and patient preferences into account. Given the subjective nature of many of these factors, it is not possible to define strict criteria for these considerations. A 10-year CVD risk <7.5% is considered ‘low-to-moderate risk’, and would generally not qualify for risk factor treatment unless one or several risk modifiers (section 3.3) increase risk or the estimated lifetime risk and treatment benefit is considered substantial.^75–79

3.2.3.6 Risk estimation and risk factor treatment in apparently healthy people <50 years of age

Stopping smoking, lifestyle recommendations, and SBP <160 mmHg are recommended for all (Figure 6). The 10-year CVD risk in relatively young, apparently healthy people is on average low, even in the presence of high risk factor levels, but the lifetime CVD risk is in these circumstances very high. In apparently healthy people <50 years of age, a 10-year CVD risk ≥7.5% is generally considered ‘very high risk’ as this risk relates to a high lifetime risk, and treatment of ASCVD risk factors is recommended. A 10-year CVD risk of 2.5 to <7.5% is considered ‘high risk’, and treatment of risk factors should be considered, taking CVD risk modifiers, lifetime risk and treatment benefit (in low- and moderate-risk regions), and patient preferences into account. A 10-year CVD risk <2.5% is considered ‘low-to-moderate risk’, and would generally not qualify for risk factor treatment unless one or several risk modifiers (see section 3.3) increase risk or the estimated lifetime risk and treatment benefit is considered substantial (see Box 1) (Figure 6).^75–78

In risk communication with younger people, the lifetime benefit perspective may be useful, as well as discussing the potential of avoiding a devastating CVD event in the short-to-intermediate term, despite the fact that 10-year CVD risk may be very low.

CVD risk predictions, as well as predictions of lifetime benefit of risk factor treatment, are likely to be imprecise at very young age (<40 years). At that age, lipid-lowering and BP-lowering drug treatment are not usually considered, except for patients with FH or specific BP disorders. A healthy lifestyle that is maintained throughout life is more relevant for the very young. Mendelian randomization studies illustrate very nicely that relatively small differences in LDL-C or SBP maintained throughout life have large implications on CVD risk over a lifespan.⁸⁰

3.2.3.7 Risk estimation and risk factor treatment in patients with established atherosclerotic cardiovascular disease

Patients with clinically established ASCVD are, on average, at very high risk of recurrent CVD events if risk factors are not treated. Therefore, smoking cessation, adoption of a healthy lifestyle, and risk factor treatment is recommended in all patients (STEP 1). Further intensification of risk factor treatment by aiming at lower treatment goals (STEP 2) is beneficial in most patients and must be considered, taking 10-year CVD risk, comorbidities, lifetime risk and treatment benefit (Box 1), frailty, and patient preferences into account in a shared decision-making process (Figure 7).

Box 1. Lifetime CVD risk and treatment benefit estimation

Prevention of CVD by treating risk factors is usually done with a lifetime perspective. Lifetime CVD risk can be approximated by clinical experience with clinical criteria such as age, (change in) risk factor levels, risk modifiers, etc. or estimated in apparently healthy people, patients with established ASCVD, and persons with type 2 DM with specific lifetime CVD risk scores.^75–77 Lifetime benefit from risk factor management can be estimated by combining lifetime risk models with HRs derived from RCTs, meta-analyses of RCTs, or Mendelian randomization studies, which may provide estimates of the effects of longer-term treatment of risk factors. Online calculators (such as the ESC CVD Risk app) can be used to estimate the average lifetime benefit of smoking cessation (see also Figure 11), lipid lowering (see also Figure 12), and BP lowering (see also Figure 15) on an individual patient level expressed as extra CVD-free life-years.⁷⁸ Average lifetime benefit is easy to interpret and may improve the communication of potential therapy benefits to patients in a shared decision-making process. This may in turn increase patient engagement, self-efficacy, and motivation to adhere to lifestyle changes and drug treatment.

The lifetime risk is an estimate of the age at which there is a 50% probability that a person will either have experienced a CVD event or have died. Lifetime benefit is the numerical difference between the predicted age at which there is a 50% probability that a person will either have experienced a CVD event or have died with and without a proposed treatment. Currently there are no formal treatment thresholds for average lifetime benefit. In addition, the estimated individual lifetime benefit should be viewed in the light of the estimated duration of treatment. Duration of lifelong treatment will generally be longer in young persons compared to older people. Both treatment effect and treatment duration determine the individual ‘return on investment’ of risk factor treatment. In a shared decision-making process between healthcare provider and patient, the minimum desired benefit of a certain treatment needs to be established, a process in which patient preference, expected treatment harms, and costs can be taken into account.

BP = blood pressure; CVD = cardiovascular disease; DM = diabetes mellitus; ESC = European Society of Cardiology; HR = hazard ratio; RCT = randomized controlled trial.

Figure 7

Flow chart of cardiovascular risk and risk factor treatment in patients with established atherosclerotic cardiovascular disease. Ultimate treatment goals for SBP (<130 mmHg) and LDL-C (according to level of risk) according to the respective ESC Guidelines³^,⁴ are to be pursued as indicated. The stepwise approach has to be applied as a whole: after STEP 1, considering proceeding to the intensified goals of STEP 2 is mandatory. ACS = acute coronary syndromes; ASCVD = atherosclerotic cardiovascular disease; CR = cardiac rehabilitation; CVD = cardiovascular disease; DAPT = dual antiplatelet therapy; DM = diabetes mellitus; ESC = European Society of Cardiology; EUROASPIRE = European Action on Secondary and Primary Prevention by Intervention to Reduce Events; LDL-C = low-density lipoprotein cholesterol; SBP = systolic blood pressure; SMART = Secondary Manifestations of Arterial Disease. Risk scores are available in the ESC CVD Risk Calculator app for mobile devices (https://www.escardio.org/Education/ESC-Prevention-of-CVD-Programme/Risk-assessment/esc-cvd-risk-calculation-app) and at websites such as https://www.u-prevent.com. ^aFor patients with DM see DM flow chart (Figure 8). ^bFor patients with recent ACS, these prevention goals are part of participation in CR (Class I/A). ^cFor patients aged ≥70 years, a high 10-year risk may be associated with a lower absolute lifetime benefit from treatment due to limited life expectancy. ^dLifetime treatment benefit is expressed as extra CVD-free life gained from a certain intervention or treatment intensification.

After initial risk factor treatment and the achievement of risk factor treatment goals, the individual residual risk for recurrent CVD varies widely and should be considered.⁸¹ It is evident that patients with a recent ACS or progressive vascular disease, and patients with DM and vascular disease, are all at exceptionally high risk for recurrent CVD events. For other patients with established ASCVD, the residual risk may be less evident and could be estimated based on clinical criteria such as age, (change in) risk factor levels, and risk modifiers, or by calculation of residual CVD risk with a calculator.

The risk of recurrent CVD is influenced mainly by classical risk factors, vascular disease site, and kidney function. Risk stratification tools for secondary prevention include the SMART (Secondary Manifestations of Arterial Disease) risk score (available in the ESC CVD Risk app) for estimating 10-year residual CVD risk in patients with stable ASCVD, defined as CAD, PAD, or cerebrovascular disease,⁸¹ and the European Action on Secondary and Primary Prevention by Intervention to Reduce Events (EUROASPIRE) risk model, which estimates 2-year risk of recurrent CVD in patients with stable CAD.⁸²

Occasionally, recurrent CVD risk is very high despite maximum (tolerated) conventional treatments. In such cases, novel but less well-established preventive treatments such as dual antithrombotic pathway inhibition,⁸³ icosapent ethyl,⁸⁴ or anti-inflammatory therapy with colchicine (see section 4.10)⁸⁵^,⁸⁶ may be considered.

3.2.3.8 Risk estimation and risk factor treatment in persons with type 2 diabetes mellitus

Most adults with type 2 DM are at high or very high risk for future CVD, particularly from middle age onwards. On average, type 2 DM doubles CVD risk and reduces life expectancy by 4 − 6 years, with absolute risks highest in those with any target organ damage (TOD). Type 2 DM also increases the risk for cardiorenal outcomes, in particular HF and CKD. Relative risks (RRs) for CVD in type 2 DM are higher at younger ages of onset and are modestly higher in women compared with men.⁸⁷ Smoking cessation and adoption of a healthy lifestyle are recommended for all people with type 2 DM, and risk factor treatment should be considered in all people with DM, at least those above the age of 40 years (see sections 4.6 and 4.7). Still, there is a wide range in individual risk for CVD events, especially after initial risk factor management.⁸⁸

Persons with DM with severe TOD (for definition: see Table 4) can be considered to be at very high CVD risk, similar to people with established CVD (see Table 4). Most others with DM are considered to be at high ASCVD risk.⁶⁴ However, an exception can be made for patients with well-controlled short-standing DM (e.g. <10 years), no evidence of TOD, and no additional ASCVD risk factors, who may be considered as being at moderate CVD risk.

In addition to the semi-quantitative division into three risk categories described above, DM-specific risk models may refine risk estimates and illustrate the impact of treatments. These models generally include duration of DM, glycated haemoglobin (HbA1c) level, and presence of TOD. Examples are the ADVANCE (Action in Diabetes and Vascular disease: preterAx and diamicroN-MR Controlled Evaluation) risk score, which predicts 10-year CVD risk, and the UKPDS (UK Prospective Diabetes Study) risk engine, which predicts fatal and non-fatal CVD risk and is available for use in the UK. However, we recommend cautious use of these calculators, since both are based on older cohort data⁸⁹^,⁹⁰ (Figure 8).

Recommendations for CVD risk estimation

ASCVD = atherosclerotic cardiovascular disease; BP = blood pressure; CKD = chronic kidney disease (see definition in Table 4); DM = diabetes mellitus; SCORE2 = Systemic Coronary Risk Estimation 2; SCORE2-OP = Systemic Coronary Risk Estimation 2-Older Persons.

a

Class of recommendation.

b

Level of evidence.

Intensification of risk factor treatment in STEP 2 must be considered in all patients, taking into account 10-year CVD risk, comorbidities, lifetime risk and treatment benefit (Box 1), frailty, and patient preferences in a shared decision-making process.⁷⁵

3.2.3.9 Risk estimation and risk factor treatment in persons with type 1 diabetes mellitus

People with type 1 DM are at increased CVD risk, and earlier manifestation of type 1 DM relates to more life-years lost in women than men, mostly due to CVD.⁹¹ RRs of CVD are, on average, higher in type 1 vs. type 2 DM, due to an average of three to four extra decades of hyperglycaemia, and usual risk factors contribute strongly to CVD outcomes in type 1 DM.⁹² CVD risks have declined over time, commensurate with improvements in life expectancy.⁹³ Lifetime CVD risks in type 1 DM are higher with poorer glycaemic control, lower social class, and younger age of onset. The absolute risk of CVD events or CVD mortality is highest among those with any evidence of microvascular disease, particularly renal complications, and is strongly influenced by age. CVD risk stratification in persons with type 1 DM may be based on the same risk classification as for type 2 DM, summarized in Table 4, although the level of evidence for type 1 DM is weaker.

3.2.4. Communication of cardiovascular disease risk

Reducing CVD risk at the individual level begins with appropriate assessment of individual risk and effective communication of risk and anticipated risk reduction by risk factor treatment. Patient−doctor interactions are complex and communicating risk is challenging.⁹⁴^,⁹⁵ There is no single ‘correct’ approach; rather, it will depend on the individual’s preferences and understanding, which may differ with education status and numeracy. Risk perception is also strongly affected by emotional factors such as fear, optimism, etc. (‘patients don’t think risk, they feel risk’).⁹⁶

It is important to explore whether patients understand their risk, the anticipated risk reduction, and the pros and cons of intervention, and to identify what is important to them. For example, one patient may focus on living free of medications, whereas another may be less able to change their lifestyle. In terms of outcomes, reducing mortality risk is crucial to some, whereas disease risk is more important to others. Short-term risk may motivate some patients, whereas lifetime benefit (see Box 1) will have more impact in others. In general, visual aids (graphs etc.) improve risk understanding, absolute risk (reduction) is better understood than RR (reduction), and the use of ‘numbers needed to treat’ is less well understood.

In apparently healthy people, the standard approach is to report absolute 10-year risk of a CVD event with SCORE2 or SCORE2-OP, which can be found at the ESC CVD Risk Calculator app (https://www.escardio.org/Education/ESC-Prevention-of-CVD-Programme/Risk-assessment/esc-cvd-risk-calculation-app) or at http://www.heartscore.org or https://www.u-prevent.com. In specific situations, one may opt for expressing risk in terms other than absolute 10-year risk. Examples of such situations include risks in young or very old people. In young people, lifetime risk might be more informative, as 10-year CVD risk is usually low even in the presence of risk factors. In older persons, specific risk estimation is required, taking competing non-CVD mortality into account.⁷⁸ Direct translation of RRs to treatment decisions is not recommended, as absolute risk remains the key criterion for starting treatment.

Recommendation for CVD risk communication

CVD = cardiovascular disease.

a

Class of recommendation.

b

Level of evidence.

Recommendations for CVD risk modifiers

CVD = cardiovascular disease; CAC = coronary artery calcium; RR = relative risk.

a

Class of recommendation.

b

Level of evidence.

An alternative way of expressing individual risk is to calculate a person’s ‘risk age’.⁹⁶ The risk age of a person with several ASCVD risk factors is the age of a person of the same sex with the same level of risk but with low levels of risk factors. Risk age is an intuitive and easily understood way of illustrating the likely reduction in life expectancy that a young person with a low absolute but high RR of CVD will be exposed to if preventive measures are not adopted. Risk age is also automatically calculated as part of HeartScore (http://www.heartscore.org/).^97–99

CVD risk may also be expressed with a lifetime rather than a 10-year horizon, for example, the LIFE-CVD (LIFEtime-perspective CardioVascular Disease) calculator (ESC CVD Risk Calculation app or https://www.u-prevent.com) (also see Box 1).⁷⁸ Lifetime CVD risk-prediction models identify high-risk individuals both in the short and long term. Such models account for predicted risk in the context of competing risks from other diseases over the remaining expected lifespan of an individual. A similar approach also employing lifetime perspective is to calculate lifetime benefit of preventive interventions.⁷⁸ Lifetime benefit of preventive interventions can be expressed as gain in CVD-free life (years), which is easier to communicate to a patient and may support the shared decision-making process.

3.3. Potential risk modifiers

Apart from the conventional CVD risk factors included in the risk charts, additional risk factors or types of individual information can also modify calculated risk. Assessment of a potential modifier may be considered if:

It improves measures of risk prediction, such as discrimination or reclassification (e.g. by calculation of net reclassification index)
Public health impact is clear (e.g. number needed to screen or net benefit)
It is feasible in daily practice
Information is not just available on how risk increases with an unfavourable result, but also on how risk decreases if the modifier shows a favourable result
The literature on this potential modifier is not distorted by publication bias.

Very few potential modifiers meet all of these criteria. Meta-analyses in this field are, for example, susceptible to substantial publication bias.¹⁰⁶ Also, the exact way of integrating additional information on top of regular risk calculator input parameters is mostly unknown. Finally, RCTs to determine whether the added risk information eventually leads to improved health outcomes are generally lacking.

Assessment of potential risk modifiers seems particularly relevant if the individual’s risk is close to a decision threshold. In low-risk or very-high-risk situations, additional information is less likely to alter management decisions. The number of individuals in this ‘grey zone’ is large. Therefore, feasibility becomes a limitation as modifiers become more complex or expensive, such as some imaging techniques.

Care should be taken not to use risk modifiers solely to increase risk estimates when the modifier profile is unfavourable, but also vice versa. Although an unfavourable risk modifier may increase an individual’s estimated risk, a more favourable profile than would be expected based on other patient characteristics must have the opposite effect. Finally, it is important to acknowledge that the degree to which calculated absolute risk is affected by modifiers is generally much smaller than the (independent) RRs reported for these modifiers in the literature.¹⁰⁷

Taking the above into account, we summarize the literature on several popular risk modifiers in this section.

3.3.1. Psychosocial factors

Psychosocial stress is associated, in a dose-response pattern, with the development and progression of ASCVD, independently of conventional risk factors and sex. Psychosocial stress includes stress symptoms (i.e. symptoms of mental disorders), as well as stressors such as loneliness and critical life events. The RRs of psychosocial stress are commonly between 1.2 and 2.0¹⁰⁸^,¹⁰⁹ (Supplementary Table 4). Conversely, indicators of mental health, such as optimism and a strong sense of purpose, are associated with lower risk.¹⁰⁹ Psychosocial stress has direct biological effects, but is also highly correlated with socioeconomic and behavioural risk factors (e.g. smoking, poor adherence).¹⁰⁰^,^109–113 Although the associations of psychosocial stress with CV health are robust, only ‘vital exhaustion’ has been proven to improve risk reclassification.¹⁰¹ Owing to the importance of stress symptoms among ASCVD patients, several guidelines and scientific statements recommend screening of ASCVD patients for psychological stress^113–115 (Box 2 and Supplementary Table 5). A recent prospective cohort study with a median follow-up of 8.4 years reported favourable effects of screening for depression on major ASCVD events.¹⁰²

Box 2. Core topics for psychosocial assessment

Simultaneous diagnostic assessment At least one in five patients carries a diagnosis of a mental disorder, usually presenting with bodily symptoms (e.g. chest tightness, shortness of breath). Therefore, physicians should be equally attentive to somatic as to emotional causes of symptoms.

Screening Screening instruments assessing depression, anxiety, and insomnia are recommended (e.g. Patient Health Questionnaire,¹¹⁶ see Supplementary Table 5).¹¹⁷^,¹¹⁸

Stressors There are simple questions to get into a conversation about significant stressors¹¹²: Are you bothered by stress at work, financial problems, difficulties in the family, loneliness, or any stressful events?

Need for mental health support Are you interested in a referral to a psychotherapist or mental health service?

3.3.2. Ethnicity

Europe includes many citizens whose ethnic background originates in countries such as India, China, North Africa, and Pakistan. Given the considerable variability in ASCVD risk factors between immigrant groups, no single CVD risk score performs adequately in all groups. Rather, the use of a multiplying factor would be helpful to take account of CVD risk imposed by ethnicity independent of other risk factors in the risk score. The most contemporary relevant data come from the QRISK3 findings in the UK,¹⁰⁵ although this focuses on a wider range of CVD outcomes and not simply on CVD mortality.

Immigrants from South Asia (notably India and Pakistan) present higher CVD rates independent of other risk factors, whereas adjusted CVD risks appear lower in most other ethnic groups. The reasons for such differences remain inadequately studied, as do the risks associated with other ethnic backgrounds. Based on such data, the following correction factors, based on data from the UK, could be applied when assessing CVD risk using risk calculators.¹⁰⁵ Ideally, country and risk-calculator-specific RRs should be used, as the impact of ethnicity may vary between regions and risk calculators.

Southern Asian: multiply the risk by 1.3 for Indians and Bangladeshis, and 1.7 for Pakistanis.
Other Asian: multiply the risk by 1.1.
Black Caribbean: multiply the risk by 0.85.
Black African and Chinese: multiply the risk by 0.7.

3.3.3. Imaging

3.3.3.1 Coronary artery calcium

Coronary artery calcium (CAC) scoring can reclassify CVD risk upwards and downwards in addition to conventional risk factors, and may thus be considered in men and women with calculated risks around decision thresholds.¹⁰³^,¹⁰⁴ Availability and cost-effectiveness of large-scale CAC scanning must, however, be considered in a locoregional context (see section 2.3 on cost-effectiveness). If CAC is detected, its extent should be compared with what would be expected for a patient of the same sex and age. Higher-than-expected CAC increases the person’s calculated risk, whereas absent or lower-than-expected CAC is associated with lower than calculated risk. CAC scoring does not provide direct information on total plaque burden or stenosis severity, and can be low or even zero in middle-aged patients with soft non-calcified plaque. Clinicians are advised to consult existing protocols for details of how to assess and interpret CAC scores.

3.3.3.2 Contrast computed tomography coronary angiography

Contrast computed tomography angiography (CCTA) allows identification of coronary stenoses and predicts cardiac events.¹¹⁹ In the SCOT-HEART (Scottish Computed Tomography of the Heart) study, 5-year rates of coronary death or myocardial infarction were reduced when CCTA was used in patients with stable chest pain.¹²⁰ The relative reduction in myocardial infarction was similar in patients with non-cardiac chest pain. Whether CCTA improves risk classification or adds prognostic value over CAC scoring is unknown.

3.3.3.3 Carotid ultrasound

Systematic use of intima-media thickness (IMT) to improve risk assessment is not recommended due to the lack of methodological standardization, and the absence of added value of IMT in predicting future CVD events, even in the intermediate-risk group.¹²¹

Plaque is defined as the presence of a focal wall thickening that is ≥50% greater than the surrounding vessel wall, or as a focal region with an IMT measurement ≥1.5 mm that protrudes into the lumen.¹²² Although the evidence is less extensive than it is for CAC, carotid artery plaque assessment using ultrasonography probably also reclassifies CVD risk,¹⁰⁴^,¹²² and may be considered as a risk modifier in patients at intermediate risk when a CAC score is not feasible.

3.3.3.4 Arterial stiffness

Arterial stiffness is commonly measured using either aortic pulse wave velocity or arterial augmentation index. Studies suggest that arterial stiffness predicts future CVD risk and improves risk classification.¹²³ However, measurement difficulties and substantial publication bias¹⁰⁶ argue against widespread use.

3.3.3.5 Ankle brachial index

Estimates are that 12–27% of middle-aged individuals have an ankle brachial index (ABI) <0.9, around 50–89% of whom do not have typical claudication.¹²⁴ An individual patient data meta-analysis concluded that the reclassification potential of ABI was limited, perhaps with the exception of women at intermediate risk.¹²⁵

3.3.3.6 Echocardiography

In view of the lack of convincing evidence that it improves CVD risk reclassification, echocardiography is not recommended to improve CV risk prediction.

3.3.4.Frailty

Frailty is a multidimensional state, independent of age and multimorbidity, that makes the individual more vulnerable to the effect of stressors. It constitutes a functional risk factor for unfavourable outcomes, including both high CV and non-CV morbidity and mortality.¹²⁶^,¹²⁷

Frailty is not the same as ageing and the two should not be confused. The incidence of frailty increases with age, but people of the same chronological age can differ significantly in terms of health status and vitality. ‘Biological age’ is much more important in the context of clinical status (including frailty features) and hard clinical outcomes (including CVD events).¹²⁶^,¹²⁷ Similarly, although the presence of comorbidities can exacerbate frailty within an individual, frailty is not the same as multimorbidity (see section 6.7).

Frailty screening is indicated in every elderly patient, but should also be performed in every individual regardless of his/her age, when being at risk of accelerated ageing.¹²⁶^,¹²⁷ Most of the tools relate to frail features, including slowness, weakness, low physical activity (PA), exhaustion, and shrinking (e.g. Fried scale, Short Physical Performance Battery, Rockwood Clinical Frailty Scale, handgrip strength, gait speed).^126–129 Frailty assessment is important at each stage of an ASCVD trajectory. During an acute CVD event, however, frailty assessment is more difficult, and either relies on history taking or should be postponed to when patients return to a stable condition.

Frailty is a potential modifier of global CVD risk. The impact of frailty on CVD risk has been demonstrated across the spectrum of ASCVD, including people with ASCVD risk factors, patients with subclinical ASCVD, stable ASCVD, acute cerebral and coronary syndromes, and HF,^126–130 with frailty itself rather than classical CVD risk factors predicting both all-cause and CVD mortality in the very old.¹³⁰^,¹³¹ Importantly, the ability of frailty measures to improve CVD risk prediction has not been formally assessed. Hence, we do not recommend that frailty measures are integrated into formal CVD risk assessment.

Importantly, frailty may influence treatment. Non-pharmacological interventions (e.g. balanced nutrition, micronutrient supplementation, exercise training, social activation) aiming to prevent, attenuate, or reverse frailty are of utmost importance.¹²⁶^,¹²⁷^,¹³² In terms of pharmacotherapy and device implantations, frailty assessment is not a method to determine the eligibility for any particular treatment, but rather serves to build an individualized care plan with predefined priorities. Frail individuals often have comorbidities, polypharmacy, and may be more susceptible to drug side-effects and serious complications during invasive and surgical procedures.¹²⁶^,¹²⁷

3.3.5. Family history

Family history of premature CVD is a simple indicator of CVD risk, reflecting the genetic and environment interplay.¹³³ In the few studies that simultaneously assessed the effects of family history and genetics, family history remained significantly associated with CVD after adjusting for genetic scores.¹³⁴^,¹³⁵ However, family history only marginally improves the prediction of CVD risk beyond conventional ASCVD risk factors.^136–141 Possible explanations are the varying definitions of family history applied and that conventional ASCVD risk factors largely explain the impact of family history.

A family history of premature CVD is simple, inexpensive information that can trigger comprehensive risk assessment in individuals with a family history of premature CVD.¹³⁶

3.3.6. Genetics

The aetiology of ASCVD has a genetic component, but this information is not currently used in preventive approaches.¹⁴² Advances on polygenic risk scores for risk stratification could increase the use of genetics in prevention.^143–145 For ASCVD, there is, however, a lack of consensus regarding which genes and corresponding single nucleotide polymorphisms should be included, and whether to use risk factor-specific or outcome-specific polygenic risk scores.¹⁴⁶ Polygenic risk scoring has shown some potential to improve ASCVD risk prediction for primary prevention,^147–149 but the incremental prediction accuracy is relatively modest and needs further evaluation in both men and women.¹⁵⁰^,¹⁵¹ Additional evidence is also needed to evaluate the clinical utility of polygenic risk scores in other clinical settings, such as in patients with pre-existing ASCVD.¹⁵²

3.3.7. Socioeconomic determinants

Low socioeconomic status and work stress are independently associated with ASCVD development and prognosis in both sexes.¹⁵³^,¹⁵⁴ The strongest association has been found between low income and CVD mortality, with a RR of 1.76 [95% confidence interval (CI) 1.45–2.14].¹⁵⁵ Work stress is determined by job strain (i.e. the combination of high demands and low control at work) and effort−reward imbalance. There is preliminary evidence that the detrimental impact of work stress on ASCVD health is independent of conventional risk factors and their treatment.¹⁵⁶

3.3.8. Environmental exposure

Environmental exposures with CVD risk modifying potential include air and soil pollution as well as above-threshold noise levels. Evaluating individual cumulative exposure to pollutants and noise remains challenging, but when available, might impact on individual risk assessment.

Components of outdoor air pollution include airborne particulate matter [PM; ranging in size from coarse particles 2.5–10 µm in diameter, to fine (<2.5 µm; PM_2.5), and ultrafine (<0.1 µm)] and gaseous pollutants (e.g. ozone, nitrogen dioxide, volatile organic compounds, carbon monoxide, sulphur dioxide), produced primarily by combustion of fossil fuels. Soil and water pollutions are also CVD risk modifiers; increased exposure to lead, arsenic, and cadmium is associated with multiple CVD outcomes including hypertension, coronary heart disease (CHD), stroke, and CVD mortality.¹⁵⁷ Ambient PM pollution recently ranked as a leading modifiable mortality risk factor and also responsible for attributable disability adjusted life-years at the global level.¹⁵⁸ A recent model estimated that loss of life expectancy due to ambient air pollution is similar to, if not exceeding, that due to tobacco smoking, and accounts for a global excess mortality estimated at 8.8 million/year.¹⁵⁹

The short-term attributable effects on mortality are linked primarily to exposure to PM, nitrogen dioxide, and ozone, with an average 1.0% increase of all-cause mortality for an increment of 10 μg/m³ in exposure to PM_2.5; the long-term effects are associated mainly with PM_2.5. The evidence linking exposure to PM and CVD events is based on large-scale epidemiological studies and experimental studies. Associations with ASCVD mortality vary, but the majority of cohort studies link long-term air pollution with an increased risk of fatal or non-fatal CAD, and with subclinical atherosclerosis. Evidence suggests that reduction of PM_2.5 is associated with improvements in inflammation, thrombosis, and oxidative stress, and a decrease in death from ischaemic heart disease.³⁸^,¹⁶⁰^,¹⁶¹ As sufficiently precise individual exposure estimates are hard to obtain, formal risk reclassification is difficult to quantify at present.

Recommendations for cardiovascular disease risk related to air pollution

CVD = cardiovascular disease.

a

Class of recommendation.

b

Level of evidence.

3.3.9. Biomarkers in blood or urine

Many biomarkers have been suggested to improve risk stratification. Some may be causal [e.g. lipoprotein(a), reflecting a pathogenic lipid fraction], whereas others may reflect underlying mechanisms (e.g. C-reactive protein reflecting inflammation) or indicate early cardiac damage (e.g. natriuretic peptides or high-sensitivity cardiac troponin).

In the 2016 Guidelines,² we recommended against the routine use of biomarkers because most do not improve risk prediction, and publication bias seriously distorts the evidence.¹⁰⁶^,¹⁶² New studies confirm that C-reactive protein has limited additional value.¹⁰³ There is renewed interest in lipoprotein(a), but it too provides limited additional value in terms of reclassification potential.¹⁶³^,¹⁶⁴ Cardiac biomarkers are promising,¹⁶⁵^,¹⁶⁶ but further work is needed.

3.3.10. Body composition

Worldwide, BMI has increased substantially in recent decades, in children, adolescents, and adults.⁴³ In observational studies, all-cause mortality is minimal at a BMI of 20 − 25 kg/m², with a J- or U-shaped relation in current smokers.⁴⁵^,⁴⁶ Mendelian randomization analyses suggest a linear relation between BMI and mortality in never-smokers and a J-shaped relation in ever-smokers.⁴⁴ A meta-analysis concluded that both BMI and waist circumference are similarly strongly and continuously associated with ASCVD in the elderly and the young and in men and women.⁴⁷

Among those with established ASCVD, the evidence is contradictory. Systematic reviews of patients with ACS or HF have suggested an ‘obesity paradox’ whereby obesity appears protective.¹⁶⁷^,¹⁶⁸ ¹⁶⁹ However, this evidence should be interpreted with caution as reverse causality and other biases may be operating.⁴⁵

3.3.10.1 Which index of obesity is the best predictor of cardiovascular risk?

BMI can be measured easily and is used extensively to define categories of body weight (see Supplementary Table 6). Body fat stored in visceral and other ectopic depots carries a higher risk than subcutaneous fat. Several measures of global and abdominal fat are available, of which waist circumference is the simplest to measure. The WHO thresholds for waist circumference are widely accepted in Europe. Two action levels are recommended:

Waist circumference ≥94 cm in men and ≥80 cm in women: no further weight gain
Waist circumference ≥102 cm in men and ≥88 cm in women: weight reduction advised.

Different cut-offs for anthropometric measurements may be required in different ethnicities.

The phenotype of ‘metabolically healthy obesity’, defined by the presence of obesity in the absence of metabolic risk factors, has gained interest. Long-term results support the notion that metabolically healthy obesity is a transient phase moving towards glucometabolic abnormalities rather than a specific ‘state’.¹⁷⁰

3.3.10.2 Risk reclassification

The associations between BMI, waist circumference, and waist-to-hip ratio and CVD are maintained after adjustment for conventional risk factors. However, these measures did not improve CVD risk prediction as assessed by reclassification.⁴⁷

Recommendations for cardiovascular disease assessment in specific clinical conditions

ASCVD = atherosclerotic cardiovascular disease; CKD = chronic kidney disease; COPD = chronic obstructive pulmonary disease; CV = cardiovascular; CVD = cardiovascular disease; DM = diabetes mellitus; ED = erectile dysfunction; LV = left ventricular; OSA = obstructive sleep apnoea.

a

Class of recommendation.

b

Level of evidence.

3.3.10.3 Assess risk factors and cardiovascular disease risk in persons with obesity

Comprehensive CVD risk assessment should be considered in individuals with unfavourable body composition. The main risk-related sequalae of adiposity include hypertension, dyslipidaemia, insulin resistance, systemic inflammation, a prothrombotic state, albuminuria, as well as a decline in estimated glomerular filtration rate (eGFR)¹⁷¹ and the development of type 2 DM, CVD events, as well as HF and AF.

3.4. Clinical conditions

Individual calculated risks of CVD, as evaluated by conventional risk factors in risk scores, are subject to refinement by potential risk modifiers as highlighted in section 3.3. Beyond these potential modifiers, specific clinical conditions can influence CVD risk. These clinical conditions often increase the likelihood of CVD, or are associated with poorer clinical prognosis. The current section reviews some of these conditions, which are not often included in traditional risk scores but may be integrated in some national risk scores. Here we discuss how these conditions increase this risk.

Many clinical conditions share common CVD and ASCVD risk factors and therefore treating these allows a synergistic reduction in the overall burden of disease.

3.4.1. Chronic kidney disease

Worldwide, the total number of individuals with chronic kidney disease (CKD) who are not treated with kidney replacement therapy was approximately 850 million in 2017.¹⁹⁴ This number accounts to a prevalence of 10 − 12% among men and women. CKD is the third fastest growing cause of death globally.¹⁹⁵

CKD is defined as abnormalities of kidney structure or function, present for >3 months, with health implications. Criteria and markers of kidney damage, especially kidney disease due to DM, are albuminuria [albumin-to-creatinine ratio (ACR) >30 mg/g in spot urine specimens] and glomerular filtration rate (GFR) <60 mL/min/1.73 m². GFR can be estimated (eGFR) from calibrated serum creatinine and estimating equations using the CKD-EPI (Chronic Kidney Disease Epidemiology) Collaboration formula. Kidney disease severity is differentiated into stages (categories) according to the level of GFR and albuminuria; a patient with an eGFR <60 mL/min/1.73 m² is classified as having CKD stage 3a, which represents an advanced kidney function impairment.¹⁷²

Among persons with CKD, CVD is the leading cause of morbidity and death.¹⁹⁶ Even after adjustment for known CAD risk factors, including DM and hypertension, mortality risk progressively increases with worsening CKD.¹⁹⁷ As GFR declines below approximately 60 − 75 mL/min/1.73 m², the probability of developing CAD increases linearly,¹⁹⁸ with up to triple the CVD mortality risk when reaching an eGFR of 15 mL/min/1.73 m². Kidney disease is associated with a very high CVD risk. Among persons with CKD, there is a high prevalence of traditional CAD risk factors, such as DM and hypertension. The use of CAC score to risk stratify patients with CKD might be a promising tool.^199–203 Furthermore, persons with CKD are also exposed to other non-traditional ASCVD risk factors such as uraemia-related ones, including inflammation, oxidative stress, and promotors of vascular calcification. CKD and kidney failure not only increase the risk of CAD, they also modify its clinical presentation and cardinal symptoms.²⁰⁴

3.4.2. Atrial fibrillation

Atrial fibrillation (AF) appears to be associated with an increased risk of death and of CVD and kidney disease.²⁰⁵ Furthermore, AF appears to be a stronger risk factor for CVD in women than in men.²⁰⁶

The prevalence of AF ranges between 2% and 4%, and a 2.3-fold rise is expected, owing in part to ageing of the population and intensified searching for undiagnosed AF, as well as lower CV death.²⁰⁷ The age-adjusted incidence, prevalence, and lifetime risk of AF are lower in women vs. men and in non-white vs. white cohorts.²⁰⁸^,²⁰⁹ The lifetime AF risk estimate is now 1 in 3 individuals of European ancestry at an index age of 55 years.²¹⁰ ASCVD risk factor burden and comorbidities, including lifestyle factors, and age significantly affect the lifetime risk for AF development.^211–213 The observed effect of clinical ASCVD risk factor burden and multiple comorbidities on the lifetime risk of AF (significantly increasing from 23.4% among individuals with an optimal clinical risk factor profile to 33.4% and 38.4% in those with borderline and elevated clinical risk factors, respectively²¹⁴) suggests that early intervention and control of modifiable ASCVD risk factors could reduce incident AF. The continuum of unhealthy lifestyle, risk factor(s), and CVDs can contribute to atrial remodelling/cardiomyopathy and development of AF that commonly results from a combined effect of multiple interacting factors (Figure 9).²¹⁵ Risk factor and CVD management reduces AF burden. Targeted therapy of underlying conditions may significantly improve maintenance of sinus rhythm in patients with persistent AF and HF.²¹⁶ However, studies addressing isolated management of specific conditions alone (e.g. hypertension) yielded inconsistent findings.²¹⁷

The overall annual risk of ischaemic stroke in patients with AF is 5%, but varies considerably according to comorbidities.²¹⁵ Cardioembolic strokes associated with AF are usually more severe, and often recurrent.²¹⁸ Furthermore, AF appears to be a stronger predictor of stroke in women than in men.²¹⁵ AF is also associated with impaired cognitive function, ranging from mild cognitive impairment to dementia.²¹⁹ AF is independently associated with a two-fold increased risk of all-cause mortality in women and a 1.5-fold increased risk in men.²²⁰ In one population, the most common causes of death were HF (14.5%), malignancy (23.1%), and infection/sepsis (17.3%), while stroke-related mortality was only 6.5%.²²¹ These data indicate that, in addition to anticoagulation and HF treatment, comorbid conditions need to be actively treated to reduce AF-related mortality and morbidity.

Regarding PA, both sedentary lifestyles and very high levels of PA are associated with development of AF (U-shaped association), through different mechanisms. Furthermore, when AF develops in athletes it is not associated with the same increased risk of stroke.

3.4.3. Heart failure

Heart failure (HF) of ischaemic origin constitutes a severe clinical manifestation of ASCVD. Conversely, HF itself (predominantly of ischaemic aetiology) increases the risk of CVD events (myocardial infarction, arrhythmias, ischaemic stroke, CV death).

Asymptomatic LV dysfunction (systolic or/and diastolic dysfunction) as well as overt symptomatic HF [across the spectrum of LVEF, i.e. HF with reduced ejection fraction (HFrEF), HF with mid-range ejection fraction,²²² and HF with preserved ejection fraction (HFpEF)] increases the risk of urgent CV hospitalizations (including hospitalizations due to HF worsening) and CV and all-cause deaths. These unfavourable effects on clinical outcomes have been demonstrated in asymptomatic subjects without overt CVD, in patients with acute and previous myocardial infarction, in patients with acute and previous stroke, and in patients with other clinical manifestations of CVD.²²³

The diagnosis of ischaemic HF positions individuals at very high CV risk, and justifies recommendations as for secondary prevention therapeutic strategies. Additionally, for patients with symptomatic HFrEF, several drugs are recommended to reduce the risk of CV morbidity and mortality (see section 6.2).

3.4.4. Cancer

In patients with cancer, there is an overlap between cancer and ASCVD risk factors, with shared biological mechanisms and genetic predispositions. Prevention and treatment of these is therefore beneficial in reducing both CVD as well as cancer risk. Moreover, the rates of the extent of CVD risk depend on both the CVD toxicity of treatments and patient-related factors. Owing to recent improvements in clinical outcomes for many patients with cancer, CVD mortality may ultimately exceed those from most forms of cancer recurrence.²²⁴^,²²⁵

The rapidly expanding variety of novel anticancer drugs/adjuvant therapies has demonstrated a wide range of both early and late CVD side-effects, including cardiomyopathy, LV dysfunction, HF, hypertension, CAD, arrhythmias, and other injuries. Therefore, effective strategies for the prediction and prevention of CVD toxicities are critically important. The latency and severity of radiotherapy cardiotoxicity, as well as accelerated atherosclerosis and cerebral vascular disease, is related to multiple factors, including the dose (total per fraction), the volume of the heart irradiated, concomitant administration of other cardiotoxic drugs, and patient factors (which include, amongst other factors, younger age, traditional risk factors, and history of heart disease).²²⁶^,²²⁷ Furthermore, radio- and chemotherapy may exert direct vascular effects and increase atherosclerosis-related CVD outcomes.²²⁷^,²²⁸

3.4.4.1 Diagnosis and screening

Signs or symptoms of cardiac dysfunction should be monitored before and periodically during and after cancer treatment for early detection of abnormalities in patients receiving potentially cardiotoxic chemotherapy. Detection of subclinical abnormalities using imaging and measurement of circulating biomarkers (such as cardiac troponins and natriuretic peptides) is currently recommended.¹⁷³^,²²⁹ Measures of myocardial strain, particularly systolic global longitudinal strain, may precede a significant decline in LVEF.^230–233

3.4.4.2 Prevention of cardiotoxicity and cardiovascular risk factors

RCTs of preventive therapy with renin−angiotensin−aldosterone system (RAAS) inhibitors and/or beta-blockers after trastuzumab or anthracyclines have reported contradictory results.²³⁰^,²³⁴^,²³⁵ The main benefits are less marked LV remodelling or a reduced decline in LVEF observed with cardiac magnetic resonance, but translation into better outcomes remains speculative.

Exercise should be strongly advised. In particular, aerobic exercise is considered a promising non-pharmacological strategy to prevent and/or treat chemotherapy toxicity.²³⁶ A study showed a significantly higher risk of CVD in survivors of childhood cancer than in non-cancer adult controls, and particularly in survivors of adult-onset cancer with underlying ASCVD risk factors.²³⁷ Therefore, aggressive management of ASCVD risk factors in this population is recommended.

3.4.5. Chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is a complex, progressive respiratory disorder and currently the fourth leading cause of death worldwide. It is characterized by chronic airflow limitation with respiratory symptoms and is associated with an increased inflammatory response and abnormalities of the airways caused by significant exposure to noxious particles or gases (mainly smoking). Although COPD is recognized and thoroughly investigated as a CVD comorbidity, its role as an ASCVD risk factor is not well established. Nevertheless, COPD patients have a two- to three- fold increased risk of CVD compared with age-matched controls when adjusted for tobacco smoking. Patients with mild-to-moderate COPD are 8–10 times more likely to die from ASCVD than respiratory failure, having higher rates of hospitalization and death due to CVD, stroke, and HF.²³⁸^,²³⁹ CVD also runs undiagnosed; less than one-third of COPD patients with electrocardiographic (ECG) evidence of myocardial infarction are diagnosed with CVD.²⁴⁰ CVD mortality increases by 28%, and the frequency of non-fatal coronary events by 20%, for every 10% decrease in the forced expiratory volume in 1 second (FEV1).²⁴¹ Acute COPD exacerbations, mainly due to infections, are frequent and are responsible for a four-fold increase of CVD events.²⁴² The risk of both myocardial infarction and ischaemic stroke is increased during the 3 months after an acute exacerbation.²⁴³

The high prevalence of CVD in COPD patients may be explained by the fact that both diseases share common risk factors, such as smoking, ageing, hypertension, and dyslipidaemia.²⁴⁴ Metabolic syndrome and reduced PA is present in 34% of COPD patients, with its most prevalent components being hypertension (56%), abdominal obesity (39%), and hyperglycaemia (44%).²⁴⁵ CVD may be caused by hypoxia during exercise due to lung hyperinflation, high resting heart rates, impaired vasodilatory capacity, and peripheral, cardiac, and neurohumoral sympathetic stress. Atherosclerosis and coronary artery calcification may be the result of oxidative stress, and reductions in antiaging molecules causing both lung and vascular ageing.²⁴⁶ Systemic inflammation is prominent in COPD, with circulating biomarkers in high concentrations and associated with increased mortality.²⁴⁷ Troponin is elevated during an acute exacerbation of COPD, and 10% of hospitalized patients meet the definition of acute myocardial infarction (AMI).²⁴⁸ B-natriuretic peptide level, if elevated, increases the mortality risk.²⁴⁹

Systemic inflammation and oxidative stress caused by COPD promote vascular remodelling, stiffness, and atherosclerosis, and induce a ‘procoagulant’ state that affects all vasculature types.²⁵⁰ Cognitive impairment and dementia due to cerebral microvascular damage is correlated with COPD severity; patients have a 20% increased risk for both ischaemic and haemorrhagic stroke, which may be up to seven-fold higher following an acute exacerbation.²⁵¹ PAD is present in about 9% of COPD patients,²⁵² who have an almost doubled risk of developing PAD,²⁵³ as well as an increased prevalence of carotid plaques related to the disease severity.²⁵⁴ Finally, COPD is positively associated with abdominal aortic aneurysm, regardless of smoking status.²⁵⁵

Cardiac arrhythmias are common and may be due to the haemodynamic effects (pulmonary hypertension, diastolic dysfunction, atrial structural, and electrical remodelling) caused by the disease in combination with autonomic imbalance and abnormal ventricular repolarization.²⁵⁶ AF is frequent, directly associated with FEV1, usually triggered by acute exacerbations of COPD, and an independent predictor of in-hospital COPD mortality.²⁵⁷^,²⁵⁸ COPD is also a risk factor for ventricular tachycardia independent of LVEF,²⁵⁹ and for sudden cardiac death independent of CVD risk profile.²⁶⁰

Unrecognized ventricular dysfunction is common in COPD,²⁶¹ although HF is 3.8 times more common in COPD patients than in controls.²⁶² Patients with frequent acute exacerbations have a high frequency of diastolic dysfunction; HFpEF risk is higher because of a high prevalence of hypertension and DM.²⁶³

Considering these facts, it seems of upmost importance to screen COPD patients for ASCVD and ASCVD risk factors, bearing in mind that COPD affects the accuracy of CVD diagnostic tests. Achieving adequate exercise is difficult, vasodilators for myocardial perfusion scanning may be contraindicated because of the risk of bronchospasm, and stress or transthoracic echocardiography is often disturbed by poor ultrasound windows. Computed tomography coronary angiography or magnetic resonance imaging may be alternatives, but remain expensive, time consuming, and not always available.

The use of COPD medications (i.e. long-acting muscarinic antagonists and long-acting beta agonists) is not associated with overall CV adverse events in patients with stable COPD. Olodaterol may reduce the risk of overall CV adverse events and formoterol may decrease the risk of cardiac ischaemia. Long-acting beta agonists may reduce the incidence of hypertension, but may also increase the risk of HF, so should be used with caution in HF patients.²⁶⁴

3.4.6. Inflammatory conditions

Inflammatory conditions increase CVD risk both acutely and over time. The best evidence for chronic inflammation increasing CVD risk is available for rheumatoid arthritis, which increases CVD risk by approximately 50% beyond established risk factors.¹⁷⁶ Hence, a low threshold for assessment of total CVD risk is appropriate in adults with rheumatoid arthritis, and one should consider increasing the risk estimate based on the level of disease activity.¹⁷⁶ There is also evidence for an approximately 20% increased CVD risk in patients with active inflammatory bowel disease.²⁶⁵

In other chronic inflammatory conditions, such as psoriasis¹⁷⁷ and ankylosing spondylitis,¹⁷⁸ CVD risk may also be increased. However, the strength of the evidence is less strong, as is the independence of such increased risks from the classical ASCVD risk factors. Nonetheless, it seems prudent to at least consider CVD risk assessment in patients with any chronic inflammatory condition, and to take into account the presence of such conditions when there is doubt regarding initiation of preventive interventions. The cumulative disease burden and recent degree of inflammation are important determinants of the risk-enhancing effect.

Apart from optimal anti-inflammatory treatment, CVD risk in inflammatory conditions should be treated with similar interventions as in the general high-risk population, as there is evidence that traditional methods to lessen risk (e.g. lipid-lowering treatment) are just as beneficial in preventing ASCVD.

3.4.7. Infections (human immunodeficiency virus, influenza, periodontitis)

Infection with human immunodeficiency virus (HIV) is associated with a 19% increased risk of LEAD and CAD beyond that explained by traditional atherosclerotic risk factors.²⁶⁶^,²⁶⁷ However, for those with sustained CD4 cell counts <200 cells/mm³, the risk of incident LEAD events is nearly two-fold higher, whereas for those with sustained CD4 cell counts ≥500 cells/mm³, there is no excess risk of incident LEAD events compared with uninfected people.²⁶⁸

CVD and influenza have long been associated, due to an overlap in the peak incidence of each disease during winter months. Epidemiological studies have noted an increase in CV deaths during influenza epidemics, indicating that CV complications of influenza infection, including acute ischaemic heart disease and, less often, stroke, are important contributors to morbidity and mortality during influenza infection.

The risk of AMI or stroke is more than four times higher after a respiratory tract infection, with the highest risk in the first 3 days after diagnosis.²⁶⁹ Preventing influenza, particularly by means of vaccination, could prevent influenza-triggered AMI.²⁷⁰

Studies have linked periodontal disease to both atherosclerosis and CVD,^271–273 and serological studies have linked elevated antibody titres of periodontal bacteria to atherosclerotic disease.²⁷⁴ Nevertheless, if active treatment or prevention of periodontitis improves, clinical prognosis requires further studies despite preliminary evidence.^275–277

3.4.8. Migraine

Migraine is a highly prevalent condition affecting around 15% of the general population.²⁷⁸ There are two main types of migraine—migraine without aura, which is the most common subtype, and migraine with aura, which accounts for about one-third of all migraines; in many patients the two forms coexist.

Available data indicate that migraine overall is associated with a two-fold increased risk of ischaemic stroke and a 1.5-fold increase in the risk of cardiac ischaemic disease.^179–181^,²⁷⁹^,²⁸⁰ The associations are more evident for migraine with aura.¹⁷⁹^,¹⁸⁰^,²⁸⁰ Given the young mean age of the population affected by migraine, the absolute increase in risk is small at the individual level, but high at the population level because of the high migraine prevalence.²⁸¹

Several lines of evidence also indicate that the vascular risk of subjects with migraine may be magnified by cigarette smoking¹⁸² and by the use of combined hormonal contraceptives.¹⁸³^,^281–283 Contraception using combined hormonal contraceptives should therefore be avoided in women with migraine.²⁸²^,²⁸³ However, further information is needed as good-quality studies assessing risk of stroke associated with low-dose oestrogen use in women with migraine are lacking.

3.4.9.Sleep disorders and obstructive sleep apnoea

Sleep disturbances or abnormal sleep durations are associated with increased CVD risk.^284–286 Regarding sleep duration, 7 h seems to be optimal for CV health.²⁸⁷

In the general population, the prevalence of general sleep disturbances is around 32.1%: 8.2% for insomnia, 6.1% for parasomnia, 5.9% for hypersomnolence, 12.5% for restless legs disorder and limb movements during sleep, and 7.1% for sleep-related breathing disorder [e.g. obstructive sleep apnoea (OSA)].²⁸⁸ All sleep disturbances are strongly associated with mental disorders and share hyperarousal as an underlying mechanism.²⁸⁹^,²⁹⁰

The most important sleep-related breathing disorder is OSA, which is characterized by repetitive episodes of apnoea, each exceeding 10 seconds. Despite the strong associations of OSA with CVD, including hypertension, stroke, HF, CAD, and AF, treatment of OSA by positive airway pressure (PAP) has failed to improve hard CV outcomes in patients with established CVD.^291–293 Therefore, interventions that include behaviour change (reduction of obesity, alcohol abstinence), sleep hygiene, and stress reduction in addition to PAP are needed.²⁹⁰^,²⁹⁴ Regarding hypertension and OSA, there are modest effects of PAP on BP levels, but only in patients with ABPM-confirmed resistant hypertension who use PAP for more than 5.8 h/night.²⁹⁵

3.4.10. Mental disorders

The 12-month prevalence of mental disorders or mental health disorders in the general European population is between 27% and 38% depending on sources and definitions.²⁹⁶ All mental disorders (e.g. anxiety disorders, somatoform disorders, substance disorders, personality disorders, mood disorders, and psychotic disorders) are associated with the development of CVD and reduced life expectancy in both sexes.^297–300 The risk increases with the severity of the mental disturbance and vigilance for (often non-specific) symptoms is crucial.³⁰¹ The onset of CVD is associated with an approximately 2–3-fold increased risk of mental disorders compared to a healthy population.¹¹⁵^,³⁰² In this context, screening should be performed at every consultation (or 2–4 times/year). The 12-month prevalence of mental disorders in CVD patients is around 40%, leading to significantly worse prognosis.¹⁰⁰^,¹⁰⁸^,³⁰³^,³⁰⁴ The onset of CVD increases the risk of committing suicide.³⁰⁵ In this context, awareness of anxiety and depression symptoms should be increased.

The precise mechanism by which mental disorders increase CVD remains uncertain. The detrimental effects are potentially caused by unhealthy lifestyle, increased exposure to socioeconomic stressors, and cardiometabolic side-effects of some medications,¹¹³ but also by direct effects of the amygdala-based fear-defence system and other direct pathophysiological pathways.³⁰³ Abuse of psychostimulants (e.g. cocaine) is a powerful trigger of myocardial ischaemia.³⁰⁶ Further, the capacity of these patients to adaptively use the healthcare systems is impaired due to their mental condition (e.g. not being able to trust other people and seek help, impaired capacity to be adherent).¹⁰⁰ Barriers on the part of healthcare providers are stigmatizing attitudes, insufficient mental health literacy, and lack of confidence in mental healthcare.^307–309 Although patients with mental disorders have an increased CVD risk, they receive a lower rate of recognition and treatment of traditional ASCVD risk factors.³¹⁰ Preliminary evidence suggests that taking mental disorders into account improves classical CVD risk models.³¹¹^,³¹²

Certain categories of patients with learning difficulties and associated disorders (such as Down’s syndrome) are at increased risk of CVD disease, but perhaps not specifically ASCVD. However, health inequalities and the prevalence of CV risk factors may be greater in these populations, although epidemiology research is scarce.

3.4.11. Non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) has been associated with an increased risk of myocardial infarction and stroke. NAFLD represents accumulation of ectopic fat; persons with NAFLD are often overweight or obese, and not uncommonly have abnormal BP, glucose, and lipid levels. A recent study investigating whether NAFLD increases CV risk beyond traditional risk factors³¹³ shows that after adjusting for established risk factors, the associations did not persist. Nevertheless, patients with NAFLD should have their CVD risk calculated, be screened for DM, and be recommended a healthy lifestyle with a reduction of alcohol intake.

3.4.12. Sex-specific conditions

3.4.12.1 Obstetric conditions

Pre-eclampsia (defined as pregnancy-related hypertension accompanied by proteinuria) occurs in 1–2% of all pregnancies and is associated with an increase in CVD risk by a factor of 1.5–2.7 compared with all women,¹⁸⁵^,¹⁸⁶^,³¹⁴ while the RR of developing hypertension is 3¹⁸⁷ and DM is 2.¹⁸⁴^,¹⁸⁵ It has not been established whether the increased CVD risk after preeclampsia occurs independently of CV risk factors. The rationale for screening these women for the occurrence of hypertension and DM is, however, quite strong. At present, no separate risk model for women with a history of hypertensive disorders of pregnancy seems necessary, despite their higher baseline risk.³¹⁵

Pregnancy-related hypertension affects 10–15% of all pregnancies. The associated risk of later CVD is lower than for preeclampsia but is still elevated (RR 1.7–2.5).¹⁹³^,³¹⁴^,³¹⁶^,³¹⁷ Also, the risk for sustained or future hypertension is elevated (RRs vary, from 2.0 to 7.2 or even higher).¹⁸⁷^,³¹⁸ Again, however, there was incomplete adjustment for conventional risk factors. The risk of developing DM is also elevated in these women (RR 1.6–2.0).³¹⁴^,³¹⁹ Both preterm (RR 1.6) and stillbirth (RR 1.5) have been associated with a moderate increase in risk of CVD.³¹⁶

Finally, gestational DM confers a sharply elevated risk of future DM, with up to 50% of affected women developing DM within 5 years after pregnancy, and an up to two-fold increased risk of CVD in the future.¹⁸⁸^,³²⁰ Screening by fasting glucose or HbA1c may be preferable to oral glucose tolerance testing.¹⁹¹^,³²¹

3.4.12.2 Non-obstetric conditions

Polycystic ovary syndrome affects 5% of all women in their fertile years.³²²^,³²³ It has been associated with an increased risk of CVD.³¹⁴ The risk of developing hypertension is probably increased, but data are conflicting.³²⁴ Polycystic ovary syndrome is associated with a higher risk of developing DM (RR 2–4),¹⁸⁹^,¹⁹⁰ suggesting that periodic screening for DM is appropriate.

Premature menopause occurs in roughly 1% of women ≤40 years of age. Up to 10% of women experience an early menopause, defined as that occurring by 45 years of age.³¹⁴^,³²⁵ Early menopause is associated with an increased risk of CVD (RR 1.5).^326–328 A linear inverse relationship between earlier menopause and CHD risk has been found, whereby each 1-year decrease in age at menopause portended a 2% increased risk of CHD.³²⁹

3.4.12.3 Erectile dysfunction

Erectile dysfunction (ED), defined as the consistent inability to reach and maintain an erection satisfactory for sexual activity, has a multifactorial cause. It affects almost 40% and more than 50% of men over 40 years and 60 years of age, respectively.³³⁰^,³³¹ Men with ED have an increased risk of all-cause mortality [odds ratio (OR) 1.26, 95% CI 1.01–1.57] and CVD mortality (OR 1.43, 95% CI 1.00–2.05). ED and CVD share common risk factors (hypercholesterolaemia, hypertension, insulin resistance and DM, smoking, obesity, metabolic syndrome, sedentary lifestyle, and depression) and a common pathophysiological basis of aetiology and progression.³³²^,³³³

Medication used to prevent CVD, such as aldosterone receptor antagonists, some beta-blockers, and thiazide diuretics, can cause ED.³³⁰^,^332–335 ED is associated with subclinical vascular disease,³³⁶ and precedes CAD, stroke, and PAD by a period that usually ranges from 2 to 5 years (average 3 years). Men with ED have a 44–59% higher risk for total CV events, 62% for AMI, 39% for stroke, and 24–33% for all-cause mortality, with a higher risk in those with severe ED.^337–341

There is strong evidence that CVD risk assessment is needed in men presenting with ED.³³⁶^,³⁴² In men with ED and low-to-intermediate CVD risk, detailed risk profiling by, for example, CAC score is suggested, but so far not supported by evidence.³³⁸^,³⁴¹ Assessment of ED severity and physical examination should be part of the first-line CVD risk assessment in men.³³³^,³⁴¹ Lifestyle changes are effective in improving sexual function in men: these include vigorous physical exercise,³³⁴^,³⁴³ improved nutrition, weight control, and smoking cessation.^343–345

4. Risk factors and interventions at the individual level

4.1. Treatment recommendations: classes, grades, and freedom of choice

Clear communication about risks and benefits is crucial before any treatment is initiated. Risk communication is discussed in section 3.2.4, and benefits of individual treatment are the topic of this section. In all scenarios where recommendations for individual interventions to reduce risk are ‘strong’ (class I or IIa), it is important to realize that many patients who have received appropriate risk information often (in up to 50% of cases, some studies suggest) consciously opt to forego the proposed intervention. This applies not only to lifestyle measures, but also to drug interventions. Apparently, what professionals feel is sufficient risk reduction for a reasonable effort or initiation of a drug with few side-effects does not always correspond to patients’ views. The reverse is also true: not only may some patients at (very) high risk forego interventions, some patients with low-to-moderate risk may be highly motivated to decrease their risk even further. Hence, treatment recommendations are never ‘imperative’ for (very) high risk patients, nor are interventions ever ‘prohibited’ for patients at low-to-moderate risk. There is evidence that a higher proportion of women, compared to men, have a low awareness of their CVD risk and the need for therapeutic interventions. This warrants efforts to improve awareness, risk assessment, and treatment in women.⁵²^,^346–351

4.2. Optimizing cardiovascular risk management

4.2.1. Goals of clinician−patient communication

Clinicians should provide a personalized presentation of guidelines to improve understanding, encourage lifestyle changes, and support adherence to drug therapy. Applying this in daily practice faces different barriers.³⁵² Patients’ ability to adopt a healthy lifestyle depends on cognitive and emotional factors, the impact of a diagnosis or symptoms, socioeconomic factors, educational level, and mental health. Perceived susceptibility to illness and the anticipated severity of the consequences are also prominent components of patients’ motivation.³⁵³

4.2.2. How to improve motivation?

Communication strategies such as motivational interviewing are useful.³⁵⁴ Consultation sessions may include a family member or friend, especially for elderly patients. Connection is paramount: focus before greeting; listen intently; agree on what matters most; connect with the person’s story; and explore emotions.³⁵⁵ The OARS (Open-ended questions, Affirmation, Reflective listening, and Summarizing) principle helps patients to present their perceptions, and clinicians to summarize. The SMART (Specific, Measurable, Achievable, Realistic, Timely) principle may help with setting goals for behavioural change.³⁵³^,³⁵⁶ Healthcare professionals must consider capability, opportunity (physical, social, or environmental) and motivation for behavioural change.³⁵⁷ Multidisciplinary behavioural approaches that combine the knowledge and skills of different caregivers are recommended.³⁵⁸

4.2.3. Optimizing drug adherence

Medication adherence ranges from 50% for primary ASCVD prevention to 66% for secondary prevention.³⁵⁹ Physicians should consider non-adherence in every patient and inquire non-judgmentally about it.³⁶⁰ Approximately 9% of cases of ASCVD in Europe can be attributed to poor medication adherence.³⁶¹ Contributors to non-adherence include polypharmacy, complexity of drug/dose regimes, poor doctor−patient relationship, lack of disease acceptance, beliefs about consequences and side-effects, intellectual/cognitive abilities, mental disorders, physical limitations, financial aspects, and living alone.³⁶⁰^,^362–364 Importantly, only substantial risk reduction motivates patients for preventive drug treatment, which obviates the need for appropriate risk communication.³⁶⁵^,³⁶⁶ Depression is another important factor, and adequate treatment thereof improves adherence.³⁶⁷^,³⁶⁸

Mobile phone applications may improve adherence to both medication and behavioural changes.³⁶⁹ Their use is easy and probably cost-effective.³⁷⁰

4.2.4. Treatment goals

In the subsequent sections, different domains of individual treatment are discussed. Table 6 summarizes the treatment goals and some key interventions for different categories of patients. For additional information on risk categories and the principle of a stepwise approach to treatment targets, please refer to section 3.2.3.1. For details on treatment goals, how to achieve them, strengths of recommendations and levels of supporting evidence, please go to the relevant subsections.

Table 6

Treatment goals for different patient categories

Patient category	Prevention goals (STEP 1)	Intensified/additional prevention goals^a (STEP 2)
Apparently healthy persons	For BP and lipids: initiation of drug treatment based on CVD risk assessment (Table 5) or SBP >160 mmHg
<50 years	Stop smoking and lifestyle optimization SBP <140 down to 130 mmHg if tolerated^b LDL-C <2.6 mmol/L (100 mg/dL)	SBP <130 mmHg if tolerated^b LDL-C <1.8 mmol/L (70 mg/dL) and ≥50% reduction in high-risk patients LDL-C <1.4 mmol/L (55 mg/dL) and ≥50% reduction in very-high-risk patients
50 − 69 years	Stop smoking and lifestyle optimization SBP <140 down to 130 mmHg if tolerated^b LDL-C <2.6 mmol/L (100 mg/dL)	SBP <130 mmHg if tolerated^b LDL-C <1.8 mmol/L (70 mg/dL) and ≥50% reduction in high-risk patients LDL-C <1.4 mmol/L (55 mg/dL) and ≥50% reduction in very-high-risk patients
≥70 years	Stop smoking and lifestyle optimization SBP <140 mmHg if tolerated^b LDL-C <2.6 mmol/L (100 mg/dL)	For specific risk factor management in patients ≥70 years old, please see relevant sections in section 4.
Patients with CKD	Stop smoking and lifestyle optimization SBP <140 down to 130 mmHg if tolerated^b LDL-C <2.6 mmol/L (100 mg/dL) and ≥50% LDL-C reduction Otherwise according to ASCVD and DM history	LDL-C <1.8 mmol/L (70 mg/dL) in high-risk patients and <1.4 mmol/L (55 mg/dL) in very-high risk patients (see Table 4)
Patients with FH	Stop smoking and lifestyle optimization SBP <140 down to 130 mmHg if tolerated^b LDL-C <2.6 mmol/L (100 mg/dL) and ≥50% LDL-C reduction Otherwise according to ASCVD and DM history	LDL-C <1.8 mmol/L (70 mg/dL) in high-risk patients and <1.4 mmol/L (55 mg/dL) in very-high risk patients (see Table 4)
People with type 2 DM
Well-controlled short-standing DM (e.g. <10 years), no evidence of TOD and no additional ASCVD risk factors	Stop smoking and lifestyle optimization
Without established ASCVD or severe TOD (see Table 4 for definitions)	Stop smoking and lifestyle optimization SBP <140 down to 130 mmHg if tolerated^b LDL-C <2.6 mmol/L (100 mg/dL) HbA1c <53 mmol/mol (7.0%)	SBP <130 mmHg if tolerated^b LDL-C <1.8 mmol/L (70 mg/dL) and ≥50% reduction SGLT2 inhibitor or GLP-1RA
With established ASCVD and/or severe TOD (see Table 4 for definitions)	Stop smoking and lifestyle optimisation SBP <140 down to 130 mmHg if tolerated^b LDL-C <1.8 mmol/L (70 mg/dL) HbA1c <64 mmol/mol (8.0%) SGLT2 inhibitor or GLP1-RA CVD: antiplatelet therapy	SBP <130 mmHg if tolerated^b LDL-C <1.4 mmol/L (55 mg/dL) and ≥50% reduction SGLT2 inhibitor or GLP-1RA if not already on May additionally consider novel upcoming treatments: DAPT, dual pathway inhibition,a colchicine, icosapent ethyl
Patients with established ASCVD	Stop smoking and lifestyle optimization SBP <140 down to 130 mmHg if tolerated^b Intensive oral lipid-lowering therapy aiming at ≥50% LDL-C reduction and LDL-C <1.8 mmol/L (70 mg/dL) Antiplatelet therapy	SBP <130 mmHg if tolerated^b LDL-C <1.4 mmol/L (55 mg/dL) May additionally consider novel upcoming treatments: DAPT, dual pathway inhibition, colchicine, icosapent ethyl, etc.

Patient category	Prevention goals (STEP 1)	Intensified/additional prevention goals^a (STEP 2)
Apparently healthy persons	For BP and lipids: initiation of drug treatment based on CVD risk assessment (Table 5) or SBP >160 mmHg
<50 years	Stop smoking and lifestyle optimization SBP <140 down to 130 mmHg if tolerated^b LDL-C <2.6 mmol/L (100 mg/dL)	SBP <130 mmHg if tolerated^b LDL-C <1.8 mmol/L (70 mg/dL) and ≥50% reduction in high-risk patients LDL-C <1.4 mmol/L (55 mg/dL) and ≥50% reduction in very-high-risk patients
50 − 69 years	Stop smoking and lifestyle optimization SBP <140 down to 130 mmHg if tolerated^b LDL-C <2.6 mmol/L (100 mg/dL)	SBP <130 mmHg if tolerated^b LDL-C <1.8 mmol/L (70 mg/dL) and ≥50% reduction in high-risk patients LDL-C <1.4 mmol/L (55 mg/dL) and ≥50% reduction in very-high-risk patients
≥70 years	Stop smoking and lifestyle optimization SBP <140 mmHg if tolerated^b LDL-C <2.6 mmol/L (100 mg/dL)	For specific risk factor management in patients ≥70 years old, please see relevant sections in section 4.
Patients with CKD	Stop smoking and lifestyle optimization SBP <140 down to 130 mmHg if tolerated^b LDL-C <2.6 mmol/L (100 mg/dL) and ≥50% LDL-C reduction Otherwise according to ASCVD and DM history	LDL-C <1.8 mmol/L (70 mg/dL) in high-risk patients and <1.4 mmol/L (55 mg/dL) in very-high risk patients (see Table 4)
Patients with FH	Stop smoking and lifestyle optimization SBP <140 down to 130 mmHg if tolerated^b LDL-C <2.6 mmol/L (100 mg/dL) and ≥50% LDL-C reduction Otherwise according to ASCVD and DM history	LDL-C <1.8 mmol/L (70 mg/dL) in high-risk patients and <1.4 mmol/L (55 mg/dL) in very-high risk patients (see Table 4)
People with type 2 DM
Well-controlled short-standing DM (e.g. <10 years), no evidence of TOD and no additional ASCVD risk factors	Stop smoking and lifestyle optimization
Without established ASCVD or severe TOD (see Table 4 for definitions)	Stop smoking and lifestyle optimization SBP <140 down to 130 mmHg if tolerated^b LDL-C <2.6 mmol/L (100 mg/dL) HbA1c <53 mmol/mol (7.0%)	SBP <130 mmHg if tolerated^b LDL-C <1.8 mmol/L (70 mg/dL) and ≥50% reduction SGLT2 inhibitor or GLP-1RA
With established ASCVD and/or severe TOD (see Table 4 for definitions)	Stop smoking and lifestyle optimisation SBP <140 down to 130 mmHg if tolerated^b LDL-C <1.8 mmol/L (70 mg/dL) HbA1c <64 mmol/mol (8.0%) SGLT2 inhibitor or GLP1-RA CVD: antiplatelet therapy	SBP <130 mmHg if tolerated^b LDL-C <1.4 mmol/L (55 mg/dL) and ≥50% reduction SGLT2 inhibitor or GLP-1RA if not already on May additionally consider novel upcoming treatments: DAPT, dual pathway inhibition,a colchicine, icosapent ethyl
Patients with established ASCVD	Stop smoking and lifestyle optimization SBP <140 down to 130 mmHg if tolerated^b Intensive oral lipid-lowering therapy aiming at ≥50% LDL-C reduction and LDL-C <1.8 mmol/L (70 mg/dL) Antiplatelet therapy	SBP <130 mmHg if tolerated^b LDL-C <1.4 mmol/L (55 mg/dL) May additionally consider novel upcoming treatments: DAPT, dual pathway inhibition, colchicine, icosapent ethyl, etc.

ASCVD = atherosclerotic cardiovascular disease; BP = blood pressure; CKD = chronic kidney disease; CVD = cardiovascular disease; DAPT = dual antiplatelet therapy; DBP = diastolic blood pressure; DM = diabetes mellitus; EAS = European Atherosclerosis Society; ESC = European Society of Cardiology; FH = familial hypercholesterolaemia; GLP-1RA = glucagon-like peptide-1receptor agonist; HbA1c = glycated haemoglobin; LDL-C = low-density lipoprotein cholesterol; SBP = systolic blood pressure (office); SGLT2 = sodium-glucose cotransporter 2; TOD = target organ damage.

a

Depending on 10-year (residual) risk and/or estimated lifetime benefit (see Table 4 for details), comorbidities, and patient preference. Levels of evidence of intensified goals vary, see recommendation tables in sections 4.6 and 4.7. For CKD and FH, LDL-C targets are taken form the 2019 ESC/EAS Guidelines for the treatment of dyslipidaemias.³

b

Office DBP treatment target range <80 mmHg.

Table 6

Treatment goals for different patient categories

Patient category	Prevention goals (STEP 1)	Intensified/additional prevention goals^a (STEP 2)
Apparently healthy persons	For BP and lipids: initiation of drug treatment based on CVD risk assessment (Table 5) or SBP >160 mmHg
<50 years	Stop smoking and lifestyle optimization SBP <140 down to 130 mmHg if tolerated^b LDL-C <2.6 mmol/L (100 mg/dL)	SBP <130 mmHg if tolerated^b LDL-C <1.8 mmol/L (70 mg/dL) and ≥50% reduction in high-risk patients LDL-C <1.4 mmol/L (55 mg/dL) and ≥50% reduction in very-high-risk patients
50 − 69 years	Stop smoking and lifestyle optimization SBP <140 down to 130 mmHg if tolerated^b LDL-C <2.6 mmol/L (100 mg/dL)	SBP <130 mmHg if tolerated^b LDL-C <1.8 mmol/L (70 mg/dL) and ≥50% reduction in high-risk patients LDL-C <1.4 mmol/L (55 mg/dL) and ≥50% reduction in very-high-risk patients
≥70 years	Stop smoking and lifestyle optimization SBP <140 mmHg if tolerated^b LDL-C <2.6 mmol/L (100 mg/dL)	For specific risk factor management in patients ≥70 years old, please see relevant sections in section 4.
Patients with CKD	Stop smoking and lifestyle optimization SBP <140 down to 130 mmHg if tolerated^b LDL-C <2.6 mmol/L (100 mg/dL) and ≥50% LDL-C reduction Otherwise according to ASCVD and DM history	LDL-C <1.8 mmol/L (70 mg/dL) in high-risk patients and <1.4 mmol/L (55 mg/dL) in very-high risk patients (see Table 4)
Patients with FH	Stop smoking and lifestyle optimization SBP <140 down to 130 mmHg if tolerated^b LDL-C <2.6 mmol/L (100 mg/dL) and ≥50% LDL-C reduction Otherwise according to ASCVD and DM history	LDL-C <1.8 mmol/L (70 mg/dL) in high-risk patients and <1.4 mmol/L (55 mg/dL) in very-high risk patients (see Table 4)
People with type 2 DM
Well-controlled short-standing DM (e.g. <10 years), no evidence of TOD and no additional ASCVD risk factors	Stop smoking and lifestyle optimization
Without established ASCVD or severe TOD (see Table 4 for definitions)	Stop smoking and lifestyle optimization SBP <140 down to 130 mmHg if tolerated^b LDL-C <2.6 mmol/L (100 mg/dL) HbA1c <53 mmol/mol (7.0%)	SBP <130 mmHg if tolerated^b LDL-C <1.8 mmol/L (70 mg/dL) and ≥50% reduction SGLT2 inhibitor or GLP-1RA
With established ASCVD and/or severe TOD (see Table 4 for definitions)	Stop smoking and lifestyle optimisation SBP <140 down to 130 mmHg if tolerated^b LDL-C <1.8 mmol/L (70 mg/dL) HbA1c <64 mmol/mol (8.0%) SGLT2 inhibitor or GLP1-RA CVD: antiplatelet therapy	SBP <130 mmHg if tolerated^b LDL-C <1.4 mmol/L (55 mg/dL) and ≥50% reduction SGLT2 inhibitor or GLP-1RA if not already on May additionally consider novel upcoming treatments: DAPT, dual pathway inhibition,a colchicine, icosapent ethyl
Patients with established ASCVD	Stop smoking and lifestyle optimization SBP <140 down to 130 mmHg if tolerated^b Intensive oral lipid-lowering therapy aiming at ≥50% LDL-C reduction and LDL-C <1.8 mmol/L (70 mg/dL) Antiplatelet therapy	SBP <130 mmHg if tolerated^b LDL-C <1.4 mmol/L (55 mg/dL) May additionally consider novel upcoming treatments: DAPT, dual pathway inhibition, colchicine, icosapent ethyl, etc.

Patient category	Prevention goals (STEP 1)	Intensified/additional prevention goals^a (STEP 2)
Apparently healthy persons	For BP and lipids: initiation of drug treatment based on CVD risk assessment (Table 5) or SBP >160 mmHg
<50 years	Stop smoking and lifestyle optimization SBP <140 down to 130 mmHg if tolerated^b LDL-C <2.6 mmol/L (100 mg/dL)	SBP <130 mmHg if tolerated^b LDL-C <1.8 mmol/L (70 mg/dL) and ≥50% reduction in high-risk patients LDL-C <1.4 mmol/L (55 mg/dL) and ≥50% reduction in very-high-risk patients
50 − 69 years	Stop smoking and lifestyle optimization SBP <140 down to 130 mmHg if tolerated^b LDL-C <2.6 mmol/L (100 mg/dL)	SBP <130 mmHg if tolerated^b LDL-C <1.8 mmol/L (70 mg/dL) and ≥50% reduction in high-risk patients LDL-C <1.4 mmol/L (55 mg/dL) and ≥50% reduction in very-high-risk patients
≥70 years	Stop smoking and lifestyle optimization SBP <140 mmHg if tolerated^b LDL-C <2.6 mmol/L (100 mg/dL)	For specific risk factor management in patients ≥70 years old, please see relevant sections in section 4.
Patients with CKD	Stop smoking and lifestyle optimization SBP <140 down to 130 mmHg if tolerated^b LDL-C <2.6 mmol/L (100 mg/dL) and ≥50% LDL-C reduction Otherwise according to ASCVD and DM history	LDL-C <1.8 mmol/L (70 mg/dL) in high-risk patients and <1.4 mmol/L (55 mg/dL) in very-high risk patients (see Table 4)
Patients with FH	Stop smoking and lifestyle optimization SBP <140 down to 130 mmHg if tolerated^b LDL-C <2.6 mmol/L (100 mg/dL) and ≥50% LDL-C reduction Otherwise according to ASCVD and DM history	LDL-C <1.8 mmol/L (70 mg/dL) in high-risk patients and <1.4 mmol/L (55 mg/dL) in very-high risk patients (see Table 4)
People with type 2 DM
Well-controlled short-standing DM (e.g. <10 years), no evidence of TOD and no additional ASCVD risk factors	Stop smoking and lifestyle optimization
Without established ASCVD or severe TOD (see Table 4 for definitions)	Stop smoking and lifestyle optimization SBP <140 down to 130 mmHg if tolerated^b LDL-C <2.6 mmol/L (100 mg/dL) HbA1c <53 mmol/mol (7.0%)	SBP <130 mmHg if tolerated^b LDL-C <1.8 mmol/L (70 mg/dL) and ≥50% reduction SGLT2 inhibitor or GLP-1RA
With established ASCVD and/or severe TOD (see Table 4 for definitions)	Stop smoking and lifestyle optimisation SBP <140 down to 130 mmHg if tolerated^b LDL-C <1.8 mmol/L (70 mg/dL) HbA1c <64 mmol/mol (8.0%) SGLT2 inhibitor or GLP1-RA CVD: antiplatelet therapy	SBP <130 mmHg if tolerated^b LDL-C <1.4 mmol/L (55 mg/dL) and ≥50% reduction SGLT2 inhibitor or GLP-1RA if not already on May additionally consider novel upcoming treatments: DAPT, dual pathway inhibition,a colchicine, icosapent ethyl
Patients with established ASCVD	Stop smoking and lifestyle optimization SBP <140 down to 130 mmHg if tolerated^b Intensive oral lipid-lowering therapy aiming at ≥50% LDL-C reduction and LDL-C <1.8 mmol/L (70 mg/dL) Antiplatelet therapy	SBP <130 mmHg if tolerated^b LDL-C <1.4 mmol/L (55 mg/dL) May additionally consider novel upcoming treatments: DAPT, dual pathway inhibition, colchicine, icosapent ethyl, etc.

ASCVD = atherosclerotic cardiovascular disease; BP = blood pressure; CKD = chronic kidney disease; CVD = cardiovascular disease; DAPT = dual antiplatelet therapy; DBP = diastolic blood pressure; DM = diabetes mellitus; EAS = European Atherosclerosis Society; ESC = European Society of Cardiology; FH = familial hypercholesterolaemia; GLP-1RA = glucagon-like peptide-1receptor agonist; HbA1c = glycated haemoglobin; LDL-C = low-density lipoprotein cholesterol; SBP = systolic blood pressure (office); SGLT2 = sodium-glucose cotransporter 2; TOD = target organ damage.

a

Depending on 10-year (residual) risk and/or estimated lifetime benefit (see Table 4 for details), comorbidities, and patient preference. Levels of evidence of intensified goals vary, see recommendation tables in sections 4.6 and 4.7. For CKD and FH, LDL-C targets are taken form the 2019 ESC/EAS Guidelines for the treatment of dyslipidaemias.³

b

Office DBP treatment target range <80 mmHg.

4.3.Optimizing lifestyle

4.3.1. Physical activity and exercise

Recommendations for physical activity

CV = cardiovascular; PA = physical activity.

a

Class of recommendation.

b

Level of evidence.

PA reduces the risk of many adverse health outcomes and risk factors in all ages and both sexes. There is an inverse relationship between moderate-to-vigorous PA and all-cause mortality, CV morbidity and mortality, as well as incidence of type 2 DM.^371–373^,^383–387 The reduction in risk continues across the full range of PA volumes, and the slope of risk decline is steepest for the least active individuals.^371–374^,³⁸⁶^,³⁸⁷ More information on PA prescription can be found in a recent ESC Guideline.³⁸⁸

4.3.1.1 Physical activity prescription

PA should be individually assessed and prescribed in terms of frequency, intensity, time (duration), type, and progression.³⁸⁹ Recommendations regarding pre-participation screening can be found in previous ESC Guidelines.³⁸⁸ Interventions shown to increase PA level or reduce sedentary behaviour include behaviour theory-based interventions, such as goal-setting, re-evaluation of goals, self-monitoring, and feedback.³⁷²^,³⁸⁰^,³⁸¹ Using a wearable activity tracker may help increase PA.³⁸² Most important is to encourage activity that people enjoy and/or can include in their daily routines, as such activities are more likely to be sustainable.

4.3.1.2 Aerobic physical activity

Examples of aerobic PA include walking, jogging, cycling, etc.³⁸⁹ Adults are recommended to perform at least 150–300 min a week of moderate-intensity PA, or 75–150 min of vigorous-intensity PA, or an equivalent combination of both, spread throughout the week.³⁷¹^,³⁷² Additional benefits are gained with even more PA. Practising PA should still be encouraged in individuals unable to meet the minimum. In sedentary individuals, a gradual increase in activity level is recommended. When older adults or individuals with chronic conditions cannot achieve 150 min of moderate-intensity PA a week, they should be as active as their abilities and conditions allow.^371–375^,³⁸⁴^,³⁸⁵ PA accumulated in bouts of even <10 min is associated with favourable outcomes, including mortality.³⁷¹^,³⁹⁰

PA can be expressed in absolute or relative terms.³⁸⁹ Absolute intensity is the amount of energy expended per minute of activity, assessed by oxygen uptake per unit of time (mL/min or L/min) or by metabolic equivalent of task (MET). A compendium of the energy cost in MET values for various activities is available.³⁹¹ An absolute measure does not consider individual factors such as body weight, sex, and fitness level.³⁸⁹

Relative intensity is determined based on an individual’s maximum (peak) effort, e.g. percentage of cardiorespiratory fitness (%VO₂ max), percentage of maximum (peak) heart rate (%HR_max) or using rating of perceived exertion according to the Borg scale. Less fit individuals generally require a higher level of effort than fitter people to perform the same activity. A relative intensity measure is necessary to provide an individualized PA prescription.³⁸⁹

Classification for both absolute and relative intensity and examples are presented in Table 7.

Table 7

Classification of physical activity intensity and examples of absolute and relative intensity levels.

Absolute intensity

Relative intensity

Intensity

MET^a

Examples

%HR_max

RPE (Borg scale score)

Talk test

Light

1.1–2.9

Walking <4.7 km/h, light household work

57–63

10–11

Moderate

3–5.9

Walking at moderate or brisk pace (4.1–6.5 km/h), slow cycling (15 km/h), painting/decorating, vacuuming, gardening (mowing lawn), golf (pulling clubs in trolley), tennis (doubles), ballroom dancing, water aerobics

64–76

12–13

Breathing is faster but compatible with speaking full sentences

Vigorous

≥6

Race-walking, jogging, or running, cycling >15 km/h, heavy gardening (continuous digging or hoeing), swimming laps, tennis (singles)

77–95

14–17

Breathing very hard, incompatible with carrying on a conversation comfortably

%HR_max = percentage of measured or estimated maximum heart rate (220–age); MET = metabolic equivalent of task; RPE = rating of perceived exertion (Borg-scale 6–20); VO₂ = oxygen consumption.

a

MET is estimated as the energy cost of a given activity divided by resting energy expenditure: 1 MET = 3.5 mL oxygen kg^–1 min^–1 VO₂. Modified from ³⁹²

4.3.1.3 Resistance exercise

Resistance exercise in addition to aerobic PA is associated with lower risks of total CV events and all-cause mortality.³⁷⁸^,³⁷⁹^,^393–395 The suggested prescription is one to three sets of 8–12 repetitions at the intensity of 60–80% of the individual’s 1 repetition maximum at a frequency of at least 2 days a week in a variety of 8–10 different exercises involving each major muscle group. For older adults or deconditioned individuals, it is suggested to start with one set of 10–15 repetitions at 40–50% of 1 repetition maximum.³⁸⁹ In addition, older adults are recommended to perform multicomponent PA that combines aerobic, muscle-strengthening, and balance exercises to prevent falls.³⁷²

4.3.1.4 Sedentary behaviour

Sedentary time is associated with greater risk for several major chronic diseases and mortality.³⁷¹^,³⁷²^,^375–377^,^396–399 For physically inactive adults, light-intensity PA, even as little as 15 minutes a day, is likely to produce benefits. There is mixed evidence to suggest how activity bouts that interrupt sedentary behaviour are associated with health outcomes.³⁷⁵^,³⁹⁸^,⁴⁰⁰

4.3.2. Nutrition and alcohol

Recommendations for nutrition and alcohol

CVD = cardiovascular disease; BP = blood pressure.

a

Class of recommendation.

b

Level of evidence.

Dietary habits influence CV risk, mainly through risk factors such as lipids, BP, body weight, and DM.⁴⁰¹^,⁴⁰² Table 8 summarizes the characteristics of a healthy diet. Although recommendations about nutrients and foods remain important for CV health, there is a growing concern about environmental sustainability, supporting a shift from an animal- to a more plant-based food pattern.⁴¹¹^,⁴¹²

Table 8

Healthy diet characteristics

Adopt a more plant- and less animal-based food pattern

Saturated fatty acids should account for <10% of total energy intake, through replacement by PUFAs, MUFAs, and carbohydrates from whole grains

Trans unsaturated fatty acids should be minimized as far as possible, with none from processed foods

<5 g total salt intake per day

30–45 g of fibre of per day, preferably from wholegrains

≥200 g of fruit per day (≥2–3 servings)

≥200 g of vegetables per day (≥2–3 servings)

Red meat should be reduced to a maximum of 350 − 500 g a week, in particular processed meat should be minimized

Fish is recommended 1–2 times per week, in particular fatty fish

30 g unsalted nuts per day

Consumption of alcohol should be limited to a maximum of 100 g per week

Sugar-sweetened beverages, such as soft drinks and fruit juices, must be discouraged

MUFA = monounsaturated fatty acid; PUFA = polyunsaturated fatty acid.

4.3.2.1 Fatty acids

Risk of CHD is reduced when dietary saturated fats are replaced appropriately (Figure 10). This is also the case when replacing meat and dairy foods.⁴⁰⁶^,⁴⁰⁷ Polyunsaturated fats (−25%), monounsaturated fats (−15%), and to a lesser extent carbohydrates from whole grains (−9%), were all associated with reduced CHD risk when isocalorically substituted for dietary saturated fat.⁴⁰⁸^,⁴⁰⁹

Reducing saturated fatty acid intake to less than 10% of energy may have additional benefits.⁴⁰⁵ However, the LDL-C-lowering effect of substituting polyunsaturated fatty acids (PUFAs) for saturated fatty acids may be less in obese (5.3%) than in normal-weight persons (9.7%).⁴²¹

Trans fatty acids, formed during industrial processing of fats, have unfavourable effects on total cholesterol (increase) and HDL-C (decrease). On average, a 2% increase in energy intake from trans fatty acids is associated with a 23% higher CHD risk.⁴²² A regulation of the European Union (EU) Commission has set the upper limit to 2 g per 100 g of fat (April 2019) (https://ec.europa.eu/food/safety/labelling_nutrition/trans-fat-food_en).

When guidelines to lower saturated fat intake are followed, reductions in dietary cholesterol intake follow.

4.3.2.2 Minerals and vitamins

A reduction in sodium intake may reduce SBP by, on average, 5.8 mmHg in hypertensive, and 1.9 mmHg in normotensive patients.⁴¹⁰ The DASH (Dietary Approaches to Stop Hypertension) trial showed a dose–response relation between sodium reduction and BP reduction.⁴²³ In a meta-analysis, salt reduction of 2.5 g/day resulted in a 20% reduction of ASCVD events (RR 0.80).⁴¹⁰ A U- or J-shaped relation between a low salt intake and ASCVD is debated.⁴²⁴ Underlying illness and malnutrition may explain both low food and salt intakes as well as increased ASCVD.⁴¹⁰^,⁴²⁵^,⁴²⁶ The totality of evidence warrants salt reduction to prevent CHD and stroke.

In most Western countries, salt intake is high (≈9–10 g/day), whereas the recommended maximum intake is 5 g/day. Optimal intake might be as low as ≈3 g/day. Salt reduction can be achieved by dietary choices (fewer processed foods) and the reformulation of foods by lowering their salt content (see section 5.2.2).

Potassium (e.g. in fruits and vegetables) has favourable effects on BP and risk of stroke (RR 0.76).⁴²⁷

As for vitamins, observational studies have found inverse associations between vitamins A and E and risk of ASCVD. However, intervention trials have failed to confirm these findings. Also, trials of supplementation with B vitamins (B6, folic acid, and B12), and vitamins C and D have not shown beneficial effects.⁴²⁸^,⁴²⁹

4.3.2.3 Fibre

Each 7 g/day higher intake of total fibre is associated with a 9% lower risk of CAD (RR 0.91).⁴³⁰ A 10 g/day higher fibre intake was associated with a 16% lower risk of stroke (RR 0.84) and a 6% lower risk of type 2 DM (RR 0.94).⁴³¹^,⁴³² A high fibre intake may reduce postprandial glucose responses after carbohydrate-rich meals and also lower triglyceride levels.⁴³³

4.3.2.4 Specific foods and food groups

4.3.2.4.1. Fruits, vegetables, and pulses

A meta-analysis reported a 4% lower risk in CV mortality for each additional serving of fruits (equivalent to 77 g) and vegetables (equivalent to 80 g) per day, while all-cause mortality was not reduced further with intakes of more than five servings.⁴³⁴ A meta-analysis reported an 11% lower risk for stroke associated with three to five daily servings of fruits and vegetables and of 26% with five servings a day compared with fewer than three servings.⁴³⁵^,⁴³⁶ A single portion of pulses (legumes) a day lowers LDL-C by 0.2 mmol/L and is associated with a lower risk of CHD.⁴³⁷^,⁴³⁸

4.3.2.4.2. Nuts

A meta-analysis of prospective cohort studies suggested that daily consumption of 30 g of (mixed) nuts was associated with a ≈30% lower risk of ASCVD.⁴³⁷ Both pulses and nuts contain fibre and other bioactive components.⁴³⁸

4.3.2.4.3. Meat

From both a health and an environmental point of view, a lower consumption of meat, especially processed meat, is recommended.⁴¹¹ A restriction of red meat may have little or no effect on major cardiometabolic outcomes.⁴¹⁶ However, substituting red meat with high-quality plant foods (i.e. nuts, soy, and legumes) does improve LDL-C concentrations.⁴⁰⁶ A recent analysis showed that higher intake of processed meat and unprocessed red meat is associated with a 7% and 3%, respectively, increased risk of ASCVD.⁴¹⁷

By reducing processed meats, salt intake will also be reduced. The World Cancer Research Fund recommends limiting red meat consumption to 350–500 g per week.⁴³⁹

4.3.2.4.4. Fish and fish oil supplements

Studies indicate that eating fish, particularly fish rich in n-3 PUFA, at least once a week, is associated with a 16% lower risk of CAD,⁴¹⁸ and eating fish two to four times a week is associated with a 6% lower risk of stroke.⁴⁴⁰ The highest risk was observed in the range of no or very low intakes.

Several meta-analyses and a recent Cochrane review showed no benefits of fish oils on CV outcomes and/or mortality,^441–443 although a 7% lower risk of CHD events was observed. A meta-analysis of 13 RCTs included the results of VITAL (Vitamin D and Omega-3 Trial), ASCEND (A Study of Cardiovascular Events in Diabetes), and REDUCE-IT (Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial).⁴⁴⁴ In the analysis excluding REDUCE-IT, fish oil reduced total ASCVD (RR 0.97) and CHD death (RR 0.92).⁴⁴⁴ Including REDUCE-IT (a study done in participants with high triglycerides, comparing very high icosapent ethyl doses vs. mineral oil placebo) strengthened the results.⁴⁴⁴ However, this is the only study that tested a high icosapent ethyl dose and questions have been raised regarding the choice of placebo. Very recently, STRENGTH (Long-Term Outcomes Study to Assess Statin Residual Risk with Epanova in High Cardiovascular Risk Patients with Hypertriglyceridemia) failed to demonstrate benefit of a combined eicosapentaenoic acid and docosahexaenoic acid preparation.⁴⁴⁵

4.3.2.4.5. Alcoholic beverages

The upper safe limit of drinking alcoholic beverages is about 100 g of pure alcohol per week. How this translates into number of drinks depends on portion size, the standards of which differ per country, mostly between 8 and 14 g per drink. This limit is similar for men and women.⁴¹³ Drinking above this limit lowers life expectancy.

Results from epidemiological studies have suggested that, whereas higher alcohol consumption is roughly linearly associated with a higher risk of all stroke subtypes, coronary disease, HF, and several less common CVD subtypes, it appeared approximately log-linearly associated with a lower risk of myocardial infarction.⁴¹³ Moreover, Mendelian randomization studies do not support the apparently protective effects of moderate amounts vs. no alcohol against ASCVD, suggesting that the lowest risks for CVD outcomes are in abstainers and that any amount of alcohol uniformly increases BP and BMI.⁴¹⁴^,⁴¹⁵ These data challenge the concept that moderate alcohol consumption is universally associated with lower CVD risk.

4.3.2.4.6. Soft drinks and sugar

Regular consumption of sugar-sweetened beverages (i.e. two servings per day compared with one serving per month) was associated with a 35% higher risk of CAD in women in the Nurses’ Health Study, whereas artificially sweetened beverages were not associated with CAD. In the EPIC (European Prospective Investigation into Cancer and Nutrition) cohort, both artificially and sugar-sweetened soft drinks were associated with all-cause mortality, while only the former was associated with circulatory diseases.⁴¹⁹ The WHO guideline recommends a maximum intake of 10% of energy from free sugars (mono- and disaccharides), which includes added sugars as well as sugars present in fruit juices.⁴²⁰

4.3.2.4.7. Coffee

Non-filtered coffee contains LDL-C-raising cafestol and kahweol, and may be associated with an up to 25% increased risk of ASCVD mortality by consumption of nine or more drinks a day.⁴⁴⁶ Non-filtered coffee includes boiled, Greek, and Turkish coffee and some espresso coffees. Moderate coffee consumption (3–4 cups per day) is probably not harmful, perhaps even moderately beneficial.⁴⁴⁷

4.3.2.4.8. Functional foods

Functional foods containing phytosterols (plant sterols and stanols) are effective in lowering LDL-C levels by an average of 10% when consumed in amounts of 2 g/day.⁴⁴⁸ The effect is in addition to that obtained with a low-fat diet or use of statins. No studies with clinical endpoints have been performed yet.

Red yeast rice supplements are not recommended and may even cause side-effects.⁴⁴⁹

4.3.2.4.9. Dietary patterns

Studying the impact of a total dietary pattern shows the full preventive potential of diet. The Mediterranean diet includes high intakes of fruits, vegetables, pulses, wholegrain products, fish, and olive oil, moderate consumption of alcohol, and low consumption of (red) meat, dairy products, and saturated fatty acids. Greater adherence to a Mediterranean diet is associated with a 10% reduction in CV incidence or mortality and an 8% reduction in all-cause mortality.⁴⁰³ Following a Mediterranean diet enriched with nuts over a 5-year period, compared with a control diet, lowered the risk of ASCVD by 28% and by 31% with a diet enriched with extra-virgin olive oil.⁴⁰⁴

Also, a shift from a more animal-based to a plant-based food pattern may reduce ASCVD.⁴¹¹

4.3.3. Body weight and composition

Recommendations for body weight

CVD = cardiovascular disease; BP = blood pressure; DM = diabetes mellitus.

a

Class of recommendation.

b

Level of evidence.

4.3.3.1 Treatment goals and modalities

Although diet, exercise, and behaviour modification are the main therapies for overweight and obesity, they are often unsuccessful in the long term. Yet, maintaining even a moderate weight loss of 5 − 10% from baseline has salutary effects on risk factors including BP, lipids, and glycaemic control,⁴⁵⁰^,⁴⁵¹ as well as on premature all-cause mortality.⁴⁵⁶ Weight loss is associated with lower morbidity but higher mortality in (biologically) older adults (the ‘obesity paradox’). In this group, emphasis should be less on weight loss and more on maintaining muscle mass and good nutrition.

4.3.3.2 Diets for weight loss

Energy restriction is the cornerstone of management. PA is essential to maintain weight loss and prevent rebound weight gain, but is not reviewed here. Hypocaloric diets may be categorized as:

Diets that aim to reduce ASCVD, including plant-based⁴⁵⁷^,⁴⁵⁸ and hypocaloric Mediterranean diets,⁴⁵⁸^,⁴⁵⁹ with modifications to suit local food availability and preferences.
Changes to the fat and carbohydrate macronutrient composition of the diet, including low or very low carbohydrate diets (with 50–130 g and 20–49 g carbohydrates/day, respectively), moderate carbohydrate diets (>130–225 g carbohydrates/day), and low-fat diets (<30% of energy from fat).
High-protein diets to preserve lean muscle mass and enhance satiety.
Diets focusing on specific food groups (e.g. increasing fruit and vegetables or avoiding refined sugars).
Diets that restrict energy intake for specified time periods, for example on 2 days a week or alternate days (intermittent fasting) or during certain hours of the day (time-restricted eating).

These diets give broadly similar short-term weight loss.^452–454 By 12 months, the effects tend to diminish.⁴⁵³ Benefits of the Mediterranean diet, however, tend to persist. The quality of nutrients in a diet, for example substituting unsaturated for saturated fats (see section 4.3.2.1) and including fibre-rich carbohydrates⁴⁶⁰ determines whether a diet is healthy in the long term.

Low or very low carbohydrate diets may have advantages regarding appetite control, lowering triglycerides, and reducing medications for type 2 DM.⁴⁶¹ Such diets may be ketogenic and need medical or at least dietetic supervision. Studies beyond 2 years are scarce. Extreme carbohydrate intakes should be avoided in the long term and plant substitutions of fat and protein for carbohydrates are advantageous over animal ones.⁴⁶²

Intermittent fasting diets produce equivalent weight loss to continuous energy restriction when matched for energy intake.⁴⁶³

Medications approved in Europe as aids to weight loss (orlistat, naltrexone/bupropion, high-dose liraglutide) may supplement lifestyle change to achieve weight loss and maintenance, although sometimes at the expense of side-effects. Meta-analysis of medication-assisted weight loss found favourable effects on BP, glycaemic control, and ASCVD mortality.⁴⁶⁴

A very effective treatment option for extreme obesity or obesity with comorbidities is bariatric surgery. A meta-analysis indicated that patients undergoing bariatric surgery had over 50% lower risks of total, ASCVD, and cancer mortality compared with people of similar weight who did not have surgery.⁴⁵⁵

4.4. Mental healthcare and psychosocial interventions

Recommendations for mental healthcare and psychosocial interventions at the individual level

ASCVD = atherosclerotic cardiovascular disease; CHD = coronary heart disease; CV = cardiovascular; HF = heart failure; SNRI = serotonin-noradrenaline reuptake inhibitor; SSRI = selective serotonin reuptake inhibitor.

a

Class of recommendation.

b

Level of evidence.

c

Details explaining this recommendation are provided in the supplementary material section 2.1.

Treatment of an unhealthy lifestyle will reduce CVD risk as well as improve mental health. Smoking cessation, for instance, has a positive effect on depression outcomes,⁴⁷⁴^,⁴⁷⁵ as do exercise therapy¹¹³^,⁴⁷⁶ and healthy dietary practices.⁴⁷⁷ Evidence-based interventions for smoking cessation, and improving PA and diet, are considered useful and applicable for persons with mental disorders.⁴⁶⁵^,^478–480

Mental disorders are associated with an increased risk of CVD and a worse prognosis in patients with ASCVD, due to CVD events or other death causes, including suicide.¹⁰⁰^,¹¹³^,³⁰⁵ Mental-health treatments effectively reduce stress symptoms and improve quality of life. Several observational studies indicate that treatment or remission of depression reduces CVD risk.¹¹³^,^481–484 Psychological interventions in patients with CHD may reduce cardiac mortality (RR 0.79) and alleviate psychological symptoms.⁴⁶⁶ Psychotherapy focusing on stress management in ASCVD patients improves CVD outcomes. In SUPRIM (Secondary Prevention in Uppsala Primary Health Care project), patients in the intervention group had a 41% lower rate of fatal and non-fatal first recurrent ASCVD events [hazard ratio (HR 0.59)] and fewer recurrent AMIs (HR 0.55).⁴⁶⁷ In SWITCHD (Stockholm Women’s Intervention Trial for Coronary Heart Disease), the intervention yielded a substantial reduction in all-cause mortality (OR 0.33).⁴⁶⁸ A recent RCT reported that cardiac rehabilitation (CR) enhanced by stress management produced significant reductions in ASCVD events compared with standard CR alone (HR 0.49).⁴⁶⁹ Concerning psychopharmacotherapy of patients with CHD and depression, selective serotonin reuptake inhibitor (SSRI) treatment lowers rates of CHD readmission (risk ratio 0.63) and all-cause mortality (risk ratio 0.56).⁴⁷⁰ A recent RCT reported that, in patients with ACS and depression, treatment with the SSRI, escitalopram, resulted in a lower rate of the composite endpoint of all-cause mortality, myocardial infarction, or percutaneous coronary intervention (PCI) (HR 0.69).⁴⁷¹ Collaborative care for patients with CHD and depression has small beneficial effects on depression, but significantly reduces short-term major cardiac events.⁴⁸⁵

Concerning side-effects of psychopharmacological treatments, many psychiatric drugs are associated with an increased risk of sudden cardiac death.⁴⁸⁶ In patients with HF, antidepressants are associated with increased risk of cardiac and all-cause mortality (HR 1.27; for details see supplementary material for section 4.4).⁴⁷² Therefore, ASCVD patients with complex mental disorders, and particularly those needing psychiatric drug treatment, require interdisciplinary cooperation.

4.5. Smoking intervention

Recommendations for smoking intervention strategies

ASCVD = atherosclerotic cardiovascular disease.

a

Class of recommendation.

b

Level of evidence.

4.5.1. Smoking cessation

Stopping smoking is potentially the most effective of all preventive measures, with substantial reductions in (repeat) myocardial infarctions or death.⁴⁸⁷^,⁴⁸⁸ Lifetime gains in CVD-free years are substantial at all ages, and benefits are obviously even more substantial if other complications from smoking would be accounted for. From age 45 years, gains of 3 − 5 years persist in men to age 65 and in women to age 75 years (Figure 11). Even in heavy smokers (≥20 cigarettes/day), cessation lowers CVD risk within 5 years, although it remains elevated beyond 5 years. Total health benefits will be even larger because of gain in non-CVD health.

Quitting must be encouraged in all smokers, and passive smoking should be avoided as much as possible. Very brief advice may be advantageous when time is limited (Table 9). A major impetus for cessation occurs at the time of diagnosis or treatment of CVD. Prompting a person to try to quit, brief reiteration of CV and other benefits of quitting, and agreeing on a specific plan with a follow-up arrangement are evidence-based interventions.

Table 9

‘Very brief advice’ for smoking cessation

‘Very brief advice’ on smoking is a proven 30-second clinical intervention, developed in the UK, which identifies smokers, advises them on the best method of quitting, and supports subsequent quit attempts. There are three elements to very brief advice:

ASK − establishing and recording smoking status

ADVISE − advising on the best ways of stopping

ACT − offering help

UK = United Kingdom.

Smokers who quit may expect an average weight gain of 5 kg, but the health benefits of tobacco cessation outweigh risks from weight gain.⁴⁹⁵ Persistent or reuptake of smoking is common in patients with CHD, in particular in those with severe depression and environmental exposures.⁴⁹⁸ Mood-management therapies may improve outcomes in patients with current or past depression.⁴⁹⁹

4.5.2. Evidence-based drug interventions

Drug support for stopping smoking should be considered in all smokers who are ready to undertake this action. Evidence-based drug interventions include nicotine-replacement therapy (NRT), bupropion, varenicline, and cytisine (not widely available).^489–491 All forms of NRT (chewing gum, transdermal nicotine patches, nasal spray, inhaler, sublingual tablets) are effective. Combination vs. single-form NRT and 4 mg vs. 2 mg gum can increase success.⁴⁹² NRT shows no adverse effects in patients with ASCVD,⁴⁹³ but evidence of efficacy in this group is inconclusive.⁴⁹⁴ In patients with ASCVD, varenicline (RR 2.6), bupropion (RR 1.4), telephone therapy (RR 1.5), and individual counselling (RR 1.6) all increase success rates.⁴⁹⁴ The antidepressant, bupropion, aids long-term smoking cessation with similar efficacy to NRT.⁴⁹⁰

Varenicline 1 mg b.i.d. (twice a day) increases quitting rates more than two-fold compared with placebo.⁴⁹¹ The RR for abstinence vs. NRT was 1.25 and vs. bupropion, 1.4. Lower or variable doses are also effective and reduce side-effects. Varenicline beyond the 12-week standard regimen is well tolerated. Varenicline initiated in hospital following ACS is efficacious and safe.⁵⁰⁰

The main side-effect of varenicline is nausea, but this usually subsides. A causal link between varenicline and neuropsychiatric adverse events is unlikely.⁵⁰¹ Varenicline, bupropion, and NRT do not increase serious CV adverse event risks during or after treatment.⁵⁰²

Cytisine is effective for smoking cessation, but evidence to date is limited.⁴⁹¹

4.5.2.1 Electronic cigarettes

Electronic cigarettes (e-cigarettes) simulate combustible cigarettes by heating nicotine and other chemicals into a vapour. E-cigarettes deliver nicotine without most of the tobacco chemicals, and are probably less harmful than tobacco.

Recent evidence suggests that e-cigarettes are probably more effective than NRT in terms of smoking cessation.^503–505 The long-term effects of e-cigarettes on CV and pulmonary health, however, require more research.⁵⁰⁶ Dual use with cigarettes should be avoided. Furthermore, as e-cigarettes are addictive, their use should be subject to similar marketing controls as standard cigarettes, especially the flavoured varieties that appeal to children.⁵⁰⁷ Despite being lower in toxicants than regular cigarettes, ‘heat-not-burn’ cigarettes do contain tobacco and should be discouraged.

4.6. Lipids

This section covers recommendations for the diagnosis and treatment of unfavourable blood lipid levels. More detail and guidance for complex cases/tertiary care, including genetic lipid disorders, are available in the 2019 ESC/European Atherosclerosis Society (EAS) Guidelines for the management of dyslipidaemias.³

Recent evidence has confirmed that the key initiating event in atherogenesis is the retention of LDL and other cholesterol-rich lipoproteins within the arterial wall. The causal role of LDL-C, and other apo-B-containing lipoproteins, in the development of ASCVD is demonstrated beyond any doubt by genetic, observational, and interventional studies.²⁰ Meta-analysis of clinical trials has indicated that the relative reduction in CVD risk is proportional to the absolute reduction of LDL-C, irrespective of the drug(s) used to achieve such change, with no evidence of a lower limit for LDL-C values or ‘J-curve’ effect.²¹ The absolute benefit of lowering LDL-C depends on the absolute risk of ASCVD and the absolute reduction in LDL-C, so even a small absolute reduction in LDL-C may translate to significant absolute risk reduction in a high- or very-high-risk patient.²² A recent LDL-C target-driven RCT in patients after ischaemic stroke or transient ischaemic attack (TIA) demonstrated a target LDL-C level of <1.8 mmol/L (70 mg/dL) with the use of statin and, if required, ezetimibe, was associated with a lower CVD risk than those who had a target range of 2.3–2.8 mmol/L (90–110 mg/dL).⁵⁰⁸ Studies on the clinical safety of (very) low achieved LDL-C values have not caused particular concerns, although monitoring for longer periods is required.

4.6.1. Measurement of lipids and lipoproteins

4.6.1.1 Fasting vs. non-fasting measurements

Non-fasting sampling of lipid parameters is recommended for general risk screening, since it has the same prognostic value as fasting samples.⁵⁰⁹^,⁵¹⁰ In patients with metabolic syndrome, DM, or hypertriglyceridaemia, calculated LDL-C from non-fasting samples should be interpreted with care.

4.6.1.2 Low-density lipoprotein cholesterol measurement

LDL-C can be measured directly, but in most studies and many laboratories, LDL-C is calculated using the Friedewald formula:

In mmol/L: LDL-C = total cholesterol – HDL-C – (0.45 × trigly-cerides)
In mg/dL: LDL-C = total cholesterol – HDL-C – (0.2 × trigly-cerides)

The calculation is only valid when the concentration of triglycerides is <4.5 mmol/L (∼400 mg/dL), and not precise when LDL-C is very low [<1.3 mmol/L (50 mg/dL)]. In patients with low LDL-C levels and/or hypertriglyceridaemia (≤800 mg/dL), alternative formulae are available⁵¹¹^,⁵¹² or LDL-C can be measured directly.

4.6.1.3 Non-high-density lipoprotein cholesterol

The non-HDL-C value is calculated by subtracting HDL-C from total cholesterol. Non-HDL-C, unlike LDL-C, does not require the triglyceride concentration to be <4.5 mmol/L (400 mg/dL). It also has an advantage in that it is accurate in a non-fasting setting, and may be more accurate in patients with DM. There is evidence for a role of non-HDL-C as a treatment target as it captures the information regarding all apolipoprotein-B-containing lipoproteins.⁵¹³ We suggest it as a reasonable alternative treatment goal for all patients, particularly for those with hypertriglyceridaemia or DM. How non-HDL-C levels correspond to commonly used LDL-C goals is shown in Table 10.

Table 10

Corresponding non-high-density lipoprotein cholesterol and apolipoprotein B levels for commonly used low-density lipoprotein cholesterol goals

LDL-C	Non-HDL-C	Apolipoprotein B
2.6 mmol/L (100 mg/dL)	3.4 mmol/L (131 mg/dL)	100 mg/dL
1.8 mmol/L (70 mg/dL)	2.6 mmol/L (100 mg/dL)	80 mg/dL
1.4 mmol/L (55 mg/dL)	2.2 mmol/L (85 mg/dL)	65 mg/dL

LDL-C	Non-HDL-C	Apolipoprotein B
2.6 mmol/L (100 mg/dL)	3.4 mmol/L (131 mg/dL)	100 mg/dL
1.8 mmol/L (70 mg/dL)	2.6 mmol/L (100 mg/dL)	80 mg/dL
1.4 mmol/L (55 mg/dL)	2.2 mmol/L (85 mg/dL)	65 mg/dL

HDL-C = high-density lipoprotein cholesterol; LDL-C = low-density lipoprotein cholesterol.

Table 10

Corresponding non-high-density lipoprotein cholesterol and apolipoprotein B levels for commonly used low-density lipoprotein cholesterol goals

LDL-C	Non-HDL-C	Apolipoprotein B
2.6 mmol/L (100 mg/dL)	3.4 mmol/L (131 mg/dL)	100 mg/dL
1.8 mmol/L (70 mg/dL)	2.6 mmol/L (100 mg/dL)	80 mg/dL
1.4 mmol/L (55 mg/dL)	2.2 mmol/L (85 mg/dL)	65 mg/dL

LDL-C	Non-HDL-C	Apolipoprotein B
2.6 mmol/L (100 mg/dL)	3.4 mmol/L (131 mg/dL)	100 mg/dL
1.8 mmol/L (70 mg/dL)	2.6 mmol/L (100 mg/dL)	80 mg/dL
1.4 mmol/L (55 mg/dL)	2.2 mmol/L (85 mg/dL)	65 mg/dL

HDL-C = high-density lipoprotein cholesterol; LDL-C = low-density lipoprotein cholesterol.

4.6.1.4 Apolipoprotein B

Apolipoprotein B provides a direct estimate of the total concentration of atherogenic lipid particles, particularly in patients with elevated triglycerides. However, on average, the information conferred by apolipoprotein B is similar to that of calculated LDL-C.⁵¹⁴ How apolipoprotein B levels correspond to commonly used LDL-C goals is shown in Table 10.

4.6.2. Defining lipid goals

4.6.2.1 Low-density lipoprotein cholesterol goals

Recommendation on low-density lipoprotein cholesterol goals^a

ASCVD = atherosclerotic cardiovascular disease; DM = diabetes mellitus.

a

Recommendation from section 3.2.

b

Class of recommendation.

c

Level of evidence.

LDL-C goals are summarized in the recommendations below. As not all drugs are tolerated or available/affordable, treatment should focus on achieving LDL-C levels as close as possible to the given goals. Treatment should be a shared decision-making process between physicians and the patient.

As explained earlier in these guidelines (section 3.2.3.1), we propose a stepwise approach to treatment goals, also for LDL-C (Figures 6–8). This approach may seem novel but, in reality, resembles clinical practice, where treatment intensification is considered based on anticipated benefit, side-effects, and—importantly—patient preferences. The ultimate lipid goals are the same as in the 2019 ESC/EAS dyslipidaemia Guidelines.³ Evidence from glucose-lowering treatment studies indicates that stepwise treatment does not compromise goal attainment, and is associated with fewer side-effects and higher patient satisfaction.⁶⁶^,⁶⁷ In specific cases (at very high risk), the physician may opt to merge both steps and proceed directly to the low LDL-C target level of STEP 2. In apparently healthy people, lifetime treatment benefit of LDL-C reduction may play a role in shared decision-making, together with risk modifiers, comorbidities, patient preference, and frailty. Figure 12 may support decision-making, as it shows the estimated lifetime benefits in years-free-of-CVD in relation to the total CVD risk profile, calibrated in low-to-moderate CVD risk countries.

After STEP 1, treatment intensification with STEP 2 must be considered in all patients. Given that lower is better, we encourage liberal intensification of treatment, particularly if submaximal doses of (low-cost) generic statins are used and side-effects are not apparent.

The treatment goal of LDL-C <1.4 mmol/L (55 mg/dL) in STEP 2, in patients with established ASCVD or without ASCVD but at very high risk, is lower than the lowest LDL-C goal of 1.8 mmol/L (70 mg/dL) in the 2016 ESC prevention Guidelines.² This low goal was established based on data from recent Mendelian randomization studies,⁸⁰ meta-analyses from the Cholesterol Treatment Trialists’ Collaboration,²¹ RCTs such as IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial),⁵¹⁵ and—more recently—proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor clinical outcome studies.^516–518 The class and level of evidence supporting this LDL-C target of <1.4 mmol/L (55 mg/dL) for patients with ASCVD is identical to that in the recent ESC/EAS dyslipidaemia guidelines.³ For primary prevention in very-high-risk patients, however, the class of recommendation is lower (Class I in the dyslipidaemia guidelines, Class IIa in the current guidelines), because the Task Force was less unanimous with regards to this low LDL-C target in the primary prevention context.

For patients with ASCVD who experience a second vascular event within 2 years (not necessarily of the same type as the first) while taking maximum tolerated statin-based therapy, an even lower LDL-C goal of <1.0 mmol/L (40 mg/dL) may be considered. Importantly, there are no differences in the RR reductions between men and women and between younger and older patients (at least up to age 75 years), or between those with and without DM.³

4.6.2.2 Triglyceride-rich lipoproteins and their remnants

There are no treatment goals for triglycerides, but <1.7 mmol/L (150 mg/dL) is considered to indicate lower risk, whereas higher levels indicate a need to look for other risk factors.

4.6.2.3 High-density lipoprotein cholesterol

To date, no specific goals for HDL-C levels have been determined in clinical trials, although low HDL-C is associated with (residual) risk in ASCVD patients. PA and other lifestyle factors, rather than drug treatment, remain important means of increasing HDL-C levels.

4.6.3. Strategies to control dyslipidaemias

The presence of dyslipidaemias secondary to other conditions must be excluded before beginning treatment, as treatment of underlying disease may improve hyperlipidaemia without requiring lipid-lowering therapy. This is particularly true for hypothyroidism. Secondary dyslipidaemias can also be caused by alcohol abuse, DM, Cushing’s syndrome, diseases of the liver and kidneys, as well as by drugs (e.g. corticosteroids). In addition, lifestyle optimization is crucial in all patients with higher than optimal lipid levels.

4.6.3.1 Strategies to control low-density lipoprotein cholesterol

4.6.3.1.1. Diet and lifestyle modifications

Dietary factors influence the development of ASCVD, either directly or through their action on traditional risk factors, such as plasma lipids, BP, or glucose levels. Consistent evidence from epidemiological studies indicates that higher consumption of fruit, non-starchy vegetables, nuts, legumes, fish, vegetable oils, yoghurt, and wholegrains, along with a lower intake of red and processed meats, foods higher in refined carbohydrates, and salt, is associated with a lower incidence of CV events.⁵¹⁹ Moreover, the replacement of animal fats, including dairy fat, with vegetable sources of fats and PUFAs may decrease the risk of ASCVD.⁴⁰⁷ More detail on lifestyle recommendations can be found earlier in this section.

4.6.3.1.2. Drugs for treatment of dyslipidaemias

The currently available lipid-lowering drugs include inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (statins), fibrates, bile acid sequestrants, selective cholesterol absorption inhibitors (e.g. ezetimibe), and—more recently—PCSK9 inhibitors. Bempedoic acid, an oral cholesterol synthesis inhibitor, has recently been approved in several countries. Usage is mainly intended in combination with ezetimibe in patients with statin intolerance. ASCVD outcome trials are not expected before the end of 2022. Additionally, inclisiran, a new small interfering ribonucleic acid, has shown to reduce LDL-C by 50–55% when applied subcutaneously twice a year. These results were obtained either on top of statin or without other lipid-lowering therapies, and with almost no side-effects. Inclisiran has been approved in several European countries. Results from the ASCVD outcomes trial are expected for 2023.

The expected LDL-C reductions in response to therapy are shown in Figure 13, and may vary widely among individuals. Therefore, monitoring the effect on LDL-C levels is recommended, with assessment of LDL-C levels 4 − 6 weeks after any treatment strategy initiation or change.

Recommendations for pharmacological low-density lipoprotein cholesterol lowering for those <70 years of age (for recommendations for persons aged ≥70 years, see respective recommendations tables).

ASCVD = atherosclerotic cardiovascular disease; FH = familial hypercholesterolaemia; LDL-C = low-density lipoprotein cholesterol; PCSK9 = proprotein convertase subtilisin/kexin type 9.

a

Class of recommendation.

b

Level of evidence.

c

A stepwise approach to LDL-C targets is recommended; see section 3.2.3.1 and Figures 6 and 7. Adapted from ³

4.6.3.1.3. Statins

Statins decrease LDL-C, thereby reducing ASCVD morbidity and mortality as well as the need for coronary artery interventions. Statins also lower triglycerides, and may reduce pancreatitis risk. Therefore, they are the drug of first choice in patients at increased risk of ASCVD.³

4.6.3.1.3.1. Adverse effects, interactions, and adherence to statin therapy

The most frequent adverse effect of statin therapy is myopathy, but this is rare. A meta-analysis ruled out any contribution to an increase in non-CV mortality.⁵²² Increased blood sugar and HbA1c levels (i.e. increased risk of type 2 DM) can occur after treatment initiation and are dose dependent, in part linked to slight weight gain, but the benefits of statins outweigh the risks for the majority of patients.⁵²⁷ Adhering to lifestyle changes when prescribed a statin should lessen the risk of DM. Increased levels of liver enzymes may occur during statin therapy, and are usually reversible. Routine monitoring of liver enzyme values is not indicated.

Although 5–10% of patients receiving statins complain of myalgia, in most cases it is not attributable to statins.³ The risk of myopathy (severe muscular symptoms) can be minimized by identifying vulnerable patients and/or by avoiding statin interactions with specific drugs. Rhabdomyolysis is extremely rare. As statins are prescribed on a long-term basis, possible interactions with other drugs deserve particular and continuous attention, as many patients will receive pharmacological therapy for concomitant conditions. In practice, management of a patient with myalgia but without a major increase in creatine kinase is based on trial and error, and usually involves switching to a different statin or use of a very low dosage several days a week, with a gradual increase in frequency and dosage. A management algorithm may help to manage these patients.³

4.6.3.1.4. Cholesterol absorption inhibitors (ezetimibe)

The combination of statin with ezetimibe brings a benefit that is in line with meta-analyses showing that LDL-C reduction has benefits independent of the approach used.³^,²¹ The beneficial effect of ezetimibe is also supported by genetic studies.⁵²⁸ Together, these data support the position that ezetimibe should be considered as second-line therapy, either on top of statins when the therapeutic goal is not achieved, or when a statin cannot be prescribed.

4.6.3.1.5. Proprotein convertase subtilisin/kexin type 9 inhibitors

PCSK9 inhibitors (monoclonal antibodies to PCSK9) decrease LDL-C by up to 60%, either as monotherapy or in addition to the maximum tolerated dose of statin and/or other lipid-lowering therapies, such as ezetimibe. Their efficacy appears to be largely independent of background therapy. In combination with high-intensity or maximum tolerated statins, alirocumab and evolocumab reduced LDL-C by 46–73% more than placebo, and by 30% more than ezetimibe.⁵¹⁶^,⁵¹⁷ Among patients in whom statins cannot be prescribed, PCSK9 inhibition reduced LDL-C levels when administered in combination with ezetimibe.⁵²⁹ Both alirocumab and evolocumab effectively lower LDL-C levels in patients who are at high or very high CVD risk, including those with DM, with a large reduction in future ASCVD events.⁵¹⁶^,⁵¹⁷ PCSK9 inhibitors also lower triglycerides, raise HDL-C and apolipoprotein A-I, and lower lipoprotein(a), although the relative contributions of these lipid modifications remain unknown. PCSK9 inhibitors are costly, and their cost-effectiveness, long-term safety, and effect in primary prevention are as yet unknown. We recommend considering cost-effectiveness in a loco-regional context before implementing recommendations that involve their use. Recommendations for the use of PCSK9 inhibitors are described in the Recommendations for pharmacological LDL-C lowering. Inclisiran is a long-acting hepatic PCSK9 synthesis inhibitor that also lowers LDL-C levels considerably.⁵³⁰ Its effect on clinical outcomes remains to be established.

4.6.3.2 Strategies to control plasma triglycerides

Although CVD risk is increased when fasting triglycerides are >1.7 mmol/L (150 mg/dL),⁵³¹ the use of drugs to lower triglyceride levels may only be considered in high-risk patients when triglycerides are >2.3 mmol/L (200 mg/dL) and triglycerides cannot be lowered by lifestyle measures. The available pharmacological interventions include statins, fibrates, PCSK9 inhibitors, and n-3 PUFAs (in particular icosapent ethyl in doses of 2–4 g/day; see section 4.3.2.4.4).

Recommendations for the treatment of hypertriglyceridaemia are shown in the Recommendations below.

4.6.3.2.1. Fibrates

Fibrates are used primarily for triglyceride lowering and, occasionally, for increasing HDL-C. Evidence supporting the use of these drugs for CVD event reduction is limited, and given the strong evidence favouring statins, routine use of these drugs in CVD prevention is not recommended.³ To prevent pancreatitis, when triglycerides are >10 mmol/L (900 mg/dL), they must be reduced not only by drugs, but also by restriction of alcohol, treatment of DM, withdrawal of oestrogen therapy, etc. In patients with severe primary hypertriglyceridaemia, referral to a specialist must be considered.

An evidence-based approach to the use of lipid-lowering nutraceuticals could improve the quality of the treatment, including therapy adherence, and achievement of the LDL-C goal in clinical practice. However, it has to be clearly stressed that there are still no outcome studies proving that nutraceuticals can prevent CVD morbidity or mortality.⁵³²

Recommendations for drug treatments of patients with hypertriglyceridaemia.

CVD = cardiovascular disease; LDL-C = low-density lipoprotein cholesterol; PUFA = polyunsaturated fatty acid.

a

Class of recommendation.

b

Level of evidence. Adapted from ³

4.6.4. Important groups

4.6.4.1 Women

The proportional reductions per mmol/L reduction in LDL-C in major vascular events, major coronary events, coronary revascularization, and stroke are similar in women and men. In addition, the relative effects of non-statin drugs that lower LDL-C (ezetimibe and PCSK9 inhibitors, on top of high-intensity statin therapy) are also similar in both women and men.³

4.6.4.2 Older patients (≥70 years)

Compared to the 2019 ESC/EAS dyslipidaemia guidelines,³ we provide a single cut-off for identifying ‘older persons’ as those ≥70 years of age, as opposed to 75 years, for reasons of consistency with other parts of the current guidelines. As a result, class and level of evidence have been modified in some age groups, in particular the category of patients between 70 and 75 years. Although a single age cut-off is now used, it is important to stress that all such age cut-offs are relatively arbitrary, and biological age influences this threshold in clinical practice. For example, a very fit 75-year-old person may qualify for a treatment normally reserved for those <70 and, conversely, a very frail 65-year-old person should sometimes be considered ‘older’. General recommendations for lipid-lowering treatment in older patients are summarized below.

Recent evidence has strengthened the role of LDL-C as an ASCVD risk factor in older patients.⁵³⁷ Evidence from trials indicates that statins and other lipid-lowering drugs produce significant reductions in major vascular events irrespective of age.⁵³⁸^,⁵³⁹ However, there is less direct evidence of statin benefit in those without evidence of ASCVD. Under the age of 70 years, statins are recommended for primary prevention depending on the level of risk. Above that age, initiation of statin treatment for primary prevention may be considered when at (very) high risk, but we explicitly recommend also taking other arguments into account, such as risk modifiers, frailty, estimated life-time benefit, comorbidities, and patient preferences (see section 3.2.3.3 and Figure 12). In case of renal function impairment or risk for drug interactions, the statin dose should be up-titrated carefully. In terms of LDL-C targets, there is insufficient evidence to support targets for primary prevention in older patients. Although the conventional LDL-C target of <2.6 mmol/L (100 mg/dL) may seem reasonable, the results of ongoing primary prevention trials in older patients must be awaited [STAREE (STAtin Therapy for Reducing Events in the Elderly) trial; clinicatrials.gov registration: NCT02099123]. Frailty, polypharmacy, and muscle symptoms remain relevant factors to consider in older patients.

Recommendations for the treatment of dyslipidaemias in older people (≥70 years).

ASCVD = atherosclerotic cardiovascular disease.

a

Class of recommendation.

b

Level of evidence. Adapted from ³

4.6.4.3 Diabetes mellitus

Lowering of LDL-C in patients with DM is consistently associated with lower CVD risk. Similar to prevention in apparently healthy individuals, we propose a stepwise approach to lipid control, dependent on risk, estimated lifetime benefit, comorbidities, and patient preferences (Figure 8). PCSK9 inhibitors can also be used in patients with DM not reaching their LDL-C targets with statins and/or ezetimibe.

Recommendations for the treatment of dyslipidaemias in diabetes mellitus.

ASCVD = atherosclerotic cardiovascular disease; DM = diabetes mellitus; eGFR = estimated glomerular filtration rate; LDL-C = low-density lipoprotein cholesterol; TOD = target organ damage.

a

Class of recommendation.

b

Level of evidence.

c

Severe TOD in this specific context includes eGFR <45 mL/min/1.73 m²; eGFR 46–79 mL/min/1.73 m² plus microalbuminuria; proteinuria; presence of microvascular disease in at least three different sites (e.g. albuminuria plus retinopathy plus neuropathy). See Table 4 for details.

d

A stepwise approach to LDL-C targets is recommended; see section 3.2.3.1 and Figure 8. Adapted from ³

Figure 8

Flow chart of cardiovascular risk and risk factor treatment in patients with type 2 diabetes mellitus. Ultimate treatment goals for SBP (<130 mmHg) and LDL-C (according to level of risk) according to the respective ESC Guidelines³^,⁴ are to be pursued as indicated. The stepwise approach has to be applied as a whole: after STEP 1, considering proceeding to the intensified goals of STEP 2 is mandatory. Risk scores are available in the ESC CVD Risk Calculator app for mobile devices (https://www.escardio.org/Education/ESC-Prevention-of-CVD-Programme/Risk-assessment/esc-cvd-risk-calculation-app) and at websites such as https://www.u-prevent.com. ACR = albumin-to-creatinine ratio; ASCVD = atherosclerotic cardiovascular disease; CKD = chronic kidney disease; CVD = cardiovascular disease; DAPT = dual antiplatelet therapy; DM = diabetes mellitus; eGFR = estimated glomerular filtration rate; ESC = European Society of Cardiology; GLP-1RA = glucagon-like peptide-1 receptor agonist; HbA1c = glycated haemoglobin; HF = heart failure; LDL-C = low-density lipoprotein cholesterol; SBP = systolic blood pressure; SGLT2 = sodium-glucose cotransporter 2; TOD = target organ damage (retinopathy, nephropathy, neuropathy). ^aSevere TOD is defined as at least one of: eGFR <45 mL/min/1.73 m² irrespective of the presence or absence of albuminuria; eGFR 46–59 mL/min/1.73 m² and microalbuminuria (ACR 30–300 mg/g or 3–30 mg/mmol); proteinuria (ACR >300 mg/g or >30 mg/mmol); presence of microvascular disease in at least three different sites (e.g. microalbuminuria plus retinopathy plus neuropathy). ^bSee Table 4 for CVD risk groups. ^cPatients with prevalent HF or CKD are recommended for SGLT2 inhibitor, and patients post stroke are recommended for GLP-1RA treatment. ^dLifetime treatment benefit is expressed as extra CVD-free life gained from a certain intervention or treatment intensification. See Box 1.

The role of risk factors and comorbidities in atrial fibrillation.215 AF = atrial fibrillation; CAD = coronary artery disease; COPD = chronic obstructive pulmonary disease; CV = cardiovascular; DM = diabetes mellitus; HF = heart failure; OSA = obstructive sleep apnoea.

Figure 9

The role of risk factors and comorbidities in atrial fibrillation.²¹⁵ AF = atrial fibrillation; CAD = coronary artery disease; COPD = chronic obstructive pulmonary disease; CV = cardiovascular; DM = diabetes mellitus; HF = heart failure; OSA = obstructive sleep apnoea.

Figure 10

Estimated percentage change in risk of coronary heart disease associated with isocaloric substitutions of saturated fat for other types of fat or carbohydrates. Reproduced from Sacks et al.⁴⁰⁹ MUFA = monounsaturated fatty acid; PUFA = polyunsaturated fatty acid.

Figure 11

Lifetime atherosclerotic cardiovascular disease benefit from smoking cessation for apparently healthy persons, based on the following risk factors: age, sex, systolic blood pressure, and non-high-density lipoprotein-cholesterol. The model is currently validated for low- and moderate-risk countries. CVD = cardiovascular disease; ESC = European Society of Cardiology; HDL-C = high-density lipoprotein cholesterol; HR = hazard ratio; LIFE-CVD = LIFEtime-perspective CardioVascular Disease; SBP = systolic blood pressure. The lifetime benefit is expressed as ‘years of median life expectancy free from myocardial infarction or stroke’ gained from smoking cessation. The lifetime benefit is calculated by estimating lifetime CVD risk with the LIFE-CVD model⁷⁶ multiplied by the HR compared to sustained smoking (0.60) from a meta-analysis of studies on the CVD risk of smoking⁴⁹⁶ and multiplied by the HR (0.73) for non-CVD competing mortality.⁴⁹⁷ For individualized estimations of lifetime benefit, this table can be used or the electronic version of LIFE-CVD, assessable via the ESC CVD risk app or https://u-prevent.com/.

Figure 12

Average years-free-of-cardiovascular disease gained per 1 mmol/L (40 mg/dL) low-density lipoprotein cholesterol reduction in apparently healthy persons. The model is currently validated for low- and moderate-risk countries. Lifetime benefit of 1 mmol/L LDL-C lowering for apparently healthy persons, based on the following risk factors: age, sex, current smoking, SBP, and non-HDL-C. The lifetime benefit is expressed as ‘years of median life expectancy free from myocardial infarction or stroke’ gained from 1 mmol/L LDL-C lowering. For 2 mmol/L LDL-C lowering, the average effect is almost twice as large, and so on. The lifetime benefit is calculated by estimating lifetime CVD risk with the LIFE-CVD model⁷⁶ multiplied by the HR (0.78) from a meta-analysis of the effect of lipid lowering.²² For individualized estimations of lifetime benefit, this table can be used or the electronic version of LIFE-CVD, assessable via the ESC CVD risk app or https://u-prevent.com/. CVD = cardiovascular disease; ESC = European Society of Cardiology; HDL-C = high-density lipoprotein cholesterol; HR = hazard ratio; LDL-C = low-density lipoprotein cholesterol; LIFE-CVD = LIFEtime-perspective CardioVascular Disease; SBP = systolic blood pressure.

4.6.4.4 Chronic kidney disease

Patients with CKD are at high or very high risk of ASCVD, and have a characteristic dyslipidaemia (high triglycerides, normal LDL-C, and low HDL-C). Statin therapy or statin therapy in combination with ezetimibe (which allows larger LDL-C reductions without increasing the statin dose) has a beneficial effect on ASCVD outcomes in CKD.⁵⁴³ For patients with end-stage renal disease, however, we recommend that hypolipidaemic therapy should not be initiated (see Recommendations below). If patients with CKD already on a hypolipidaemic therapy enter end-stage renal disease, the therapy may be maintained.

Recommendations for lipid management in patients with moderate-to-severe chronic kidney disease (Kidney Disease Outcomes Quality Initiative stages 3–5).

ASCVD = atherosclerotic cardiovascular disease; CKD = chronic kidney disease.

a

Class of recommendation.

b

Level of evidence. Adapted from ³

4.6.4.5 Familial Hypercholesterolaemia

Patients who could have genetic dyslipidaemias, such as heterozygous FH, can be identified by extreme lipid abnormalities and/or family history (Table 11). An LDL-C >4.9 mmol/L (190 mg/dL) in therapy-naïve patients requires careful evaluation for possible FH. However, in the presence of premature ASCVD or family history, possible FH should be considered at lower LDL-C levels. Besides genetic testing (not always affordable), use of the Dutch Clinical Lipid Network criteria (Table 11) is recommended to identify possible FH. Homozygous FH is rare and should always be placed under the care of lipid experts.

Table 11

Dutch Lipid Clinic Network diagnostic criteria for familial hypercholesterolaemia

Criteria (choose only one score per group, the highest applicable; diagnosis is based on the total number of points obtained)	Points
1) Family history
First-degree relative with known premature (men aged <55 years; women <60 years) coronary or vascular disease, or first-degree relative with known LDL-C above the 95^th percentile	1
First-degree relative with tendinous xanthomata and/or arcus cornealis, or children aged <18 years with LDL-C above the 95th percentile	2
2) Clinical history
Patient with premature (men aged <55 years; women <60 years) CAD	2
Patient with premature (men aged <55 years; women <60 years) cerebral or peripheral vascular disease	1
3) Physical examination
Tendinous xanthomata	6
Arcus cornealis before age 45 years	4
4) LDL-C levels (without treatment)
LDL-C ≥8.5 mmol/L (326 mg/dL)	8
LDL-C 6.5–8.4 mmol/L (251–325 mg/dL)	5
LDL-C 5.0–6.4 mmol/L (191–250 mg/dL)	3
LDL-C 4.0–4.9 mmol/L (155–190 mg/dL)	1
5) DNA analysis
Functional mutation in the LDLR, apolipoprotein B, or PCSK9 genes	8
A ‘definite’ FH diagnosis requires >8 points
A ‘probable’ FH diagnosis requires 6–8 points
A ‘possible’ FH diagnosis requires 3–5 points

Criteria (choose only one score per group, the highest applicable; diagnosis is based on the total number of points obtained)	Points
1) Family history
First-degree relative with known premature (men aged <55 years; women <60 years) coronary or vascular disease, or first-degree relative with known LDL-C above the 95^th percentile	1
First-degree relative with tendinous xanthomata and/or arcus cornealis, or children aged <18 years with LDL-C above the 95th percentile	2
2) Clinical history
Patient with premature (men aged <55 years; women <60 years) CAD	2
Patient with premature (men aged <55 years; women <60 years) cerebral or peripheral vascular disease	1
3) Physical examination
Tendinous xanthomata	6
Arcus cornealis before age 45 years	4
4) LDL-C levels (without treatment)
LDL-C ≥8.5 mmol/L (326 mg/dL)	8
LDL-C 6.5–8.4 mmol/L (251–325 mg/dL)	5
LDL-C 5.0–6.4 mmol/L (191–250 mg/dL)	3
LDL-C 4.0–4.9 mmol/L (155–190 mg/dL)	1
5) DNA analysis
Functional mutation in the LDLR, apolipoprotein B, or PCSK9 genes	8
A ‘definite’ FH diagnosis requires >8 points
A ‘probable’ FH diagnosis requires 6–8 points
A ‘possible’ FH diagnosis requires 3–5 points

CAD = coronary artery disease; DNA = deoxyribonucleic acid; FH = familial hypercholesterolaemia; LDL-C = low-density lipoprotein cholesterol; LDLR = low-density lipoprotein receptor; PCSK9 = proprotein convertase subtilisin/kexin type 9.

Table 11

Dutch Lipid Clinic Network diagnostic criteria for familial hypercholesterolaemia

Criteria (choose only one score per group, the highest applicable; diagnosis is based on the total number of points obtained)	Points
1) Family history
First-degree relative with known premature (men aged <55 years; women <60 years) coronary or vascular disease, or first-degree relative with known LDL-C above the 95^th percentile	1
First-degree relative with tendinous xanthomata and/or arcus cornealis, or children aged <18 years with LDL-C above the 95th percentile	2
2) Clinical history
Patient with premature (men aged <55 years; women <60 years) CAD	2
Patient with premature (men aged <55 years; women <60 years) cerebral or peripheral vascular disease	1
3) Physical examination
Tendinous xanthomata	6
Arcus cornealis before age 45 years	4
4) LDL-C levels (without treatment)
LDL-C ≥8.5 mmol/L (326 mg/dL)	8
LDL-C 6.5–8.4 mmol/L (251–325 mg/dL)	5
LDL-C 5.0–6.4 mmol/L (191–250 mg/dL)	3
LDL-C 4.0–4.9 mmol/L (155–190 mg/dL)	1
5) DNA analysis
Functional mutation in the LDLR, apolipoprotein B, or PCSK9 genes	8
A ‘definite’ FH diagnosis requires >8 points
A ‘probable’ FH diagnosis requires 6–8 points
A ‘possible’ FH diagnosis requires 3–5 points

Criteria (choose only one score per group, the highest applicable; diagnosis is based on the total number of points obtained)	Points
1) Family history
First-degree relative with known premature (men aged <55 years; women <60 years) coronary or vascular disease, or first-degree relative with known LDL-C above the 95^th percentile	1
First-degree relative with tendinous xanthomata and/or arcus cornealis, or children aged <18 years with LDL-C above the 95th percentile	2
2) Clinical history
Patient with premature (men aged <55 years; women <60 years) CAD	2
Patient with premature (men aged <55 years; women <60 years) cerebral or peripheral vascular disease	1
3) Physical examination
Tendinous xanthomata	6
Arcus cornealis before age 45 years	4
4) LDL-C levels (without treatment)
LDL-C ≥8.5 mmol/L (326 mg/dL)	8
LDL-C 6.5–8.4 mmol/L (251–325 mg/dL)	5
LDL-C 5.0–6.4 mmol/L (191–250 mg/dL)	3
LDL-C 4.0–4.9 mmol/L (155–190 mg/dL)	1
5) DNA analysis
Functional mutation in the LDLR, apolipoprotein B, or PCSK9 genes	8
A ‘definite’ FH diagnosis requires >8 points
A ‘probable’ FH diagnosis requires 6–8 points
A ‘possible’ FH diagnosis requires 3–5 points

CAD = coronary artery disease; DNA = deoxyribonucleic acid; FH = familial hypercholesterolaemia; LDL-C = low-density lipoprotein cholesterol; LDLR = low-density lipoprotein receptor; PCSK9 = proprotein convertase subtilisin/kexin type 9.

Table 12

Categories for conventionally measured seated office blood pressure^a

Category	SBP (mmHg)		DBP (mmHg)
Optimal	<120	and	<80
Normal	120–129	and/or	80–84
High-normal	130–139	and/or	85–89
Grade 1 hypertension	140–159	and/or	90–99
Grade 2 hypertension	160–179	and/or	100–109
Grade 3 hypertension	≥180	and/or	≥110
Isolated systolic hypertension^b	≥140	and	<90

Category	SBP (mmHg)		DBP (mmHg)
Optimal	<120	and	<80
Normal	120–129	and/or	80–84
High-normal	130–139	and/or	85–89
Grade 1 hypertension	140–159	and/or	90–99
Grade 2 hypertension	160–179	and/or	100–109
Grade 3 hypertension	≥180	and/or	≥110
Isolated systolic hypertension^b	≥140	and	<90

BP = blood pressure; DBP = diastolic blood pressure; SBP = systolic blood pressure.

a

BP category is defined according to seated clinic BP and by the highest level of BP, whether systolic or diastolic.

b

Isolated systolic hypertension is graded 1, 2, or 3 according to SBP values in the ranges indicated.

Table 12

Categories for conventionally measured seated office blood pressure^a

Category	SBP (mmHg)		DBP (mmHg)
Optimal	<120	and	<80
Normal	120–129	and/or	80–84
High-normal	130–139	and/or	85–89
Grade 1 hypertension	140–159	and/or	90–99
Grade 2 hypertension	160–179	and/or	100–109
Grade 3 hypertension	≥180	and/or	≥110
Isolated systolic hypertension^b	≥140	and	<90

Category	SBP (mmHg)		DBP (mmHg)
Optimal	<120	and	<80
Normal	120–129	and/or	80–84
High-normal	130–139	and/or	85–89
Grade 1 hypertension	140–159	and/or	90–99
Grade 2 hypertension	160–179	and/or	100–109
Grade 3 hypertension	≥180	and/or	≥110
Isolated systolic hypertension^b	≥140	and	<90

BP = blood pressure; DBP = diastolic blood pressure; SBP = systolic blood pressure.

a

BP category is defined according to seated clinic BP and by the highest level of BP, whether systolic or diastolic.

b

Isolated systolic hypertension is graded 1, 2, or 3 according to SBP values in the ranges indicated.

Treatment guidelines for people with FH can be found in the 2019 ESC/EAS dyslipidaemia Guidelines.³

4.7. Blood pressure

Summary of recommendations for the clinical management of hypertension

ABPM = ambulatory blood pressure monitoring; ACE = angiotensin-converting enzyme; ACR = albumin-to-creatinine ratio; ARB = angiotensin receptor blocker; ASCVD = atherosclerotic cardiovascular disease; BP = blood pressure; CCB = calcium channel blocker; DBP = diastolic blood pressure; DM = diabetes mellitus; ECG = electrocardiogram; eGFR = estimated glomerular filtration rate; HBPM = home blood pressure monitoring; HMOD = hypertension-mediated organ damage; LV = left ventricular; RAS = renin–angiotensin system; SBP = systolic blood pressure.

a

Class of recommendation.

b

Level of evidence.

c

See section 4.3 for details.

d

See section 4.6 for details.

e

See section 4.9 for details.

Hypertension is one of the most important preventable causes of premature morbidity and mortality. It affects more than 150 million people across Europe, over 1 billion globally, with a prevalence of ∼30–45% in adults, increasing with age to more than 60% in people aged >60 years, and accounting for ∼10 million deaths globally per annum.⁵⁷⁷ Despite extensive evidence for the effectiveness of BP-lowering treatments at reducing CVD risk and death, the detection, treatment, and control of BP in Europe and globally remains suboptimal.⁵⁷⁸

This section covers recommendations for the diagnosis and treatment of hypertension to be applied in routine primary and secondary care. More detail and guidance for complex cases/tertiary care are available in the 2018 ESC/European Society of Hypertension (ESH) Guidelines for the management of arterial hypertension.⁴

4.7.1. Definition and classification of hypertension

BP is classified according to seated office BP (Table 12), with approximately corresponding values according to ABPM or home BP average values in Table 13.

Table 13

Definitions of hypertension according to office, ambulatory, and home blood pressure

Category	SBP (mmHg)		DBP (mmHg)
Office BP^a	≥140	and/or	≥90
Ambulatory BP
Daytime (or awake) mean	≥135	and/or	≥85
Night-time (or asleep) mean	≥120	and/or	≥70
24-h mean	≥130	and/or	≥80
Home BP mean	≥135	and/or	≥85

Category	SBP (mmHg)		DBP (mmHg)
Office BP^a	≥140	and/or	≥90
Ambulatory BP
Daytime (or awake) mean	≥135	and/or	≥85
Night-time (or asleep) mean	≥120	and/or	≥70
24-h mean	≥130	and/or	≥80
Home BP mean	≥135	and/or	≥85

BP = blood pressure; DBP = diastolic blood pressure; SBP = systolic blood pressure.

a

Refers to conventional office BP rather than unattended office BP.

Table 13

Definitions of hypertension according to office, ambulatory, and home blood pressure

Category	SBP (mmHg)		DBP (mmHg)
Office BP^a	≥140	and/or	≥90
Ambulatory BP
Daytime (or awake) mean	≥135	and/or	≥85
Night-time (or asleep) mean	≥120	and/or	≥70
24-h mean	≥130	and/or	≥80
Home BP mean	≥135	and/or	≥85

Category	SBP (mmHg)		DBP (mmHg)
Office BP^a	≥140	and/or	≥90
Ambulatory BP
Daytime (or awake) mean	≥135	and/or	≥85
Night-time (or asleep) mean	≥120	and/or	≥70
24-h mean	≥130	and/or	≥80
Home BP mean	≥135	and/or	≥85

BP = blood pressure; DBP = diastolic blood pressure; SBP = systolic blood pressure.

a

Refers to conventional office BP rather than unattended office BP.

4.7.2. Blood pressure measurement

4.7.2.1 Office blood pressure measurement

Office BP should be measured in standardized conditions using validated auscultatory or (semi)automatic devices, as described in Table 14.

Table 14