ESC GUIDELINES European Heart Journal (2021) 00,1 111 doi:10.1093/eurheartj/ehab484
2021 ESC Guidelines on cardiovascular disease prevention in clinical practice Downloaded from https://academic.oup.com/eurheartj/advance-article/doi/10.1093/eurheartj/ehab484/6358713 by guest on 30 August 2021 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) Authors/Task Force Members: Frank L.J. Visseren* (Chairperson) (Netherlands), Franc¸ois Mach* (Chairperson) (Switzerland), Yvo M. Smulders† (Task Force Coordinator) (Netherlands), David Carballo† (Task Force Coordinator) (Switzerland), Konstantinos C. Koskinas (Switzerland), Maria Back€ (Sweden), Athanase Benetos8 (France), Alessandro Biffi7,10 (Italy), Jose´-ManuelBoavida9 (Portugal), Davide Capodanno (Italy), Bernard Cosyns (Belgium), Carolyn Crawford (Northern Ireland), Constantinos H. Davos (Greece), Ileana Desormais (France), Emanuele Di Angelantonio (United Kingdom), Oscar H. Franco (Switzerland), Sigrun Halvorsen(Norway),F.D.RichardHobbs13 (United Kingdom), Monika Hollander (Netherlands), Ewa A. Jankowska (Poland), Matthias Michal11 (Germany), Simona Sacco6 (Italy), Naveed Sattar (United Kingdom), Lale Tokgozoglu2 (Turkey), Serena Tonstad (Norway), Konstantinos P.Tsioufis5 (Greece), Ineke van Dis3 (Netherlands), Isabelle C. van Gelder (Netherlands), Christoph Wanner4 (Germany), Bryan Williams (United Kingdom), ESC Scientific Document Group
* Corresponding authors: The two chairpersons contributed equally to the document. Frank Visseren, Department of Vascular Medicine, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, Netherlands. Tel: þ31 (0)88 7557324, E-mail: [email protected]. Franc¸ois Mach, Cardiology Department, Geneva University Hospital, Perret-Gentil 4, 1211 Geneva, Switzerland. Tel: þ41 (0)22 372 71 92, E-mail: [email protected]. † The two task force coordinators contributed equally to the document. Author/Task Force Member affiliations: listed in Author information. ESC Clinical Practice Guidelines Committee (CPG): listed in the Appendix. ESC subspecialty communities having participated in the development of this document. Associations: Association of Cardiovascular Nursing & Allied Professions (ACNAP), European Association of Cardiovascular Imaging (EACVI), European Association of Preventive Cardiology (EAPC), European Heart Rhythm Association (EHRA), Heart Failure Association (HFA). Councils: Council on Valvular Heart Disease. Working Groups: Aorta and Peripheral Vascular Diseases, Atherosclerosis and Vascular Biology, Cardiovascular Pharmacotherapy. Patient Forum The content of these European Society of Cardiology (ESC) Guidelines has been published for personal and educational use only. No commercial use is authorized. No part of the ESC Guidelines may be translated or reproduced in any form without written permission from the ESC. Permission can be obtained upon submission of a written request to Oxford University Press, the publisher of the European Heart Journal and the party authorized to handle such permissions on behalf of the ESC ([email protected]). Disclaimer: The ESC Guidelines represent the views of the ESC and were produced after careful consideration of the scientific and medical knowledge and the evidence available at the time of their publication. The ESC is not responsible in the event of any contradiction, discrepancy and/or ambiguity between the ESC Guidelines and any other official recommen- dations or guidelines issued by the relevant public health authorities, in particular in relation to good use of healthcare or therapeutic strategies. Health professionals are encouraged to take the ESC Guidelines fully into account when exercising their clinical judgment, as well as in the determination and the implementation of preventive, diagnostic or therapeutic medical strategies; however, the ESC Guidelines do not override, in any way whatsoever, the individual responsibility of health professionals to make appropriate and accurate deci- sions in consideration of each patient’s health condition and in consultation with that patient and, where appropriate and/or necessary, the patient’s caregiver. Nor do the ESC Guidelines exempt health professionals from taking into full and careful consideration the relevant official updated recommendations or guidelines issued by the competent public health authorities, in order to manage each patient’s case in light of the scientifically accepted data pursuant to their respective ethical and professional obligations. It is also the health professional’s responsibility to verify the applicable rules and regulations relating to drugs and medical devices at the time of prescription.
This article has been co-published with permission in the European Heart Journal and the European Journal of Preventive Cardiology. VC The European Society of Cardiology 2021. All rights reserved. The articles are identical except for minor stylistic and spelling differences in keeping with each journal’s style. Either citation can be used when citing this article. For ermissions, please email: [email protected]. 2 ESC Guidelines
Document Reviewers: Guy De Backer (CPG Review Coordinator) (Belgium), Vera Regitz-Zagrosek (CPG Review Coordinator) (Germany), Anne Hege Aamodt6 (Norway), Magdy Abdelhamid (Egypt), Victor Aboyans (France), Christian Albus11 (Germany), Riccardo Asteggiano (Italy), Magnus Back€ (Sweden), Michael A. Borger (Germany), Carlos Brotons13 (Spain), Jelena Celutkien e_ (Lithuania), Renata Cifkova (Czech Republic), Maja Cikes (Croatia), Francesco Cosentino (Italy), Nikolaos Dagres (Germany), Tine De Backer (Belgium), Dirk De Bacquer (Belgium), Victoria Delgado (Netherlands), Hester Den Ruijter (Netherlands), Paul Dendale (Belgium), Heinz Drexel (Austria), Volkmar Falk (Germany), Laurent Fauchier (France), Brian A. Ference (United Kingdom), Jean Ferrie` res (France), Marc 1 4 Ferrini (France), Miles Fisher (United Kingdom), Danilo Fliser (Germany), Zlatko Fras (Slovenia), Dan Downloaded from https://academic.oup.com/eurheartj/advance-article/doi/10.1093/eurheartj/ehab484/6358713 by guest on 30 August 2021 Gaita3 (Romania), Simona Giampaoli (Italy), Stephan Gielen (Germany), Ian Graham (Ireland), Catriona Jennings (Ireland), Torben Jorgensen (Denmark), Alexandra Kautzky-Willer12 (Austria), Maryam Kavousi (Netherlands), Wolfgang Koenig (Germany), Aleksandra Konradi (Russia), Dipak Kotecha (United Kingdom), Ulf Landmesser (Germany), Madalena Lettino (Italy), Basil S. Lewis (Israel), Ale s Linhart (Czech Republic), Maja-Lisa Løchen (Norway), Konstantinos Makrilakis9 (Greece), Giuseppe Mancia5 (Italy), Pedro Marques-Vidal (Switzerland), John William McEvoy (Ireland), Paul McGreavy (United Kingdom), Bela Merkely (Hungary), Lis Neubeck (United Kingdom), Jens Cosedis Nielsen (Denmark), Joep Perk (Sweden), Steffen E. Petersen (United Kingdom), Anna Sonia Petronio (Italy), Massimo Piepoli (Italy), Nana Goar Pogosova (Russia), Eva Irene Bossano Prescott (Denmark), Kausik K. Ray2 (United Kingdom), Zeljko Reiner (Croatia), Dimitrios J. Richter (Greece), Lars Ryde´ n (Sweden), Evgeny Shlyakhto (Russia), Marta Sitges (Spain), Miguel Sousa-Uva (Portugal), Isabella Sudano (Switzerland), Monica Tiberi7,10 (Italy), Rhian M. Touyz (United Kingdom), Andrea Ungar8 (Italy), W.M. Monique Verschuren (Netherlands), Olov Wiklund (Sweden), David Wood (United Kingdom/Ireland), Jose Luis Zamorano (Spain)
All experts involved in the development of these guidelines have submitted declarations of interest. These have been compiled in a report and published in a supplementary document simultaneously to the guidelines. The report is also available on the ESC website www.escardio.org/guidelines
Collaborating and endorsing societies: 1European Association for the Study of Diabetes (EASD); 2European Atherosclerosis Society (EAS); 3European Heart Network (EHN); 4European Renal Association - European Dialysis and Transplant Association (ERA-EDTA); 5European Society of Hypertension (ESH); 6European Stroke Organization (ESO); 7European Federation of Sports Medicine Association (EFSMA); 8European Geriatric Medicine Society (EuGMS); 9International Diabetes Federation Europe (IDF Europe); 10International Federation of Sport Medicine (FIMS); 11International Society of Behavioural Medicine (ISBM); 12International Society of Gender Medicine (IGM); 13World Organization of National Colleges, Academies and Academic Associations of General Practitioners/Family Physicians (WONCA) Europe
...... Keywords Guidelines • prevention • personalized • population • risk estimation • lifetime risk • lifetime benefit • risk management • shared decision-making • stepwise approach • nutrition • smoking • healthy lifestyle • psychosocial factors • blood pressure • lipids • diabetes • smoking • air pollution • climate change
. Table of Contents . 3.2.1.3 Cigarette smoking ...... 16 . 3.2.1.4 Diabetes mellitus ...... 17 1.Preamble ...... 7 . . 3.2.1.5 Adiposity ...... 17 2.Introduction ...... 8 . . 3.2.2. Sex and gender and their impact on health ...... 17 2.1.Definitionandrationale ...... 9 . . 3.2.3. Atherosclerotic cardiovascular disease risk classification . . . . 17 2.2.Development...... 10 . . 3.2.3.1 A stepwise approach to risk factor treatment and 2.3.Cost-effectiveness ...... 10 . . treatment intensification ...... 17 2.4.Whatisnew? ...... 10 . . 3.2.3.2 Risk estimation in apparently healthy people ...... 19 3.Riskfactorsandclinicalconditions ...... 10 . . 3.2.3.3 Translating cardiovascular disease risk to 3.1. Target population for assessing cardiovascular disease risk . . . . 10 . . treatment thresholds ...... 24 3.2. Risk factors and risk classification ...... 10 . . 3.2.3.4 Risk estimation and risk factor treatment in 3.2.1.Riskfactors...... 10 . . apparently healthy people 50 69 years of age ...... 27 3.2.1.1 Cholesterol ...... 16 . . 3.2.3.5 Risk estimation and risk factor treatment 3.2.1.2 Blood pressure ...... 16 . . estimation in apparently healthy people 70 years of age ...... 27 . ESC Guidelines 3
. 3.2.3.6 Risk estimation and risk factor treatment in . 4.2.2.Howtoimprovemotivation?...... 42 < . apparently healthy people 50 years of age ...... 28 . 4.2.3.Optimizingdrugadherence ...... 42 3.2.3.7 Risk estimation and risk factor treatment in patients . 4.2.4.Treatmentgoals ...... 42 . with established atherosclerotic cardiovascular disease ...... 28 . 4.3.Optimizinglifestyle...... 42 3.2.3.8 Risk estimation and risk factor treatment in persons . 4.3.1.Physicalactivityandexercise ...... 42 . with type 2 diabetes mellitus ...... 30 . 4.3.1.1 Physical activity prescription ...... 43 3.2.3.9 Risk estimation and risk factor treatment in . 4.3.1.2 Aerobic physical activity ...... 43 . persons with type 1 diabetes mellitus ...... 31 . 4.3.1.3 Resistance exercise ...... 43 Downloaded from https://academic.oup.com/eurheartj/advance-article/doi/10.1093/eurheartj/ehab484/6358713 by guest on 30 August 2021 3.2.4. Communication of cardiovascular disease risk ...... 31 . 4.3.1.4 Sedentary behaviour ...... 43 . 3.3.Potentialriskmodifiers ...... 32 . 4.3.2.Nutritionandalcohol ...... 43 3.3.1.Psychosocialfactors ...... 32 . 4.3.2.1 Fatty acids ...... 44 . 3.3.2.Ethnicity...... 32 . 4.3.2.2 Minerals and vitamins ...... 44 3.3.3.Imaging...... 33 . 4.3.2.3 Fibre ...... 44 . 3.3.3.1 Coronary artery calcium ...... 33 . 4.3.2.4 Specific foods and food groups ...... 44 3.3.3.2 Contrast computed tomography coronary . 4.3.2.4.1. Fruits, vegetables, and pulses ...... 44 . angiography ...... 33 . 4.3.2.4.2.Nuts...... 45 3.3.3.3 Carotid ultrasound ...... 33 . 4.3.2.4.3.Meat...... 45 . 3.3.3.4 Arterial stiffness ...... 33 . 4.3.2.4.4. Fish and fish oil supplements ...... 45 3.3.3.5 Ankle brachial index ...... 33 . 4.3.2.4.5.Alcoholicbeverages ...... 45 . 3.3.3.6 Echocardiography ...... 33 . 4.3.2.4.6.Softdrinksandsugar...... 46 3.3.4.Frailty ...... 33 . 4.3.2.4.7.Coffee ...... 46 . 3.3.5.Familyhistory...... 33 . 4.3.2.4.8.Functionalfoods...... 46 3.3.6.Genetics ...... 34 . 4.3.2.4.9.Dietarypatterns...... 46 . 3.3.7.Socioeconomicdeterminants ...... 34 . 4.3.3.Bodyweightandcomposition...... 46 . 3.3.8.Environmentalexposure ...... 34 . 4.3.3.1 Treatment goals and modalities ...... 46 3.3.9.Biomarkersinbloodorurine...... 34 . 4.3.3.2 Diets for weight loss ...... 46 . 3.3.10.Bodycomposition ...... 34 . 4.4. Mental healthcare and psychosocial interventions ...... 47 3.3.10.1 Which index of obesity is the best predictor of . 4.5.Smokingintervention ...... 47 . cardiovascular risk? ...... 35 . 4.5.1.Smokingcessation ...... 47 3.3.10.2 Risk reclassification ...... 35 . 4.5.2. Evidence-based drug interventions ...... 49 . 3.3.10.3 Assess risk factors and cardiovascular disease . 4.5.2.1 Electronic cigarettes ...... 49 risk in persons with obesity ...... 36 . 4.6.Lipids...... 49 . 3.4.Clinicalconditions ...... 36 . 4.6.1. Measurement of lipids and lipoproteins ...... 49 3.4.1.Chronickidneydisease...... 36 . 4.6.1.1 Fasting vs. non-fasting measurements ...... 49 . 3.4.2.Atrialfibrillation...... 36 . 4.6.1.2 Low-density lipoprotein cholesterol measurement ...... 50 3.4.3.Heartfailure...... 36 . 4.6.1.3 Non-high-density lipoprotein cholesterol ...... 50 . 3.4.4.Cancer...... 37 . 4.6.1.4 Apolipoprotein B ...... 50 3.4.4.1 Diagnosis and screening ...... 38 . 4.6.2.Defininglipidgoals ...... 50 . 3.4.4.2 Prevention of cardiotoxicity and cardiovascular . 4.6.2.1 Low-density lipoprotein cholesterol goals ...... 50 risk factors ...... 38 . 4.6.2.2 Triglyceride-rich lipoproteins and their remnants ...... 50 . 3.4.5. Chronic obstructive pulmonary disease ...... 38 . 4.6.2.3 High-density lipoprotein cholesterol ...... 50 3.4.6.Inflammatoryconditions ...... 39 . 4.6.3. Strategies to control dyslipidaemias ...... 52 . 3.4.7. Infections (human immunodeficiency virus, influenza, . 4.6.3.1 Strategies to control low-density lipoprotein cholesterol .... 52 periodontitis) ...... 39 . 4.6.3.1.1. Diet and lifestyle modifications ...... 52 . 3.4.8.Migraine...... 39 . 4.6.3.1.2. Drugs for treatment of dyslipidaemias ...... 52 . 3.4.9. Sleep disorders and obstructive sleep apnoea ...... 39 . 4.6.3.1.3.Statins ...... 53 3.4.10.Mentaldisorders ...... 39 . 4.6.3.1.3.1. Adverse effects, interactions, and . 3.4.11. Non-alcoholic fatty liver disease ...... 40 . adherencetostatintherapy ...... 53 3.4.12.Sex-specificconditions...... 40 . 4.6.3.1.4. Cholesterol absorption inhibitors (ezetimibe) . . . 53 . 3.4.12.1 Obstetric conditions ...... 40 . 4.6.3.1.5. Proprotein convertase subtilisin/kexin type 9 3.4.12.2 Non-obstetric conditions ...... 40 . inhibitors...... 53 . 3.4.12.3 Erectile dysfunction ...... 40 . 4.6.3.2 Strategies to control plasma triglycerides ...... 53 4. Risk factors and interventions at the individual level ...... 40 . 4.6.3.2.1.Fibrates ...... 53 . 4.1. Treatment recommendations: classes, grades, and . 4.6.4.Importantgroups ...... 54 freedomofchoice ...... 40 . 4.6.4.1 Women ...... 54 . 4.2. Optimizing cardiovascular risk management ...... 42 . 4.6.4.2 Older patients ( 70 years) ...... 54 4.2.1. Goals of clinician-patient communication ...... 42 . 4.6.4.3 Diabetes mellitus ...... 54 4 ESC Guidelines
. 4.6.4.4 Chronic kidney disease ...... 55 . 6.5.Chronickidneydisease...... 72 . 4.6.4.5 Familial hypercholesterolaemia ...... 55 . 6.6.Atrialfibrillation...... 72 4.7.Bloodpressure ...... 55 . 6.7.Multimorbidity...... 73 . 4.7.1. Definition and classification of hypertension ...... 57 . 7.Keymessages ...... 73 4.7.2.Bloodpressuremeasurement ...... 57 . 8.Gapsinevidence ...... 76 . 4.7.2.1 Office blood pressure measurement ...... 57 . 9. ‘What to do’ and ‘what not to do’ messages from the guidelines . . . 79 4.7.2.2 Unattended automated office blood pressure . 10.Qualityindicators...... 84 . measurement ...... 57 . 11.Supplementarydata...... 85 Downloaded from https://academic.oup.com/eurheartj/advance-article/doi/10.1093/eurheartj/ehab484/6358713 by guest on 30 August 2021 . 4.7.2.3 Ambulatory blood pressure monitoring ...... 57 . 12.Authorinformation ...... 85 4.7.2.4 Home blood pressure monitoring ...... 57 . 13.Appendix...... 85 . 4.7.3.Screeninganddiagnosisofhypertension ...... 57 . 14.References ...... 86 4.7.3.1 White-coat and masked hypertension ...... 58 . . 4.7.4. Clinical evaluation and risk stratification in . Recommendations hypertensivepatients...... 58 . . 4.7.5.Treatmentofhypertension...... 59 . RecommendationsforCVDriskassessment...... 16 4.7.5.1 Lifestyle interventions to lower blood pressure . RecommendationsforCVDriskestimation ...... 30 . and/or reduce cardiovascular risk ...... 59 . Recommendation for CVD risk communication ...... 31 4.7.5.2 Initiation of drug treatment ...... 59 . . RecommendationsforCVDriskmodifiers...... 31 4.7.5.3 Blood pressure treatment targets ...... 59 . Recommendations for cardiovascular disease risk related to air 4.7.5.3.1. Blood pressure targets according to ambulatory . . pollution...... 34 andhomebloodpressuremonitoring ...... 61 . Recommendations for cardiovascular disease assessment in specific 4.7.5.4 Drug treatment of hypertension ...... 62 . . clinicalconditions ...... 35 4.7.6.Resistanthypertension...... 62 . Recommendationsforphysicalactivity ...... 42 . 4.7.7. Management of hypertension in women ...... 62 . Recommendationsfornutritionandalcohol ...... 43 4.7.8. Duration of treatment and follow-up ...... 62 . Recommendationsforbodyweight ...... 46 . 4.8.Diabetesmellitus ...... 62 . Recommendations for mental healthcare and psychosocial 4.8.1. Key risk factor concepts and newer paradigms ...... 63 . interventionsattheindividuallevel ...... 47 . 4.8.1.1 Lifestyle intervention ...... 63 . Recommendations for smoking intervention strategies ...... 47 4.8.1.2 Glycaemic control ...... 63 . Recommendation on low-density lipoprotein cholesterol goals ...... 50 . 4.8.1.3 Newer diabetes mellitus drug classes: cardiovascular . Recommendations for pharmacological low-density lipoprotein cholesterol disease benefits ...... 64 . lowering for those <70 years of age (for recommendations for persons . 4.8.2.Type1diabetesmellitus...... 64 . aged >_70years,seerespectiverecommendationstables)...... 52 4.9.Antithrombotictherapy...... 64 . Recommendations for drug treatments of patients with . 4.9.1. Antithrombotic therapy in individuals without . hypertriglyceridaemia...... 54 atheroscleroticdisease ...... 65 . Recommendations for the treatment of dyslipidaemias in older . 4.9.2. Antithrombotic therapy in individuals with established . people (>_70years) ...... 54 atheroscleroticdisease ...... 65 . Recommendations for the treatment of dyslipidaemias in diabetes . 4.9.3.Protonpumpinhibitors ...... 65 . mellitus...... 54 4.10.Anti-inflammatorytherapy ...... 65 . Recommendations for lipid management in patients with moderate- . 4.11. Cardiac rehabilitation and prevention programmes ...... 66 . tosevere chronic kidney disease (Kidney Disease Outcomes . 5.Policyinterventionsatthepopulationlevel ...... 66 . Quality Initiative stages 3 5) ...... 55 5.1. Population-level approaches to the prevention of . . Summary of recommendations for the clinical management of cardiovasculardisease...... 67 . hypertension...... 56 5.2. Specific risk factor interventions at the population level ...... 67 . . Recommendations for the treatment of patients with diabetes 5.2.1.Physicalactivity ...... 67 . mellitus ...... 62 . 5.2.2.Diet...... 67 . Recommendationsforantithrombotictherapy...... 64 5.2.3.Smokingandtobaccouse ...... 67 . Recommendationforanti-inflammatorytherapy ...... 65 . 5.2.4.Alcohol ...... 67 . Recommendationsforcardiacrehabilitation ...... 66 5.3. Environment, air pollution, and climate change ...... 67 . Recommendations for policy interventions at the population level . . . . . 66 . 5.3.1.Climatechange ...... 68 . Recommendations for patients with coronary artery disease ...... 68 5.4. Implications for public health policy and advocacy at the . Recommendations regarding pharmacological and non- . governmentalandnon-governmentallevel ...... 68 . pharmacological interventions for patients with symptomatic 6. Risk management of disease-specific cardiovascular disease ...... 68 . (New York Heart Association class II-IV) heart failure with reduced . 6.1.Coronaryarterydisease...... 68 . ejection fraction (left ventricular ejection fraction <40%) with 6.2.Heartfailure ...... 69 . proven benefits on clinical outcomes, including cardiovascular . 6.3.Cerebrovasculardiseases ...... 70 . morbidityandmortality...... 69 6.4.Lowerextremityarterydisease...... 71 . Recommendations for patients with cerebrovascular disease ...... 71 ESC Guidelines 5
. Recommendations for patients with lower extremity artery disease: . Figure 7 Flow chart of cardiovascular risk and risk factor . bestmedicaltherapy ...... 71 . treatment in patients with established atherosclerotic Recommendations in patients with chronic kidney disease: best . cardiovasculardisease ...... 27 . medicaltherapy ...... 72 . Figure 8 Flow chart of cardiovascular risk and risk factor treatment Recommendations for lifestyle interventions and management of risk . inpatientswithtype2diabetesmellitus...... 29 . factors and concomitant diseases in patients with atrial fibrillation . . . . 73 . Figure 9 The role of risk factors and comorbidities in atrial fibrillation . . . 37 . Figure 10 Estimated percentage change in risk of coronary heart disease . Tables . associated with isocaloric substitutions of saturated fat for other Downloaded from https://academic.oup.com/eurheartj/advance-article/doi/10.1093/eurheartj/ehab484/6358713 by guest on 30 August 2021 . typesoffatorcarbohydrates ...... 45 . Table1Classesofrecommendations...... 8 . Figure 11 Lifetime atherosclerotic cardiovascular disease benefit . from smoking cessation for apparently healthy persons, based on Table2Levelsofevidence ...... 8 . Table 3 New recommendations and new and revised concepts ...... 11 . the following risk factors: age, sex, systolic blood pressure, and . non-high-density lipoprotein-cholesterol ...... 48 Table 4 Patient categories and associated cardiovascular disease . risk ...... 18 . Figure 12 Average years-free-of-cardiovascular disease gained per . 1 mmol/L (40 mg/dL) low-density lipoprotein cholesterol Table 5 Cardiovascular disease risk categories based on . Systemic Coronary Risk Estimation 2 and Systemic Coronary . reductioninapparentlyhealthypersons ...... 51 . Figure 13 Expected low-density lipoprotein cholesterol reductions Risk Estimation 2-Older Persons in apparently healthy people . accordingtoage...... 25 . forcombinationtherapies ...... 52 . Figure 14 Screening and diagnosis of hypertension ...... 58 Table 6 Treatment goals for different patient categories ...... 41 . Table 7 Classification of physical activity intensity and examples of . Figure 15 Lifetime benefit from lowering systolic blood pressure . by 10 mmHg for apparently healthy persons, based on the absoluteandrelativeintensitylevels ...... 43 . Table8Healthydietcharacteristics...... 44 . following risk factors: age, sex, current smoking, systolic blood . pressure, non-highdensity lipoprotein cholesterol ...... 60 Table9‘Verybriefadvice’forsmokingcessation ...... 49 . Table 10 Corresponding non-high-density lipoprotein cholesterol . Figure 16 Core drug treatment strategy for hypertension ...... 61 . and apolipoprotein B levels for commonly used low-density . lipoproteincholesterolgoals...... 49 . . Table 11 Dutch Lipid ClinicNetwork diagnostic criteria for familial . Abbreviations and acronyms hypercholesterolaemia ...... 55 . . %HR Percentage of maximum heart rate Table 12 Categories for conventionally measured seated office . max . ABC Atrial fibrillation Better Care bloodpressurea...... 57 . . ABI Ankle brachial index Table 13 Definitions of hypertension according to office, . . ABPM Ambulatory blood pressure monitoring ambulatory,andhomebloodpressure ...... 57 . . ACCORD Action to Control Cardiovascular Risk in Table 14 Considerations in blood pressure measurement ...... 57 . . Diabetes Table 15 Indications for home blood pressure monitoring or . . ACE Angiotensin-converting enzyme ambulatorybloodpressuremonitoring ...... 58 . . ACR Albumin-to-creatinine ratio Table 16 Routine tests for patients with hypertension ...... 59 . . ACS Acute coronary syndromes Table 17 Patient characteristics that should raise the suspicion of . . ADA American Diabetes Association secondaryhypertension...... 59 . . ADVANCE Action in Diabetes and Vascular Disease: Table 18 Recommended office blood pressure target ranges. The . . preterAx and diamicroN-MR Controlled first step in all groups is a reduction to systolic blood pressure . . Evaluation <140mmHg ...... 61 . . AF Atrial fibrillation . AMI Acute myocardial infarction Figures . . ARB Angiotensin receptor blocker . Figure1CentralIllustration ...... 9 . ARNI Angiotensin receptor neprilysin inhibitor . ASCEND A Study of Cardiovascular Events in Diabetes Figure 2 Examples of a stepwise approach to risk stratification and . treatmentoptions ...... 19 . ASCVD Atherosclerotic cardiovascular disease . b.i.d. Bis in die (twice a day) Figure 3 Systematic Coronary Risk Estimation 2 and Systematic . Coronary Risk Estimation 2-Older Persons risk charts for . BMI Body mass index . BP Blood pressure fatal and non-fatal (myocardial infarction, stroke) cardiovascular . disease...... 20 . b.p.m. Beats per minute . CAC Coronary artery calcium Figure 4 Risk regions based on World Health Organization . cardiovascularmortalityrates...... 24 . CAD Coronary artery disease . CANTOS Canakinumab Antiinflammatory Thrombosis Figure 5 Schematic representation of increasing 10-year . cardiovascular disease risk thresholds across age groups ...... 25 . Outcome Study . CCB Calcium channel blocker Figure 6 Flow chart of cardiovascular disease risk and risk factor . treatmentinapparentlyhealthypersons...... 26 . CCS Chronic coronary syndromes 6 ESC Guidelines
CCTA Contrast computed tomography angiography . HR Hazard ratio . CHD Coronary heart disease . IL Interleukin CI Confidence interval . IMPROVE-IT Improved Reduction of Outcomes: Vytorin . CKD Chronic kidney disease . Efficacy International Trial CKD-EPI Chronic Kidney Disease Epidemiology . IMT Intima-media thickness . COLCOT Colchicine Cardiovascular Outcomes Trial . INVEST INternational VErapamil-SR/Trandolapril STudy COMPASS Cardiovascular Outcomes for People Using . LDL Low-density lipoprotein . . Downloaded from https://academic.oup.com/eurheartj/advance-article/doi/10.1093/eurheartj/ehab484/6358713 by guest on 30 August 2021 Anticoagulation Strategies . LDL-C Low-density lipoprotein cholesterol COPD Chronic obstructive pulmonary disease . LDLR Low-density lipoprotein receptor . CR Cardiac rehabilitation . LEAD Lower extremity artery disease CTA Computed tomography angiography . LIFE-CVD LIFEtime-perspective CardioVascular Disease . CV Cardiovascular . LoDoCo Low-dose colchicine CVD Cardiovascular disease . LV Left ventricular/ventricle . DAPA-CKD Dapagliflozin and Prevention of Adverse . LVEF Left ventricular ejection fraction Outcomes in Chronic Kidney Disease . MACE Major adverse cardiovascular events . DAPT Dual antiplatelet therapy . MET Metabolic equivalent of task DASH Dietary Approaches to Stop Hypertension . mHealth Mobile device-based healthcare . DBP Diastolic blood pressure . MRA Mineralocorticoid receptor antagonist DCCT Diabetes Control and Complications Trial . MUFA Monounsaturated fatty acid . DIAL Diabetes lifetime-perspective prediction . N/A Not applicable DM Diabetes mellitus . NAFLD Non-alcoholic fatty liver disease . e-cigarettes Electronic cigarettes . NRT Nicotine-replacement therapy EAPC European Association of Preventive Cardiology . NYHA New York Heart Association . EAS European Atherosclerosis Society . o.d. Omni die (once a day) EASD European Association for the Study of Diabetes . OARS Open-ended questions, Affirmation, Reflecting . EBCR Exercise-based cardiac rehabilitation . listening, and Summarizing ECG Electrocardiographic/electrocardiogram . OR Odds ratio . ED Erectile dysfunction . OSA Obstructive sleep apnoea eGFR Estimated glomerular filtration rate . PA Physical activity . EORP EURObservational Research Programme . PAD Peripheral artery disease . EPIC European Prospective Investigation into Cancer . PAP Positive airway pressure and Nutrition . PCI Percutaneous coronary intervention . ESC European Society of Cardiology . PCSK9 Proprotein convertase subtilisin/kexin type 9 ESH European Society of Hypertension . PM Particulate matter . ESVS European Society for Vascular Surgery . PM2.5 Particulate matter <2.5 mm . EU European Union . PUFA Polyunsaturated fatty acid EUROASPIRE European Action on Secondary and Primary . QI Quality indicator . Prevention by Intervention to Reduce Events . RAAS Renin-angiotensin-aldosterone system EuroHeart European Unified Registries On Heart Care . RAS Renin-angiotensin system . Evaluation and Randomized Trials . RCT Randomized controlled trial EXPERT EXercise Prescription in Everyday practice & . REDUCE-IT Reduction of Cardiovascular Events with . Rehabilitation Training . Icosapent Ethyl Intervention Trial FEV1 Forced expiratory volume in 1 second . REWIND Researching Cardiovascular Events With a . FH Familial hypercholesterolaemia . Weekly Incretin in Diabetes FITT Frequency, intensity, time duration, and type of . RPE Rating of perceived exertion . exercise . RR Relative risk GFR Glomerular filtration rate . SAVOR-TIMI 53 Saxagliptin Assessment of Vascular Outcomes . GLP-1RA Glucagon-like peptide-1 receptor agonist . Recorded in Patients with Diabetes Mellitus HbA1c Glycated haemoglobin . Thrombolysis in Myocardial Infarction . HBPM Home blood pressure monitoring . SBP Systolic blood pressure HDL-C High-density lipoprotein cholesterol . SCORE Systemic Coronary Risk Estimation . HF Heart failure . SCORE2 Systemic Coronary Risk Estimation 2 . HFpEF Heart failure with preserved ejection fraction . SCORE2-OP Systematic Coronary Risk Estimation 2-Older HFrEF Heart failure with reduced ejection fraction . Persons . HIV Human immunodeficiency virus . SCOT-HEART Scottish Computed Tomography of the Heart HMOD Hypertension-mediated organ damage . SGLT2 Sodium-glucose cotransporter 2 . ESC Guidelines 7
. SHARP Study of Heart and Renal Protection . providing a better understanding of medical practice in Europe and . SMART Secondary Manifestations of Arterial Disease . around the world, based on high-quality data collected during routine SMART Specific, Measurable, Achievable, Realistic, . clinical practice. . Timely . Furthermore, the ESC has developed and embedded in this docu- SMART-REACH Secondary Manifestations of Arterial . ment a set of quality indicators (QIs), which are tools to evaluate the . Disease-Reduction of Atherothrombosis for . level of implementation of the guidelines and may be used by the . ESC, hospitals, healthcare providers and professionals to measure Continued Health . . clinical practice as well as used in educational programmes, alongside Downloaded from https://academic.oup.com/eurheartj/advance-article/doi/10.1093/eurheartj/ehab484/6358713 by guest on 30 August 2021 SNRI Serotonin-noradrenaline reuptake inhibitor . SPRINT Systolic Blood Pressure Intervention Trial . the key messages from the guidelines, to improve quality of care and . clinical outcomes. SSRI Selective serotonin reuptake inhibitor . STAREE STAtin Therapy for Reducing Events in the . The Members of this Task Force were selected by the ESC, . including representation from its relevant ESC sub-specialty Elderly . STRENGTH Long-Term Outcomes Study to Assess Statin . groups, in order to represent professionals involved with the . medical care of patients with this pathology. Selected experts in Residual Risk with Epanova in High . Cardiovascular Risk Patients with . the field undertook a comprehensive review of the published evi- . dence for management of a given condition according to ESC Hypertriglyceridemia . SUPRIM Secondary Prevention in Uppsala Primary . Clinical Practice Guidelines Committee (CPG) policy. A critical . evaluation of diagnostic and therapeutic procedures was per- Health Care project . . formed, including assessment of the risk benefit ratio. The level SWITCHD Stockholm Women’s Intervention Trial for . Coronary Heart Disease . of evidence and the strength of the recommendation of particular . TIA Transient ischaemic attack . management options were weighed and graded according to pre- TNF Tumour necrosis factor . defined scales, as outlined below. . TOD Target organ damage . The experts of the writing and reviewing panels provided decla- UK United Kingdom . ration of interest forms for all relationships that might be per- . UKPDS UK Prospective Diabetes Study . ceived as real or potential sources of conflicts of interest. Their VADT Veterans Affairs Diabetes Trial . declarations of interest were reviewed according to the ESC dec- . VITAL Vitamin D and Omega-3 Trial . laration of interest rules and can be found on the ESC website . (http://www.escardio.org/guidelines)and have been compiled in a VO2 Oxygen consumption . WHO World Health Organization . report and published in a supplementary document simultane- . ously to the guidelines. . . This process ensures transparency and prevents potential . biases in the development and review processes. Any changes in 1. Preamble . . declarations of interest that arise during the writing period were Guidelines summarize and evaluate available evidence with the aim of . notified to the ESC and updated. The Task Force received its . assisting health professionals in proposing the best management . entire financial support from the ESC without any involvement strategies for an individual patient with a given condition. Guidelines . fromthehealthcareindustry. . and their recommendations should facilitate decision making of . The ESC CPG supervises and coordinates the preparation of new health professionals in their daily practice. However, the final deci- . guidelines. The Committee is also responsible for the endorsement . sions concerning an individual patient must be made by the responsi- . process of these guidelines. The ESC Guidelines undergo extensive . review by the CPG and external experts. After appropriate revisions ble health professional(s) in consultation with the patient and . caregiver as appropriate. . the guidelines are signed-off by all the experts involved in the Task . Force. The finalized document is signed-off by the CPG for publica- A great number of guidelines have been issued in recent years by . the European Society of Cardiology (ESC), as well as by other soci- . tion in the European Heart Journal. The guidelines were developed . eties and organizations. Because of their impact on clinical practice, . after careful consideration of the scientific and medical knowledge quality criteria for the development of guidelines have been estab- . and the evidence available at the time of their dating. . lished in order to make all decisions transparent to the user. The rec- . The task of developing ESC Guidelines also includes the creation ommendations for formulating and issuing ESC Guidelines can be . of educational tools and implementation programmes for the recom- . found on the ESC website (https://www.escardio.org/Guidelines). . mendations including condensed pocket guideline versions, summary The ESC Guidelines represent the official position of the ESC on a . slides, summary cards for non-specialists and an electronic version . given topic and are regularly updated. . for digital applications (smartphones, etc.). These versions are In addition to the publication of Clinical Practice Guidelines, the . abridged and thus, for more detailed information, the user should . ESC carries out the EURObservational Research Programme of . always access to the full text version of the guidelines, which is freely international registries of cardiovascular diseases and interventions . available via the ESC website and hosted on the EHJ website. The . which are essential to assess diagnostic/therapeutic processes, use of . National Cardiac Societies of the ESC are encouraged to endorse, resources and adherence to guidelines. These registries aim at . adopt, translate and implement all ESC Guidelines. Implementation 8 ESC Guidelines
Table 1 Classes of recommendations Wording to use
Class I Evidence and/or general agreement Is recommended or is indicated that a given treatment or procedure is Downloaded from https://academic.oup.com/eurheartj/advance-article/doi/10.1093/eurheartj/ehab484/6358713 by guest on 30 August 2021
Class II
Class IIa Weight of evidence/opinion is in Should be considered Classes of recommendationsClasses of
Class IIb May be considered established by evidence/opinion.
Class III Evidence or general agreement that the Is not recommended given treatment or procedure is not useful/effective, and in some cases may be harmful. ©ESC 2021
Table 2 Levels of evidence
Level of Data derived from multiple randomized clinical trials evidence A or meta-analyses.
Level of Data derived from a single randomized clinical trial evidence B or large non-randomized studies.
Level of Consensus of opinion of the experts and/or small studies, evidence C retrospective studies, registries. ©ESC 2021
. programmes are needed because it has been shown that the out- . necessary. It is also the health professional’s responsibility to verify . come of disease may be favourably influenced by the thorough appli- . the rules and regulations applicable in each country to drugs and devi- cation of clinical recommendations. . ces at the time of prescription. . Health professionals are encouraged to take the ESC Guidelines . fully into account when exercising their clinical judgment, as well as in . . the determination and the implementation of preventive, diagnostic . 2. Introduction or therapeutic medical strategies. However, the ESC Guidelines do . . not override in any way whatsoever the individual responsibility of . Atherosclerotic cardiovascular (CV) disease (ASCVD) incidence health professionals to make appropriate and accurate decisions in . and mortality rates are declining in many countries in Europe, but it is . consideration of each patient’s health condition and in consultation . still a major cause of morbidity and mortality. Over the past few deca- with that patient or the patient’s caregiver where appropriate and/or . des, major ASCVD risk factors have been identified. The most ESC Guidelines 9
Prevention goals for all
Apparently healthy people
10-year CVD risk
Patients with established ASCVD
Residual CVD risk
Specific risk conditions Downloaded from https://academic.oup.com/eurheartj/advance-article/doi/10.1093/eurheartj/ehab484/6358713 by guest on 30 August 2021 Diabetes mellitus, CKD, Familial Hypercholesterolaemia Risk modifiers Psychosocial stress Ethnicity CVD risk estimation Imaging (e.g. coronary calcium scoring) Comorbidity e.g. cancer, COPD, inflammatory disease, mental disorders, sex-specific conditions Informed discussion About CVD (lifetime) risk and treatment benefits tailored to individual needs and preferences considering age, comorbidities, frailty, polypharmacy
Personalized treatment decisions
Cost-effectiveness considerations Individual-level Population-level interventions and interventions treatment goals
Lifestyle (physical activity, body weight, nutrition) Public health policy and advocacy Psychosocial factors Specific risk factor interventions Risk factor treatment (smoking, at the population level (physical lipids, blood pressure, diabetes) activity, diet, alcohol, smoking) Anti-thrombotic therapy Environment, air pollution, Disease-specific interventions climate change
Reduction of CVD burden
Figure 1 Central Illustration. ASCVD = atherosclerotic cardiovascular disease; CKD = chronic kidney disease; COPD = chronic obstructive pulmonary disease; CVD = cardiovascular disease
. important way to prevent ASCVD is to promote a healthy lifestyle . cardiovascular disease (CVD) risk and treatment benefit, as well as throughout life, especially not smoking. Effective and safe risk factor . novel treatments and treatment goals, necessitated new, up-to-date . treatments have been developed, and most drugs are now generic . guidelines. The current guidelines on CVD prevention in clinical prac- . and available at low costs. Nevertheless, the prevalence of unhealthy . tice concentrate principally but not exclusively on the risk factors, lifestyle is still high, and ASCVD risk factors are often poorly treated, . risk classification, and prevention of ASCVD. 1 . even in patients considered to be at high (residual) CVD risk. . The current guidelines provide recommendations on ASCVD pre- Prevention of CV events by reducing CVD risk is the topic of these . vention to support shared decision-making by the patient and their . guidelines. . healthcare professional based on individual patient characteristics. . Special considerations have been given to differences in age, sex and . 2.1. Definition and rationale . gender, life expectancy, risk factor profiles, ethnic, and geographic dif- The present guidelines have been developed to support healthcare . ferences. Estimating CVD risk not only in apparently healthy subjects, . professionals in their efforts to reduce the burden of ASCVD in both . but also in older persons and in patients with established ASCVD or individual patients, as well as at a population level. The previous . diabetes mellitus (DM), provides information for tailored interven- . European Guidelines on CVD prevention in clinical practice were . tion on an individual level. Treatment goals can be individualized in a published in 2016.2 Recent developments in prediction of . stepwise approach. ‘Residual’ CVD risk is defined as the risk 10 ESC Guidelines
. estimated after initial lifestyle changes and risk factor treatment, and . expensive drugs, such as novel lipid-lowering or anti-diabetic drugs). . is mostly used in patients with established ASCVD. For younger . For such recommendations, it is inappropriate to ‘unconditionally’ apparently healthy subjects, lifetime CVD risk estimates are available . implement them without first considering cost-effectiveness in a . to support treatment decisions, replacing 10-year risk algorithms that . national or regional context or, ideally, to perform formal cost- consistently estimate low 10-year risk even in the presence of high . effectiveness analyses with country-specific input parameters and . risk factor levels. In an ageing population, treatment decisions require . cost-effectiveness thresholds. a specific CVD risk score that takes competing non-CVD risk into . . account, as well as specific low-density lipoprotein cholesterol (LDL- . 2.4. What is new? Downloaded from https://academic.oup.com/eurheartj/advance-article/doi/10.1093/eurheartj/ehab484/6358713 by guest on 30 August 2021 C) and blood pressure (BP) treatment considerations. Estimating . . New recommendations, and new and revised concepts, are pre- lifetime benefit in individual patients of smoking cessation, LDL-C . sented in Table 3. 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 . . 3. Risk factors and clinical approach to treatment is more complex than a more general one- . size-fits-all prevention strategy, but reflects the diversity in patients . conditions . and patient characteristics in clinical practice. . Regarding LDL-C, BP, and glycaemic control in patients with DM, . 3.1. Target population for assessing . goals and targets remain as recommended in recent European . cardiovascular disease risk Society of Cardiology (ESC) Guidelines.3 5 These prevention . CVD risk assessment or screening can be done opportunistically or . guidelines propose a new, stepwise approach to treatment intensifi- . systematically. Opportunistic screening, which means screening with- cation as a tool to help physicians and patients pursue these targets in . out a predefined strategy, is done when a person presents for some . a way that fits patient profile and preferences. Of note, however, new . other reason. Systematic screening can be done in the general popu- . lation as part of a formal screening programme, with call and recall of evidence and/or new consensus may have resulted in some differen- . ces with these recent domain-specific ESC Guidelines. New evidence . patients, or in targeted subpopulations such as subjects with type 2 . DM, or family history of premature CVD. Systematic screening on antithrombotic treatment regimens for ASCVD prevention is also . presented. Sex-specific aspects are included. . results in improvements in risk factors, but has no effect on CVD out- . 6 9 ASCVD prevention needs an integrated, interdisciplinary approach . comes. Opportunistic screening for ASCVD risk factors, such as . BP or lipids, is effective at increasing detection rates and is recom- including input from several disciplines and areas of expertise. We . must work together in a patient- and family-centred way to address . mended, although a beneficial effect on clinical outcome is . uncertain.10 each of the core components of prevention and rehabilitation, includ- . ing lifestyle modification, psychosocial factors, risk factor treatment, . Structured national programmes aiming to identify undocumented . ASCVD risk factors in adults over 40 years of age without DM or and social determinants (Central Illustration). . . ASCVD and treat them have shown better risk factor control, but . 11,12 2.2. Development . there are conflicting results as to clinical outcomes. A high-risk . The Task Force chairs and members were appointed by the ESC . strategy of inviting the population predicted to be at the highest risk Clinical Practice Guidelines Committee (CPG). Each member of . according to an integrated risk score would be equally effective at . 13 the Task Force was assigned specific writing tasks, which were . preventing new cases of CVD and have potential cost savings. One . reviewed by other (sub)section writers, the section coordinators, . large trial of mobile ultrasound screening for aortic aneurysm, periph- and the chairs. The text was developed over 11 months, during . eral artery disease (PAD), and hypertension in males aged 65 74 . 14 which the Task Force members met collectively on three occa- . years showed a 7% mortality reduction at 5 years. . sions and corresponded intensively between meetings. The . A common criticism of screening in general is the potential that review panel consisted of experts selected by all the scientific . false positive and false negative results may cause harm. However, . societies that were involved in the development of these guide- . evidence on CVD screening shows that those who participate do not . report mental distress.15 18 lines, not only the ESC. . . Systematic CVD risk assessment assessment in the general popula- 2.3. Cost-effectiveness . tion (adult men >40 and women >50 years of age) with no known . The Task Force acknowledge the fact that healthcare budgets are, in . CV risk factors appears not cost-effective in reducing subsequent vas- . cular events and premature death, at least in short-term follow-up, many circumstances, limited and thus that certain recommendations . and goals may not always be attainable. However, the current guide- . 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, lines do not provide cost-effectiveness analyses. Large national and . regional differences in budgets and costs associated with both inter- . although there are no empirical data to guide intervals. . ventions and diseases/events preclude valid universal cost- . effectiveness analyses. However, some recommendations clearly . 3.2. Risk factors and risk classification . have financial implications, either in terms of costs for individual . 3.2.1. Risk factors patients and/or in terms of budget impact. Some of these recommen- . The main causal and modifiable ASCVD risk factors are blood . dations pertain to diagnosis (e.g. large-scale use of expensive imaging . apolipoprotein-B-containing lipoproteins [of which low-density lipo- tests such as computed tomography), others to interventions (e.g. . protein (LDL) is most abundant], high BP, cigarette smoking, and DM. ESC Guidelines 11
Table 3 What is new New or Recommendations in 2013 version Class Recommendations in 2021 version Class revised Risk factors and clinical conditions section 3 New In apparently healthy people <70 years of age without established ASCVD, DM, CKD, genetic/rarer lipid or BP disorders, estimation I of 10-year fatal and nonfatal CVD risk with SCORE2 is Downloaded from https://academic.oup.com/eurheartj/advance-article/doi/10.1093/eurheartj/ehab484/6358713 by guest on 30 August 2021 recommended. New In apparently healthy people >_70 years of age without established ASCVD, DM, CKD, genetic/rarer lipid or BP disorder, estimation I of 10-year fatal and nonfatal CVD risk with SCORE2-OP is recommended. New Patients with established ASCVD and/or DM and/or moderate- to-severe renal disease and/or genetic/rarer lipid or BP disorders I are to be considered at high or very high CVD risk. New A stepwise treatment-intensification approach aiming at intensive risk factor treatment is recommended for apparently healthy peo- ple at high or very high ASCVD risk, as well as patients with estab- I lished ASCVD and/or DM, with consideration of CVD risk, treatment benefit of risk factors, risk modifiers, comorbidities, and patient preferences. New Treatment of ASCVD risk factors is recommended in apparently healthy people without DM, CKD, genetic/rarer lipid or BP disor- ders who are at very high CVD risk (SCORE2 >_7.5% for age I under 50; SCORE2 >_10% for age 50 69; SCORE2-OP >_15% for age >_70). New An informed discussion about CVD risk and treatment benefits I tailored to the needs of a patient is recommended. New It is recommended that mental disorders with either significant functional impairment or decreased use of healthcare systems be I considered as influencing New Treatment of ASCVD risk factors should be considered in appa- rently healthy people without DM, CKD, genetic/rarer lipid, or BP disorders who are at high CVD risk (SCORE2 2.5 to <7.5% for age under 50; SCORE2 5 to <10% for age 50 69; SCORE2-OP IIa 7.5 to <15% for age >_70 years), taking ASCVD risk modifiers, life- time risk and treatment benefit, and patient preferences into account. New In apparently healthy people, after estimation of 10-year fatal and non-fatal CVD risk, lifetime risk and treatment benefit, risk modi- IIa fiers, frailty, polypharmacy, and patient preferences should be considered. New Presence of migraine with aura should be considered in CVD risk IIa assessment. New Assessment of CVD risk should be considered in men with ED. IIa New In women with a history of premature or stillbirth, periodic IIb screening for hypertension and DM may be considered. New Assessment of total CVD risk may be considered in adults with IIb chronic inflammatory conditions. New Avoidance of combined hormonal contraceptives may be consid- IIb ered in women with migraine with aura. Risk factors and interventions at the individual level section 4 New It is recommended to reduce sedentary time to engage in at least light activity throughout the day to reduce all-cause and CV mor- I tality and morbidity. Continued 12 ESC Guidelines
Table 3 Continued
New or Recommendations in 2013 version Class Recommendations in 2021 version Class revised New It is recommended to adopt a Mediterranean or similar diet to I lower risk of CVD. New It is recommended to restrict alcohol consumption to a maximum I of 100 g per week. Downloaded from https://academic.oup.com/eurheartj/advance-article/doi/10.1093/eurheartj/ehab484/6358713 by guest on 30 August 2021 New It is recommended to eat fish, preferably fatty, at least once a I week and restrict (processed) meat. New Patients with mental disorders need intensified attention and sup- port to improve adherence to lifestyle changes and drug I treatment. New Smoking cessation is recommended regardless of weight gain, as I weight gain does not lessen the ASCVD benefits of cessation. New In patients with established ASCVD, lipid-lowering treatment with an ultimate LDL-C goal of <1.4 mmol/L (55 mg/dL) and a >_50% I reduction of LDL-C vs. baseline is recommended. New For secondary prevention patients not achieving their goals on a maximum tolerated dose of a statin and ezetimibe, combination I therapy including a PCSK9 inhibitor is recommended. New In patients with type 2 DM at very high risk (e.g. with established ASCVD and/or severe TOD), intensive lipid-lowering therapy, I ultimately aiming at >_50% LDL-C reduction and an LDL-C of <1.4 mmol/L (<55 mg/dL) is recommended. New In patients with type 2 DM >40 years of age at high risk, lipid-low- ering treatment with an ultimate LDL-C goal of >_50% LDL-C I reduction and an LDL-C of <1.8 mmol/L (70 mg/dL) is recommended. New It is recommended that the first objective of treatment is to lower BP to <140/90 mmHg in all patients, and that subsequent BP tar- I gets are tailored to age and specific comorbidities. New In treated patients aged 18 69 years, it is recommended that SBP should ultimately be lowered to a target range of 120 130 I mmHg in most patients. New In treated patients aged >_70 years, it is recommended that SBP should generally be targeted to <140 and down to 130 mmHg if I tolerated. New In all treated patients, DBP is recommended to be lowered to I <80 mmHg. New In persons with type 2 DM and ASCVD, the use of a GLP-1RA or SGLT2 inhibitor with proven outcome benefits is recommended I to reduce CV and/or cardiorenal outcomes. New In patients with type 2 DM and CKD, the use of an SGLT2 inhibi- tor is recommended to improve CVD and/or cardiorenal I outcomes. New In patients with type 2 DM and HFrEF, use of an SGLT2 inhibitor with proven outcome benefits is recommended to lessen HF hos- I pitalizations and CV death. New Participation in a medically supervised, structured, comprehen- sive, multidisciplinary EBCR and prevention programme for patients after ASCVD events and/or revascularization, and for I patients with HF (mainly HFrEF), is recommended to improve patient outcomes. Continued ESC Guidelines 13
Table 3 Continued
New or Recommendations in 2013 version Class Recommendations in 2021 version Class revised New Lifestyle interventions, such as group or individual education, behaviour-change techniques, telephone counselling, and use of IIa consumer-based wearable activity trackers, should be considered to increase PA participation. Downloaded from https://academic.oup.com/eurheartj/advance-article/doi/10.1093/eurheartj/ehab484/6358713 by guest on 30 August 2021 New Bariatric surgery for obese high-risk individuals should be consid- ered when lifestyle change does not result in maintained weight IIa loss. New ASCVD patients with stress should be considered for referral to psychotherapeutic stress management to improve CVD out- IIa comes and reduce stress symptoms. New Patients with CHD and moderate-to-severe major depression IIa should be considered for antidepressive treatment with an SSRI. New An ultimate LDL-C goal of <1.4 mmol/L (55 mg/dL) and LDL-C reduction of >_50% from baseline should be considered in appa- IIa rently healthy persons <70 years at very high risk. New An ultimate LDL-C goal of <1.8 mmol/L (70 mg/dL) and LDL-C reduction of >_50% from baseline should be considered in appa- IIa rently healthy persons <70 years at high risk. New For those motivated to try, considerable weight loss with use of low-calorie diets followed by food reintroduction and weight- IIa maintenance phases early after diagnosis can lead to DM remis- sion and should be considered. New In patients with type 2 DM and TOD, the use of an SGLT2 inhibi- tor or GLP-1RA with proven outcome benefits may be consid- IIb ered to reduce future CVD and total mortality. New For primary prevention patients at very high risk, but without FH, if the LDL-C goal is not achieved on a maximum tolerated dose of IIb a statin and ezetimibe, combination therapy including a PCSK9 inhibitor may be considered. New In high-risk (or above) patients with triglycerides >1.5 mmol/L (135 mg/dL) despite statin treatment and lifestyle measures, n-3 IIb PUFAs (icosapent ethyl 2 X 2 g/day) may be considered in combi- nation with a statin. New Initiation of statin treatment for primary prevention in older peo- IIb ple aged >_70 may be considered, if at high risk or above. New Statin therapy may be considered in persons aged <_40 years with type 1 or type 2 DM with evidence of TOD and/or an LDL-C IIb level >2.6 mmol/L (100 mg/dL), as long as pregnancy is not being planned. New In patients with DM at high or very high CVD risk, low-dose aspirin may be considered for primary prevention in the absence IIb of clear contraindications. New Home-based CR, telehealth, and mHealth interventions may be considered to increase patient participation and long-term adher- IIb ence to healthy behaviours. New In patients with HF and major depression, SSRIs, SNRIs, and tricy- III clic antidepressants are not recommended. New In patients with dialysis-dependent CKD who are free of ASCVD, III commencing statin therapy is not recommended. Continued 14 ESC Guidelines
Table 3 Continued
New or Recommendations in 2013 version Class Recommendations in 2021 version Class revised Policy interventions at the population level section 5 New Putting in place measures to reduce air pollution, including reduc- ing PM emission and gaseous pollutants, reducing the use of fossil I fuels, and limiting carbon dioxide emissions, are recommended to Downloaded from https://academic.oup.com/eurheartj/advance-article/doi/10.1093/eurheartj/ehab484/6358713 by guest on 30 August 2021 reduce CVD mortality and morbidity. Risk management of disease-specific cardiovascular disease section 6 New It is recommended that patients with HF are enrolled in a com- prehensive CR programme to reduce the risk of HF hospitaliza- I tion and death. New It is recommended to screen patients with HF for both CV and non-CV comorbidities which, if present, should be treated, pro- I vided safe and effective interventions exist, not only to alleviate symptoms but also to improve prognosis. New In patients with a cerebrovascular event, improvement of lifestyle factors in addition to appropriate pharmacological management is I recommended. New Identification and management of risk factors and concomitant diseases are recommended to be an integral part of treatment in I patients with AF.
New Adding a second antithrombotic drug (a P2Y12 inhibitor or low- dose rivaroxaban) to aspirin for long-term secondary prevention IIa should be considered in patients with a high risk of ischaemic events and without high bleeding risk. New In patients with DM and chronic symptomatic LEAD without high bleeding risk, a combination of low-dose rivaroxaban (2.5 mg IIb b.i.d.) and aspirin (100 mg o.d.) may be considered. Adding a second antithrombotic drug to aspirin for long-term sec- ondary prevention may be considered in patients with a moderate IIb risk of ischaemic events and without a high bleeding risk. Risk factors and clinical conditions section 3 Revised ABI may be considered as a risk modifier in The routine collection of other potential modifiers, such as CVD risk assessment. genetic risk scores, circulating or urinary biomarkers, or vascular IIb III tests or imaging methods (other than CAC scoring or carotid ultrasound for plaque determination), is not recommended. Risk factors and interventions at the individual level section 4 Revised Drug treatment should be considered in For grade 1 hypertension, treatment initiation based on absolute patients with grade 1 or 2 hypertension IIa CVD risk, estimated lifetime benefit, and the presence of HMOD I who are at high CVD risk. is recommended. Revised In patients with type 2 DM and CVD, use In persons with type 2 DM and ASCVD, the use of a GLP-1RA or of an SGLT2 inhibitor should be consid- SGLT2 inhibitor with proven outcome benefits is recommended IIa I ered early in the course of the disease to to reduce CV and/or cardiorenal outcomes.
reduce CVD and total mortality. ESC 2021 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 melli- tus; 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 seroto- nin reuptake inhibitor; TOD = target organ damage. ESC Guidelines 15
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 Downloaded from https://academic.oup.com/eurheartj/advance-article/doi/10.1093/eurheartj/ehab484/6358713 by guest on 30 August 2021 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 Section 4 • 4.10 Anti-inflammatory treatment New /revised concepts Section 3 • 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 Section 4 • 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 Section 5 • Taking into consideration population level interventions to mitigate the effects of pollution on CVD health Section 6 • 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 ESC 2021
ASCVD = atherosclerotic cardiovascular disease; CVD = cardiovascular disease; DM =diabetes mellitus; LDL-C = low-density lipoprotein cholesterol; SBP = systolic blood- pressure; SCORE2 = Systematic Coronary Risk Estimation 2; SCORE2-OP = Systematic Coronary Risk Estimation 2-Older Persons. 16 ESC Guidelines
. Recommendations for CVD risk assessment . even a small absolute reduction in LDL-C may be beneficial in a . 22 . high- or very-high-risk patient. a b . Recommendations Class Level . • Non-high-density lipoprotein cholesterol (HDL-C) encom- . passes all atherogenic (apo-B-containing) lipoproteins, and is cal- Systematic global CVD risk assessment is recom- . . culated as: total cholesterol HDL-C = non-HDL-C. The mended in individuals with any major vascular . relationship between non-HDL-C and CV risk is at least as risk factor (i.e. family history of premature CVD, . IC. strong as the relationship with LDL-C. Non-HDL-C levels con- FH, CVD risk factors such as smoking, arterial . . tain, in essence, the same information as a measurement of apo- Downloaded from https://academic.oup.com/eurheartj/advance-article/doi/10.1093/eurheartj/ehab484/6358713 by guest on 30 August 2021 hypertension, DM, raised lipid level, obesity, or . B plasma concentration.23,24 Non-HDL-C is used as an input in comorbidities increasing CVD risk). . . the Systemic Coronary Risk Estimation 2 (SCORE2) and Systematic or opportunistic CV risk assessment . . SCORE2-Older Persons (SCORE2-OP) risk algorithms. in the general population in men >40 years of . IIb C . HDL-C is inversely associated with CVD risk. Very high HDL-C levels age and in women >50 years of age or postme- . nopausal with no known ASCVD risk factors . may signal an increased CVD risk. There is, however, no evidence 9 . from Mendelian randomization studies, or randomized trials of cho- may be considered. . In those individuals who have undergone CVD . lesteryl ester transfer protein inhibitors, that raising plasma HDL-C . reduces CVD risk.25 28 HDL-C is nonetheless a useful biomarker to risk assessment in the context of opportunistic . screening, a repetition of screening after 5 years IIb C . refine risk estimation using the SCORE2 algorithms. The SCORE2 . (or sooner if risk was close to treatment thresh- . algorithm cannot be used for patients with a genetic lipid disorder, olds) may be considered. . such as familial hypercholesterolaemia (FH). Specific LDL-C thresh- . Opportunistic screening of BP in adults at risk . olds and targets are recommended irrespective of estimated CV risk . for patients with FH or other rare/genetic lipid disorders. for the development of hypertension, such as . those who are overweight or with a known fam- IIa B . . 3.2.1.2 Blood pressure ily history of hypertension, should be . considered.19 . Longitudinal studies, genetic epidemiological studies, and RCTs have . shown that raised BP is a major cause of both ASCVD and non- Systematic CVD risk assessment in men <40 . . atherosclerotic CVD [particularly heart failure (HF)], accounting for years of age and women <50 years of age with III C . . 29
ESC 2021 9.4 million deaths and 7% of global disability adjusted life-years. no known CV risk factors is not recommended.9 . . Elevated BP is a risk factor for the development of coronary artery . ASCVD = atherosclerotic cardiovascular disease; BP = blood pressure; CV = car- . disease (CAD), HF, cerebrovascular disease, lower extremity arterial diovascular; CVD = cardiovascular disease; DM = diabetes mellitus; FH = familial . disease (LEAD), chronic kidney disease (CKD), and atrial fibrillation hypercholesterolaemia. . aClass of recommendation. . (AF). The risk of death from either CAD or stroke increases linearly b . Level of evidence. . from BP levels as low as 90 mmHg systolic and 75 mmHg diastolic . 30,31 . upwards. The absolute benefit of reducing systolic BP (SBP) . depends on absolute risk and the absolute reduction in SBP, except Another important risk factor is adiposity, which increases CVD risk . . that lower limits of SBP are imposed by tolerability and safety consid- via both major conventional risk factors and other mechanisms. In . . erations. Management is determined by the category of hypertension addition to these, there are many other relevant risk factors, modi- . . (optimal, normal, high-normal, stages 1 to 3, and isolated systolic fiers, and clinical conditions, which are addressed under risk modifiers . . hypertension), defined according to seated office BP, ambulatory BP and clinical conditions (sections 3.3 and 3.4). . . monitoring (ABPM), or home BP average values (see section . 4.7). Evidence suggests that lifetime BP evolution differs in women 3.2.1.1 Cholesterol . . compared to men, potentially resulting in an increased CVD risk at The causal role of LDL-C, and other apo-B-containing lipoproteins, . . lower BP thresholds.32 34 The SCORE2 algorithm cannot be used in the development of ASCVD is demonstrated beyond any doubt by . . for patients with secondary causes and rarer forms of hypertension, genetic, observational, and interventional studies.20 The key attrib- . . such as primary hyperaldosteronism. utes of LDL-C as a risk factor for ASCVD are: . . • Prolonged lower LDL-C is associated with lower risk of ASCVD . 3.2.1.3 Cigarette smoking . throughout the range studied, and the results of randomized . Cigarette smoking is responsible for 50% of all avoidable deaths in controlled trials (RCTs) indicate that lowering LDL-C safely . smokers, with half of these due to ASCVD. A lifetime smoker has a . reduces CVD risk even at low LDL-C levels [e.g. LDL-C <1.4 . 50% probability of dying due to smoking, and on average will lose 10 mmol/L (55 mg/dL)].20 . years of life.35 The CVD risk in smokers <50 years of age is five-fold . 36 • The relative reduction in CVD risk is proportional to the abso- . higher than in non-smokers. Prolonged smoking is more hazardous . 37 lute size of the change in LDL-C, irrespective of the drug(s) used . for women than for men. Worldwide, after high SBP, smoking is 21 . 38 to achieve such change. . the leading risk factor for disability adjusted life-years. Second-hand . 39 • The absolute benefit of lowering LDL-C depends on the abso- . smoke is associated with an increase in CVD risk. Some smokeless lute risk of ASCVD and the absolute reduction in LDL-C, so . tobacco is also associated with increased risk of CVD.40 ESC Guidelines 17
. 3.2.1.4 Diabetes mellitus . studied include left ventricular (LV) ejection fraction (LVEF), adverse . Type 1 DM, type 2 DM, and prediabetes are independent risk factors . drug reactions, trends in ASCVD risk factors and awareness, sex dis- for ASCVD, increasing risk of ASCVD by about two-fold, depending . parities in the management of and outcomes after acute coronary 41 . 51 58 on the population and therapeutic control. Women with type 2 . syndromes (ACS). Furthermore, CVD health after menopause DM appear to have a particularly higher risk for stroke.42 Patients . transition, pregnancy disorders, and gynaecologic conditions have . 59 with type 2 DM are likely to have multiple ASCVD risk factors . recently been reviewed. (including dyslipidaemia and hypertension), each of which mediates . . an increase in risk of both ASCVD and non-ASCVD. . 3.2.3. Cardiovascular disease risk classification Downloaded from https://academic.oup.com/eurheartj/advance-article/doi/10.1093/eurheartj/ehab484/6358713 by guest on 30 August 2021 . The current guidelines on CVD prevention in clinical practice con- . 3.2.1.5 Adiposity . centrate principally, but not exclusively, on risk and prevention of Over recent decades, body mass index (BMI)—measured as weight . ASCVD. This includes risk factors, risk prediction, risk modifiers, as 2 . (in kg) divided by squared height (in m )—has increased substantially . well as clinical conditions that often increase the likelihood of worldwide in children, adolescents, and adults.43 Mendelian random- . ASCVD. . ization analyses suggest a linear relation between BMI and mortality . Identifying patients who will benefit most from ASCVD risk factor 44 . in non-smokers and a J-shaped relation in ever-smokers. All-cause . treatment is central to ASCVD prevention efforts. In general, the 2 . mortality is lowest at a BMI of 20 25 kg/m in apparently healthy . higher the absolute CVD risk, the higher the absolute benefit of risk 45,46 . people, with a J-shaped or U-shaped relation. In HF patients, . factor treatment, and thus the lower the number needed to treat to . 60,61 there is evidence for an obesity paradox, with lower mortality risk in . prevent one CVD event during a period of time. With this in patients with higher BMI. A meta-analysis concluded that both BMI . . mind, the estimation of CVD risk remains the cornerstone of these and waist circumference are similarly, strongly, and continuously . guidelines and thus appears at the forefront of the proposed manage- 47 . associated with ASCVD and type 2 DM. . ment schemes, which are summarized in flowcharts. . . Age is the major driver of CVD risk. Women below 50 years and 3.2.2. Sex and gender and their impact on health . men below 40 years of age are almost invariably at low 10-year CVD . The current prevention guidelines recognize the importance of inte- . risk, but may have unfavourable modifiable risk factors that sharply grating sex, gender, and gender identity considerations into the risk . increase their longer-term CVD risk. Conversely, men over 65 years . assessment and clinical management of individuals and populations. . and women over 75 years of age are almost always at high 10-year These guidelines also acknowledge the complexity of the inter- . CVD risk. Only between the ages of 55 and 75 years in women and . relationship between these concepts and CV, as well as psychologi- . 40 and 65 years in men does the 10-year CVD risk vary around com- cal, health. There is, at present, no official ESC position on the specific . monly used thresholds for intervention. The age categories <50, . terminology to be used. According to the World Health . 50 69, and >_70 years should be used with common sense and flexi- Organization (WHO), sex ‘refers to the different biological and phys- . bility. Different age ranges may be considered for men and women . iological characteristics of females, males, and intersex persons, such . and may differ according to geographic region. Uncertainty around as chromosomes, hormones and reproductive organs’.48 . risk estimations should also be considered. . This is to be distinguished from gender, which ‘refers to the char- . CVD risk can also be assessed in patients with type 2 DM and in acteristics of women, men, girls and boys that are socially con- . patients with established ASCVD. The populations or patient groups . structed. This includes norms, behaviours and roles associated with . in whom CVD risk needs to be considered are summarized and pre- being a woman, man, girl or boy, as well as relationships with each . sented in Table 4. Lifetime CVD risk estimation is available for various . other. As a social construct, gender varies from society to society . groups of patients, and enables estimation of lifetime benefit from 48 . and can change over time’. The Global Health 50/50 definition fur- . preventive interventions such as smoking cessation (see section 4.5.1), ther states that gender refers ‘to the socially constructed norms that . lipid-lowering (see section 4.6.2.1), and BP treatment (see section . impose and determine roles, relationships, and positional power for . 4.7.5.2). Lifetime risk and benefit estimation may be used for commu- 49 . all people across their lifetime’. . nication in the shared decision-making process, together with consid- Where evidence exists on the risk modifying effect of sex or . eration of comorbidities, frailty, patient preferences for initiating . where sex-specific clinical conditions and clinical management strat- . (STEP 1) and intensifying (STEP 2) risk factor treatment (Figure 2). egies exist, this has been included in these guidelines.50 The influence . . of gender on an individual’s experience and access to healthcare is . 3.2.3.1 A stepwise approach to risk factor treatment and treatment paramount.50 The specific health concerns related to gender are thus . intensification . also acknowledged in these prevention Guidelines. . As explained before, targets and goals for LDL-C, BP, and glycaemic Epigenetic effects of social constructs appear to condition the . control in DM remain as recommended in recent ESC Guidelines.3 5 . translation of biological sex into disease pathophysiology. . These guidelines propose a stepwise approach to treatment intensifi- Furthermore, social constructs can also be determinants of health . cation as a tool to help physicians and patients pursue these targets in . access, healthcare utilization, disease perception, decision-making, . a way that fits patient profiles and preferences. This principle (out- and perhaps therapeutic response,50 including in the field of CVD and . lined in Figure 2, using the example of a stepwise approach) is not . ASCVD prevention. Research is ongoing, but gaps in evidence remain . conceptually novel, but rather reflects routine clinical practice, in and this has also been recognized in the guidelines. . which treatment strategies are initiated and then intensified, both as . Examples of specific topics regarding physiological, pathological, . part of a shared decision-making process involving healthcare profes- and clinical differences related to sex and gender that have been . sionals and patients. 18 ESC Guidelines
Table 4 Patient categories and associated cardiovascular disease risk.
Patient category Subgroups Risk categories Apparently healthy persons Persons without established 10-year CVD risk estimation (SCORE2). Lifetime risk ASCVD, diabetes mellitus, CKD, Low- to <50 years Familial Hypercholesterolemia high-risk (e.g. with the LIFE-CVD lifetime model) to facilitate the Downloaded from https://academic.oup.com/eurheartj/advance-article/doi/10.1093/eurheartj/ehab484/6358713 by guest on 30 August 2021
10-year CVD risk estimation (SCORE2). Lifetime Low- to 50-69 years very high-risk (e.g. with the LIFE-CVD lifetime model) to facilitate the
10-year CVD risk estimation (SCORE2-OP). Lifetime Low- to ≥70 years very high-risk (e.g. with the LIFE-CVD lifetime model) to facilitate the
Patients with CKD CKD without diabetes or ASCVD Moderate CKD (eGFR 30−44 mL/min/1.73 m2 and ACR <30 or eGFR 45−59 mL/min/1.73 m2 and High-risk N/A ACR 30−300 or eGFR ≥60 mL/min/1.73 m2 and ACR >300) Severe CKD (eGFR<30 mL/min/1.73 m2 or Very N/A eGFR 30−44 mL/min/1.73 m2 and ACR >30) high-risk Familial Hypercholesterolemia Associated with markedly elevated N/A High-risk N/A cholesterol levels Patients with type 2 diabetes mellitus Patients with type 1 DM above Patients with well controlled short-standing DM (e.g. <10 years), no evidence of TOD Moderate- N/A according to these criteria and no additional ASCVD risk factors risk
Patients with DM without ASCVD and/or Residual 10-year CVD risk estimation after general prevention goals (e.g. with the ADVANCE risk score or High-risk risk criteria. estimation of risk factor treatment (e.g. DIAL model). Patients with DM with established ASCVD and/or severe TOD:87, 93-95 • eGFR <45 mL/min/1.73 m2 irrespective Residual 10-year CVD risk estimation after general of albuminuria prevention goals (e.g. with the SMART risk score for • eGFR 45-59 mL/min/1.73 m2 and Very established CVD or with the ADVANCE risk score or microalbuminuria (ACR 30 -300 mg/g) high-risk with the DIAL model). Consider lifetime CVD risk and • Proteinuria (ACR >300 mg/g) • Presence of microvascular disease model).
microalbuminuria plus retinopathy plus neuropathy) Patients with established ASCVD Documented ASCVD, clinical or unequivocal on imaging. Documented clinical ASCVD includes previous AMI, ACS, coronary revascularization Residual CVD risk estimation after general prevention and other arterial revascularization goals (e.g. 10-year risk with the SMART risk score for procedures, stroke and TIA, aortic patients with established CVD or 1- or 2-year risk aneurysm and PAD. Unequivocally Very N/A with EUROASPIRE risk score for patients with CHD). documented ASCVD on imaging high-risk includes plaque on coronary risk factor treatment (e.g. SMART-REACH model; or angiography or carotid ultrasound DIAL model if diabetes). or on CTA. It does NOT include some increase in continuous imaging parameters such as intima–media
thickness of the carotid artery. ESC 2021
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. ESC Guidelines 19
Categories of individuals considered for prevention
Apparently healthy Patients with Patients with Patients with specific risk persons established ASCVD type 2 diabetes mellitus factors such as CKD (See Figure 6) (See Figure 7) (See Figure 8) and FH (See Table 4)
STEP 1 Downloaded from https://academic.oup.com/eurheartj/advance-article/doi/10.1093/eurheartj/ehab484/6358713 by guest on 30 August 2021 Prevention goals for all Prevention goals for all Prevention goals for all
Estimate 10-year CVD risk
Consider risk modifiers, lifetime CVD risk, treatment benefit and patient preferences Prevention goals based Specific risk factor on whether patients are prevention and without or with treatment goals established ASCVD based on Prevention goals and/or severe TOD risk categories
STEP 2 Intensified prevention and Intensified prevention and Intensified prevention and treatment goals based on: treatment goals based on: treatment goals based on: 10-year CVD risk 10-year CVD risk 10-year CVD risk Lifetime CVD risk Lifetime CVD risk Lifetime CVD risk and treatment benefit and treatment benefit and treatment benefit Comorbidities Comorbidities Comorbidities Patient preferences Patient preferences Patient preferences
Ultimate prevention goals Ultimate prevention goals Ultimate prevention goals
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.
. A stepwise approach starts with prevention goals for all, regardless . 3.2.3.2 Risk estimation in apparently healthy people of CVD risk. This is followed by CVD risk stratification and discussion . Apparently healthy people are those without established ASCVD, . of potential benefits of treatment with the patient. If treatment is initi- . type 2 DM, or severe comorbidities. In the 2016 ESC prevention . 2 ated, its effect must be evaluated, and subsequent treatment intensifi- . guidelines, the Systemic Coronary Risk Estimation (SCORE) algo- . cation to reach ultimate risk factor goals must be considered in all . rithm was used to estimate 10-year risk of CVD death. However, . patients, taking into account additional benefit, comorbidities, and . CVD morbidity (non-fatal myocardial infarction, non-fatal stroke) frailty, all of which converge with patient preferences in a shared . combined with CVD mortality better reflects the total burden of . decision-making process. . ASCVD. The updated SCORE algorithm—SCORE2—used in these In the field of DM, studies have shown benefit of a stepwise . guidelines (see Figure 3), estimates an individual’s 10-year risk of fatal . approach to treatment intensification and do not support the conten- . and non-fatal CVD events (myocardial infarction, stroke) in appa- tion of ‘therapeutic nihilism’ occurring in either physicians or patients. . rently healthy people aged 40 69 years with risk factors that are . 68 In fact, it appears that attainment of treatment goals is similar, side- . untreated or have been stable for several years. effects are fewer, and patient satisfaction is significantly higher with . Several specific considerations apply to CVD risk estimation in 66,67 . such an approach. We do, however, emphasize that stopping . older people. First, the gradient of the relationship between classical assessment of treatment goals and/or treatment routinely after the . risk factors, such as lipids and BP, with CVD risk attenuates with . 69 first step is inappropriate. The evidence-based ultimate targets of . age. Second, CVD-free survival dissociates from overall survival treatment intensification are optimal from the perspective of CVD . progressively with increasing age, because risk for non-CVD mortal- . 70 risk reduction and are to be considered in all patients. . ity increases (‘competing risk’). For these reasons, traditional risk 20 ESC Guidelines
SCORE2 & SCORE2-OP <50 years 50-69 years ≥70 years 10-year risk of (fatal and non-fatal) CV <2.5% <5% <7.5% 2.5 to <7.5% 5 to <10% 7.5 to <15% events in populations at low CVD risk ≥7.5% ≥10% ≥15% Women Men Non-smoking Smoking Non-smoking Smoking Non-HDL cholesterol Systolic blood mmol/L pressure (mmHg)
3.0-3.9 4.0-4.9 5.0-5.9 6.0-6.9 3.0-3.9 4.0-4.9 5.0-5.9 6.0-6.9 3.0-3.9 4.0-4.9 5.0-5.9 6.0-6.9 3.0-3.9 4.0-4.9 5.0-5.9 6.0-6.9 Downloaded from https://academic.oup.com/eurheartj/advance-article/doi/10.1093/eurheartj/ehab484/6358713 by guest on 30 August 2021 SCORE2-OP 150 200 250 150 200 250 mg/dL 150 200 250 150 200 250 160-179 28 29 30 31 31 32 33 34 Age 29 35 42 49 29 35 42 49 (y) 140-159 26 27 28 29 29 30 31 32 28 33 40 47 27 33 40 47 85-89 120-139 24 25 26 27 27 28 29 30 26 32 38 45 26 32 38 45 100-119 23 24 25 26 25 26 27 28 25 30 36 43 25 30 36 43 160-179 20 21 22 23 25 26 28 29 23 27 32 37 26 31 36 41 140-159 18 19 20 21 23 24 25 26 21 25 29 34 24 28 33 38 80-84 120-139 16 17 18 19 20 21 22 23 19 22 26 31 22 25 30 34 100-119 15 15 16 17 18 19 20 21 17 20 24 28 19 23 27 31 160-179 15 15 16 17 21 22 23 24 19 21 24 27 24 27 31 34 140-159 13 13 14 15 18 19 20 21 16 18 21 23 21 23 26 30 75-79 120-139 11 11 12 13 15 16 17 18 14 15 18 20 18 20 23 26 100-119 9101011 13 14 15 15 12 13 15 17 15 17 19 22 160-179 10 1112 12 17 1819 20 15 1618 19 22 2426 28 140-159 991010 14 15 16 16 12 13 14 16 18 19 21 23 70-74 120-139 7788 11 12 13 14 10 11 12 13 14 16 17 19 100-119 6 667 91010 11 88910 12 13 14 15
SCORE2 160-179 8899 12 12 13 13 11 12 12 13 15 16 17 19 140-159 7777 10 10 11 11 9 101111 13 14 15 16 65-69 120-139 5666 8999 88910 11 12 13 13 100-119 5555 7778 6778 9101111 160-179 667 7 10 1011 11 8910 11 13 1415 17 140-159 5556 8899 7889 10 11 13 14 60-64 120-139 4445 6778 6678 9101011 100-119 3344 5666 5566 78910 160-179 4555 88910 7789 10 12 13 15 140-159 3444 6778 5678 9101112 55-59 120-139 3333 5666 4556 78910 100-119 2233 4455 4445 6678 160-179 3444 6778 5678 9101113 140-159 3333 5566 4556 78910 50-54 120-139 2223 4455 3445 6678 100-119 2222 3344 3334 4567 160-179 2333 5567 4566 7 8 10 11 140-159 2223 4455 3445 6789 45-49 120-139 1222 3344 2334 4567 100-119 1 111 223 3 2 233 3 455 160-179 2223 4456 3455 67810 140-159 1222 3344 2334 5568 40-44 120-139 1111 2333 2233 3456 100-119 1 111 2 222 1 2 22 334 5
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. ESC Guidelines 21
SCORE2 & SCORE2-OP <50 years 50-69 years ≥70 years 10-year risk of (fatal and non-fatal) CV <2.5% <5% <7.5% 2.5 to <7.5% 5 to <10% 7.5 to <15% events in populations at moderate CVD risk ≥7.5% ≥10% ≥15% Women Men Non-smoking Smoking Non-smoking Smoking Non-HDL cholesterol Systolic blood
mmol/L Downloaded from https://academic.oup.com/eurheartj/advance-article/doi/10.1093/eurheartj/ehab484/6358713 by guest on 30 August 2021 pressure (mmHg) 3.0-3.9 4.0-4.9 5.0-5.9 6.0-6.9 3.0-3.9 4.0-4.9 5.0-5.9 6.0-6.9 3.0-3.9 4.0-4.9 5.0-5.9 6.0-6.9 3.0-3.9 4.0-4.9 5.0-5.9 6.0-6.9 SCORE2-OP 150 200 250 150 200 250 mg/dL 150 200 250 150 200 250 160-179 37 39 40 42 41 43 44 46 Age 37 45 53 62 37 45 53 61 (y) 140-159 35 36 38 39 39 40 42 43 36 43 51 59 35 43 51 59 85-89 120-139 32 34 35 37 36 38 39 41 34 41 49 57 34 41 48 57 100-119 30 32 33 34 34 35 37 38 32 39 47 55 32 39 46 55 160-179 27 28 30 31 34 35 37 39 30 35 41 47 34 40 46 53 140-159 24 25 27 28 30 32 33 35 27 32 37 43 31 36 42 48 80-84 120-139 21 22 24 25 27 28 30 31 25 29 34 40 28 33 38 44 100-119 19 20 21 22 24 25 27 28 22 26 31 36 25 30 35 40 160-179 19 20 21 23 27 29 30 32 24 27 31 35 31 35 39 44 140-159 16 17 18 19 24 25 26 28 21 23 27 30 27 30 34 38 75-79 120-139 14 15 15 16 20 21 22 24 17 20 23 26 23 26 29 33 100-119 12 12 13 14 17 18 19 20 15 17 19 22 19 22 25 29 160-179 13 1415 16 22 2325 26 19 2123 25 28 3134 36 140-159 11 11 12 13 18 19 20 22 15 17 18 20 23 25 28 30 70-74 120-139 9 9 10 11 15 16 17 18 12 13 15 16 19 20 22 24 100-119 7 788 12 13 13 14 10 11 12 13 15 16 18 20
SCORE2 160-179 10 10 11 12 15 16 17 18 14 15 17 18 20 22 23 25 140-159 8999 13 13 14 15 12 13 14 15 17 18 20 21 65-69 120-139 7778 10 11 12 12 10 11 12 13 14 15 17 18 100-119 5666 99910 8 9 10 10 12 13 14 15 160-179 788 9 12 1314 15 11 1213 15 17 1820 22 140-159 6677 10 11 11 12 9101112 14 15 17 18 60-64 120-139 5556 89910 78910 11 13 14 15 100-119 4445 6778 6778 9101112 160-179 5667 10 11 11 12 9101112 14 16 17 20 140-159 4455 88910 78910 11 13 14 16 55-59 120-139 3344 6778 5678 9101113 100-119 3333 5566 4566 78910 160-179 4455 88910 78910 11 13 15 17 140-159 3344 6678 5678 9 101214 50-54 120-139 2233 5566 4556 78911 100-119 2222 3445 3445 5678 160-179 3334 6789 5678 9111315 140-159 2233 5566 4556 7810 12 45-49 120-139 2222 3445 3445 5789 100-119 1 112 333 4 2 334 4 567 160-179 2233 5567 4567 8 9 11 13 140-159 1222 3455 3445 67810 40-44 120-139 1112 3334 2334 4568 100-119 1 111 2 223 2 2 23 345 6
Figure 3 Continued. 22 ESC Guidelines
SCORE2 & SCORE2-OP <50 years 50-69 years ≥70 years 10-year risk of (fatal and non-fatal) CV <2.5% <5% <7.5% 2.5 to <7.5% 5 to <10% 7.5 to <15% events in populations at high CVD risk ≥7.5% ≥10% ≥15% Women Men Non-smoking Smoking Non-smoking Smoking Non-HDL cholesterol Systolic blood
mmol/L Downloaded from https://academic.oup.com/eurheartj/advance-article/doi/10.1093/eurheartj/ehab484/6358713 by guest on 30 August 2021 pressure (mmHg) 3.0-3.9 4.0-4.9 5.0-5.9 6.0-6.9 3.0-3.9 4.0-4.9 5.0-5.9 6.0-6.9 3.0-3.9 4.0-4.9 5.0-5.9 6.0-6.9 3.0-3.9 4.0-4.9 5.0-5.9 6.0-6.9 SCORE2-OP 150 200 250 150 200 250 mg/dL 150 200 250 150 200 250 160-179 53 55 57 58 58 59 61 63 Age 42 49 57 65 41 49 56 65 (y) 140-159 50 52 54 55 55 56 58 60 40 47 55 63 40 47 54 62 85-89 120-139 47 49 51 52 52 53 55 57 38 45 53 61 38 45 52 60 100-119 44 46 48 50 49 51 52 54 36 43 51 58 36 43 50 58 160-179 40 42 44 45 49 51 53 55 34 40 45 51 38 44 50 56 140-159 36 38 39 41 44 46 48 50 31 36 42 47 35 40 46 52 80-84 120-139 32 34 36 37 40 42 44 46 29 33 38 44 32 37 42 48 100-119 29 31 32 34 36 38 40 41 26 30 35 40 29 34 39 44 160-179 29 31 32 34 41 43 45 47 28 32 35 39 35 39 44 48 140-159 25 27 28 29 35 37 39 41 24 27 31 34 31 34 38 43 75-79 120-139 22 23 24 25 31 32 34 36 21 24 27 30 27 30 34 37 100-119 18 19 20 22 26 28 29 31 18 20 23 26 23 26 29 33 160-179 21 2224 25 33 3537 39 23 2527 29 33 3538 41 140-159 17 18 19 20 28 29 31 33 19 20 22 24 27 29 32 34 70-74 120-139 14 15 16 17 23 24 26 27 15 17 18 20 22 24 26 28 100-119 11 12 13 14 19 20 21 22 12 14 15 16 18 20 22 23
SCORE2 160-179 15 16 17 18 26 27 29 30 17 18 20 22 25 28 30 32 140-159 12 13 14 14 21 22 23 24 14 15 16 18 21 23 25 27 65-69 120-139 10 10 11 11 16 17 18 19 11 12 13 15 17 19 20 22 100-119 8889 13 14 14 15 9101112 14 15 17 18 160-179 11 1112 13 20 2123 25 13 1316 18 20 2325 28 140-159 89910 15 16 18 19 10 11 13 14 16 18 20 23 60-64 120-139 6778 12 13 14 15 8910 11 13 15 16 18 100-119 5566 91011 11 6789 10 12 13 15 160-179 78910 15 16 18 20 9111214 16 19 21 24 140-159 5677 11 12 14 15 7810 11 13 15 17 19 55-59 120-139 4455 8910 11 6679 10 11 13 15 100-119 3344 6788 4567 8 9 10 12 160-179 5567 11 13 14 16 7 8 10 11 13 15 18 21 140-159 3445 8 9 10 12 5679 10 12 14 16 50-54 120-139 3334 6789 4556 7 9 10 12 100-119 2223 4566 3345 6789 160-179 3445 8 101113 5689 10 13 15 18 140-159 2334 6789 4567 8911 14 45-49 120-139 2222 4566 3345 67810 100-119 1 122 334 5 2 234 4 567 160-179 2234 67910 4567 8101316 140-159 1222 4567 3345 67911 40-44 120-139 1112 3445 2234 4578 100-119 1 111 2 233 1 2 23 345 6
Figure 3 Continued. ESC Guidelines 23
SCORE2 & SCORE2-OP <50 years 50-69 years ≥70 years 10-year risk of (fatal and non-fatal) CV <2.5% <5% <7.5% 2.5 to <7.5% 5 to <10% 7.5 to <15% events in populations at very high CVD risk ≥7.5% ≥10% ≥15% Women Men Non-smoking Smoking Non-smoking Smoking Non-HDL cholesterol Systolic blood
mmol/L Downloaded from https://academic.oup.com/eurheartj/advance-article/doi/10.1093/eurheartj/ehab484/6358713 by guest on 30 August 2021 pressure (mmHg) 3.0-3.9 4.0-4.9 5.0-5.9 6.0-6.9 3.0-3.9 4.0-4.9 5.0-5.9 6.0-6.9 3.0-3.9 4.0-4.9 5.0-5.9 6.0-6.9 3.0-3.9 4.0-4.9 5.0-5.9 6.0-6.9 SCORE2-OP 150 200 250 150 200 250 mg/dL 150 200 250 150 200 250 160-179 62 63 64 65 65 66 67 68 Age 49 54 59 64 49 54 59 64 (y) 140-159 60 61 62 63 63 64 65 66 48 53 58 63 48 53 58 63 85-89 120-139 58 59 60 61 61 62 63 65 47 52 56 61 47 52 56 61 100-119 56 57 58 60 59 60 61 63 46 50 55 60 46 50 55 60 160-179 53 54 55 57 59 60 62 63 44 48 52 56 47 51 55 59 140-159 50 51 52 54 56 57 59 60 42 46 49 53 45 49 52 56 80-84 120-139 47 48 49 51 53 54 56 57 40 43 47 51 43 46 50 54 100-119 44 45 47 48 50 51 53 54 38 41 45 48 40 44 48 51 160-179 44 46 47 48 53 55 56 58 40 42 45 48 45 48 51 54 140-159 41 42 43 45 49 51 52 53 37 39 42 44 42 44 47 50 75-79 120-139 37 39 40 41 46 47 48 49 34 36 39 41 39 41 44 47 100-119 34 35 36 37 42 43 44 46 31 33 36 38 36 38 41 43 160-179 37 3839 41 48 4951 52 35 3739 40 43 4547 49 140-159 33 34 35 36 43 44 46 47 32 33 35 36 39 41 42 44 70-74 120-139 29 30 31 32 39 40 41 43 28 30 31 33 35 36 38 40 100-119 26 27 28 29 34 36 37 38 25 26 28 29 31 33 34 36
SCORE2 160-179 27 28 30 31 41 42 44 46 26 28 30 32 36 39 42 44 140-159 22 23 24 26 34 36 37 39 22 24 26 27 31 33 36 38 65-69 120-139 18 19 20 21 28 30 31 33 18 20 21 23 26 28 30 33 100-119 15 16 16 17 23 24 26 27 15 17 18 19 22 24 26 28 160-179 20 2122 24 33 3537 39 20 2325 27 31 3336 40 140-159 16 17 18 19 27 29 30 32 17 19 20 22 25 28 31 33 60-64 120-139 12 13 14 15 22 23 25 26 14 15 17 18 21 23 25 28 100-119 10 11 11 12 17 18 20 21 11 12 14 15 17 19 21 23 160-179 14 15 17 18 26 28 31 33 16 18 20 23 25 28 32 35 140-159 11 12 13 14 21 23 24 26 13 14 16 18 21 23 26 29 55-59 120-139 8910 11 16 18 19 21 10 11 13 15 17 19 21 24 100-119 7789 13 14 15 16 8 9 10 12 13 15 17 19 160-179 10 11 12 14 21 23 25 28 12 14 16 19 21 24 28 31 140-159 89911 16 18 19 22 10 11 13 15 17 19 22 25 50-54 120-139 6678 12 13 15 17 7910 12 13 15 17 20 100-119 4556 9 101113 6789 10 12 14 16 160-179 78910 16 18 21 23 9111316 17 20 24 28 140-159 5678 12 14 15 17 7 8 10 12 13 16 18 22 45-49 120-139 4456 9 101213 5689 10 12 14 17 100-119 3 344 789 10 4 567 8 91113 160-179 5678 13 15 17 19 7 9 11 13 14 17 20 24 140-159 4456 9111214 56810 11 13 16 19 40-44 120-139 3334 78910 4567 8101214 100-119 2223 5 6 67 344 5 679 11
Figure 3 Continued. 24 ESC Guidelines Downloaded from https://academic.oup.com/eurheartj/advance-article/doi/10.1093/eurheartj/ehab484/6358713 by guest on 30 August 2021
Low risk Moderate risk High risk Very high risk
Figure 4 Risk regions based on World Health Organization cardiovascular mortality rates.68,72,73 models that do not take into account the competing risk of non- . rates to fatal and non-fatal CVD events.74 The SCORE2 algorithm . CVD mortality, tend to overestimate the actual 10-year risk of CVD, . can be accessed in the ESC CVD Risk app (freely available from app 71 . and hence overestimate the potential benefit of treatment. The . stores) and in risk charts for the four clusters of countries (Figure 4). SCORE2-OP algorithm estimates 5-year and 10-year fatal and non- . The SCORE2 charts do not apply to persons with documented CVD . fatal CVD events (myocardial infarction, stroke) adjusted for compet- . or other high-risk conditions such as DM, FH, or other genetic or ing risks in apparently healthy people aged >_70 years.72 . rarelipidorBPdisorders,CKD,andinpregnantwomen. . SCORE2 and SCORE2-OP are calibrated to four clusters of coun- . To estimate a person’s 10-year risk of total CVD events, one must tries (low, moderate, high, and very high CVD risk) that are grouped . first identify the correct cluster of countries and the accompanying . . risk table for their sex, smoking status, and (nearest) age. Within that based on national CVD mortality rates published by the WHO . (Supplementary Table 3 and Figure 4).73 Low-risk countries: . table, one then finds the cell nearest to the person’s BP and non- . Belgium, Denmark, France, Israel, Luxembourg, Norway, Spain, . HDL-C. Risk estimates then need to be adjusted upwards as the per- Switzerland, the Netherlands, and the United Kingdom (UK). . son approaches the next age category. . Moderate-risk countries: Austria, Cyprus, Finland, Germany, . Greece, Iceland, Ireland, Italy, Malta, Portugal, San Marino, Slovenia, . 3.2.3.3 Translating cardiovascular disease risk to treatment thresholds . and Sweden. High-risk countries: Albania, Bosnia and . While no risk threshold is universally applicable, the intensity of treat- Herzegovina, Croatia, Czech Republic, Estonia, Hungary, Kazakhstan, . ment should increase with increasing CVD risk. In individual cases, . Poland, Slovakia, and Turkey. Very high-risk countries: Algeria, . however, no lower threshold of total CVD risk precludes treatment Armenia, Azerbaijan, Belarus, Bulgaria, Egypt, Georgia, Kyrgyzstan, . of risk factors. Conversely, no high threshold for total CVD risk . Latvia, Lebanon, Libya, Lithuania, Montenegro, Morocco, Republic of . implies ‘mandatory’ treatment. Across the entire range of CVD risk, Moldova, Romania, Russian Federation, Serbia, Syria, The Former . the decision to initiate interventions remains a matter of individual . Yugoslav Republic (Macedonia), Tunisia, Ukraine, and Uzbekistan. A . consideration and shared decision-making (see also section 4.1). In multiplier approach has been used for converting CVD mortality . general, risk factor treatment recommendations are based on ESC Guidelines 25
Table 5 Cardiovascular disease risk categories based on . categories of CVD risk (‘low-to-moderate’, ‘high’, and ‘very high’). . SCORE2 and SCORE2-OP in apparently healthy people . The cut-off risk levels for these categories are numerically different according to age . for various age groups to avoid undertreatment in the young and to . <50 years 50 69 70 yearsa . avoid overtreatment in older persons. As age is a major driver of . CVD risk, but lifelong risk factor treatment benefit is higher in years . . younger people, the risk thresholds for considering treatment are Low-to-moderate CVD <2.5% <5% <7.5% . . lower for younger people (Table 5). risk: risk factor treatment gen- .
. Risk categories do not ‘automatically’ translate into recommenda- Downloaded from https://academic.oup.com/eurheartj/advance-article/doi/10.1093/eurheartj/ehab484/6358713 by guest on 30 August 2021 erally not recommended . . tions for starting drug treatment. In all age groups, consideration of High CVD risk: risk factor 2.5 to <7.5% 5 to <10% 7.5 to <15% . . risk modifiers, lifetime CVD risk, treatment benefit, comorbidities, treatment should be . . frailty, and patient preferences may further guide treatment considered . . decisions. Very high CVD risk: risk fac- >_7.5% >_10% >_15% . . Also, note that many patients can move themselves towards a tor treatment generally . . lower risk category without taking drugs just by stopping smoking.
ESC 2021 . recommendeda . . Finally, note that persons >_70 years old may be at very high risk whilst CVD = cardiovascular disease. . a . being at target SBP, and primary prevention with lipid-lowering drugs In apparently healthy people >_70 years old, the treatment recommendation for . . in older persons is a Class IIb (‘may consider’) recommendation; see lipid-lowering drugs is Class IIb (‘may be considered’). . The division of the population into three distinct age groups (<50, 50 69, and . section 4.6. >_70 years) results in a discontinuous increase in risk thresholds for low-to-mod- . In the 50 69-year age range, a 10-year CVD mortality risk thresh- erate, high, and very high risk. In reality, age is obviously continuous, and a sensi- . . old of 5% estimated with the previously used SCORE algorithm cor- ble 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 . responds, on average, to a 10-year fatal and non-fatal CVD risk recently passed the age cut-off. Figure 5 illustrates how a continuous increase in . threshold of 10% estimated with SCORE2, as approximately the age relates to increasing risk thresholds, and may be used as a guide for daily . practice. . same number of people are above the risk threshold and would qual- . ify for treatment.68 .
10-year CVD risk (%) 25 22.5 20 17.5 15 12.5 10 7.5 5
2.5
30 40 50 60 70 80 90 <50 50-69 ≥70
Age groups (years)
CVD risk thresholds (%)
Very high CVD risk
High CVD risk
Low-to-moderate CVD risk
Figure 5 Schematic representation of increasing 10-year cardiovascular disease risk thresholds across age groups. CVD = atherosclerotic cardiovascular disease. 26 ESC Guidelines
Apparently healthy personsa
STEP 1 Stop smoking, lifestyle recommendations and SBP <160 mmHg (Class I) Downloaded from https://academic.oup.com/eurheartj/advance-article/doi/10.1093/eurheartj/ehab484/6358713 by guest on 30 August 2021 Age < 50 years Age 50 – 69 yearsAge ≥ 70 year sb
Estimate 10-year CVD risk Estimate 10-year CVD risk Estimate 10-year CVD risk (SCORE2) (SCORE2) (SCORE2-OP)
<2.5% 2.5 to <7.5% ≥7.5% <5% 5 to <10% ≥10% <7.5% 7.5 to <15% ≥15%
Consider risk modifiers, Consider risk modifiers, Consider risk modifiers, lifetime treatment lifetime CVD risk lifetime CVD risk benefitb, comorbidities, and treatment benefitb, and treatment benefitb, frailty, polypharmacy, patient preferences patient preferences patient preferences
No additional No additional No additional No additional prevention prevention prevention prevention goals goals goals goals
SBP <140 LDL-C SBP <140 LDL-C to 130 mmHg <2.6 mmol/L to 130 mmHg <2.6 mmol/L AND AND if tolerated (<100 mg/dL) if tolerated (<100 mg/dL) (Class I) (Class IIa) (Class I) (Class IIb)
STEP 2 STEP 2 Intensified treatment based on: 10-year CVD risk (SCORE2) Lifetime CVD risk and treatment benefitb Comorbidities, frailty For specific risk factor Patient preferences management in patients ≥70 years, LDL-C (Class IIa) please see Section 4 SBP <130 mmHg AND High risk Very high risk if tolerated <1.8 mmol/L <1.4 mmol/L (Class I) (<70 mg/dL) (<55 mg/dL)
Figure 6 Flow chart of cardiovascular disease risk and risk factor treatment in apparently healthy persons. ASCVD = atherosclerotic cardiovascular dis- ease; CKD = chronic kidney disease; CVD = cardiovascular disease; DM = diabetes mellitus; ESC = European Society of Cardiology; FH = familial hyper- cholesterolaemia; 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 condi- tions 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). ESC Guidelines 27
Patients with established ASCVDa
STEP 1b
Stop smoking SBP <140
and lifestyle to 130 mmHg Downloaded from https://academic.oup.com/eurheartj/advance-article/doi/10.1093/eurheartj/ehab484/6358713 by guest on 30 August 2021 recommendations if tolerated (Class I) (Class I)
AND
LDL-C Antithrombotic ≥50% reduction and Therapy <1.8 mmol/L (<70 mg/dL) (Class I) (Class I)
STEP 2
Intensified treatment based on: Residual 10-year CVD riskc Lifetime CVD risk and treatment benefitd Comorbidities, frailty Patient preferences
DAPT, DPI, SBP LDL-C novel upcoming <130 mmHg <1.4 mmol/L AND AND interventions if tolerated (<55 mg/dL) (e.g. colchicine, EPA) (Class I) (Class I) (Class IIb)
Figure 7 Flow chart of cardiovascular risk and risk factor treatment in patients with established atherosclerotic cardiovascular disease. Ultimate treat- ment 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 coro- nary 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.
. As the 10-year CVD risk thresholds guide treatment decisions and . be considered, taking CVD risk modifiers, lifetime risk and treatment have an impact on healthcare costs and resources, countries or . benefit (in low- and moderate-risk regions, Box 1), and patient preferen- . regions may decide on using higher or lower treatment thresholds. . ces into account. A 10-year CVD risk <5% is considered ‘low-to-mod- . erate risk’, and would generally not qualify for risk factor treatment . 3.2.3.4 Risk estimation and risk factor treatment in apparently healthy . unless one or several risk modifiers (see section 3.3)increaserisk,orthe people 50 69 years of age . estimated lifetime risk and treatment benefit is considered substantial. . Stopping smoking, lifestyle recommendations, and SBP <160 mmHg . are recommended for all (Figure 6). A 10-year CVD risk (fatal and non- . 3.2.3.5 Risk estimation and risk factor treatment estimation in appa- . fatal ASCVD events) >_10% is generally considered ‘very high risk’, and . rently healthy people 70 years of age treatment of CVD risk factors is recommended. A 10-year CVD risk of . Stop smoking, lifestyle recommendations and a SBP <160 mmHg are . 5 to <10% is considered ‘high risk’, and treatment of risk factors should . recommended for all (Figure 6). Age is the dominant driver of CVD 28 ESC Guidelines risk, and estimated 10-year CVD risk of almost all individuals >_70 . moderate-risk regions), and patient preferences into account. A 10- . years exceeds conventional risk thresholds. Also, lifetime benefit of . year CVD risk <2.5% is considered ‘low-to-moderate risk’, and would treatment in terms of time gained free of CVD is lower in older peo- . generally not qualify for risk factor treatment unless one or several risk . ple. Therefore, the CVD risk thresholds for risk factor treatment are . modifiers (see section 3.3) increase risk or the estimated lifetime risk and higher in apparently healthy people >_70 years. A 10-year CVD risk . treatment benefit is considered substantial (see Box 1)(Figure 6).75 78 . >15% is generally considered ‘very high risk’, and treatment of . In risk communication with younger people, the lifetime benefit ASCVD risk factors is recommended (note: the recommendation for . perspective may be useful, as well as discussing the potential of avoid- . lipid-lowering treatment in apparently healthy people >_70 years is . ing a devastating CVD event in the short-to-intermediate term, Downloaded from https://academic.oup.com/eurheartj/advance-article/doi/10.1093/eurheartj/ehab484/6358713 by guest on 30 August 2021 class IIb; ‘may be considered’; see section 4.6). A 10-year CVD risk of . despite the fact that 10-year CVD risk may be very low. . 7.5 to <15% is considered ‘high risk’, and treatment of risk factors . CVD risk predictions, as well as predictions of lifetime benefit of . should be considered taking CVD risk modifiers, frailty, lifetime treat- . risk factor treatment, are likely to be imprecise at very young age ment benefit (in low and moderate risk regions, Box 1), comorbid- . (<40 years). At that age, lipid-lowering and BP-lowering drug treat- . ities, polypharmacy, and patient preferences into account. Given the . ment are not usually considered, except for patients with FH or spe- subjective nature of many of these factors, it is not possible to define . cific BP disorders. A healthy lifestyle that is maintained throughout . strict criteria for these considerations. A 10-year CVD risk <7.5% is . life is more relevant for the very young. Mendelian randomization considered ‘low-to-moderate risk’, and would generally not qualify . studies illustrate very nicely that relatively small differences in LDL-C . for risk factor treatment unless one or several risk modifiers (section . or SBP maintained throughout life have large implications on CVD 3.3) increase risk or the estimated lifetime risk and treatment benefit . risk over a lifespan.80 75 79 . is considered substantial. . . 3.2.3.7 Risk estimation and risk factor treatment in patients with estab- . 3.2.3.6 Risk estimation and risk factor treatment in apparently healthy . lished atherosclerotic cardiovascular disease people <50 years of age . Patients with clinically established ASCVD are, on average, at very . Stopping smoking, lifestyle recommendations, and SBP <160 mmHg are . high risk of recurrent CVD events if risk factors are not treated. recommended for all (Figure 6). The 10-year CVD risk in relatively . Therefore, smoking cessation, adoption of a healthy lifestyle, and risk . young, apparently healthy people is on average low, even in the pres- . factor treatment is recommended in all patients (STEP 1). Further ence of high risk factor levels, but the lifetime CVD risk is in these cir- . intensification of risk factor treatment by aiming at lower treatment . cumstances very high. In apparently healthy people <50 years of age, a . goals (STEP 2) is beneficial in most patients and must be considered, 10-year CVD risk >_7.5% is generally considered ‘very high risk’ as this . taking 10-year CVD risk, comorbidities, lifetime risk and treatment . risk relates to a high lifetime risk, and treatment of ASCVD risk factors . benefit (Box 1), frailty, and patient preferences into account in a is recommended. A 10-year CVD risk of 2.5 to <7.5% is considered . shared decision-making process (Figure 7). . ‘high risk’, and treatment of risk factors should be considered, taking . After initial risk factor treatment and the achievement of risk CVD risk modifiers, lifetime risk and treatment benefit (in low- and . factor treatment goals, the individual residual risk for recurrent .
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 expe- rience 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 manage- ment 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. Thelifetimeriskisanestimateoftheageatwhichthereisa50% 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 aver- age 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 dura- tion 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. ESC Guidelines 29
Patients with type 2 diabetes mellitus
STEP 1 Stop smoking and lifestyle recommendations (Class I)AND HbA1c: <53 mmol/mol (<7.0%) (Class I) Downloaded from https://academic.oup.com/eurheartj/advance-article/doi/10.1093/eurheartj/ehab484/6358713 by guest on 30 August 2021 Established ASCVD or severe TODa Without With
Risk
Moderateb Highb
SBP <140 to SBP <140 to Antithrombotic 130 mmHg 130 mmHg therapy Additional if tolerated if tolerated (Class I) prevention (Class I) (Class I) goals generally not LDL-C SGLT2-i or GLP-1RA...c recommended LDL-C ≥50% reduction and (Class III) <2.6 mmol/ <1.8 mmol/L … for CVD: Class I (<100 mg/dL) (<70 mg/dL) (Class I) (Class I) … for TOD: Class IIb
STEP 2
Intensified treatment based on: Intensified treatment based on: 10-year CVD risk Residual 10-year CVD risk Lifetime CVD risk and treatment benefitd Lifetime CVD risk and treatment benefitd Comorbidities, frailty Comorbidities, frailty Patient preferences Patient preferences
SBP LDL-C SBP LDL-C <130 mmHg <1.8 mmol/L <130 mmHg <1.4 mmol/L DAPT, DPI, if tolerated (<70 mg/dL) if tolerated (<55 mg/dL) novel upcoming (Class I) (Class I) (Class I) (Class I) interventions (e.g. colchicine, SGLT2-i or GLP-1RA SGLT2-i or GLP-1RA EPA) if not already on it if not already on itc (Class IIb) (Class IIb) (Class I)
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 (retin- opathy, 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 albumi- nuria; 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. 30 ESC Guidelines
81 . CVD varies widely and should be considered. It is evident that . Recommendations for CVD risk estimation patients with a recent ACS or progressive vascular disease, and . . a b patients with DM and vascular disease, are all at exceptionally high . Recommendations Class Level risk for recurrent CVD events. For other patients with established . . In apparently healthy people <70 years without ASCVD, the residual risk may be less evident and could be esti- . . established ASCVD, DM, CKD, genetic/rarer mated based on clinical criteria such as age, (change in) risk factor . . lipid or BP disorders, estimation of 10-year fatal IB levels, and risk modifiers, or by calculation of residual CVD risk . . and non-fatal CVD risk with SCORE2 is with a calculator. . Downloaded from https://academic.oup.com/eurheartj/advance-article/doi/10.1093/eurheartj/ehab484/6358713 by guest on 30 August 2021 . recommended.68 The risk of recurrent CVD is influenced mainly by classical risk fac- . . In apparently healthy people >_70 years without tors, vascular disease site, and kidney function. Risk stratification tools . for secondary prevention include the SMART (Secondary . established ASCVD, DM, CKD, genetic/rarer . lipid or BP disorders, estimation of 10-year fatal IB Manifestations of Arterial Disease) risk score (available in the ESC . CVD Risk app) for estimating 10-year residual CVD risk in patients . and non-fatal CVD risk with SCORE2-OP is . recommended.72 with stable ASCVD, defined as CAD, PAD, or cerebrovascular dis- . 81 . ease, and the European Action on Secondary and Primary . In apparently healthy people, after estimation of Prevention by Intervention to Reduce Events (EUROASPIRE) risk . 10-year fatal and non-fatal CVD risk, lifetime . model, which estimates 2-year risk of recurrent CVD in patients with . risk and treatment benefit, risk modifiers, frailty, IIa C stable CAD.82 . polypharmacy, and patient preferences should . Occasionally, recurrent CVD risk is very high despite maximum . be considered. (tolerated) conventional treatments. In such cases, novel but less . Patients with established ASCVD and/or DM . well-established preventive treatments such as dual antithrombotic . and/or moderate-to-severe renal disease and/or 83 84 . pathway inhibition, icosapent ethyl, or anti-inflammatory therapy . genetic/rarer lipid or BP disorders are to be IA 85,86 . with colchicine (see section 4.10) may be considered. . considered at high or very high CVD . 75,77,81,88 90 . risk. . 3.2.3.8 Risk estimation and risk factor treatment in persons with type 2 . A stepwise treatment-intensification approach diabetes mellitus . aiming at intensive risk factor treatment is rec- . Most adults with type 2 DM are at high or very high risk for future . ommended for apparently healthy people at CVD, particularly from middle age onwards. On average, type 2 DM . high or very high CVD risk, as well as patients . IB doubles CVD risk and reduces life expectancy by 4 - 6 years, with . with established ASCVD and/or DM, with con- absolute risks highest in those with any target organ damage (TOD). . sideration of CVD risk, treatment benefit of risk . Type 2 DM also increases the risk for cardiorenal outcomes, in par- . factors, risk modifiers, comorbidities, and . 66,67 ticular HF and CKD. Relative risks (RRs) for CVD in type 2 DM are . patient preferences. higher at younger ages of onset and are modestly higher in women . Treatment of ASCVD risk factors is recom- 87 . compared with men. Smoking cessation and adoption of a healthy . mended in apparently healthy people lifestyle are recommended for all people with type 2 DM, and risk fac- . without DM, CKD, genetic/rarer lipid, or BP . tor treatment should be considered in all people with DM, at least . disorders who are at very high CVD risk IC those above the age of 40 years (see sections 4.6 and 4.7). Still, there . (SCORE2 >_7.5% for age under 50; SCORE2 . is a wide range in individual risk for CVD events, especially after initial . >_10% for age 50 69; SCORE2-OP >_15% for risk factor management.88 . 68,72 . age >_70 years). Persons with DM with severe TOD (for definition: see Table 4) . Treatment of ASCVD risk factors should can be considered to be at very high CVD risk, similar to people with . . be considered in apparently healthy people established CVD (see Table 4). Most others with DM are considered . without DM, CKD, genetic/rarer lipid, or BP to be at high ASCVD risk.64 However, an exception can be made for . . disorders who are at high CVD risk (SCORE2 patients with well-controlled short-standing DM (e.g. <10 years), no . 2.5 to <7.5% for age under 50; SCORE2 5 to . IIa C evidence of TOD, and no additional ASCVD risk factors, who may . <10% for age 50 69; SCORE2-OP 7.5 to . be considered as being at moderate CVD risk. . <15% for age >_70 years), taking CVD risk In addition to the semi-quantitative division into three risk catego- . modifiers, lifetime risk and treatment . ries described above, DM-specific risk models may refine risk esti- . benefit, and patient preferences into mates and illustrate the impact of treatments. These models . account. ESC 2021 . generally include duration of DM, glycated haemoglobin (HbA1c) . level, and presence of TOD. Examples are the ADVANCE (Action in . ASCVD = atherosclerotic cardiovascular disease; BP = blood pressure; CKD = . chronic kidney disease (see definition in Table 4); DM = diabetes mellitus; Diabetes and Vascular disease: preterAx and diamicroN-MR . SCORE2 = Systemic Coronary Risk Estimation 2; SCORE2-OP = Systemic Controlled Evaluation) risk score, which predicts 10-year CVD risk, . Coronary Risk Estimation 2-Older Persons. . a and the UKPDS (UK Prospective Diabetes Study) risk engine, which . Class of recommendation. . bLevel of evidence. 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). . ESC Guidelines 31
. Recommendation for CVD risk communication Intensification of risk factor treatment in STEP 2 must be consid- . ered in all patients, taking into account 10-year CVD risk, comorbid- . . a b ities, lifetime risk and treatment benefit (Box 1), frailty, and patient . Recommendation Class Level 75 . preferences in a shared decision-making process. . An informed discussion about CVD risk and . . treatment benefits tailored to the needs of a IC
. 96 ESC 2021 3.2.3.9 Risk estimation and risk factor treatment in persons with type 1 . patient is recommended. diabetes mellitus . . CVD = cardiovascular disease. People with type 1 DM are at increased CVD risk, and earlier manifes- Downloaded from https://academic.oup.com/eurheartj/advance-article/doi/10.1093/eurheartj/ehab484/6358713 by guest on 30 August 2021 . aClass of recommendation. . b tation of type 1 DM relates to more life-years lost in women than men, . Level of evidence. 91 . mostly due to CVD. 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 hyper- . . glycaemia, and usual risk factors contribute strongly to CVD outcomes . 92 . in type 1 DM. CVD risks have declined over time, commensurate . Recommendations for CVD risk modifiers 93 . with improvements in life expectancy. Lifetime CVD risks in type 1 . . a b DM are higher with poorer glycaemic control, lower social class, and . Recommendations Class Level younger age of onset. The absolute risk of CVD events or CVD mor- . . Stress symptoms and psychosocial stressors tality is highest among those with any evidence of microvascular dis- . . modify CVD risk. Assessment of these stressors IIa B ease, particularly renal complications, and is strongly influenced by age. . . should be considered.100 102 CVD risk stratification in persons with type 1 DM may be based on the . . CAC scoring may be considered to improve risk same risk classification as for type 2 DM, summarized in Table 4, . although the level of evidence for type 1 DM is weaker. . classification around treatment decision thresh- . olds. Plaque detection by carotid ultrasound is IIb B . . an alternative when CAC scoring is unavailable . or not feasible.103,104 . . Multiplication of calculated risk by RR for specific 3.2.4. Communication of cardiovascular disease risk . IIa B . 105 Reducing CVD risk at the individual level begins with appropriate . ethnic subgroups should be considered. . The routine collection of other potential modi- assessment of individual risk and effective communication of risk and . anticipated risk reduction by risk factor treatment. Patient-doctor . fiers, such as genetic risk scores, circulating or 94,95 . urinary biomarkers, or vascular tests or imaging interactions are complex and communicating risk is challenging. . III B There is no single ‘correct’ approach; rather, it will depend on the . methods (other than CAC scoring or carotid . ultrasound for plaque determination), is not individual’s preferences and understanding, which may differ with . education status and numeracy. Risk perception is also strongly . recommended. ESC 2021 . affected by emotional factors such as fear, optimism, etc. (‘patients . CVD = cardiovascular disease; CAC = coronary artery calcium; RR = relative 96 . don’t think risk, they feel risk’). . risk. . a It is important to explore whether patients understand their risk, . Class of recommendation. . bLevel of evidence. 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 . of RRs to treatment decisions is not recommended, as absolute risk able to change their lifestyle. In terms of outcomes, reducing mortal- . remains the key criterion for starting treatment. . ity risk is crucial to some, whereas disease risk is more important to . An alternative way of expressing individual risk is to calculate a per- . 96 others. Short-term risk may motivate some patients, whereas lifetime . son’s ‘risk age’. 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 benefit (see Box 1) will have more impact in others. In general, visual . aids (graphs etc.) improve risk understanding, absolute risk (reduc- . 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 tion) is better understood than RR (reduction), and the use of ‘num- . bers needed to treat’ is less well understood. . that a young person with a low absolute but high RR of CVD will be . In apparently healthy people, the standard approach is to report . exposed to if preventive measures are not adopted. Risk age is also absolute 10-year risk of a CVD event with SCORE2 or SCORE2-OP, . automatically calculated as part of HeartScore (http://www.hearts- . 97 99 which can be found at the ESC CVD Risk Calculator app (https:// . core.org/). www.escardio.org/Education/ESC-Prevention-of-CVD-Programme/ . CVD risk may also be expressed with a lifetime rather than a 10- . Risk-assessment/esc-cvd-risk-calculation-app) or at http:// . year horizon, for example, the LIFE-CVD (LIFEtime-perspective www.heartscore.org or https://www.u-prevent.com. In specific situa- . CardioVascular Disease) calculator (ESC CVD Risk Calculation app . 78 tions, one may opt for expressing risk in terms other than absolute . or https://www.u-prevent.com) (also see Box 1). Lifetime CVD 10-year risk. Examples of such situations include risks in young or . risk-prediction models identify high-risk individuals both in the short . very old people. In young people, lifetime risk might be more infor- . and long term. Such models account for predicted risk in the context mative, as 10-year CVD risk is usually low even in the presence of . of competing risks from other diseases over the remaining expected . risk factors. In older persons, specific risk estimation is required, tak- . lifespan of an individual. A similar approach also employing lifetime ing competing non-CVD mortality into account.78 Direct translation . perspective is to calculate lifetime benefit of preventive 32 ESC Guidelines
. interventions.78 Lifetime benefit of preventive interventions can be . 3.3.1. Psychosocial factors . expressed as gain in CVD-free life (years), which is easier to commu- . Psychosocial stress is associated, in a dose-response pattern, with the nicate to a patient and may support the shared decision-making . development and progression of ASCVD, independently of conven- . process. . tional risk factors and sex. Psychosocial stress includes stress symptoms . (i.e. symptoms of mental disorders), as well as stressors such as loneli- . 3.3. Potential risk modifiers . ness and critical life events. The RRs of psychosocial stress are com- . monly between 1.2 and 2.0108,109 (Supplementary Table 4). Conversely, Apart from the conventional CVD risk factors included in the risk . charts, additional risk factors or types of individual information can . indicators of mental health, such as optimism and a strong sense of pur- Downloaded from https://academic.oup.com/eurheartj/advance-article/doi/10.1093/eurheartj/ehab484/6358713 by guest on 30 August 2021 . pose, are associated with lower risk.109 Psychosocial stress has direct also modify calculated risk. Assessment of a potential modifier may . be considered if: . biological effects, but is also highly correlated with socioeconomic and . 100,109 113 . behavioural risk factors (e.g. smoking, poor adherence). • It improves measures of risk prediction, such as discrimination or . Although the associations of psychosocial stress with CV health are . reclassification (e.g. by calculation of net reclassification index) . robust, only ‘vital exhaustion’ has been proven to improve risk reclassi- • Public health impact is clear (e.g. number needed to screen or . 101 . fication. Owing to the importance of stress symptoms among net benefit) . ASCVD patients, several guidelines and scientific statements recom- It is feasible in daily practice . • . mend screening of ASCVD patients for psychological stress113 115 • Information is not just available on how risk increases with an . . (Box 2 and Supplementary Table 5). A recent prospective cohort study unfavourable result, but also on how risk decreases if the modi- . . with a median follow-up of 8.4 years reported favourable effects of fier shows a favourable result . . screening for depression on major ASCVD events.102 • The literature on this potential modifier is not distorted by publi- . . cation bias. . . Very few potential modifiers meet all of these criteria. Meta- . 3.3.2. Ethnicity . Europe includes many citizens whose ethnic background originates in analyses in this field are, for example, susceptible to substantial publi- . cation bias.106 Also, the exact way of integrating additional informa- . countries such as India, China, North Africa, and Pakistan. Given the . considerable variability in ASCVD risk factors between immigrant tion on top of regular risk calculator input parameters is mostly . unknown. Finally, RCTs to determine whether the added risk infor- . groups, no single CVD risk score performs adequately in all groups. . mation eventually leads to improved health outcomes are generally . Rather, the use of a multiplying factor would be helpful to take lacking. . account of CVD risk imposed by ethnicity independent of other risk . Assessment of potential risk modifiers seems particularly relevant if . factors in the risk score. The most contemporary relevant data come . from the QRISK3 findings in the UK,105 although this focuses on a 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 . wider range of CVD outcomes and not simply on CVD mortality. . Immigrants from South Asia (notably India and Pakistan) present management decisions. The number of individuals in this ‘grey zone’ is . large. Therefore, feasibility becomes a limitation as modifiers become . higher CVD rates independent of other risk factors, whereas . adjusted CVD risks appear lower in most other ethnic groups. The more complex or expensive, such as some imaging techniques. . Care should be taken not to use risk modifiers solely to increase . reasons for such differences remain inadequately studied, as do the . risks associated with other ethnic backgrounds. Based on such data, risk estimates when the modifier profile is unfavourable, but also vice . versa. Although an unfavourable risk modifier may increase an indi- . the following correction factors, based on data from the UK, could . be applied when assessing CVD risk using risk calculators.105 Ideally, vidual’s estimated risk, a more favourable profile than would be . expected based on other patient characteristics must have the oppo- . country and risk-calculator-specific RRs should be used, as the impact . of ethnicity may vary between regions and risk calculators. site effect. Finally, it is important to acknowledge that the degree to . which calculated absolute risk is affected by modifiers is generally . . • Southern Asian: multiply the risk by 1.3 for Indians and much smaller than the (independent) RRs reported for these modi- . Bangladeshis, and 1.7 for Pakistanis. fiers in the literature.107 . . • Other Asian: multiply the risk by 1.1. Taking the above into account, we summarize the literature on . • Black Caribbean: multiply the risk by 0.85. several popular risk modifiers in this section. . • Black African and Chinese: multiply the risk by 0.7.
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 atten- tive 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:Areyouboth- ered 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? ESC Guidelines 33
. 3.3.3. Imaging . 3.3.3.6 Echocardiography . 3.3.3.1 Coronary artery calcium . In view of the lack of convincing evidence that it improves CVD risk Coronary artery calcium (CAC) scoring can reclassify CVD risk . reclassification, echocardiography is not recommended to improve . upwards and downwards in addition to conventional risk factors, . CV risk prediction. and may thus be considered in men and women with calculated . 103,104 . risks around decision thresholds. Availability and cost- . 3.3.4.Frailty effectiveness of large-scale CAC scanning must, however, be con- . Frailty is a multidimensional state, independent of age and multimor- . sidered in a locoregional context (see section 2.3 on cost- . bidity, that makes the individual more vulnerable to the effect of Downloaded from https://academic.oup.com/eurheartj/advance-article/doi/10.1093/eurheartj/ehab484/6358713 by guest on 30 August 2021 effectiveness). If CAC is detected, its extent should be compared . stressors. It constitutes a functional risk factor for unfavourable out- . with what would be expected for a patient of the same sex and . comes, including both high CV and non-CV morbidity and age. Higher-than-expected CAC increases the person’s calculated . mortality.126,127 . risk, whereas absent or lower-than-expected CAC is associated . Frailty is not the same as ageing and the two should not be con- with lower than calculated risk. CAC scoring does not provide . fused. The incidence of frailty increases with age, but people of the . direct information on total plaque burden or stenosis severity, . same chronological age can differ significantly in terms of health status and can be low or even zero in middle-aged patients with soft . and vitality. ‘Biological age’ is much more important in the context of . non-calcified plaque. Clinicians are advised to consult existing pro- . clinical status (including frailty features) and hard clinical outcomes . 126,127 tocols for details of how to assess and interpret CAC scores. . (including CVD events). Similarly, although the presence of . comorbidities can exacerbate frailty within an individual, frailty is not . 3.3.3.2 Contrast computed tomography coronary angiography . thesameasmultimorbidity(seesection 6.7). Contrast computed tomography angiography (CCTA) allows . Frailty screening is indicated in every elderly patient, but should also . identification of coronary stenoses and predicts cardiac . be performed in every individual regardless of his/her age, when being 119 . events. In the SCOT-HEART (Scottish Computed . at risk of accelerated ageing.126,127 Most of the tools relate to frail fea- . Tomography of the Heart) study, 5-year rates of coronary death . tures, including slowness, weakness, low physical activity (PA), exhaus- or myocardial infarction were reduced when CCTA was used in . tion, and shrinking (e.g. Fried scale, Short Physical Performance 120 . patients with stable chest pain. Therelativereductioninmyo- . Battery, Rockwood Clinical Frailty Scale, handgrip strength, gait cardial infarction was similar in patients with non-cardiac chest . speed).126 129 Frailty assessment is important at each stage of an . pain. Whether CCTA improves risk classification or adds prog- . ASCVD trajectory. During an acute CVD event, however, frailty nostic value over CAC scoring is unknown. . assessment is more difficult, and either relies on history taking or . . should be postponed to when patients return to a stable condition. 3.3.3.3 Carotid ultrasound . Frailty is a potential modifier of global CVD risk. The impact of frailty . Systematic use of intima-media thickness (IMT) to improve risk . on CVD risk has been demonstrated across the spectrum of ASCVD, assessment is not recommended due to the lack of methodological . including people with ASCVD risk factors, patients with subclinical . standardization, and the absence of added value of IMT in predicting . ASCVD, stable ASCVD, acute cerebral and coronary syndromes, and 121 . 126 130 future CVD events, even in the intermediate-risk group. . HF, with frailty itself rather than classical CVD risk factors pre- . 130,131 Plaque is defined as the presence of a focal wall thickening that is . dicting both all-cause and CVD mortality in the very old. >_50% greater than the surrounding vessel wall, or as a focal region . Importantly, the ability of frailty measures to improve CVD risk predic- . with an IMT measurement >_1.5 mm that protrudes into the . tion has not been formally assessed. Hence, we do not recommend lumen.122 Although the evidence is less extensive than it is for CAC, . that frailty measures are integrated into formal CVD risk assessment. . carotid artery plaque assessment using ultrasonography probably . Importantly, frailty may influence treatment. Non-pharmacological also reclassifies CVD risk,104,122 and may be considered as a risk . interventions (e.g. balanced nutrition, micronutrient supplementa- . modifier in patients at intermediate risk when a CAC score is not . tion, exercise training, social activation) aiming to prevent, attenuate, feasible. . or reverse frailty are of utmost importance.126,127,132 In terms of . . pharmacotherapy and device implantations, frailty assessment is not a . 3.3.3.4 Arterial stiffness . method to determine the eligibility for any particular treatment, but Arterial stiffness is commonly measured using either aortic pulse . rather serves to build an individualized care plan with predefined pri- . wave velocity or arterial augmentation index. Studies suggest that . orities. Frail individuals often have comorbidities, polypharmacy, and arterial stiffness predicts future CVD risk and improves risk classifica- . may be more susceptible to drug side-effects and serious complica- 123 . 126,127 tion. However, measurement difficulties and substantial publica- . tions during invasive and surgical procedures. tion bias106 argue against widespread use. . . . 3.3.5. Family history 3.3.3.5 Ankle brachial index . Family history of premature CVD is a simple indicator of CVD risk, . 133 Estimates are that 12 27% of middle-aged individuals have an . reflecting the genetic and environment interplay. In the few studies ankle brachial index (ABI) <0.9, around 50 89% of whom do not . that simultaneously assessed the effects of family history and genetics, 124 . have typical claudication. An individual patient data meta- . family history remained significantly associated with CVD after adjust- analysis concluded that the reclassification potential of ABI was . ing for genetic scores.134,135 However, family history only marginally . limited, perhaps with the exception of women at intermediate . improves the prediction of CVD risk beyond conventional ASCVD risk.125 . risk factors.136 141 Possible explanations are the varying definitions 34 ESC Guidelines
. of family history applied and that conventional ASCVD risk factors . exposure to PM2.5; the long-term effects are associated mainly with largely explain the impact of family history. . PM2.5. The evidence linking exposure to PM and CVD events is based . A family history of premature CVD is simple, inexpensive informa- . on large-scale epidemiological studies and experimental studies. tion that can trigger comprehensive risk assessment in individuals . Associations with ASCVD mortality vary, but the majority of cohort 136 . with a family history of premature CVD. . studies link long-term air pollution with an increased risk of fatal or . non-fatal CAD, and with subclinical atherosclerosis. Evidence sug- . . gests that reduction of PM2.5 is associated with improvements in 3.3.6. Genetics . inflammation, thrombosis, and oxidative stress, and a decrease in Downloaded from https://academic.oup.com/eurheartj/advance-article/doi/10.1093/eurheartj/ehab484/6358713 by guest on 30 August 2021 The aetiology of ASCVD has a genetic component, but this informa- . . death from ischaemic heart disease.38,160,161 As sufficiently precise tion is not currently used in preventive approaches.142 Advances on . . individual exposure estimates are hard to obtain, formal risk reclassi- polygenic risk scores for risk stratification could increase the use of . 143 145 . fication is difficult to quantify at present. genetics in prevention. For ASCVD, there is, however, a lack . of consensus regarding which genes and corresponding single nucleo- . . tide polymorphisms should be included, and whether to use risk . Recommendations for cardiovascular disease risk 146 . related to air pollution factor-specific or outcome-specific polygenic risk scores. . Polygenic risk scoring has shown some potential to improve ASCVD . . Recommendations Classa Levelb 147 149 . risk prediction for primary prevention, but the incremental . . Patients at (very) high risk for CVD may be prediction accuracy is relatively modest and needs further evaluation . in both men and women.150,151 Additional evidence is also needed to . encouraged to try to avoid long-term exposure IIb C . to regions with high air pollution. evaluate the clinical utility of polygenic risk scores in other clinical set- . tings, such as in patients with pre-existing ASCVD.152 . In regions where people have long-term exposure . . to high levels of air pollution, (opportunistic) CVD IIb C . ESC 2021 3.3.7. Socioeconomic determinants . risk screening programmes may be considered. . Low socioeconomic status and work stress are independently associ- . CVD = cardiovascular disease. 153,154 . ated with ASCVD development and prognosis in both sexes. . aClass of recommendation. . b The strongest association has been found between low income and . Level of evidence. . 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 com- . . 3.3.9. Biomarkers in blood or urine bination of high demands and low control at work) and effort-reward . imbalance. There is preliminary evidence that the detrimental impact . Many biomarkers have been suggested to improve risk stratification. . of work stress on ASCVD health is independent of conventional risk . Some may be causal [e.g. lipoprotein(a), reflecting a pathogenic lipid factors and their treatment.156 . 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). 3.3.8. Environmental exposure . . In the 2016 Guidelines,2 we recommended against the routine use Environmental exposures with CVD risk modifying potential include . . of biomarkers because most do not improve risk prediction, and pub- air and soil pollution as well as above-threshold noise levels. . . lication bias seriously distorts the evidence.106,162 New studies con- Evaluating individual cumulative exposure to pollutants and noise . . firm that C-reactive protein has limited additional value.103 There is remains challenging, but when available, might impact on individual . . renewed interest in lipoprotein(a), but it too provides limited addi- risk assessment. . . tional value in terms of reclassification potential.163,164 Cardiac bio- Components of outdoor air pollution include airborne particulate . . markers are promising,165,166 but further work is needed. m . matter [PM; ranging in size from coarse particles 2.5 10 mindiam- . eter, to fine (<2.5 mm; PM2.5), and ultrafine (<0.1 mm)] and gaseous . . pollutants (e.g. ozone, nitrogen dioxide, volatile organic compounds, . 3.3.10. Body composition carbon monoxide, sulphur dioxide), produced primarily by combus- . Worldwide, BMI has increased substantially in recent decades, in chil- . 43 tion of fossil fuels. Soil and water pollutions are also CVD risk modi- . dren, adolescents, and adults. In observational studies, all-cause fiers; increased exposure to lead, arsenic, and cadmium is associated . mortality is minimal at a BMI of 20 - 25 kg/m2, with a J- or U-shaped . 45,46 with multiple CVD outcomes including hypertension, coronary heart . relation in current smokers. Mendelian randomization analyses disease (CHD), stroke, and CVD mortality.157 Ambient PM pollution . suggest a linear relation between BMI and mortality in never-smokers . 44 recently ranked as a leading modifiable mortality risk factor and also . and a J-shaped relation in ever-smokers. A meta-analysis concluded responsible for attributable disability adjusted life-years at the global . that both BMI and waist circumference are similarly strongly and con- 158 . level. A recent model estimated that loss of life expectancy due to . tinuously associated with ASCVD in the elderly and the young and in ambient air pollution is similar to, if not exceeding, that due to . men and women.47 . tobacco smoking, and accounts for a global excess mortality esti- . Among those with established ASCVD, the evidence is contradic- 159 . mated at 8.8 million/year. . tory. Systematic reviews of patients with ACS or HF have suggested The short-term attributable effects on mortality are linked primar- . an ‘obesity paradox’ whereby obesity appears protective.167,168 169 . ily to exposure to PM, nitrogen dioxide, and ozone, with an average . However, this evidence should be interpreted with caution as 1.0% increase of all-cause mortality for an increment of 10 lg/m3 in . reverse causality and other biases may be operating.45 ESC Guidelines 35
3.3.10.1 Which index of obesity is the best predictor of cardiovascular . . COPD It is recommended that all COPD risk? . patients be investigated for IC . BMI can be measured easily and is used extensively to define catego- . ASCVD and ASCVD risk factors. ries of body weight (see Supplementary Table 6). Body fat stored in . . Inflammatory Assessment of total CVD risk may visceral and other ectopic depots carries a higher risk than subcuta- . . conditions be considered in adults with chronic IIb B neous fat. Several measures of global and abdominal fat are available, . . inflammatory conditions.176 of which waist circumference is the simplest to measure. The WHO . . Multiplication of calculated total thresholds for waist circumference are widely accepted in Europe. Downloaded from https://academic.oup.com/eurheartj/advance-article/doi/10.1093/eurheartj/ehab484/6358713 by guest on 30 August 2021 . CVD risk by a factor of 1.5 should Two action levels are recommended: . IIa B . be considered in adults with rheu- . 177,178 Waist circumference >_94 cm in men and >_80 cm in women: no . matoid arthritis. • . further weight gain . Migraine Presence of migraine with aura Waist circumference >_102 cm in men and >_88 cm in women: . • . should be considered in CVD risk IIa B weight reduction advised. . assessment.179 181 . . Avoidance of combined hormonal Different cut-offs for anthropometric measurements may be . contraceptives may be considered required in different ethnicities. . IIb B . in women with migraine with The phenotype of ‘metabolically healthy obesity’, defined by the . aura.182,183 presence of obesity in the absence of metabolic risk factors, has . . Sleep In patients with ASCVD, obesity, gained interest. Long-term results support the notion that metabol- . . disorders and hypertension, regular screen- ically healthy obesity is a transient phase moving towards glucometa- . 170 . and OSA ing for non-restorative sleep is bolic abnormalities rather than a specific ‘state’. . . indicated (e.g. by the question: IC . ‘how often have you been both- 3.3.10.2 Risk reclassification . . ered by trouble falling or staying The associations between BMI, waist circumference, and waist-to-hip . . asleep, or sleeping too much?’). ratio and CVD are maintained after adjustment for conventional risk . . If there are significant sleep prob- factors. However, these measures did not improve CVD risk predic- . . lems, which are not responding tion as assessed by reclassification.47 . . within 4 weeks to sleep hygiene, IC . referral to a specialist is . Recommendations for cardiovascular disease assess- . recommended. ment in specific clinical conditions . . Mental It is recommended that mental dis- . Clinical Recommendations Classa Levelb . disorders orders with either significant func- . tional impairment or decreased use IC condition . . of healthcare systems be considered CKD In all CKD patients, with or with- . as influencing total CVD risk. out DM, appropriate screening for . . Sex-specific In women with a history of pree- ASCVD and kidney disease pro- . IC. conditions clampsia and/or pregnancy- gression, including monitoring . . induced hypertension, periodic IIa B changes in albuminuria is . . screening for hypertension and 172 . recommended. . 184 187 . DM should be considered. Cancer It is recommended to monitor . . In women with a history of poly- cardiac dysfunction using imaging . . cystic ovary syndrome or gesta- techniques and circulating bio- IB. IIa B . tional DM, periodic screening for markers before, periodically dur- . 188 191 . DM should be considered. ing, and after cancer treatment.173 . . In women with a history of pre- Cardioprotection in high-risk . . mature or stillbirth, periodic patients (those receiving high . IIb B . screening for hypertension and cumulative doses or combined . 192,193 . DM may be considered. radiotherapy) receiving anthracy- IIb B . . Assessment of CVD risk should . IIa C cline chemotherapy may be con- . ESC 2021 . be considered in men with ED. sidered for prevention of LV . dysfunction.174,175 . ASCVD = atherosclerotic cardiovascular disease; CKD = chronic kidney disease; . COPD = chronic obstructive pulmonary disease; CV = cardiovascular; CVD = Screening for ASCVD risk factors . . cardiovascular disease; DM = diabetes mellitus; ED = erectile dysfunction; LV = and optimization of the CVD risk . left ventricular; OSA = obstructive sleep apnoea. IC. a profile is recommended in . Class of recommendation. . bLevel of evidence. patients on treatment for cancer. . Continued . 36 ESC Guidelines
. 3.3.10.3 Assess risk factors and cardiovascular disease risk in persons . 3.4.2. Atrial fibrillation . with obesity . Atrial fibrillation (AF) appears to be associated with an increased risk Comprehensive CVD risk assessment should be considered in individ- . of death and of CVD and kidney disease.205 Furthermore, AF appears . 206 uals with unfavourable body composition. The main risk-related sequa- . to be a stronger risk factor for CVD in women than in men. lae of adiposity include hypertension, dyslipidaemia, insulin resistance, . The prevalence of AF ranges between 2% and 4%, and a 2.3-fold . systemic inflammation, a prothrombotic state, albuminuria, as well as a . rise is expected, owing in part to ageing of the population and intensi- decline in estimated glomerular filtration rate (eGFR)171 and the devel- . fied searching for undiagnosed AF, as well as lower CV death.207 The . opment of type 2 DM, CVD events, as well asHFand AF. . age-adjusted incidence, prevalence, and lifetime risk of AF are lower Downloaded from https://academic.oup.com/eurheartj/advance-article/doi/10.1093/eurheartj/ehab484/6358713 by guest on 30 August 2021 . in women vs. men and in non-white vs. white cohorts.208,209 The life- . 3.4. Clinical conditions . time 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 comor- Individual calculated risks of CVD, as evaluated by conventional risk . . bidities, including lifestyle factors, and age significantly affect the life- factors in risk scores, are subject to refinement by potential risk . . time risk for AF development.211 213 The observed effect of clinical modifiers as highlighted in section 3.3.Beyondthesepotentialmodi- . . ASCVD risk factor burden and multiple comorbidities on the lifetime fiers, specific clinical conditions can influence CVD risk. These clinical . . risk of AF (significantly increasing from 23.4% among individuals with conditions often increase the likelihood of CVD, or are associated . . an optimal clinical risk factor profile to 33.4% and 38.4% in those with with poorer clinical prognosis. The current section reviews some of . . borderline and elevated clinical risk factors, respectively214) suggests these conditions, which are not often included in traditional risk . . that early intervention and control of modifiable ASCVD risk factors scores but may be integrated in some national risk scores. Here we . . could reduce incident AF. The continuum of unhealthy lifestyle, risk discuss how these conditions increase this risk. . . factor(s), and CVDs can contribute to atrial remodelling/cardiomy- Many clinical conditions share common CVD and ASCVD risk fac- . . opathy and development of AF that commonly results from a com- tors and therefore treating these allows a synergistic reduction in the . 215 . bined effect of multiple interacting factors (Figure 9). Risk factor overall burden of disease. . . and CVD management reduces AF burden. Targeted therapy of . . underlying conditions may significantly improve maintenance of sinus 3.4.1. Chronic kidney disease . rhythm in patients with persistent AF and HF.216 However, studies . Worldwide, the total number of individuals with chronic kidney dis- . addressing isolated management of specific conditions alone (e.g. ease (CKD) who are not treated with kidney replacement therapy . hypertension) yielded inconsistent findings.217 194 . was approximately 850 million in 2017. This number accounts to a . The overall annual risk of ischaemic stroke in patients with AF is prevalence of 10 - 12% among men and women. CKD is the third . 5%, but varies considerably according to comorbidities.215 195 . fastest growing cause of death globally. . Cardioembolic strokes associated with AF are usually more severe, CKD is defined as abnormalities of kidney structure or function, . and often recurrent.218 Furthermore, AF appears to be a stronger . 215 present for >3 months, with health implications. Criteria and markers . predictor of stroke in women than in men. AF is also associated of kidney damage, especially kidney disease due to DM, are albuminu- . with impaired cognitive function, ranging from mild cognitive impair- . 219 ria [albumin-to-creatinine ratio (ACR) >30 mg/g in spot urine speci- . ment to dementia. AF is independently associated with a two-fold 2 . mens] and glomerular filtration rate (GFR) <60 mL/min/1.73 m . . increased risk of all-cause mortality in women and a 1.5-fold GFR can be estimated (eGFR) from calibrated serum creatinine and . increased risk in men.220 In one population, the most common causes . estimating equations using the CKD-EPI (Chronic Kidney Disease . of death were HF (14.5%), malignancy (23.1%), and infection/sepsis Epidemiology) Collaboration formula. Kidney disease severity is dif- . (17.3%), while stroke-related mortality was only 6.5%.221 These data . ferentiated into stages (categories) according to the level of GFR and . indicate that, in addition to anticoagulation and HF treatment, comor- albuminuria; a patient with an eGFR <60 mL/min/1.73 m2 is classified . bid conditions need to be actively treated to reduce AF-related mor- . as having CKD stage 3a, which represents an advanced kidney func- . tality and morbidity. 172 . Regarding PA, both sedentary lifestyles and very high levels of PA tion impairment. . Among persons with CKD, CVD is the leading cause of morbidity . are associated with development of AF (U-shaped association), 196 . and death. Even after adjustment for known CAD risk factors, includ- . through different mechanisms. Furthermore, when AF develops in ing DM and hypertension, mortality risk progressively increases with . athletes it is not associated with the same increased risk of stroke. 197 . worsening CKD. As GFR declines below approximately 60 - 75 mL/ . min/1.73 m2, the probability of developing CAD increases linearly,198 . 3.4.3. Heart failure . with up to triple the CVD mortality risk when reaching an eGFR of 15 . Heart failure (HF) of ischaemic origin constitutes a severe clinical mL/min/1.73 m2. Kidney disease is associated with a very high CVD risk. . manifestation of ASCVD. Conversely, HF itself (predominantly of . Among persons with CKD, there is a high prevalence of traditional . ischaemic aetiology) increases the risk of CVD events (myocardial CAD risk factors, such as DM and hypertension. The use of CAC score . infarction, arrhythmias, ischaemic stroke, CV death). 199 203 . to risk stratify patients with CKD might be a promising tool. . Asymptomatic LV dysfunction (systolic or/and diastolic dysfunc- Furthermore, persons with CKD are also exposed to other non- . tion) as well as overt symptomatic HF [across the spectrum of LVEF, . traditional ASCVD risk factors such as uraemia-related ones, including . i.e. HF with reduced ejection fraction (HFrEF), HF with mid-range inflammation, oxidative stress, and promotors of vascular calcification. . ejection fraction,222 and HF with preserved ejection fraction . CKD and kidney failure not only increase the risk of CAD, they also . (HFpEF)] increases the risk of urgent CV hospitalizations (including modify its clinical presentation and cardinal symptoms.204 . hospitalizations due to HF worsening) and CV and all-cause deaths. ESC Guidelines 37
Risk factors for AF
Modifiable Non- or partly modifiable Lifestyle modification AF risk factors modification Hypertension Ageing Treatment of underlying CV conditions Obesity Genetics Diabetes mellitus Heart failure Physical activity CAD
Reduction of mortality and Downloaded from https://academic.oup.com/eurheartj/advance-article/doi/10.1093/eurheartj/ehab484/6358713 by guest on 30 August 2021 OSA Valvular heart morbidity Alcohol disease Primary prevention of AF Dyslipidemia COPD Smoking
LA remodeling
Reversible Non-reversible
Electrical Fibrosis Biochemical Scarring Inflammation Dilatation
Stroke prevention Cardioversion Rate control Catheter ablation AAD therapy Surgery AF development and progression
Paroxysmal Persistent Permanent Lifestyle modification AF risk factors modification Treatment of underlying CV conditions
Reduction of mortality and AF outcomes morbidity Symptomatic improvement Mortality Secondary prevention of AF Stroke/systemic thromboembolism Symptoms and quality of life Heart failure Dementia Myocardial infarction Hospitalizations and healthcare costs
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.
. These unfavourable effects on clinical outcomes have been demon- . beneficial in reducing both CVD as well as cancer risk. Moreover, the . strated in asymptomatic subjects without overt CVD, in patients with . rates of the extent of CVD risk depend on both the CVD toxicity of acute and previous myocardial infarction, in patients with acute and . treatments and patient-related factors. Owing to recent improve- . previous stroke, and in patients with other clinical manifestations of . ments in clinical outcomes for many patients with cancer, CVD mor- CVD.223 . tality may ultimately exceed those from most forms of cancer . 224,225 The diagnosis of ischaemic HF positions individuals at very high CV . recurrence. risk, and justifies recommendations as for secondary prevention ther- . The rapidly expanding variety of novel anticancer drugs/adjuvant . apeutic strategies. Additionally, for patients with symptomatic HFrEF, . therapies has demonstrated a wide range of both early and late CVD several drugs are recommended to reduce the risk of CV morbidity . side-effects, including cardiomyopathy, LV dysfunction, HF, hyperten- . and mortality (see section 6.2). . sion, CAD, arrhythmias, and other injuries. Therefore, effective strat- . egies for the prediction and prevention of CVD toxicities are . 3.4.4. Cancer . critically important. The latency and severity of radiotherapy cardio- In patients with cancer, there is an overlap between cancer and . toxicity, as well as accelerated atherosclerosis and cerebral vascular . ASCVD risk factors, with shared biological mechanisms and genetic . disease, is related to multiple factors, including the dose (total per predispositions. Prevention and treatment of these is therefore . fraction), the volume of the heart irradiated, concomitant 38 ESC Guidelines
. administration of other cardiotoxic drugs, and patient factors (which . syndrome and reduced PA is present in 34% of COPD patients, with . include, amongst other factors, younger age, traditional risk factors, . its most prevalent components being hypertension (56%), abdominal and history of heart disease).226,227 Furthermore, radio- and chemo- . obesity (39%), and hyperglycaemia (44%).245 CVD may be caused by . therapy may exert direct vascular effects and increase . hypoxia during exercise due to lung hyperinflation, high resting heart atherosclerosis-related CVD outcomes.227,228 . rates, impaired vasodilatory capacity, and peripheral, cardiac, and . . neurohumoral sympathetic stress. Atherosclerosis and coronary 3.4.4.1 Diagnosis and screening . artery calcification may be the result of oxidative stress, and reduc- . 246 Signs or symptoms of cardiac dysfunction should be monitored . tions in antiaging molecules causing both lung and vascular ageing. Downloaded from https://academic.oup.com/eurheartj/advance-article/doi/10.1093/eurheartj/ehab484/6358713 by guest on 30 August 2021 before and periodically during and after cancer treatment for early . Systemic inflammation is prominent in COPD, with circulating bio- . detection of abnormalities in patients receiving potentially cardio- . markers in high concentrations and associated with increased mortal- toxic chemotherapy. Detection of subclinical abnormalities using . ity.247 Troponin is elevated during an acute exacerbation of COPD, . imaging and measurement of circulating biomarkers (such as cardiac . and 10% of hospitalized patients meet the definition of acute myocar- 173,229 . 248 troponins and natriuretic peptides) is currently recommended. . dial infarction (AMI). B-natriuretic peptide level, if elevated, . 249 Measures of myocardial strain, particularly systolic global longitudinal . increases the mortality risk. strain, may precede a significant decline in LVEF.230 233 . Systemic inflammation and oxidative stress caused by COPD pro- . . mote vascular remodelling, stiffness, and atherosclerosis, and induce . 250 3.4.4.2 Prevention of cardiotoxicity and cardiovascular risk factors . a ‘procoagulant’ state that affects all vasculature types. Cognitive RCTs of preventive therapy with renin-angiotensin-aldosterone sys- . impairment and dementia due to cerebral microvascular damage is . tem (RAAS) inhibitors and/or beta-blockers after trastuzumab or . correlated with COPD severity; patients have a 20% increased risk 230,234,235 . anthracyclines have reported contradictory results. The . for both ischaemic and haemorrhagic stroke, which may be up to . 251 main benefits are less marked LV remodelling or a reduced decline in . seven-fold higher following an acute exacerbation. PAD is present . 252 LVEF observed with cardiac magnetic resonance, but translation into . in about 9% of COPD patients, who have an almost doubled risk . 253 better outcomes remains speculative. . of developing PAD, as well as an increased prevalence of carotid . 254 Exercise should be strongly advised. In particular, aerobic exercise is . plaques related to the disease severity. Finally, COPD is positively considered a promising non-pharmacological strategy to prevent and/ . associated with abdominal aortic aneurysm, regardless of smoking 236 . 255 or treat chemotherapy toxicity. A study showed a significantly . status. higher risk of CVD in survivors of childhood cancer than in non-cancer . Cardiac arrhythmias are common and may be due to the haemo- . adult controls, and particularly in survivors of adult-onset cancer with . dynamic effects (pulmonary hypertension, diastolic dysfunction, atrial underlying ASCVD risk factors.237 Therefore, aggressive management . structural, and electrical remodelling) caused by the disease in combi- . of ASCVD risk factors in this population is recommended. . nation with autonomic imbalance and abnormal ventricular repolari- . zation.256 AF is frequent, directly associated with FEV1, usually . 3.4.5. Chronic obstructive pulmonary disease . triggered by acute exacerbations of COPD, and an independent pre- Chronic obstructive pulmonary disease (COPD) is a complex, pro- . dictor of in-hospital COPD mortality.257,258 COPD is also a risk fac- . 259 gressive respiratory disorder and currently the fourth leading cause . tor for ventricular tachycardia independent of LVEF, and for . 260 of death worldwide. It is characterized by chronic airflow limitation . sudden cardiac death independent of CVD risk profile. with respiratory symptoms and is associated with an increased . Unrecognized ventricular dysfunction is common in COPD,261 . inflammatory response and abnormalities of the airways caused by . although HF is 3.8 times more common in COPD patients than in significant exposure to noxious particles or gases (mainly smoking). . controls.262 Patients with frequent acute exacerbations have a high . Although COPD is recognized and thoroughly investigated as a CVD . frequency of diastolic dysfunction; HFpEF risk is higher because of a comorbidity, its role as an ASCVD risk factor is not well established. . high prevalence of hypertension and DM.263 . Nevertheless, COPD patients have a two- to three- fold increased . Considering these facts, it seems of upmost importance to screen . COPD patients for ASCVD and ASCVD risk factors, bearing in mind risk of CVD compared with age-matched controls when adjusted for . tobacco smoking. Patients with mild-to-moderate COPD are 8 10 . that COPD affects the accuracy of CVD diagnostic tests. Achieving . adequate exercise is difficult, vasodilators for myocardial perfusion times more likely to die from ASCVD than respiratory failure, having . higher rates of hospitalization and death due to CVD, stroke, and . scanning may be contraindicated because of the risk of broncho- 238,239 . HF. CVD also runs undiagnosed; less than one-third of COPD . spasm, and stress or transthoracic echocardiography is often dis- patients with electrocardiographic (ECG) evidence of myocardial . turbed by poor ultrasound windows. Computed tomography 240 . infarction are diagnosed with CVD. CVD mortality increases by . coronary angiography or magnetic resonance imaging may be alterna- 28%, and the frequency of non-fatal coronary events by 20%, for . tives, but remain expensive, time consuming, and not always . every 10% decrease in the forced expiratory volume in 1 second . available. (FEV1).241 Acute COPD exacerbations, mainly due to infections, are . The use of COPD medications (i.e. long-acting muscarinic antago- . frequent and are responsible for a four-fold increase of CVD . nists and long-acting beta agonists) is not associated with overall CV 242 . events. The risk of both myocardial infarction and ischaemic stroke . adverse events in patients with stable COPD. Olodaterol may reduce 243 . is increased during the 3 months after an acute exacerbation. . the risk of overall CV adverse events and formoterol may decrease The high prevalence of CVD in COPD patients may be explained . the risk of cardiac ischaemia. Long-acting beta agonists may reduce . by the fact that both diseases share common risk factors, such as . the incidence of hypertension, but may also increase the risk of HF, smoking, ageing, hypertension, and dyslipidaemia.244 Metabolic . so should be used with caution in HF patients.264 ESC Guidelines 39
. 3.4.6. Inflammatory conditions . migraine with aura, which accounts for about one-third of all . Inflammatory conditions increase CVD risk both acutely and over . migraines; in many patients the two forms coexist. time. The best evidence for chronic inflammation increasing CVD . Available data indicate that migraine overall is associated with a . risk is available for rheumatoid arthritis, which increases CVD risk by . two-fold increased risk of ischaemic stroke and a 1.5-fold increase in approximately 50% beyond established risk factors.176 Hence, a low . the risk of cardiac ischaemic disease.179 181,279,280 The associations . 179,180,280 threshold for assessment of total CVD risk is appropriate in adults . are more evident for migraine with aura. Given the young with rheumatoid arthritis, and one should consider increasing the risk . mean age of the population affected by migraine, the absolute 176 . estimate based on the level of disease activity. There is also evi- . increase in risk is small at the individual level, but high at the popula- Downloaded from https://academic.oup.com/eurheartj/advance-article/doi/10.1093/eurheartj/ehab484/6358713 by guest on 30 August 2021 . 281 dence for an approximately 20% increased CVD risk in patients with . tion level because of the high migraine prevalence. active inflammatory bowel disease.265 . Several lines of evidence also indicate that the vascular risk of sub- 177 . 182 In other chronic inflammatory conditions, such as psoriasis and . jects with migraine may be magnified by cigarette smoking and by the ankylosing spondylitis,178 CVD risk may also be increased. However, . use of combined hormonal contraceptives.183,281 283 Contraception . the strength of the evidence is less strong, as is the independence of . using combined hormonal contraceptives should therefore be avoided such increased risks from the classical ASCVD risk factors. . in women with migraine.282,283 However, further information is needed . Nonetheless, it seems prudent to at least consider CVD risk assess- . as good-quality studies assessing risk of stroke associated with low- ment in patients with any chronic inflammatory condition, and to . dose oestrogen use in women with migraine are lacking. . take into account the presence of such conditions when there is . doubt regarding initiation of preventive interventions. The cumulative . 3.4.9.Sleep disorders and obstructive sleep apnoea . disease burden and recent degree of inflammation are important . Sleep disturbances or abnormal sleep durations are associated with . 284 286 determinants of the risk-enhancing effect. . increased CVD risk. Regarding sleep duration, 7 h seems to . 287 Apart from optimal anti-inflammatory treatment, CVD risk in . be optimal for CV health. . In the general population, the prevalence of general sleep distur- inflammatory conditions should be treated with similar interventions . as in the general high-risk population, as there is evidence that tradi- . bances is around 32.1%: 8.2% for insomnia, 6.1% for parasomnia, . 5.9% for hypersomnolence, 12.5% for restless legs disorder and limb tional methods to lessen risk (e.g. lipid-lowering treatment) are just . as beneficial in preventing ASCVD. . movements during sleep, and 7.1% for sleep-related breathing disor- . 288 . der [e.g. obstructive sleep apnoea (OSA)]. All sleep disturbances . . are strongly associated with mental disorders and share hyperarousal 3.4.7. Infections (human immunodeficiency virus, . . as an underlying mechanism.289,290 influenza, periodontitis) . . The most important sleep-related breathing disorder is OSA, Infection with human immunodeficiency virus (HIV) is associated . . which is characterized by repetitive episodes of apnoea, each exceed- with a 19% increased risk of LEAD and CAD beyond that explained . 266,267 . ing 10 seconds. Despite the strong associations of OSA with CVD, by traditional atherosclerotic risk factors. However, for those . . including hypertension, stroke, HF, CAD, and AF, treatment of OSA with sustained CD4 cell counts <200 cells/mm3, the risk of incident . . by positive airway pressure (PAP) has failed to improve hard CV out- LEAD events is nearly two-fold higher, whereas for those with sus- . . comes in patients with established CVD.291 293 Therefore, interven- tained CD4 cell counts >_500 cells/mm3, there is no excess risk of . . tions that include behaviour change (reduction of obesity, alcohol incident LEAD events compared with uninfected people.268 . . abstinence), sleep hygiene, and stress reduction in addition to PAP are CVD and influenza have long been associated, due to an overlap in . . needed.290,294 Regarding hypertension and OSA, there are modest the peak incidence of each disease during winter months. . . effects of PAP on BP levels, but only in patients with ABPM-confirmed Epidemiological studies have noted an increase in CV deaths during . 295 . resistant hypertension who use PAP for more than 5.8 h/night. influenza epidemics, indicating that CV complications of influenza . infection, including acute ischaemic heart disease and, less often, . . 3.4.10. Mental disorders stroke, are important contributors to morbidity and mortality during . . The 12-month prevalence of mental disorders or mental health dis- influenza infection. . . orders in the general European population is between 27% and 38% The risk of AMI or stroke is more than four times higher after a . . depending on sources and definitions.296 All mental disorders (e.g. respiratory tract infection, with the highest risk in the first 3 days after . . anxiety disorders, somatoform disorders, substance disorders, per- diagnosis.269 Preventing influenza, particularly by means of vaccina- . . sonality disorders, mood disorders, and psychotic disorders) are tion, could prevent influenza-triggered AMI.270 . . associated with the development of CVD and reduced life expect- Studies have linked periodontal disease to both atherosclerosis and . . ancy in both sexes.297 300 The risk increases with the severity of the CVD,271 273 andserologicalstudieshavelinkedelevatedantibodytitres . . mental disturbance and vigilance for (often non-specific) symptoms is of periodontal bacteria to atherosclerotic disease.274 Nevertheless, if . . crucial.301 The onset of CVD is associated with an approximately active treatment or prevention of periodontitis improves, clinical prog- . 275 277 . 2 3-fold increased risk of mental disorders compared to a healthy nosis requires further studies despite preliminary evidence. . 115,302 . population. In this context, screening should be performed at . every consultation (or 2 4 times/year). The 12-month prevalence of . 3.4.8. Migraine . mental disorders in CVD patients is around 40%, leading to signifi- . 100,108,303,304 Migraine is a highly prevalent condition affecting around 15% of the . cantly worse prognosis. The onset of CVD increases the 278 . 305 general population. There are two main types of migraine— . risk of committing suicide. In this context, awareness of anxiety migraine without aura, which is the most common subtype, and . and depression symptoms should be increased. 40 ESC Guidelines
. The precise mechanism by which mental disorders increase CVD . Finally, gestational DM confers a sharply elevated risk of future . remains uncertain. The detrimental effects are potentially caused by . DM, with up to 50% of affected women developing DM within 5 unhealthy lifestyle, increased exposure to socioeconomic stressors, . years after pregnancy, and an up to two-fold increased risk of CVD in 113 . 188,320 and cardiometabolic side-effects of some medications, but also by . the future. Screening by fasting glucose or HbA1c may be pref- direct effects of the amygdala-based fear-defence system and other . erable to oral glucose tolerance testing.191,321 303 . direct pathophysiological pathways. Abuse of psychostimulants . (e.g. cocaine) is a powerful trigger of myocardial ischaemia.306 . 3.4.12.2 Non-obstetric conditions . Further, the capacity of these patients to adaptively use the health- . Polycystic ovary syndrome affects 5% of all women in their fertile Downloaded from https://academic.oup.com/eurheartj/advance-article/doi/10.1093/eurheartj/ehab484/6358713 by guest on 30 August 2021 care systems is impaired due to their mental condition (e.g. not being . years.322,323 It has been associated with an increased risk of CVD.314 . able to trust other people and seek help, impaired capacity to be . The risk of developing hypertension is probably increased, but data adherent).100 Barriers on the part of healthcare providers are stigma- . are conflicting.324 Polycystic ovary syndrome is associated with a . 189,190 tizing attitudes, insufficient mental health literacy, and lack of confi- . higher risk of developing DM (RR 2 4), suggesting that peri- dence in mental healthcare.307 309 Although patients with mental . odic screening for DM is appropriate. . disorders have an increased CVD risk, they receive a lower rate of . Premature menopause occurs in roughly 1% of women <_40 years 310 . recognition and treatment of traditional ASCVD risk factors. . of age. Up to 10% of women experience an early menopause, defined . 314,325 Preliminary evidence suggests that taking mental disorders into . as that occurring by 45 years of age. Early menopause is associ- 311,312 . 326 328 account improves classical CVD risk models. . ated with an increased risk of CVD (RR 1.5). A linear inverse Certain categories of patients with learning difficulties and associ- . relationship between earlier menopause and CHD risk has been . ated disorders (such as Down’s syndrome) are at increased risk of . found, whereby each 1-year decrease in age at menopause por- . 329 CVD disease, but perhaps not specifically ASCVD. However, health . tended a 2% increased risk of CHD. inequalities and the prevalence of CV risk factors may be greater in . . these populations, although epidemiology research is scarce. . 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 multi- 3.4.11. Non-alcoholic fatty liver disease . . factorial cause. It affects almost 40% and more than 50% of men over Non-alcoholic fatty liver disease (NAFLD) has been associated with . . 40 years and 60 years of age, respectively.330,331 Men with ED have an increased risk of myocardial infarction and stroke. NAFLD repre- . . an increased risk of all-cause mortality [odds ratio (OR) 1.26, 95% CI sents accumulation of ectopic fat; persons with NAFLD are often . . 1.01 1.57] and CVD mortality (OR 1.43, 95% CI 1.00 2.05). ED overweight or obese, and not uncommonly have abnormal BP, glu- . . and CVD share common risk factors (hypercholesterolaemia, hyper- cose, and lipid levels. A recent study investigating whether NAFLD . . tension, insulin resistance and DM, smoking, obesity, metabolic syn- increases CV risk beyond traditional risk factors313 shows that after . . drome, sedentary lifestyle, and depression) and a common adjusting for established risk factors, the associations did not persist. . . pathophysiological basis of aetiology and progression.332,333 Nevertheless, patients with NAFLD should have their CVD risk cal- . . Medication used to prevent CVD, such as aldosterone receptor culated, be screened for DM, and be recommended a healthy lifestyle . . antagonists, some beta-blockers, and thiazide diuretics, can cause with a reduction of alcohol intake. . . 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 3.4.12. Sex-specific conditions . to5years(average3years).MenwithEDhavea44 59% higher risk . 3.4.12.1 Obstetric conditions . fortotalCVevents,62%forAMI,39%forstroke,and24 33% for all- Pre-eclampsia (defined as pregnancy-related hypertension accompa- . cause mortality, with a higher risk in those with severe ED.337 341 . nied by proteinuria) occurs in 1 2% of all pregnancies and is associated . There is strong evidence that CVD risk assessment is needed in men . presenting with ED.336,342 InmenwithEDandlow-to-intermediate with an increase in CVD risk by a factor of 1.5 2.7comparedwithall . women,185,186,314 while the RR of developing hypertension is 3187 and . CVD risk, detailed risk profiling by, for example, CAC score is sug- 184,185 . gested, but so far not supported by evidence.338,341 Assessment of ED DM is 2. It has not been established whether the increased CVD . risk after preeclampsia occurs independently of CV risk factors. The . severity and physical examination should be part of the first-line CVD . 333,341 rationale for screening these women for the occurrence of hyperten- . risk assessment in men. Lifestyle changes are effective in improving . 334,343 sion and DM is, however, quite strong. At present, no separate risk . sexual function in men: these include vigorous physical exercise, modelforwomenwithahistoryofhypertensivedisordersofpreg- . improved nutrition, weight control, and smoking cessation.343 345 315 . nancy seems necessary, despite their higher baseline risk. . Pregnancy-related hypertension affects 10 15% of all pregnancies. . . The associated risk of later CVD is lower than for preeclampsia but is . 4. Risk factors and interventions 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 . at the individual level higher).187,318 Again, however, there was incomplete adjustment for . . 4.1. Treatment recommendations: 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 still- . classes, grades, and freedom of choice . birth (RR 1.5) have been associated with a moderate increase in risk . Clear communication about risks and benefits is crucial before any of CVD.316 . treatment is initiated. Risk communication is discussed in section 3.2.4, ESC Guidelines 41
Table 6 Treatment goals for different patient categories Patient category Prevention goals (STEP 1) Intensified/additional prevention goalsa (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 <130 mmHg if toleratedb SBP <140 down to 130 mmHg if toleratedb LDL-C <1.8 mmol/L (70 mg/dL) and >_50% reduction
LDL-C <2.6 mmol/L (100 mg/dL) in high-risk patients Downloaded from https://academic.oup.com/eurheartj/advance-article/doi/10.1093/eurheartj/ehab484/6358713 by guest on 30 August 2021 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 <130 mmHg if toleratedb SBP <140 down to 130 mmHg if toleratedb LDL-C <1.8 mmol/L (70 mg/dL) and >_50% reduction LDL-C <2.6 mmol/L (100 mg/dL) 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 For specific risk factor management in patients >_70 SBP <140 mmHg if toleratedb years old, please see relevant sections in section 4. LDL-C <2.6 mmol/L (100 mg/dL) Patients with CKD Stop smoking and lifestyle optimization LDL-C <1.8 mmol/L (70 mg/dL) in high-risk patients SBP <140 down to 130 mmHg if toleratedb and <1.4 mmol/L (55 mg/dL) in very-high risk patients LDL-C <2.6 mmol/L (100 mg/dL) and >_50% LDL-C (see Table 4) reduction Otherwise according to ASCVD and DM history Patients with FH Stop smoking and lifestyle optimization LDL-C <1.8 mmol/L (70 mg/dL) in high-risk patients SBP <140 down to 130 mmHg if toleratedb and <1.4 mmol/L (55 mg/dL) in very-high risk patients LDL-C <2.6 mmol/L (100 mg/dL) and >_50% LDL-C (see Table 4) reduction Otherwise according to ASCVD and DM history People with type 2 DM Well-controlled short-standing Stop smoking and lifestyle optimization DM (e.g. <10 years), no evidence of TOD and no additional ASCVD risk factors Without established ASCVD or Stop smoking and lifestyle optimization SBP <130 mmHg if toleratedb severe TOD (see Table 4 for SBP <140 down to 130 mmHg if toleratedb LDL-C <1.8 mmol/L (70 mg/dL) and >_50% reduction definitions) LDL-C <2.6 mmol/L (100 mg/dL) SGLT2 inhibitor or GLP-1RA HbA1c <53 mmol/mol (7.0%) With established ASCVD and/or Stop smoking and lifestyle optimisation SBP <130 mmHg if toleratedb severe TOD (see Table 4 for SBP <140 down to 130 mmHg if toleratedb LDL-C <1.4 mmol/L (55 mg/dL) and >_50% reduction definitions) LDL-C <1.8 mmol/L (70 mg/dL) SGLT2 inhibitor or GLP-1RA if not already on HbA1c <64 mmol/mol (8.0%) May additionally consider novel upcoming treatments: SGLT2 inhibitor or GLP1-RA DAPT, dual pathway inhibition,a colchicine, icosapent ethyl CVD: antiplatelet therapy Patients with established Stop smoking and lifestyle optimization SBP <130 mmHg if toleratedb ASCVD SBP <140 down to 130 mmHg if toleratedb LDL-C <1.4 mmol/L (55 mg/dL) Intensive oral lipid-lowering therapy aiming at >_50% May additionally consider novel upcoming treatments: LDL-C reduction and LDL-C <1.8 mmol/L (70 mg/dL) DAPT, dual pathway inhibition, colchicine, icosapent ethyl, Antiplatelet therapy etc. ESC 2021
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. aDepending 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 bOffice DBP treatment target range <80 mmHg. 42 ESC Guidelines and benefits of individual treatment are the topic of this section. In all . about consequences and side-effects, intellectual/cognitive abilities, . scenarios where recommendations for individual interventions to . mental disorders, physical limitations, financial aspects, and living . reduce risk are ‘strong’ (class I or IIa), it is important to realize that . alone.360,362 364 Importantly, only substantial risk reduction moti- . many patients who have received appropriate risk information often . vates patients for preventive drug treatment, which obviates the (in up to 50% of cases, some studies suggest) consciously opt to . need for appropriate risk communication.365,366 Depression is . forego the proposed intervention. This applies not only to lifestyle . another important factor, and adequate treatment thereof improves measures, but also to drug interventions. Apparently, what professio- . adherence.367,368 . nals feel is sufficient risk reduction for a reasonable effort or initiation . Mobile phone applications may improve adherence to both medi- Downloaded from https://academic.oup.com/eurheartj/advance-article/doi/10.1093/eurheartj/ehab484/6358713 by guest on 30 August 2021 of a drug with few side-effects does not always correspond to . cation and behavioural changes.369 Their use is easy and probably . 370 patients’ views. The reverse is also true: not only may some patients . cost-effective. at (very) high risk forego interventions, some patients with low-to- . . moderate risk may be highly motivated to decrease their risk even . 4.2.4. Treatment goals further. Hence, treatment recommendations are never ‘imperative’ . . In the subsequent sections, different domains of individual treatment for (very) high risk patients, nor are interventions ever ‘prohibited’ . are discussed. Table 6 summarizes the treatment goals and some key for patients at low-to-moderate risk. There is evidence that a higher . . interventions for different categories of patients. For additional infor- proportion of women, compared to men, have a low awareness of . mation on risk categories and the principle of a stepwise approach to their CVD risk and the need for therapeutic interventions. This war- . . treatment targets, please refer to section 3.2.3.1. For details on treat- rants efforts to improve awareness, risk assessment, and treatment in . ment goals, how to achieve them, strengths of recommendations and women.52,346 351 . . levels of supporting evidence, please go to the relevant subsections. . . 4.2. Optimizing cardiovascular risk . 4.3.Optimizing lifestyle management . 4.3.1. Physical activity and exercise . 4.2.1. Goals of clinicianpatient communication . . Recommendations for physical activity Clinicians should provide a personalized presentation of guidelines to . . a b improve understanding, encourage lifestyle changes, and support . Recommendations Class Level adherence to drug therapy. Applying this in daily practice faces differ- . 352 . It is recommended for adults of all ages to strive ent barriers. Patients’ ability to adopt a healthy lifestyle depends . on cognitive and emotional factors, the impact of a diagnosis or symp- . for at least 150 - 300 min a week of moderate- . intensity or 75 - 150 min a week of vigorous- toms, socioeconomic factors, educational level, and mental health. . IA . intensity aerobic PA, or an equivalent combina- Perceived susceptibility to illness and the anticipated severity of the . consequences are also prominent components of patients’ . tion thereof, to reduce all-cause mortality, CV . 371,372 motivation.353 . mortality, and morbidity. . . It is recommended that adults who cannot per- . form 150 min of moderate-intensity PA a week 4.2.2. How to improve motivation? . IB . should stay as active as their abilities and health Communication strategies such as motivational interviewing are use- . . condition allow.373,374 ful.354 Consultation sessions may include a family member or friend, . . It is recommended to reduce sedentary time to especially for elderly patients. Connection is paramount: focus before . . engage in at least light activity throughout the greeting; listen intently; agree on what matters most; connect with the . IB 355 . day to reduce all-cause and CV mortality and person’s story; and explore emotions. The OARS (Open-ended . . 375 377 . morbidity. questions, Affirmation, Reflective listening, and Summarizing) principle . helps patients to present their perceptions, and clinicians to summa- . Performing resistance exercise, in addition to . aerobic activity, is recommended on 2 or more rize. The SMART (Specific, Measurable, Achievable, Realistic, Timely) . IB principle may help with setting goals for behavioural change.353,356 . days per week to reduce all-cause . 378,379 Healthcare professionals must consider capability, opportunity (physi- . mortality. . Lifestyle interventions, such as group or individ- cal, social, or environmental) and motivation for behavioural . change.357 Multidisciplinary behavioural approaches that combine the . ual education, behaviour-change techniques, tel- 358 . ephone counselling, and use of consumer-based IIa B knowledge and skills of different caregivers are recommended. . . wearable activity trackers, should be considered
. 380 382 ESC 2021 . to increase PA participation. 4.2.3. Optimizing drug adherence . Medication adherence ranges from 50% for primary ASCVD preven- . CV = cardiovascular; PA = physical activity. 359 . aClass of recommendation. tion to 66% for secondary prevention. Physicians should consider . b . Level of evidence. non-adherence in every patient and inquire non-judgmentally about . 360 . it. Approximately 9% of cases of ASCVD in Europe can be attrib- . uted to poor medication adherence.361 Contributors to non- . PA reduces the risk of many adverse health outcomes and risk factors . adherence include polypharmacy, complexity of drug/dose regimes, . in all ages and both sexes. There is an inverse relationship between poor doctor-patient relationship, lack of disease acceptance, beliefs . moderate-to-vigorous PA and all-cause mortality, CV morbidity and ESC Guidelines 43
Table 7 Classification of physical activity intensity and examples of absolute and relative intensity levels.
Absolute intensity Relative intensity ...... a Intensity MET Examples %HRmax RPE (Borg Talk test scale score) 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), 64 76 12 13 Breathing is faster but compatible with Downloaded from https://academic.oup.com/eurheartj/advance-article/doi/10.1093/eurheartj/ehab484/6358713 by guest on 30 August 2021 slow cycling (15 km/h), painting/decorating, vacuuming, speaking full sentences gardening (mowing lawn), golf (pulling clubs in trolley), tennis (doubles), ballroom dancing, water aerobics Vigorous >_6 Race-walking, jogging, or running, cycling >15 km/h, 77 95 14 17 Breathing very hard, incompatible heavy gardening (continuous digging or hoeing), swim- with carrying on a conversation
ming laps, tennis (singles) comfortably ESC 2021
%HRmax = 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 1 1 MET is estimated as the energy cost of a given activity divided by resting energy expenditure: 1 MET = 3.5 mL oxygen kg min VO2. Modified from 392 . mortality, as well as incidence of type 2 DM.371 373,383 387 The . Relative intensity is determined based on an individual’s maximum . reduction in risk continues across the full range of PA volumes, and . (peak) effort, e.g. percentage of cardiorespiratory fitness (%VO2 . the slope of risk decline is steepest for the least active individu- . max), percentage of maximum (peak) heart rate (%HRmax)orusing 371 374,386,387 . als. More information on PA prescription can be found . rating of perceived exertion according to the Borg scale. Less fit indi- in a recent ESC Guideline.388 . viduals generally require a higher level of effort than fitter people to . . perform the same activity. A relative intensity measure is necessary 4.3.1.1 Physical activity prescription . to provide an individualized PA prescription.389 . PA should be individually assessed and prescribed in terms of fre- . Classification for both absolute and relative intensity and examples quency, intensity, time (duration), type, and progression.389 . are presented in Table 7. . Recommendations regarding pre-participation screening can be . found in previous ESC Guidelines.388 Interventions shown to increase . 4.3.1.3 Resistance exercise . PA level or reduce sedentary behaviour include behaviour theory- . Resistance exercise in addition to aerobic PA is associated with lower . 378,379,393 395 based interventions, such as goal-setting, re-evaluation of goals, self- . risks of total CV events and all-cause mortality. The sug- 372,380,381 . monitoring, and feedback. Using a wearable activity tracker . gested prescription is one to three sets of 8 12 repetitions at the may help increase PA.382 Most important is to encourage activity that . intensity of 60 80% of the individual’s 1 repetition maximum at a fre- . people enjoy and/or can include in their daily routines, as such activ- . quencyofatleast2daysaweekinavarietyof8 10 different exercises ities are more likely to be sustainable. . involving each major muscle group. For older adults or deconditioned . . individuals, it is suggested to start with one set of 10 15 repetitions at 4.3.1.2 Aerobic physical activity . 40 50% of 1 repetition maximum.389 In addition, older adults are rec- . Examples of aerobic PA include walking, jogging, cycling, etc.389 . ommended to perform multicomponent PA that combines aerobic, . 372 Adults are recommended to perform at least 150 300 min a week . muscle-strengthening, and balance exercises to prevent falls. of moderate-intensity PA, or 75 150 min of vigorous-intensity PA, . . or an equivalent combination of both, spread throughout the . 4.3.1.4 Sedentary behaviour week.371,372 Additional benefits are gained with even more PA. . Sedentary time is associated with greater risk for several major . 371,372,375 377,396 399 Practising PA should still be encouraged in individuals unable to meet . chronic diseases and mortality. For physically the minimum. In sedentary individuals, a gradual increase in activity . inactive adults, light-intensity PA, even as little as 15 minutes a day, is . level is recommended. When older adults or individuals with chronic . likely to produce benefits. There is mixed evidence to suggest how conditions cannot achieve 150 min of moderate-intensity PA a week, . activity bouts that interrupt sedentary behaviour are associated with . 375,398,400 they should be as active as their abilities and conditions . health outcomes. allow.371 375,384,385 PA accumulated in bouts of even <10 min is . 371,390 . associated with favourable outcomes, including mortality. . 4.3.2. Nutrition and alcohol PA can be expressed in absolute or relative terms.389 Absolute . . Recommendations for nutrition and alcohol intensity is the amount of energy expended per minute of activity, . . a b assessed by oxygen uptake per unit of time (mL/min or L/min) or by . Recommendations Class Level metabolic equivalent of task (MET). A compendium of the energy . . A healthy diet is recommended as a cornerstone cost in MET values for various activities is available.391 An absolute . IA . of CVD prevention in all individuals.401,402 measure does not consider individual factors such as body weight, . . Continued sex, and fitness level.389 . 44 ESC Guidelines
It is recommended to adopt a Mediterranean or . Table 8 Healthy diet characteristics IA. 403,404 . similar diet to lower risk of CVD. . Adopt a more plant- and less animal-based food pattern . It is recommended to replace saturated with . Saturated fatty acids should account for <10% of total energy IA. unsaturated fats to lower the risk of . intake, through replacement by PUFAs, MUFAs, and carbohydrates from 405 409 . CVD. . whole grains It is recommended to reduce salt intake to lower . IA. Trans unsaturated fatty acids should be minimized as far as possible, with 410 . BP and risk of CVD. . none from processed foods
. Downloaded from https://academic.oup.com/eurheartj/advance-article/doi/10.1093/eurheartj/ehab484/6358713 by guest on 30 August 2021 . It is recommended to choose a more plant- . <5 g total salt intake per day based food pattern, rich in fibre, that includes . IB. 30 45 g of fibre of per day, preferably from wholegrains whole grains, fruits, vegetables, pulses, and . . >_200 g of fruit per day (>_2 3 servings) nuts.411,412 . . >_200 g of vegetables per day (>_2 3 servings) It is recommended to restrict alcohol consump- . IB. Red meat should be reduced to a maximum of 350 - 500 g a week, in par- tion to a maximum of 100 g per week.413 415 . . ticular processed meat should be minimized It is recommended to eat fish, preferably fatty, at . . Fish is recommended 1 2 times per week, in particular fatty fish least once a week and restrict (processed) IB. 406,416 418 . meat. . 30 g unsalted nuts per day . Consumption of alcohol should be limited to a maximum of 100 g per It is recommended to restrict free sugar con- . sumption, in particular sugar-sweetened bever- . week IB. ages, to a maximum of 10% of energy . Sugar-sweetened beverages, such as soft drinks and fruit juices, must be
. ESC 2021 419,420 ESC 2021 . discouraged intake. . . MUFA = monounsaturated fatty acid; PUFA = polyunsaturated fatty acid. CVD = cardiovascular disease; BP = blood pressure. . aClass of recommendation. . b . Level of evidence. . . The DASH (Dietary Approaches to Stop Hypertension) trial showed . Dietary habits influence CV risk, mainly through risk factors such as . a dose response relation between sodium reduction and BP . 423 lipids, BP, body weight, and DM.401,402 Table 8 summarizes the char- . reduction. In a meta-analysis, salt reduction of 2.5 g/day resulted in . 410 acteristics of a healthy diet. Although recommendations about . a 20% reduction of ASCVD events (RR 0.80). AU-orJ-shaped . relation between a low salt intake and ASCVD is debated.424 nutrients and foods remain important for CV health, there is a grow- . ing concern about environmental sustainability, supporting a shift . Underlying illness and malnutrition may explain both low food and 411,412 . salt intakes as well as increased ASCVD.410,425,426 The totality of evi- from an animal- to a more plant-based food pattern. . . dence warrants salt reduction to prevent CHD and stroke. . 4.3.2.1 Fatty acids . In most Western countries, salt intake is high ( 9 10 g/day), . Risk of CHD is reduced when dietary saturated fats are replaced . whereas the recommended maximum intake is 5 g/day. Optimal appropriately (Figure 10). This is also the case when replacing meat . intake might be as low as 3 g/day. Salt reduction can be achieved by 406,407 . and dairy foods. Polyunsaturated fats (-25%), monounsaturated . dietary choices (fewer processed foods) and the reformulation of fats (-15%), and to a lesser extent carbohydrates from whole grains . foods by lowering their salt content (see section 5.2.2). . (-9%), were all associated with reduced CHD risk when isocalorically . Potassium (e.g. in fruits and vegetables) has favourable effects on substituted for dietary saturated fat.408,409 . BP and risk of stroke (RR 0.76).427 . Reducing saturated fatty acid intake to less than 10% of energy . As for vitamins, observational studies have found inverse associa- 405 . may have additional benefits. However, the LDL-C-lowering effect . tions between vitamins A and E and risk of ASCVD. However, inter- of substituting polyunsaturated fatty acids (PUFAs) for saturated fatty . vention trials have failed to confirm these findings. Also, trials of . acids may be less in obese (5.3%) than in normal-weight persons . supplementation with B vitamins (B6, folic acid, and B12), and vita- (9.7%).421 . mins C and D have not shown beneficial effects.428,429 . Trans fatty acids, formed during industrial processing of fats, have . unfavourable effects on total cholesterol (increase) and HDL-C . 4.3.2.3 Fibre . (decrease). On average, a 2% increase in energy intake from trans . Each 7 g/day higher intake of total fibre is associated with a 9% lower fatty acids is associated with a 23% higher CHD risk.422 Aregulation . risk of CAD (RR 0.91).430 A 10 g/day higher fibre intake was associ- . of the European Union (EU) Commission has set the upper limit to 2 . ated 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 postpran- g per 100 g of fat (April 2019) (https://ec.europa.eu/food/safety/label- . ling_nutrition/trans-fat-food_en). . dial glucose responses after carbohydrate-rich meals and also lower . triglyceride levels.433 When guidelines to lower saturated fat intake are followed, reduc- . tions in dietary cholesterol intake follow. . . . 4.3.2.4 Specific foods and food groups 4.3.2.2 Minerals and vitamins . . A reduction in sodium intake may reduce SBP by, on average, 5.8 . 4.3.2.4.1. Fruits, vegetables, and pulses. A meta-analysis reported a mmHg in hypertensive, and 1.9 mmHg in normotensive patients.410 . 4% lower risk in CV mortality for each additional serving of fruits ESC Guidelines 45
Trans fat (2%)
MUFA (5%) Downloaded from https://academic.oup.com/eurheartj/advance-article/doi/10.1093/eurheartj/ehab484/6358713 by guest on 30 August 2021
PUFA (5%)
Carbohydrates from refined starches/sugars (5%)
Carbohydrates from whole grains (5%)
-35 -30 -25 -20 -15 -10 -5 0 5 10 15 20 Changes in risk (%)
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.
. (equivalent to 77 g) and vegetables (equivalent to 80 g) per day, while . although a 7% lower risk of CHD events was observed. A meta-anal- . all-cause mortality was not reduced further with intakes of more . ysis of 13 RCTs included the results of VITAL (Vitamin D and than five servings.434 A meta-analysis reported an 11% lower risk for . Omega-3 Trial), ASCEND (A Study of Cardiovascular Events in . stroke associated with three to five daily servings of fruits and vegeta- . Diabetes), and REDUCE-IT (Reduction of Cardiovascular Events . 444 bles and of 26% with five servings a day compared with fewer than . with Icosapent Ethyl Intervention Trial). In the analysis excluding 435,436 . three servings. A single portion of pulses (legumes) a day low- . REDUCE-IT, fish oil reduced total ASCVD (RR 0.97) and CHD death . 444 ers LDL-C by 0.2 mmol/L and is associated with a lower risk of . (RR 0.92). Including REDUCE-IT (a study done in participants with 437,438 . CHD. . high triglycerides, comparing very high icosapent ethyl doses vs. min- . eral oil placebo) strengthened the results.444 However, this is the . 4.3.2.4.2. Nuts. A meta-analysis of prospective cohort studies sug- . only study that tested a high icosapent ethyl dose and questions have . been raised regarding the choice of placebo. Very recently, gested that daily consumption of 30 g of (mixed) nuts was associated . with a 30% lower risk of ASCVD.437 Both pulses and nuts contain . STRENGTH (Long-Term Outcomes Study to Assess Statin Residual 438 . Risk with Epanova in High Cardiovascular Risk Patients with fibre and other bioactive components. . . Hypertriglyceridemia) failed to demonstrate benefit of a combined . 445 4.3.2.4.3. Meat. From both a health and an environmental point of . eicosapentaenoic acid and docosahexaenoic acid preparation. . view, a lower consumption of meat, especially processed meat, is rec- . 411 . ommended. A restriction of red meat may have little or no effect . 4.3.2.4.5. Alcoholic beverages. The upper safe limit of drinking alco- on major cardiometabolic outcomes.416 However, substituting red . holic beverages is about 100 g of pure alcohol per week. How this . meat with high-quality plant foods (i.e. nuts, soy, and legumes) does . translates into number of drinks depends on portion size, the stand- improve LDL-C concentrations.406 A recent analysis showed that . ards of which differ per country, mostly between 8 and 14 g per . 413 higher intake of processed meat and unprocessed red meat is associ- . drink. This limit is similar for men and women. Drinking above this 417 . ated with a 7% and 3%, respectively, increased risk of ASCVD. . limit lowers life expectancy. By reducing processed meats, salt intake will also be reduced. The . Results from epidemiological studies have suggested that, whereas . World Cancer Research Fund recommends limiting red meat con- . higher alcohol consumption is roughly linearly associated with a sumption to 350 500 g per week.439 . 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, 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 associ- . Mendelian randomization studies do not support the apparently pro- 418 . tective effects of moderate amounts vs. no alcohol against ASCVD, ated with a 16% lower risk of CAD, and eating fish two to four . 440 . suggesting that the lowest risks for CVD outcomes are in abstainers times a week is associated with a 6% lower risk of stroke. The . highest risk was observed in the range of no or very low intakes. . and that any amount of alcohol uniformly increases BP and . 414,415 Several meta-analyses and a recent Cochrane review showed no . BMI. These data challenge the concept that moderate alcohol 441 443 . benefits of fish oils on CV outcomes and/or mortality, . consumption is universally associated with lower CVD risk. 46 ESC Guidelines
4.3.2.4.6. Soft drinks and sugar. Regular consumption of sugar- . Bariatric surgery for obese high-risk individuals sweetened beverages (i.e. two servings per day compared with one . . should be considered when lifestyle change does IIa B serving per month) was associated with a 35% higher risk of CAD in . not result in maintained weight loss.455 ESC 2021 . women in the Nurses’ Health Study, whereas artificially sweetened . beverages were not associated with CAD. In the EPIC (European . CVD = cardiovascular disease; BP = blood pressure; DM = diabetes mellitus. . a . Class of recommendation. Prospective Investigation into Cancer and Nutrition) cohort, both arti- . b . Level of evidence. ficially and sugar-sweetened soft drinks were associated with all-cause . . mortality, while only the former was associated with circulatory dis- Downloaded from https://academic.oup.com/eurheartj/advance-article/doi/10.1093/eurheartj/ehab484/6358713 by guest on 30 August 2021 . 4.3.3.1 Treatment goals and modalities eases.419 The WHO guideline recommends a maximum intake of 10% . . Although diet, exercise, and behaviour modification are the main of energy from free sugars (mono- and disaccharides), which includes . . therapies for overweight and obesity, they are often unsuccessful in added sugars as well as sugars present in fruit juices.420 . . the long term. Yet, maintaining even a moderate weight loss of . . 5 - 10% from baseline has salutary effects on risk factors including BP, 4.3.2.4.7. Coffee. Non-filtered coffee contains LDL-C-raising cafestol . 450,451 . lipids, and glycaemic control, as well as on premature all-cause and kahweol, and may be associated with an up to 25% increased risk . mortality.456 Weight loss is associated with lower morbidity but of ASCVD mortality by consumption of nine or more drinks a day.446 . . higher mortality in (biologically) older adults (the ‘obesity paradox’). Non-filtered coffee includes boiled, Greek, and Turkish coffee and . In this group, emphasis should be less on weight loss and more on some espresso coffees. Moderate coffee consumption (3 4 cups . . maintaining muscle mass and good nutrition. per day) is probably not harmful, perhaps even moderately . 447 . beneficial. . 4.3.3.2 Diets for weight loss . . Energy restriction is the cornerstone of management. PA is essential 4.3.2.4.8. Functional foods. Functional foods containing phytosterols . . to maintain weight loss and prevent rebound weight gain, but is not (plant sterols and stanols) are effective in lowering LDL-C levels by . reviewed here. Hypocaloric diets may be categorized as: an average of 10% when consumed in amounts of 2 g/day.448 The . . 457,458 effect is in addition to that obtained with a low-fat diet or use of sta- . 1. Diets that aim to reduce ASCVD, including plant-based and . 458,459 tins. No studies with clinical endpoints have been performed yet. . hypocaloric Mediterranean diets, with modifications to suit . Red yeast rice supplements are not recommended and may even . local food availability and preferences. 449 . cause side-effects. . 2. Changes to the fat and carbohydrate macronutrient composition of . the diet, including low or very low carbohydrate diets (with . 4.3.2.4.9. Dietary patterns. Studying the impact of a total dietary pat- . 50 130 g and 20 49 g carbohydrates/day, respectively), moderate . carbohydrate diets (>130 225 g carbohydrates/day), and low-fat tern shows the full preventive potential of diet. The Mediterranean . diet includes high intakes of fruits, vegetables, pulses, wholegrain . diets (<30% of energy from fat). . 3. High-protein diets to preserve lean muscle mass and enhance products, fish, and olive oil, moderate consumption of alcohol, and . low consumption of (red) meat, dairy products, and saturated fatty . satiety. . 4. Diets focusing on specific food groups (e.g. increasing fruit and vege- acids. Greater adherence to a Mediterranean diet is associated with a . 10% reduction in CV incidence or mortality and an 8% reduction in . tables or avoiding refined sugars). 403 . 5. Diets that restrict energy intake for specified time periods, for all-cause mortality. Following a Mediterranean diet enriched with . nuts over a 5-year period, compared with a control diet, lowered the . example on 2 days a week or alternate days (intermittent fasting) or . during certain hours of the day (time-restricted eating). risk of ASCVD by 28% and by 31% with a diet enriched with extra- . virgin olive oil.404 . . 452 454 Also, a shift from a more animal-based to a plant-based food pat- . These diets give broadly similar short-term weight loss. By . 453 411 . 12 months, the effects tend to diminish. Benefits of the tern may reduce ASCVD. . . Mediterranean diet, however, tend to persist. The quality of nutrients . . in a diet, for example substituting unsaturated for saturated fats (see 4.3.3. Body weight and composition . 460 . section 4.3.2.1) and including fibre-rich carbohydrates determines . whether a diet is healthy in the long term. Recommendations for body weight . . Low or very low carbohydrate diets may have advantages regard- a b . Recommendations Class Level . ing appetite control, lowering triglycerides, and reducing medications . for type 2 DM.461 Such diets may be ketogenic and need medical or It is recommended that overweight and obese . . at least dietetic supervision. Studies beyond 2 years are scarce. people aim for a reduction in weight to reduce . IA. Extreme carbohydrate intakes should be avoided in the long term BP, dyslipidaemia, and risk of type 2 DM, and . . and plant substitutions of fat and protein for carbohydrates are 450,451 . thus improve their CVD risk profile. . 462 . advantageous over animal ones. While a range of diets are effective for weight . Intermittent fasting diets produce equivalent weight loss to contin- loss, it is recommended that a healthy diet in . 463 IA. uous energy restriction when matched for energy intake. regard to CVD risk is maintained over . Medications approved in Europe as aids to weight loss (orlistat, time.452 454 . . naltrexone/bupropion, high-dose liraglutide) may supplement Continued . lifestyle change to achieve weight loss and maintenance, although ESC Guidelines 47
. sometimes at the expense of side-effects. Meta-analysis of . fatal and non-fatal first recurrent ASCVD events [hazard ratio (HR medication-assisted weight loss found favourable effects on BP, gly- . 0.59)] and fewer recurrent AMIs (HR 0.55).467 In SWITCHD 464 . caemic control, and ASCVD mortality. . (Stockholm Women’s Intervention Trial for Coronary Heart A very effective treatment option for extreme obesity or obesity . Disease), the intervention yielded a substantial reduction in all-cause . 468 with comorbidities is bariatric surgery. A meta-analysis indicated that . mortality (OR 0.33). A recent RCT reported that cardiac rehabili- patients undergoing bariatric surgery had over 50% lower risks of . tation (CR) enhanced by stress management produced significant . total, ASCVD, and cancer mortality compared with people of similar . reductions in ASCVD events compared with standard CR alone (HR 455 . 469 weight who did not have surgery. . 0.49). Concerning psychopharmacotherapy of patients with CHD Downloaded from https://academic.oup.com/eurheartj/advance-article/doi/10.1093/eurheartj/ehab484/6358713 by guest on 30 August 2021 . and depression, selective serotonin reuptake inhibitor (SSRI) treat- . . ment lowers rates of CHD readmission (risk ratio 0.63) and all-cause 4.4. Mental healthcare and psychosocial . mortality (risk ratio 0.56).470 A recent RCT reported that, in patients . interventions . with ACS and depression, treatment with the SSRI, escitalopram, . resulted in a lower rate of the composite endpoint of all-cause mor- Recommendations for mental healthcare and psychoso- . cial interventions at the individual level . tality, myocardial infarction, or percutaneous coronary intervention . (PCI) (HR 0.69).471 Collaborative care for patients with CHD and a b . Recommendations Class Level . depression has small beneficial effects on depression, but significantly . 485 Patients with mental disorders need intensified . reduces short-term major cardiac events. . attention and support to improve adherence to IC. Concerning side-effects of psychopharmacological treatments, 3,465 . lifestyle changes and drug treatment. . many psychiatric drugs are associated with an increased risk of sud- . den cardiac death.486 In patients with HF, antidepressants are associ- In ASCVD patients with mental disorders, evi- . dence-based mental healthcare and interdiscipli- IB. ated with increased risk of cardiac and all-cause mortality (HR 1.27; . 472 100,113,466 . for details see supplementary material for section 4.4). Therefore, nary cooperation are recommended. . . ASCVD patients with complex mental disorders, and particularly ASCVD patients with stress should be consid- . . those needing psychiatric drug treatment, require interdisciplinary ered for referral to psychotherapeutic stress . IIa B . cooperation. management to improve CV outcomes and . reduce stress symptoms.467 469 . . Patients with CHD and moderate-to-severe . 4.5. Smoking intervention major depression should be considered for anti- IIa B . . Recommendations for smoking intervention strategies depressive treatment with an SSRI.470,471 . . . a b In patients with HF and major depression, SSRIs, . Recommendations Class Level SNRIs, and tricyclic antidepressants are not rec- III B . . All smoking of tobacco should be stopped, as 472,473 c ESC 2021 . ommended. . . tobacco use is strongly and independently causal IA ASCVD = atherosclerotic cardiovascular disease; CHD = coronary heart disease; . of ASCVD.487,488 CV = cardiovascular; HF = heart failure; SNRI = serotonin-noradrenaline reup- . . In smokers, offering follow-up support, nicotine take inhibitor; SSRI = selective serotonin reuptake inhibitor. . aClass of recommendation. . replacement therapy, varenicline, and bupropion b . IIa A Level of evidence. . individually or in combination should be cDetails explaining this recommendation are provided in the supplementary . . considered.489 494 material section 2.1. . . . Smoking cessation is recommended regardless . of weight gain, as weight gain does not lessen the IB Treatment of an unhealthy lifestyle will reduce CVD risk as well as . . 495 . ASCVD benefits of cessation. ESC 2021 improve mental health. Smoking cessation, for instance, has a positive . 474,475 113,476 . effect on depression outcomes, as do exercise therapy . ASCVD = atherosclerotic cardiovascular disease. and healthy dietary practices.477 Evidence-based interventions for . aClass of recommendation. . bLevel of evidence. smoking cessation, and improving PA and diet, are considered useful . 465,478 480 . and applicable for persons with mental disorders. . Mental disorders are associated with an increased risk of CVD and . 4.5.1. Smoking cessation . a worse prognosis in patients with ASCVD, due to CVD events or . Stopping smoking is potentially the most effective of all preventive 100,113,305 . other death causes, including suicide. Mental-health treat- . measures, with substantial reductions in (repeat) myocardial infarc- ments effectively reduce stress symptoms and improve quality of life. . tions or death.487,488 Lifetime gains in CVD-free years are substantial . Several observational studies indicate that treatment or remission of . at all ages, and benefits are obviously even more substantial if other depression reduces CVD risk.113,481 484 Psychological interventions . complications from smoking would be accounted for. From age 45 . in patients with CHD may reduce cardiac mortality (RR 0.79) and . years, gains of 3 - 5 years persist in men to age 65 and in women to alleviate psychological symptoms.466 Psychotherapy focusing on . age 75 years (Figure 11). Even in heavy smokers (>_20 cigarettes/day), . stress management in ASCVD patients improves CVD outcomes. In . cessation lowers CVD risk within 5 years, although it remains ele- . vated beyond 5 years. Total health benefits will be even larger SUPRIM (Secondary Prevention in Uppsala Primary Health Care . project), patients in the intervention group had a 41% lower rate of . because of gain in non-CVD health. 48 ESC Guidelines
LIFE-CVD model CVD-free lifetime gain from smoking cessation (in years)
< 0.5 years 0.5 - 0.9 years 1.0 - 1.4 years 1.5 - 2.0 years ≥ 2.0 years
Women Men Systolic blood pressure Non-HDL cholesterol (mmHg) mmol/L 3.0-3.9 4.0-4.9 5.0-5.9 6.0-6.9 3.0-3.9 4.0-4.9 5.0-5.9 6.0-6.9 150 200 250 mg/dL 150 200 250 Downloaded from https://academic.oup.com/eurheartj/advance-article/doi/10.1093/eurheartj/ehab484/6358713 by guest on 30 August 2021 160-179 0.8 0.8 0.9 0.9 Age 0.5 0.5 0.5 0.6 (y) 140-159 0.8 0.8 0.8 0.8 0.5 0.5 0.6 0.6 90+ 120-139 0.8 0.8 0.8 0.8 0.5 0.6 0.6 0.7 100-119 0.8 0.8 0.8 0.8 0.5 0.7 0.7 0.7 160-179 1.6 1.7 1.9 1.9 0.7 0.9 0.9 1.0 140-159 1.7 1.8 1.9 1.9 0.8 0.9 1.0 1.0 85-89 120-139 1.8 1.8 1.8 1.8 0.8 0.9 1.0 1.1 100-119 1.7 1.7 1.8 1.8 0.8 1.0 1.0 1.1 160-179 2.0 2.3 2.4 2.4 1.2 1.3 1.4 1.4 140-159 2.2 2.3 2.4 2.5 1.2 1.3 1.4 1.4 80-84 120-139 2.2 2.3 2.5 2.5 1.2 1.3 1.4 1.5 100-119 2.2 2.4 2.5 2.5 1.2 1.3 1.4 1.5 160-179 2.6 2.82.8 2.9 1.6 1.71.9 1.9 140-159 2.6 2.7 2.9 3.0 1.7 1.8 1.9 1.9 75-79 120-139 2.6 2.7 2.9 3.0 1.6 1.8 1.9 2.0 100-119 2.6 2.7 2.9 3.0 1.7 1.8 1.9 1.9 160-179 3.0 3.2 3.4 3.4 2.1 2.3 2.4 2.5 140-159 3.1 3.2 3.3 3.4 2.1 2.2 2.4 2.4 70-74 120-139 3.0 3.1 3.3 3.4 2.0 2.2 2.3 2.4 100-119 3.0 3.1 3.2 3.3 2.1 2.2 2.3 2.3 160-179 3.4 3.63.8 3.9 2.6 2.72.9 2.9 140-159 3.4 3.6 3.7 3.8 2.5 2.7 2.8 2.8 65-69 120-139 3.3 3.5 3.6 3.7 2.4 2.6 2.7 2.7 100-119 3.6 3.6 3.8 3.9 2.7 2.7 2.9 2.9 160-179 3.7 4.0 4.1 4.3 3.0 3.1 3.3 3.4 140-159 3.7 3.9 4.1 4.2 2.9 3.0 3.2 3.3 60-64 120-139 3.6 3.7 4.0 4.0 2.8 2.9 3.0 3.1 100-119 3.6 3.6 3.8 3.9 2.7 2.7 2.9 2.9 160-179 4.1 4.3 4.5 4.6 3.3 3.5 3.7 3.8 140-159 4.0 4.2 4.4 4.5 3.1 3.2 3.5 3.6 55-59 120-139 3.9 4.0 4.3 4.3 2.9 3.1 3.3 3.4 100-119 3.8 3.9 4.0 4.1 2.8 3.0 3.1 3.2 160-179 4.3 4.5 4.8 4.9 3.5 3.7 3.9 4.2 140-159 4.2 4.4 4.6 4.7 3.3 3.5 3.7 3.9 50-54 120-139 4.1 4.3 4.4 4.5 3.1 3.3 3.4 3.6 140-159 3.9 4.0 4.2 4.3 2.9 3.1 3.2 3.3 100-119 4.5 4.7 5.0 5.1 3.7 3.9 4.2 4.4 120-139 4.4 4.5 4.8 4.9 3.4 3.7 3.9 4.1 45-49 160-179 4.2 4.4 4.6 4.7 3.3 3.4 3.6 3.7 100-119 4.1 4.2 4.4 4.5 3.1 3.2 3.3 3.5 160-179 4.5 4.8 5.1 5.2 3.7 4.0 4.3 4.5 140-159 4.4 4.6 4.9 5.0 3.5 3.7 4.0 4.2 40-44 120-139 4.3 4.5 4.6 4.8 3.3 3.5 3.7 3.9 100-119 4.1 4.3 4.5 4.5 3.2 3.3 3.4 3.6
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 coun- tries. 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 expectancyfree 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/. ESC Guidelines 49
. deliver nicotine without most of the tobacco chemicals, and are Table 9 ‘Very brief advice’ for smoking cessation . . probably less harmful than tobacco. . ‘Very brief advice’ on smoking is a proven 30-second clinical intervention, . Recent evidence suggests that e-cigarettes are probably more . effective than NRT in terms of smoking cessation.503 505 The long- developed in the UK, which identifies smokers, advises them on the best . method of quitting, and supports subsequent quit attempts. There are . term effects of e-cigarettes on CV and pulmonary health, however, . 506 three elements to very brief advice: . require more research. Dual use with cigarettes should be . • ASK - establishing and recording smoking status . avoided. Furthermore, as e-cigarettes are addictive, their use should
. be subject to similar marketing controls as standard cigarettes, espe- Downloaded from https://academic.oup.com/eurheartj/advance-article/doi/10.1093/eurheartj/ehab484/6358713 by guest on 30 August 2021 • ADVISE - advising on the best ways of stopping . . cially the flavoured varieties that appeal to children.507 Despite being • ACT - offering help . . lower in toxicants than regular cigarettes, ‘heat-not-burn’ cigarettes ESC 2021 . . do contain tobacco and should be discouraged. UK = United Kingdom. . . . 4.6. Lipids . Quitting must be encouraged in all smokers, and passive smoking . This section covers recommendations for the diagnosis and treat- . should be avoided as much as possible. Very brief advice may be . ment of unfavourable blood lipid levels. More detail and guidance for . complex cases/tertiary care, including genetic lipid disorders, are advantageous when time is limited (Table 9). A major impetus for ces- . sation occurs at the time of diagnosis or treatment of CVD. . available in the 2019 ESC/European Atherosclerosis Society (EAS) . Guidelines for the management of dyslipidaemias.3 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 . Recent evidence has confirmed that the key initiating event in athe- . rogenesis is the retention of LDL and other cholesterol-rich lipopro- arrangement are evidence-based interventions. . Smokers who quit may expect an average weight gain of 5 kg, but . teins within the arterial wall. The causal role of LDL-C, and other apo- . B-containing lipoproteins, in the development of ASCVD is demon- the health benefits of tobacco cessation outweigh risks from weight . gain.495 Persistent or reuptake of smoking is common in patients with . strated beyond any doubt by genetic, observational, and interven- . tional studies.20 Meta-analysis of clinical trials has indicated that the CHD, in particular in those with severe depression and environmen- . tal exposures.498 Mood-management therapies may improve out- . relative reduction in CVD risk is proportional to the absolute reduc- 499 . tion of LDL-C, irrespective of the drug(s) used to achieve such comes in patients with current or past depression. . . change, with no evidence of a lower limit for LDL-C values or ‘J-curve’ . 21 . effect. The absolute benefit of lowering LDL-C depends on the 4.5.2. Evidence-based drug interventions . absolute risk of ASCVD and the absolute reduction in LDL-C, so . Drug support for stopping smoking should be considered in all smokers . even a small absolute reduction in LDL-C may translate to significant . 22 who are ready to undertake this action. Evidence-based drug interven- . absolute risk reduction in a high- or very-high-risk patient. A recent tions include nicotine-replacement therapy (NRT), bupropion, vareni- . LDL-C target-driven RCT in patients after ischaemic stroke or transi- 489 491 . cline, and cytisine (not widely available). All forms of NRT . ent ischaemic attack (TIA) demonstrated a target LDL-C level of <1.8 (chewing gum, transdermal nicotine patches, nasal spray, inhaler, sublin- . mmol/L (70 mg/dL) with the use of statin and, if required, ezetimibe, . gual tablets) are effective. Combination vs. single-form NRT and 4 mg . was associated with a lower CVD risk than those who had a target 492 . 508 vs. 2 mg gum can increase success. NRT shows no adverse effects in . range of 2.3 2.8 mmol/L (90 110 mg/dL). Studies on the clinical 493 . patients with ASCVD, but evidence of efficacy in this group is incon- . safety of (very) low achieved LDL-C values have not caused particular clusive.494 In patients with ASCVD, varenicline (RR 2.6), bupropion (RR . . concerns, although monitoring for longer periods is required. 1.4), telephone therapy (RR 1.5), and individual counselling (RR 1.6) all . 494 . increase success rates. The antidepressant, bupropion, aids long- . 4.6.1. Measurement of lipids and lipoproteins term smoking cessation with similar efficacy to NRT.490 . . 4.6.1.1 Fasting vs. non-fasting measurements Varenicline 1 mg b.i.d. (twice a day) increases quitting rates more . Non-fasting sampling of lipid parameters is recommended for general than two-fold compared with placebo.491 The RR for abstinence vs. . . risk screening, since it has the same prognostic value as fasting sam- NRT was 1.25 and vs. bupropion, 1.4. Lower or variable doses are . 509,510 . ples. In patients with metabolic syndrome, DM, or hypertrigly- also effective and reduce side-effects. Varenicline beyond the 12- . ceridaemia, calculated LDL-C from non-fasting samples should be . week standard regimen is well tolerated. Varenicline initiated in hos- . interpreted with care. pital following ACS is efficacious and safe.500 . . The main side-effect of varenicline is nausea, but this usually sub- . sides. A causal link between varenicline and neuropsychiatric adverse . Table 10 Corresponding non-high-density lipoprotein . cholesterol and apolipoprotein B levels for commonly used events is unlikely.501 Varenicline, bupropion, and NRT do not . . low-density lipoprotein cholesterol goals increase serious CV adverse event risks during or after treatment.502 . . LDL-C Non-HDL-C Apolipoprotein B Cytisine is effective for smoking cessation, but evidence to date is . limited.491 . 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 4.5.2.1 Electronic cigarettes . 1.4 mmol/L (55 mg/dL) 2.2 mmol/L (85 mg/dL) 65 mg/dL ESC 2021 . Electronic cigarettes (e-cigarettes) simulate combustible cigarettes . HDL-C = high-density lipoprotein cholesterol; LDL-C = low-density lipoprotein by heating nicotine and other chemicals into a vapour. E-cigarettes . cholesterol. 50 ESC Guidelines
4.6.1.2 Low-density lipoprotein cholesterol measurement . . As explained earlier in these guidelines (section 3.2.3.1), we propose LDL-C can be measured directly, but in most studies and many labo- . a stepwise approach to treatment goals, also for LDL-C (Figures 6 8). . ratories, LDL-C is calculated using the Friedewald formula: . This approach may seem novel but, in reality, resembles clinical prac- . tice, where treatment intensification is considered based on anticipated • In mmol/L: LDL-C = total cholesterol HDL-C (0.45 trigly- . . benefit, side-effects, and—importantly—patient preferences. The ulti- cerides) . . mate lipid goals are the same as in the 2019 ESC/EAS dyslipidaemia • In mg/dL: LDL-C = total cholesterol HDL-C (0.2 trigly- . . Guidelines.3 Evidence from glucose-lowering treatment studies indi- cerides) . . cates that stepwise treatment does not compromise goal attainment, Downloaded from https://academic.oup.com/eurheartj/advance-article/doi/10.1093/eurheartj/ehab484/6358713 by guest on 30 August 2021 . and is associated with fewer side-effects and higher patient satisfac- The calculation is only valid when the concentration of triglycer- . . tion.66,67 In specific cases (at very high risk), the physician may opt to ides is <4.5 mmol/L ( 400 mg/dL), and not precise when LDL-C is . . merge both steps and proceed directly to the low LDL-C target level very low [<1.3 mmol/L (50 mg/dL)]. In patients with low LDL-C lev- . . of STEP 2. In apparently healthy people, lifetime treatment benefit of els and/or hypertriglyceridaemia (<_800 mg/dL), alternative formulae . 511,512 . LDL-C reduction may play a role in shared decision-making, together are available or LDL-C can be measured directly. . . with risk modifiers, comorbidities, patient preference, and frailty. Figure . 12 may support decision-making, as it shows the estimated lifetime 4.6.1.3 Non-high-density lipoprotein cholesterol . . benefits in years-free-of-CVD in relation to the total CVD risk profile, The non-HDL-C value is calculated by subtracting HDL-C from total . . calibrated in low-to-moderate CVD risk countries. cholesterol. Non-HDL-C, unlike LDL-C, does not require the trigly- . . After STEP 1, treatment intensification with STEP 2 must be con- ceride concentration to be <4.5 mmol/L (400 mg/dL). It also has an . . sidered in all patients. Given that lower is better, we encourage liberal advantage in that it is accurate in a non-fasting setting, and may be . . intensification of treatment, particularly if submaximal doses of (low- more accurate in patients with DM. There is evidence for a role . . cost) generic statins are used and side-effects are not apparent. ofnon-HDL-Casatreatmenttargetasitcapturestheinformation . . The treatment goal of LDL-C <1.4 mmol/L (55 mg/dL) in STEP 2, regarding all apolipoprotein-B-containing lipoproteins.513 We suggest . . in patients with established ASCVD or without ASCVD but at very it as a reasonable alternative treatment goal for all patients, particularly . . high risk, is lower than the lowest LDL-C goal of 1.8 mmol/L (70 mg/ for those with hypertriglyceridaemia or DM. How non-HDL-C levels . . dL) in the 2016 ESC prevention Guidelines.2 This low goal was estab- correspond to commonly used LDL-C goals is shown in Table 10. . . 80 . lished based on data from recent Mendelian randomization studies, . meta-analyses from the Cholesterol Treatment Trialists’ 4.6.1.4 Apolipoprotein B . . Collaboration,21 RCTs such as IMPROVE-IT (Improved Reduction of Apolipoprotein B provides a direct estimate of the total concentra- . . Outcomes: Vytorin Efficacy International Trial),515 and—more tion of atherogenic lipid particles, particularly in patients with ele- . . recently—proprotein convertase subtilisin/kexin type 9 (PCSK9) vated triglycerides. However, on average, the information conferred . . inhibitor clinical outcome studies.516 518 The class and level of evi- by apolipoprotein B is similar to that of calculated LDL-C.514 . . dence supporting this LDL-C target of <1.4 mmol/L (55 mg/dL) for How apolipoprotein B levels correspond to commonly used LDL-C . . patients with ASCVD is identical to that in the recent ESC/EAS dysli- goals is shown in Table 10. . . 3 . pidaemia guidelines. For primary prevention in very-high-risk . patients, however, the class of recommendation is lower (Class I in . 4.6.2. Defining lipid goals . the dyslipidaemia guidelines, Class IIa in the current guidelines), 4.6.2.1 Low-density lipoprotein cholesterol goals . because the Task Force was less unanimous with regards to this low . Recommendation on low-density lipoprotein choles- . LDL-C target in the primary prevention context. terol goalsa . For patients with ASCVD who experience a second vascular event . Recommendation Classb Levelc . within 2 years (not necessarily of the same type as the first) while tak- . ing maximum tolerated statin-based therapy, an even lower LDL-C A stepwise treatment-intensification approach is . recommended for apparently healthy people at . goal of <1.0 mmol/L (40 mg/dL) may be considered. Importantly, . there are no differences in the RR reductions between men and high or very high CVD risk, as well as patients . with established ASCVD and/or DM with con- IC. women and between younger and older patients (at least up to age . 3 sideration of CVD risk, treatment benefit, risk . 75 years), or between those with and without DM. . modifiers, comorbidities, and patient .
ESC 2021 . preferences. . 4.6.2.2 Triglyceride-rich lipoproteins and their remnants . There are no treatment goals for triglycerides, but <1.7 mmol/L (150 ASCVD = atherosclerotic cardiovascular disease; DM = diabetes mellitus. . a . mg/dL) is considered to indicate lower risk, whereas higher levels Recommendation from section 3.2. . b . indicate a need to look for other risk factors. Class of recommendation. . cLevel of evidence. . . . 4.6.2.3 High-density lipoprotein cholesterol LDL-C goals are summarized in the recommendations below. As not . To date, no specific goals for HDL-C levels have been determined in . all drugs are tolerated or available/affordable, treatment should focus . clinical trials, although low HDL-C is associated with (residual) risk in on achieving LDL-C levels as close as possible to the given goals. . ASCVD patients. PA and other lifestyle factors, rather than drug . Treatment should be a shared decision-making process between . treatment, remain important means of increasing HDL-C levels. physicians and the patient. . ESC Guidelines 51
LIFE-CVD model < 0.5 years 1.5 - 2.0 years CVD-free lifetime gain from 1 mmol/L 0.5 - 0.9 years ≥ 2.0 years LDL-C reduction (in years) 1.0 - 1.4 years Women Men Non-smoking Smoking Non-smoking Smoking Non-HDL cholesterol
Systolic blood mmol/L pressure (mmHg) 3.0-3.9 4.0-4.9 5.0-5.9 6.0-6.9 3.0-3.9 4.0-4.9 5.0-5.9 6.0-6.9 3.0-3.9 4.0-4.9 5.0-5.9 6.0-6.9 3.0-3.9 4.0-4.9 5.0-5.9 6.0-6.9 150 200 250 150 200 250 mg/dL 150 200 250 150 200 250 Downloaded from https://academic.oup.com/eurheartj/advance-article/doi/10.1093/eurheartj/ehab484/6358713 by guest on 30 August 2021 160-179 0.3 0.4 0.4 0.4 0.1 0.1 0.2 0.2 Age 0.2 0.3 0.3 0.3 0.1 0.0 0.1 0.1 (y) 140-159 0.3 0.3 0.4 0.4 0.1 0.1 0.1 0.1 0.2 0.2 0.2 0.3 0.0 0.0 0.0 0.0 90+ 120-139 0.2 0.3 0.3 0.3 0.1 0.1 0.1 0.1 0.1 0.1 0.2 0.2 0.1 0.0 0.0 0.1 100-119 0.2 0.2 0.2 0.2 0.0 0.0 0.1 0.1 0.1 0.1 0.1 0.1 0.0 0.1 0.0 0.1 160-179 0.8 0.8 0.9 0.9 0.2 0.2 0.3 0.4 0.4 0.5 0.5 0.5 0.1 0.1 0.1 0.2 140-159 0.6 0.7 0.8 0.8 0.1 0.2 0.2 0.3 0.3 0.4 0.5 0.5 0.1 0.1 0.1 0.1 85-89 120-139 0.5 0.6 0.7 0.7 0.1 0.2 0.2 0.2 0.3 0.4 0.4 0.4 0.0 0.0 0.1 0.1 100-119 0.4 0.4 0.5 0.6 0.0 0.1 0.1 0.1 0.2 0.2 0.3 0.3 0.0 0.0 0.0 0.1 160-179 1.0 1.1 1.2 1.3 0.2 0.4 0.4 0.5 0.5 0.6 0.7 0.7 0.1 0.2 0.2 0.2 140-159 0.9 1.0 1.1 1.1 0.2 0.3 0.3 0.4 0.4 0.5 0.6 0.7 0.1 0.1 0.2 0.2 80-84 120-139 0.7 0.8 0.9 1.0 0.2 0.2 0.3 0.2 0.4 0.4 0.5 0.5 0.0 0.1 0.1 0.1 100-119 0.5 0.6 0.7 0.8 0.1 0.1 0.2 0.2 0.2 0.3 0.4 0.4 0.0 0.0 0.0 0.1 160-179 1.2 1.31.4 1.4 0.4 0.50.5 0.6 0.7 0.80.9 1.0 0.2 0.20.3 0.3 140-159 1.0 1.2 1.3 1.4 0.2 0.3 0.5 0.5 0.6 0.6 0.7 0.9 0.2 0.2 0.3 0.3 75-79 120-139 0.8 1.0 1.1 1.2 0.2 0.2 0.3 0.4 0.4 0.5 0.6 0.7 0.1 0.2 0.2 0.2 100-119 0.6 0.8 0.9 1.0 0.2 0.2 0.2 0.3 0.3 0.4 0.5 0.6 0.1 0.1 0.2 0.1 160-179 1.3 1.4 1.5 1.6 0.5 0.6 0.7 0.8 0.8 0.9 1.1 1.1 0.3 0.4 0.5 0.5 140-159 1.1 1.3 1.4 1.5 0.4 0.5 0.6 0.6 0.7 0.8 1.0 1.0 0.2 0.3 0.4 0.4 70-74 120-139 0.9 1.1 1.3 1.3 0.2 0.3 0.5 0.5 0.5 0.6 0.7 0.9 0.2 0.2 0.3 0.4 100-119 0.7 0.9 1.0 1.1 0.2 0.3 0.3 0.3 0.4 0.5 0.6 0.6 0.1 0.2 0.3 0.2 160-179 1.3 1.51.6 1.7 0.6 0.70.9 0.9 0.9 1.11.2 1.3 0.5 0.50.7 0.7 140-159 1.2 1.4 1.5 1.6 0.5 0.6 0.7 0.7 0.8 1.0 1.0 1.1 0.4 0.5 0.5 0.6 65-69 120-139 1.0 1.2 1.4 1.5 0.3 0.5 0.5 0.6 0.6 0.8 0.8 1.0 0.3 0.4 0.4 0.4 100-119 0.9 1.0 1.2 1.3 0.3 0.4 0.4 0.6 0.5 0.7 0.7 0.8 0.3 0.4 0.5 0.4 160-179 1.4 1.6 1.7 1.8 0.6 0.8 0.9 1.1 1.1 1.2 1.4 1.4 0.6 0.7 0.9 0.9 140-159 1.3 1.4 1.6 1.7 0.5 0.7 0.8 0.9 0.8 1.0 1.2 1.2 0.5 0.6 0.7 0.8 60-64 120-139 1.1 1.3 1.5 1.6 0.4 0.5 0.7 0.7 0.7 0.8 1.0 1.1 0.4 0.5 0.6 0.6 100-119 0.9 1.0 1.2 1.3 0.3 0.4 0.4 0.6 0.5 0.7 0.7 0.8 0.3 0.4 0.5 0.4 160-179 1.5 1.7 1.8 1.9 0.8 1.0 1.1 1.2 1.1 1.3 1.4 1.6 0.8 0.9 1.0 1.1 140-159 1.3 1.6 1.7 1.8 0.6 0.8 0.9 1.1 0.9 1.1 1.3 1.4 0.6 0.7 0.8 0.9 55-59 120-139 1.1 1.3 1.5 1.6 0.5 0.6 0.8 0.8 0.7 0.9 1.1 1.2 0.4 0.6 0.7 0.8 100-119 0.9 1.1 1.3 1.4 0.4 0.4 0.6 0.6 0.6 0.6 0.8 0.9 0.3 0.5 0.5 0.6 160-179 1.5 1.7 1.8 1.9 0.9 1.0 1.3 1.4 1.2 1.4 1.5 1.6 0.9 1.0 1.2 1.3 140-159 1.4 1.5 1.8 1.9 0.7 0.9 1.1 1.1 1.0 1.2 1.3 1.5 0.7 0.8 0.9 1.1 50-54 120-139 1.2 1.4 1.6 1.7 0.6 0.7 0.8 0.9 0.8 1.0 1.1 1.2 0.6 0.7 0.7 0.8 140-159 0.9 1.1 1.3 1.5 0.4 0.5 0.6 0.7 0.6 0.7 0.9 1.0 0.4 0.5 0.6 0.6 100-119 1.5 1.7 1.9 2.0 0.9 1.1 1.3 1.4 1.2 1.4 1.6 1.6 0.9 1.1 1.3 1.4 120-139 1.4 1.5 1.7 1.8 0.8 0.9 1.1 1.2 1.0 1.2 1.4 1.5 0.7 0.9 1.1 1.2 45-49 160-179 1.2 1.4 1.6 1.7 0.6 0.7 0.9 0.9 0.8 1.0 1.1 1.3 0.6 0.7 0.9 0.9 100-119 0.9 1.2 1.4 1.5 0.5 0.6 0.7 0.8 0.6 0.8 0.9 1.0 0.5 0.6 0.6 0.8 160-179 1.6 1.7 1.9 2.0 0.9 1.1 1.3 1.4 1.3 1.4 1.6 1.7 0.9 1.2 1.4 1.5 140-159 1.4 1.5 1.7 1.8 0.8 0.9 1.1 1.2 1.0 1.2 1.4 1.5 0.8 0.9 1.1 1.3 40-44 120-139 1.2 1.4 1.6 1.7 0.6 0.8 0.9 1.0 0.8 1.0 1.1 1.3 0.6 0.8 0.9 1.0 100-119 1.0 1.2 1.4 1.5 0.5 0.6 0.7 0.8 0.6 0.8 0.9 1.0 0.5 0.6 0.7 0.8
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. 52 ESC Guidelines
Intensity of lipid-lowering treatment
Treatment Average LDL-C reduction
Moderate-intensity statin 30%
High-intensity statin 50% Downloaded from https://academic.oup.com/eurheartj/advance-article/doi/10.1093/eurheartj/ehab484/6358713 by guest on 30 August 2021 High-intensity statin plus ezetimibe 65%
PCSK9 inhibitor 60%
PCSK9 inhibitor plus high-intensity statin 75%
PCSK9 inhibitor plus high-intensity statin plus ezetimibe 85%
Figure 13 Expected low-density lipoprotein cholesterol reductions for combination therapies. LDL-C = low-density lipoprotein cholesterol; PCSK9 = proprotein convertase subtilisin/kexin type 9. Adapted from Mach et al.3 . 4.6.3. Strategies to control dyslipidaemias . approved in several European countries. Results from the ASCVD . The presence of dyslipidaemias secondary to other conditions must . outcomes trial are expected for 2023. be excluded before beginning treatment, as treatment of underlying . The expected LDL-C reductions in response to therapy are . disease may improve hyperlipidaemia without requiring lipid- . shown in Figure 13, and may vary widely among individuals. lowering therapy. This is particularly true for hypothyroidism. . Therefore, monitoring the effect on LDL-C levels is recommended, . Secondary dyslipidaemias can also be caused by alcohol abuse, DM, . with assessment of LDL-C levels 4 - 6 weeks after any treatment Cushing’s syndrome, diseases of the liver and kidneys, as well as by . strategy initiation or change. . drugs (e.g. corticosteroids). In addition, lifestyle optimization is crucial . in all patients with higher than optimal lipid levels. . Recommendations for pharmacological low-density lip- . . oprotein cholesterol lowering for those <70 years of age 4.6.3.1 Strategies to control low-density lipoprotein cholesterol . (for recommendations for persons aged 70 years, see . respective recommendations tables). . 4.6.3.1.1. Diet and lifestyle modifications. Dietary factors influence . . Recommendations Classa Levelb the development of ASCVD, either directly or through their action . . on traditional risk factors, such as plasma lipids, BP, or glucose levels. . It is recommended that a high-intensity statin is Consistent evidence from epidemiological studies indicates that . prescribed up to the highest tolerated dose to . IA higher consumption of fruit, non-starchy vegetables, nuts, legumes, . reach the LDL-C goals set for the specific risk . 21,520,521 fish, vegetable oils, yoghurt, and wholegrains, along with a lower . group. . c intake of red and processed meats, foods higher in refined carbohy- . An ultimate LDL-C goal of <1.4 mmol/L (55 mg/ 519 . drates, and salt, is associated with a lower incidence of CV events. . dL) and LDL-C reduction of >_50% from baseline . IIa C Moreover, the replacement of animal fats, including dairy fat, with . should be considered in apparently healthy persons . vegetable sources of fats and PUFAs may decrease the risk of . <70 years at very high risk.21,22,522 407 . . c ASCVD. More detail on lifestyle recommendations can be found . An ultimate LDL-C goal of <1.8 mmol/L (70 earlier in this section. . mg/dL) and LDL-C reduction of >_50% from . IIa C . baseline should be considered in apparently 4.6.3.1.2. Drugs for treatment of dyslipidaemias. The currently . healthy persons <70 years at high risk.21,22,522 . available lipid-lowering drugs include inhibitors of 3-hydroxy-3-meth- . In patients with established ASCVD, lipid-lowering . c ylglutaryl-coenzyme A reductase (statins), fibrates, bile acid seques- . treatment with an ultimate LDL-C goal of <1.4 . IA trants, selective cholesterol absorption inhibitors (e.g. ezetimibe), . mmol/L (55 mg/dL) and a >_50% reduction in LDL- and—more recently—PCSK9 inhibitors. Bempedoic acid, an oral . 21,508,515 517,522 . C vs. baseline is recommended. cholesterol synthesis inhibitor, has recently been approved in several . If the goals are not achieved with the maximum countries. Usage is mainly intended in combination with ezetimibe in . . tolerated dose of a statin, combination with eze- IB patients with statin intolerance. ASCVD outcome trials are not . 515 . timibe is recommended. expected before the end of 2022. Additionally, inclisiran, a new small . For primary prevention patients at very high risk, interfering ribonucleic acid, has shown to reduce LDL-C by 50 55% . . but without FH, if the LDL-C goal is not when applied subcutaneously twice a year. These results were . achieved on a maximum tolerated dose of a sta- IIb C . obtained either on top of statin or without other lipid-lowering . tin and ezetimibe, combination therapy including . therapies, and with almost no side-effects. Inclisiran has been . a PCSK9 inhibitor may be considered. Continued ESC Guidelines 53
. For secondary prevention patients not achieving . pharmacological therapy for concomitant conditions. In practice, their goals on a maximum tolerated dose of a . management of a patient with myalgia but without a major increase in . statin and ezetimibe, combination therapy IA. creatine kinase is based on trial and error, and usually involves switch- . ing to a different statin or use of a very low dosage several days a including a PCSK9 inhibitor is . recommended.516,517 . week, with a gradual increase in frequency and dosage. A manage- . ment algorithm may help to manage these patients.3 For very-high-risk FH patients (that is, with . . ASCVD or with another major risk factor) who . do not achieve their goals on a maximum toler- . 4.6.3.1.4. Cholesterol absorption inhibitors (ezetimibe). The com- Downloaded from https://academic.oup.com/eurheartj/advance-article/doi/10.1093/eurheartj/ehab484/6358713 by guest on 30 August 2021 IC. bination of statin with ezetimibe brings a benefit that is in line with ated dose of a statin and ezetimibe, combination . therapy including a PCSK9 inhibitor is . meta-analyses showing that LDL-C reduction has benefits independ- . 3,21 recommended. . ent of the approach used. The beneficial effect of ezetimibe is also . supported by genetic studies.528 Together, these data support the If a statin-based regimen is not tolerated at any . . position that ezetimibe should be considered as second-line therapy, dosage (even after rechallenge), ezetimibe IIa B . . either on top of statins when the therapeutic goal is not achieved, or should be considered.515,523 525 . . when a statin cannot be prescribed. If a statin-based regimen is not tolerated at any . dosage (even after rechallenge), a PCSK9 inhibitor IIb C . . 4.6.3.1.5. Proprotein convertase subtilisin/kexin type 9 inhibitors. added to ezetimibe may be considered.523,524,526 . . PCSK9 inhibitors (monoclonal antibodies to PCSK9) decrease LDL-C If the goal is not achieved, statin combination . IIb C . by up to 60%, either as monotherapy or in addition to the maximum with a bile acid sequestrant may be considered. . . tolerated dose of statin and/or other lipid-lowering therapies, such as Statin therapy is not recommended in . ezetimibe. Their efficacy appears to be largely independent of back- premenopausal female patients who are consid- . III C . ground therapy. In combination with high-intensity or maximum toler- ering pregnancy or are not using adequate . ated statins, alirocumab and evolocumab reduced LDL-C by 46 73%
ESC 2021 . contraception. . more than placebo, and by 30% more than ezetimibe.516,517 Among . ASCVD = atherosclerotic cardiovascular disease; FH = familial hypercholestero- . patients in whom statins cannot be prescribed, PCSK9 inhibition laemia; LDL-C = low-density lipoprotein cholesterol; PCSK9 = proprotein con- . reduced LDL-C levels when administered in combination with ezeti- vertase subtilisin/kexin type 9. . 529 a . mibe. Both alirocumab and evolocumab effectively lower LDL-C Class of recommendation. . bLevel of evidence. . levels in patients who are at high or very high CVD risk, including those c . 516,517 A stepwise approach to LDL-C targets is recommended; see section 3.2.3.1 and . with DM, with a large reduction in future ASCVD events. Figures 6 and 7. . PCSK9 inhibitors also lower triglycerides, raise HDL-C and apolipo- Adapted from 3 . . protein A-I, and lower lipoprotein(a), although the relative contribu- . tions of these lipid modifications remain unknown. PCSK9 inhibitors 4.6.3.1.3. Statins. Statins decrease LDL-C, thereby reducing ASCVD . . are costly, and their cost-effectiveness, long-term safety, and effect in morbidity and mortality as well as the need for coronary artery inter- . primary prevention are as yet unknown. We recommend considering . ventions. Statins also lower triglycerides, and may reduce pancreatitis . cost-effectiveness in a loco-regional context before implementing rec- risk. Therefore, they are the drug of first choice in patients at . ommendations that involve their use. Recommendations for the use of 3 . increased risk of ASCVD. . PCSK9 inhibitors are described in the Recommendations for pharma- . . cological LDL-C lowering. Inclisiran is a long-acting hepatic PCSK9 syn- 4.6.3.1.3.1. Adverse effects, interactions, and adherence to statin . 530 . thesis inhibitor that also lowers LDL-C levels considerably. Its effect therapy . on clinical outcomes remains to be established. The most frequent adverse effect of statin therapy is myopathy, but . . this is rare. A meta-analysis ruled out any contribution to an increase . 4.6.3.2 Strategies to control plasma triglycerides 522 . in non-CV mortality. Increased blood sugar and HbA1c levels (i.e. . Although CVD risk is increased when fasting triglycerides are >1.7 increased risk of type 2 DM) can occur after treatment initiation and . mmol/L (150 mg/dL),531 the use of drugs to lower triglyceride levels . are dose dependent, in part linked to slight weight gain, but the bene- . may only be considered in high-risk patients when triglycerides are fits of statins outweigh the risks for the majority of patients.527 . . >2.3 mmol/L (200 mg/dL) and triglycerides cannot be lowered by life- Adhering to lifestyle changes when prescribed a statin should lessen . style measures. The available pharmacological interventions include the risk of DM. Increased levels of liver enzymes may occur during . . statins, fibrates, PCSK9 inhibitors, and n-3 PUFAs (in particular icosa- statin therapy, and are usually reversible. Routine monitoring of liver . pent ethyl in doses of 2 4g/day;seesection 4.3.2.4.4). enzyme values is not indicated. . . Recommendations for the treatment of hypertriglyceridaemia are Although 5 10% of patients receiving statins complain of myalgia, . shown in the Recommendations below. 3 . in most cases it is not attributable to statins. The risk of myopathy . (severe muscular symptoms) can be minimized by identifying vulner- . 4.6.3.2.1. Fibrates. Fibrates are used primarily for triglyceride lower- . able patients and/or by avoiding statin interactions with specific drugs. . ing and, occasionally, for increasing HDL-C. Evidence supporting the Rhabdomyolysis is extremely rare. As statins are prescribed on a . use of these drugs for CVD event reduction is limited, and given the . long-term basis, possible interactions with other drugs deserve par- . strong evidence favouring statins, routine use of these drugs in CVD ticular and continuous attention, as many patients will receive . prevention is not recommended.3 To prevent pancreatitis, when 54 ESC Guidelines
. triglycerides are >10 mmol/L (900 mg/dL), they must be reduced not . Recent evidence has strengthened the role of LDL-C as an ASCVD only by drugs, but also by restriction of alcohol, treatment of DM, . risk factor in older patients.537 Evidence from trials indicates that statins . withdrawal of oestrogen therapy, etc. In patients with severe primary . and other lipid-lowering drugs produce significant reductions in major . 538,539 hypertriglyceridaemia, referral to a specialist must be considered. . vascular events irrespective of age. However, there is less direct An evidence-based approach to the use of lipid-lowering nutra- . evidence of statin benefit in those without evidence of ASCVD. Under . ceuticals could improve the quality of the treatment, including ther- . the age of 70 years, statins are recommended for primary prevention apy adherence, and achievement of the LDL-C goal in clinical . depending on the level of risk. Above that age, initiation of statin treat- . practice. However, it has to be clearly stressed that there are still no . ment for primary prevention may be considered when at (very) high Downloaded from https://academic.oup.com/eurheartj/advance-article/doi/10.1093/eurheartj/ehab484/6358713 by guest on 30 August 2021 . outcome studies proving that nutraceuticals can prevent CVD mor- . risk, but we explicitly recommend also taking other arguments into 532 . bidity or mortality. . 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, . 4.6.4. Important groups . the statin dose should be up-titrated carefully. In terms of LDL-C tar- Recommendations for drug treatments of patients with . gets, there is insufficient evidence to support targets for primary pre- hypertriglyceridaemia. . . vention in older patients. Although the conventional LDL-C target of . <2.6 mmol/L (100 mg/dL) may seem reasonable, the results of ongoing Recommendations Classa Levelb . . primarypreventiontrialsinolderpatientsmustbeawaited[STAREE . Statin treatment is recommended as the first . (STAtin Therapy for Reducing Events in the Elderly) trial; clinicatrials. drug of choice for reducing CVD risk in high-risk . gov registration: NCT02099123]. Frailty, polypharmacy, and muscle IA. individuals with hypertriglyceridaemia [triglycer- . symptoms remain relevant factors to consider in older patients. 533 . ides >2.3 mmol/L (200 mg/dL)]. . In patients taking statins who are at LDL-C goal . Recommendations for the treatment of dyslipidaemias . with triglycerides >2.3 mmol/L (200 mg/dL), fenofi- IIb B . in older people ( 70 years). brate or bezafibrate may be considered.534 536 . . a b In high-risk (or above) patients with triglycerides . Recommendations Class Level . >1.5 mmol/L (135 mg/dL) despite statin treat- . Treatment with statins is recommended for ment and lifestyle measures, n-3 PUFAs (icosa- IIb B . . older people with ASCVD in the same way as IA pent ethyl 2 2 g/day) may be considered in . for younger patients.538,539
84 ESC 2021 . combination with a statin. . Initiation of statin treatment for primary preven- . CVD = cardiovascular disease; LDL-C = low-density lipoprotein cholesterol; . tion in older people aged >_70 may be consid- IIb B . 538,539 PUFA = polyunsaturated fatty acid. . ered, if at high risk or above. aClass of recommendation. . b . It is recommended that the statin is started at a Level of evidence. . 3 . Adapted from . low dose if there is significant renal impairment IC . ESC 2021 . and/or the potential for drug interactions. 4.6.4.1 Women . The proportional reductions per mmol/L reduction in LDL-C in . ASCVD = atherosclerotic cardiovascular disease. . aClass of recommendation. major vascular events, major coronary events, coronary revasculari- . bLevel of evidence. . 3 zation, and stroke are similar in women and men. In addition, the rela- . Adapted from tive effects of non-statin drugs that lower LDL-C (ezetimibe and . . 4.6.4.3 Diabetes mellitus PCSK9 inhibitors, on top of high-intensity statin therapy) are also sim- . ilar in both women and men.3 . Lowering of LDL-C in patients with DM is consistently associated . . with lower CVD risk. Similar to prevention in apparently healthy 4.6.4.2 Older patients ( 70 years) . individuals, we propose a stepwise approach to lipid control, 3 . Compared to the 2019 ESC/EAS dyslipidaemia guidelines, we pro- . dependent on risk, estimated lifetime benefit, comorbidities, and vide a single cut-off for identifying ‘older persons’ as those >_70 years . . patient preferences (Figure 8). PCSK9 inhibitors can also be used in of age, as opposed to 75 years, for reasons of consistency with other . patients with DM not reaching their LDL-C targets with statins and/ parts of the current guidelines. As a result, class and level of evidence . . or ezetimibe. have been modified in some age groups, in particular the category of . . Recommendations for the treatment of dyslipidaemias patients between 70 and 75 years. Although a single age cut-off is . . in diabetes mellitus. now used, it is important to stress that all such age cut-offs are rela- . tively arbitrary, and biological age influences this threshold in clinical . Recommendations Classa Levelb . practice. For example, a very fit 75-year-old person may qualify for a . treatment normally reserved for those <70 and, conversely, a very . In patients with type 2 DM at very high risk (e.g. . c frail 65-year-old person should sometimes be considered ‘older’. . with established ASCVD and/or severe TOD ), . intensive lipid-lowering therapy, ultimatelyd aim- General recommendations for lipid-lowering treatment in older . IA . ing at >_50% LDL-C reduction and an LDL-C of patients are summarized below. . . <1.4 mmol/L (55 mg/dL) is recommended.21,22,522,540,541 Continued ESC Guidelines 55
In patients with type 2 DM >40 years at high . . Table 11 Dutch Lipid Clinic Network diagnostic criteria risk, lipid-lowering treatment with an ultimate . for familial hypercholesterolaemia LDL-C goal of >_50% LDL-C reduction and an IA. . Criteria (choose only one score per group, the Points LDL-C of <1.8 mmol/L (70 mg/dL) is . highest applicable; diagnosis is based on the total 540,541 . recommended. . number of points obtained) Statin therapy may be considered in persons . 1) Family history . aged <_40 years with type 1 or type 2 DM with . First-degree relative with known premature (men aged 1 . Downloaded from https://academic.oup.com/eurheartj/advance-article/doi/10.1093/eurheartj/ehab484/6358713 by guest on 30 August 2021 evidence of TOD and/or an LDL-C level >2.6 IIb C . <55 years; women <60 years) coronary or vascular dis- mmol/L (100 mg/dL), as long as pregnancy is not . . ease, or first-degree relative with known LDL-C above being planned. . the 95th percentile If the LDL-C goal is not reached, statin . . First-degree relative with tendinous xanthomata and/or 2 combination with ezetimibe should be IIa B . arcus cornealis, or children aged <18 years with LDL-C
515,542 ESC 2021 . considered. . . above the 95th percentile . ASCVD = atherosclerotic cardiovascular disease; DM = diabetes mellitus; eGFR . 2) Clinical history = estimated glomerular filtration rate; LDL-C = low-density lipoprotein choles- . Patient with premature (men aged <55 years; women 2 terol; TOD = target organ damage. . . <60 years) CAD aClass of recommendation. . bLevel of evidence. . Patient with premature (men aged <55 years; women 1 c 2 . Severe TOD in this specific context includes eGFR <45 mL/min/1.73 m ; eGFR . <60 years) cerebral or peripheral vascular disease 2 . 46 79 mL/min/1.73 m plus microalbuminuria; proteinuria; presence of micro- . vascular disease in at least three different sites (e.g. albuminuria plus retinopathy . 3) Physical examination plus neuropathy). See Table 4 for details. . Tendinous xanthomata 6 dA stepwise approach to LDL-C targets is recommended; see section 3.2.3.1 and . Figure 8. . Arcus cornealis before age 45 years 4 3 . Adapted from . 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 4.6.4.4 Chronic kidney disease . . LDL-C 5.0 6.4 mmol/L (191 250 mg/dL) 3 Patients with CKD are at high or very high risk of ASCVD, and have a . characteristic dyslipidaemia (high triglycerides, normal LDL-C, and . LDL-C 4.0 4.9 mmol/L (155 190 mg/dL) 1 . 5) DNA analysis low HDL-C). Statin therapy or statin therapy in combination with . ezetimibe (which allows larger LDL-C reductions without increasing . Functional mutation in the LDLR, apolipoprotein B, or 8 . the statin dose) has a beneficial effect on ASCVD outcomes in . PCSK9 genes CKD.543 For patients with end-stage renal disease, however, we rec- . A ‘definite’ FH diagnosis requires >8 points . ommend that hypolipidaemic therapy should not be initiated (see . A ‘probable’ FH diagnosis requires 6 8 points . . ESC 2021 Recommendations below). If patients with CKD already on a hypoli- . A ‘possible’ FH diagnosis requires 3 5 points pidaemic therapy enter end-stage renal disease, the therapy may be . . CAD = coronary artery disease; DNA = deoxyribonucleic acid; FH = familial hyper- maintained. . cholesterolaemia; LDL-C = low-density lipoprotein cholesterol; LDLR = low-density . lipoprotein receptor; PCSK9 = proprotein convertase subtilisin/kexin type 9. . Recommendations for lipid management in patients . with moderate-to-severe chronic kidney disease (Kidney . Disease Outcomes Quality Initiative stages 3 5). . . 4.6.4.5 Familial Hypercholesterolaemia . Patients who could have genetic dyslipidaemias, such as heterozygous Recommendations Classa Levelb . . FH, can be identified by extreme lipid abnormalities and/or family his- The use of statins or statin/ezetimibe combina- . tory (Table 11). An LDL-C >4.9 mmol/L (190 mg/dL) in therapy- . tion is recommended in patients with non-dialy- IA. naı¨ve patients requires careful evaluation for possible FH. However, 525,544,545 . sis-dependent, stage 3 5 CKD. . in the presence of premature ASCVD or family history, possible FH . should be considered at lower LDL-C levels. Besides genetic testing In patients already on statins, ezetimibe, or a sta- . tin/ezetimibe combination at the time of dialysis . (not always affordable), use of the Dutch Clinical Lipid Network cri- IIa C . teria (Table 11) is recommended to identify possible FH. initiation, continuation of these drugs should be . considered, particularly in patients with ASCVD. . Homozygous FH is rare and should always be placed under the care . of lipid experts. In patients with dialysis-dependent CKD who . . Treatment guidelines for people with FH can be found in the 2019 are free of ASCVD, commencing statin therapy III A . . 3
546,547 ESC 2021 . ESC/EAS dyslipidaemia Guidelines. is not recommended. . . ASCVD = atherosclerotic cardiovascular disease; CKD = chronic kidney disease. . a 4.7. Blood pressure Class of recommendation. . b . Level of evidence. . 3 . Adapted from . Hypertension is one of the most important preventable causes of . premature morbidity and mortality. It affects more than 150 million 56 ESC Guidelines
. Summary of recommendations for the clinical manage- . Treatment of hypertension: drug treatment ment of hypertension . . It is recommended to initiate antihypertensive . treatment with a two-drug combination in most Recommendations Classa Levelb . . patients, preferably as a single-pill combination. . IB Classification of BP . Exceptions are frail older patients and those . It is recommended that BP should be classified . with low-risk, grade 1 hypertension (particularly . 560 565 as optimal, normal, high-normal, or grades 1 - 3 IC. if SBP <150 mmHg). hypertension, according to office BP. . It is recommended that the preferred combina- Downloaded from https://academic.oup.com/eurheartj/advance-article/doi/10.1093/eurheartj/ehab484/6358713 by guest on 30 August 2021 . Diagnosis of hypertension . tions include a RAS blocker (i.e. an ACE inhibitor . or ARB) with a CCB or diuretic, but other com- It is recommended to base the diagnosis of . IA . binations of the five major classes can be used hypertension on: . Repeated office BP measurements, on more . (ACE inhibitor, ARB, beta-blocker, CCB, thia- . 566 569 than one visit, except when hypertension is I C . zide/thiazide-like diuretic). severe (e.g. grade 3 and especially in high-risk . It is recommended, if BP remains uncontrolled . patients) . with a two-drug combination, that treatment be or . increased to a three-drug combination, usually a IA . Out-of-office BP measurement with ABPM and/ I C . RAS blocker with a CCB and a diuretic, prefera- . 563,570,571 or HBPM when feasible. . bly as a single-pill combination. . It is recommended, if BP is not controlled by a Assessment of HMOD . To evaluate for the presence of HMOD, meas- . three-drug combination, that treatment should . urement of serum creatinine, eGFR, electrolytes, . be increased by the addition of spironolactone, and ACR is recommended for all patients. A 12- . or if not tolerated, other diuretics such as ami- IB . lead ECG is recommended for all patients, and . loride or higher doses of other diuretics, an echocardiography is recommended for those . alpha-blocker or beta-blocker, or IB. 555,572 574 with ECG abnormalities or signs/symptoms of . clonidine. . The combination of two RAS blockers is not LV dysfunction. Fundoscopy or retinal imaging is . III A . recommended.575,576 recommended for patients with grades 2 or 3 . hypertension and all hypertensive patients with . Management of CVD risk in hypertensive patients 548 551 . DM. . Statin therapy is recommended for many Section 4.6 Thresholds for initiation of drug treatment of hypertension . patients with hypertension.d . For grade 1 hypertension, treatment initiation . Antiplatelet therapy is indicated for secondary Section 4.9 based on absolute CVD risk, estimated lifetime . prevention in patients with hypertension.e ESC 2021 IC. benefit, and the presence of HMOD is . . ABPM = ambulatory blood pressure monitoring; ACE = angiotensin-converting recommended.552,553 . . enzyme; ACR = albumin-to-creatinine ratio; ARB = angiotensin receptor blocker; For patients with grade 2 hypertension or higher, . ASCVD = atherosclerotic cardiovascular disease; BP = blood pressure; CCB = IA. calcium channel blocker; DBP = diastolic blood pressure; DM = diabetes mellitus; drug treatment is recommended.4,552 . . ECG = electrocardiogram; eGFR = estimated glomerular filtration rate; HBPM = Office BP treatment targets . home blood pressure monitoring; HMOD = hypertension-mediated organ dam- . age; LV = left ventricular; RAS = renin angiotensin system; SBP = systolic blood It is recommended that the first objective of . . pressure. treatment is to lower BP to <140/90 mmHg in . aClass of recommendation. IA. b all patients, and that subsequent BP targets are . Level of evidence. . c tailored to age and specific comorbidities.552,554 . See section 4.3 for details. . dSee section 4.6 for details. . e In treated patients aged 18 69 years, it is rec- . See section 4.9 for details. ommended that SBP should ultimately be low- . IA. ered to a target range of 120 - 130 mmHg in . people across Europe, over 1 billion globally, with a prevalence of most patients.552,554 556 . 30 45% in adults, increasing with age to more than 60% in people . In treated patients aged >_70 years, it is recom- . aged >60 years, and accounting for 10 million deaths globally per . 577 mended that SBP should generally be targeted to . annum. Despite extensive evidence for the effectiveness of BP- IA. <140 and down to 130 mmHg if . lowering treatments at reducing CVD risk and death, the detection, tolerated.552,554,557 . treatment, and control of BP in Europe and globally remains . 578 In all treated patients, DBP is recommended to . suboptimal. IA. 555,558,559 . be lowered to <80 mmHg. . This section covers recommendations for the diagnosis and treat- Treatment of hypertension: lifestyle interventions . ment of hypertension to be applied in routine primary and secondary . Lifestyle interventions are recommended for . care. More detail and guidance for complex cases/tertiary care are IA. c . available in the 2018 ESC/European Society of Hypertension (ESH) people with high-normal BP or higher. . . Guidelines for the management of arterial hypertension.4 Continued . ESC Guidelines 57
. 4.7.1. Definition and classification of hypertension . dictor of hypertension-mediated organ damage (HMOD) and clinical . BP is classified according to seated office BP (Table 12), with approxi- . outcomes than office BP, and identifies ‘white-coat’ hypertension and mately corresponding values according to ABPM or home BP average . masked hypertension (see below). Diagnostic thresholds for hyper- . 4 values in Table 13. . tension are lower with ABPM than office BP (Table 12). . . 4.7.2.4 Home blood pressure monitoring 4.7.2. Blood pressure measurement . . Home BP is the average of all BP readings performed with a validated 4.7.2.1 Office blood pressure measurement . . semiautomatic monitor, for at least 3 consecutive days (ideally 6 - 7 Office BP should be measured in standardized conditions using . Downloaded from https://academic.oup.com/eurheartj/advance-article/doi/10.1093/eurheartj/ehab484/6358713 by guest on 30 August 2021 . days), with readings in the morning and evening, taken seated in a validated auscultatory or (semi)automatic devices, as described in . . quiet room after 5 min of rest. Home BP monitoring (HBPM) thresh- Table 14. . . olds for the diagnosis of hypertension are lower than those for office . . BP (Table 12). Patient self-monitoring may have a beneficial effect on 4.7.2.2 Unattended automated office blood pressure measurement . . medication adherence and BP control.4 Repeated automated office BP readings may improve the reproduci- . . Clinical indications for ambulatory or home monitoring are shown bility of BP measurement. If the patient is seated alone and unob- . . in Table 15. served, unattended automated office BP measurement may reduce . or eliminate the ‘white-coat’ effect, and unattended automated office . . BP measurements are usually lower than conventional office BP . measurements, and more similar to ambulatory daytime BP or home . 4.7.3 Screening and diagnosis of hypertension . BP values. There is limited information on the prognostic value of . Ideally, all adults should be screened for the presence of hyperten- unattended automated office BP measurements.4 . sion,578,579 but most countries lack the required resources and infra- . . structure. Formally, these guidelines recommend opportunistic 4.7.2.3 Ambulatory blood pressure monitoring . screening at least in susceptible individuals, such as those who are . ABPM is the average of repeated automated measurements of BP . overweight or have a family history of hypertension (see section 3.1). during the daytime, night-time, and over 24 h. ABPM is a better pre- . . . . Table 14 Considerations in blood pressure Table 12 Categories for conventionally measured seated . measurement office blood pressurea . . Patients should be seated comfortably in a quiet environment for 5 min Category SBP (mmHg) DBP (mmHg) . . before BP measurements. Optimal <120 and <80 . . Three BP measurements should be recorded, 1 2 min apart, and addi- Normal 120 129 and/or 80 84 . tional measurements if the first two readings differ by >10 mmHg. BP is . High-normal 130 139 and/or 85 89 . recorded as the average of the last two BP readings. Grade 1 hypertension 140 159 and/or 90 99 . . Additional measurements may have to be performed in patients with Grade 2 hypertension 160 179 and/or 100 109 . unstable BP values due to arrhythmias, such as in patents with AF, in . Grade 3 hypertension >_180 and/or >_110 . whom manual auscultatory methods should be used as most automated Isolated systolic >_140 and <90 . devices have not been validated for BP measurement in AF. b . hypertension ESC 2021 . Use a standard bladder cuff (12 13 cm wide and 35 cm long) for most . BP = blood pressure; DBP = diastolic blood pressure; SBP = systolic blood pressure. . patients, but use larger and smaller cuffs for larger (arm circumference aBP category is defined according to seated clinic BP and by the highest level of . >32 cm) and smaller (arm circumference <26 cm) arms, respectively. BP, whether systolic or diastolic. . b . The cuff should be positioned at the level of the heart with the back and Isolated systolic hypertension is graded 1, 2, or 3 according to SBP values in the . ranges indicated. . arm supported, to avoid muscle contraction and isometric-exercise- . . dependant increases in BP. . When using auscultatory methods, use phase I and V (sudden reduction/ . Table 13 Definitions of hypertension according to office, . disappearance) Korotkoff sounds to identify SBP and DBP, respectively. ambulatory, and home blood pressure . . Measure BP in both arms at the first visit to detect possible between-arm Category SBP DBP . differences. Use the arm with the higher value as the reference. . (mmHg) (mmHg) . Measure BP 1 min and 3 min after standing from the seated position in all Office BPa >_140 and/or >_90 . patients at the first measurement to exclude orthostatic hypotension. . Ambulatory BP . Lying and standing BP measurements should also be considered in subse- . quent visits in older people, in people with DM, and in other conditions Daytime (or awake) mean >_135 and/or >_85 . Night-time (or asleep) mean >_120 and/or >_70 . in which orthostatic hypotension may frequently occur. Initial orthostatic . hypotension may occur <1 min after standing and may be difficult to 24-h mean >_130 and/or >_80 . . detect with conventional measurement techniques.
ESC 2021 . Home BP mean >_135 and/or >_85 . . Record heart rate and use pulse palpation to exclude arrhythmia. ESC 2021 BP = blood pressure; DBP = diastolic blood pressure; SBP = systolic blood . pressure. . AF = atrial fibrillation; BP = blood pressure; DBP = diastolic blood pressure; DM aRefers to conventional office BP rather than unattended office BP. . = diabetes mellitus; SBP = systolic blood pressure. 58 ESC Guidelines
. . When hypertension is suspected, the diagnosis of hypertension Table 15 Indications for home blood pressure monitor- . . should be confirmed, either by repeated office BP measurements ing or ambulatory blood pressure monitoring . . over a number of visits, or by 24-h ABPM or HBPM (Figure 14). . Conditions in which white-coat hypertension is more common, for . example: . 4.7.3.1 White-coat and masked hypertension . • Grade 1 hypertension on office BP measurement . White-coat hypertension refers to BP that is elevated in the office • Marked office BP elevation without HMOD . but is normal when measured by ABPM or HBPM. It occurs in up to . Conditions in which masked hypertension is more common, for example: . 30 40% of patients. The risk associated with white-coat hyperten- Downloaded from https://academic.oup.com/eurheartj/advance-article/doi/10.1093/eurheartj/ehab484/6358713 by guest on 30 August 2021 . High-normal office BP . sion is lower than sustained hypertension but may be higher than • . • Normal office BP in individuals with HMOD or at high total CV risk . normotension. People with white-coat hypertension should receive . lifestyle advice to reduce their CV risk and be offered BP measure- Postural and post-prandial hypotension in untreated and treated patients . Evaluation of resistant hypertension . ment at least every 2 years by ABPM or HBPM because of high rates . of transition to sustained hypertension. Routine drug treatment for Evaluation of BP control, especially in treated higher-risk patients . . white-coat hypertension is not indicated. Exaggerated BP response to exercise . . Masked hypertension refers to patients with a normal office BP but When there is considerable variability in the office BP . . an elevated BP on ABPM or HBPM. These patients often have Evaluating symptoms consistent with hypotension during treatment . . HMOD and are at a CV risk level at least equivalent to sustained Specific indications for ABPM rather than HBPM: . hypertension. It is more common in younger people and in those with • Assessment of nocturnal BP values and dipping status (e.g. suspicion . . high-normal office BP. In masked hypertension, lifestyle changes are of nocturnal hypertension, such as in sleep apnoea, CKD, DM, . recommended, and drug treatment should be considered to control
ESC 2021 . endocrine hypertension, or autonomic dysfunction) . ‘out-of-office’ BP, with periodic monitoring of BP, usually with HBPM. . ABPM = ambulatory blood pressure monitoring; BP = blood pressure; CKD = . chronic kidney disease; CV = cardiovascular; DM = diabetes mellitus; HBPM = . home blood pressure monitoring; HMOD = hypertension-mediated organ . 4.7.4. Clinical evaluation and risk stratification in damage. . hypertensive patients . . The routine work-up for hypertensive patients is shown in Table 16. . Alongside clinical examination, this is designed to:
Screening and diagnosis of hypertension
Blood pressure measurement
Normal High-normal Optimal Hypertension 120–129 mmHg / 130–139 mmHg / <120/80 mmHg ≥140/90 mmHg 80–84 mmHg 85–89 mmHg
Consider masked hypertension
Out-of-office Repeat visits BP measurement for office (ABPM or HBPM) BP measurement Indications OR for ABPM or HBPM Repeat BP Repeat BP Repeat BP Out-of-office measurement a measurement at measurement a BP measurement least every 5 years least every 3 years least annually (ABPM or HBPM)
Figure 14 Screening and diagnosis of hypertension. ABPM = ambulatory blood pressure monitoring; BP = blood pressure; HBPM = home blood pres- sure monitoring. ESC Guidelines 59
. Table 16 Routine tests for patients with hypertension . Table 17 Patient characteristics that should raise the . suspicion of secondary hypertension. Routine tests . . Characteristics Haemoglobin and/or haematocrit . Fasting blood glucose and/or HbA1c . Younger patients (<40 years) with grade 2 hypertension or onset of any . grade of hypertension in childhood Blood lipids: total cholesterol, LDL-C, HDL-C, triglycerides . . Acute worsening of hypertension in patients with previously documented Blood potassium and sodium . . chronically stable normotension Blood uric acid . Downloaded from https://academic.oup.com/eurheartj/advance-article/doi/10.1093/eurheartj/ehab484/6358713 by guest on 30 August 2021 . Resistant hypertension (BP uncontrolled despite treatment with optimal Blood creatinine and eGFR . . or best-tolerated doses of three or more drugs including a diuretic, and Blood liver function tests . . confirmed by ABPM or HBPM) Urine analysis: microscopic; urinary protein by dipstick or, ideally, ACR . . Severe (grade 3) hypertension or a hypertension emergency 12-lead ECG ESC 2021 . . Presence of extensive HMOD ACR = albumin-to-creatinine ratio; ECG = electrocardiogram; eGFR = estimated . . Clinical or biochemical features suggestive of endocrine causes of hyper- glomerular filtration rate; HbA1c = glycated haemoglobin; HDL-C = high-density . lipoprotein cholesterol; LDL-C = low-density lipoprotein cholesterol. . tension or CKD . . Clinical features suggestive of OSA . . Symptoms suggestive of pheochromocytoma or family history of • Assess risk factors for ASCVD (see section 3.2), or the presence . pheochromocytoma ESC 2021 . of cardiac, vascular, or renal disease . ABPM = ambulatory blood pressure monitoring; BP = blood pressure; CKD = . • Detect evidence of HMOD, e.g. LV hypertrophy, renal disease, . chronic kidney disease; HBPM = home blood pressure monitoring; HMOD = or retinopathy . hypertension-mediated organ damage; OSA = obstructive sleep apnoea. . Adapted from 4 • Consider potential secondary causes of hypertension, e.g. reno- . . vascular disease, hyperaldosteronism, or pheochromocytoma . (see Table 17). Also, carefully evaluate substance abuse (e.g. . . reduction in SBP is at least moderate to high [Figure 15 (lifetime bene- cocaine), drugs that may increase BP (e.g. cyclosporine, sympati- . . fit calibrated in low-to-moderate CVD risk countries]. Also, the pres- comimetics), liquorice, etc. More detail on work-up of suspected . . ence of HMOD mandates treatment of grade 1 hypertension. For secondary hypertension is provided elsewhere.4 . . grade 2 hypertension or higher (SBP >160 mmHg), treatment is rec- . Echocardiography is recommended in patients with ECG abnor- . ommended, because not only is the lifetime benefit of reducing BP malities, and should be considered when the result will influence clini- . almost universally high in such patients, there is also the importance . cal decision-making. Fundoscopy is recommended in grade 2 or 3 . of reducing the risk of HMOD resulting in other morbidities such as hypertension and in all patients with DM. The routine measurement . renal disease, haemorrhagic cerebrovascular disease, and HF. . of other biomarkers and use of vascular imaging are not . recommended.548 551 . 4.7.5.3 Blood pressure treatment targets . . When drug treatment is used, the aim is to control BP to target . within 3 months. Evidence now suggests that the BP targets in the 4.7.5. Treatment of hypertension . . previous iteration of this guideline2 were too conservative, especially The treatment of hypertension involves lifestyle interventions for all . . for older patients. In line with the stepwise approach (section 3.2.3.1), patients and drug therapy for most patients. . . it is now recommended that the first step in all treated patients . 4.7.5.1 Lifestyle interventions to lower blood pressure and/or reduce car- . should achieve a treated SBP <140 mmHg and diastolic BP (DBP) . <80 mmHg.552,554 The recommended ultimate SBP treatment target diovascular risk . Lifestyle interventions are indicated for all patients with high-normal . range for younger patients (18 69 years) is 120 130 mmHg, . although some patients may safely achieve lower treated SBP levels BP or hypertension because they can delay the need for drug treat- . ment or complement the BP-lowering effect of drug treatment. . than this and, if they are well tolerated, there is no need to back- . titrate treatment.552,554 556 The ultimate target SBP for patients aged Moreover, most lifestyle interventions have health benefits beyond . their effect on BP. Lifestyle is discussed extensively in section 4.3. . >_70 years is <140 mmHg and down to 130 mmHg if toler- . 552,554,557,580 . ated. This change in the BP target range for older people . 2 4.7.5.2 Initiation of drug treatment . compared with the 2016 ESC prevention guidelines is supported by . evidence that these treatment targets are safely achieved in many Drug treatment decisions in CVD prevention are mostly based on . absolute CVD risk, risk modifiers, comorbidities, estimated benefit of . older patients and are associated with significant reductions in the . 557,580 treatment, frailty, and patient preferences. The same is true for . risk of major stroke, HF, and CV death. It also takes into hypertension. Drug treatment of grade 1 hypertension (SBP . account that the even lower SBP in the intensively treated group in . 140 - 159 mmHg) has level A evidence for reducing CVD risk. In . SPRINT (Systolic Blood Pressure Intervention Trial) (mean 124 younger patients, however, the absolute 10-year CVD risk is often . mmHg) probably reflects a conventional office SBP range of . 555 low, and lifetime benefit of treatment should be considered and com- . 130 139 mmHg. It is recognized, however, that the evidence sup- . municated before instituting treatment (Figure 6 and section 3.2.3.6). . porting more strict targets is less strong for very old people (>80 In many such cases, the absolute lifetime benefit per 10-mmHg . years) and those who are frail. Also, in these older and especially frail 60 ESC Guidelines
LIFE-CVD model < 0.5 years 1.5 - 2.0 years CVD-free lifetime gain from 10 mmHg 0.5 - 0.9 years ≥ 2.0 years Systolic Blood Pressure reduction (in years) 1.0 - 1.4 years Women Men Non-smoking Smoking Non-smoking Smoking Non-HDL cholesterol
Systolic blood mmol/L pressure (mmHg) 3.0-3.9 4.0-4.9 5.0-5.9 6.0-6.9 3.0-3.9 4.0-4.9 5.0-5.9 6.0-6.9 3.0-3.9 4.0-4.9 5.0-5.9 6.0-6.9 3.0-3.9 4.0-4.9 5.0-5.9 6.0-6.9 150 200 250 150 200 250 mg/dL 150 200 250 150 200 250 Downloaded from https://academic.oup.com/eurheartj/advance-article/doi/10.1093/eurheartj/ehab484/6358713 by guest on 30 August 2021 160-179 0.3 0.3 0.4 0.4 0.1 0.1 0.2 0.2 Age 0.2 0.2 0.3 0.3 0.1 0.0 0.0 0.1 (y) 140-159 0.3 0.3 0.3 0.3 0.1 0.1 0.1 0.1 0.2 0.2 0.2 0.2 0.0 0.0 0.0 0.0 90+ 120-139 0.2 0.3 0.3 0.3 0.0 0.1 0.1 0.1 0.1 0.1 0.2 0.2 0.0 0.0 0.0 0.1 100-119 n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a 160-179 0.7 0.8 0.8 0.8 0.2 0.2 0.3 0.3 0.3 0.4 0.5 0.5 0.1 0.1 0.1 0.2 140-159 0.6 0.6 0.7 0.8 0.1 0.2 0.2 0.3 0.3 0.3 0.4 0.5 0.1 0.1 0.1 0.1 85-89 120-139 0.4 0.5 0.6 0.6 0.1 0.2 0.2 0.2 0.3 0.3 0.3 0.4 0.0 0.0 0.1 0.1 100-119 n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a 160-179 0.9 1.0 1.1 1.2 0.2 0.3 0.4 0.4 0.5 0.5 0.6 0.7 0.1 0.2 0.2 0.2 140-159 0.8 0.9 1.0 1.0 0.2 0.3 0.3 0.4 0.4 0.5 0.6 0.6 0.1 0.1 0.2 0.1 80-84 120-139 0.6 0.7 0.8 0.9 0.2 0.1 0.3 0.2 0.3 0.4 0.4 0.5 0.0 0.1 0.1 0.1 100-119 n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a 160-179 1.1 1.21.3 1.3 0.3 0.50.5 0.5 0.6 0.70.8 0.9 0.2 0.20.3 0.3 140-159 0.9 1.1 1.2 1.2 0.2 0.3 0.4 0.5 0.5 0.6 0.7 0.8 0.2 0.2 0.3 0.3 75-79 120-139 0.7 0.9 1.0 1.1 0.2 0.2 0.3 0.4 0.4 0.5 0.6 0.6 0.1 0.2 0.2 0.2 100-119 n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a 160-179 1.2 1.3 1.4 1.5 0.4 0.5 0.7 0.7 0.7 0.8 1.0 1.0 0.3 0.4 0.5 0.5 140-159 1.0 1.3 1.4 1.5 0.4 0.4 0.5 0.6 0.6 0.7 0.9 0.9 0.2 0.3 0.4 0.4 70-74 120-139 0.8 1.0 1.1 1.2 0.2 0.3 0.4 0.5 0.4 0.6 0.7 0.8 0.1 0.2 0.3 0.3 100-119 n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a 160-179 1.2 1.31.5 1.5 0.5 0.70.8 0.9 0.8 1.01.1 1.1 0.5 0.50.7 0.6 140-159 1.0 1.3 1.4 1.5 0.4 0.5 0.6 0.7 0.7 0.9 0.9 1.0 0.3 0.5 0.5 0.5 65-69 120-139 0.9 1.1 1.2 1.3 0.3 0.4 0.5 0.5 0.5 0.7 0.8 0.9 0.2 0.4 0.4 0.4 100-119 n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a 160-179 1.3 1.4 1.5 1.6 0.6 0.7 0.9 1.0 1.0 1.1 1.2 1.3 0.6 0.7 0.8 0.8 140-159 1.2 1.3 1.4 1.5 0.5 0.6 0.7 0.8 0.8 0.9 1.1 1.1 0.5 0.5 0.7 0.7 60-64 120-139 1.0 1.1 1.3 1.4 0.4 0.4 0.6 0.6 0.7 0.7 0.9 1.0 0.4 0.4 0.5 0.5 100-119 n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a 160-179 1.3 1.5 1.6 1.7 0.7 0.9 1.0 1.1 1.0 1.2 1.3 1.4 0.7 0.9 0.9 1.0 140-159 1.1 1.4 1.6 1.6 0.6 0.7 0.8 1.0 0.8 1.0 1.2 1.2 0.5 0.6 0.8 0.9 55-59 120-139 1.0 1.2 1.4 1.5 0.4 0.5 0.7 0.7 0.7 0.8 1.0 1.0 0.4 0.5 0.6 0.7 100-119 n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a 160-179 1.3 1.5 1.7 1.7 0.8 1.0 1.1 1.2 1.0 1.3 1.4 1.5 0.8 0.9 1.0 1.2 140-159 1.3 1.4 1.6 1.7 0.6 0.8 1.0 1.0 0.9 1.1 1.2 1.3 0.7 0.7 0.8 1.0 50-54 120-139 1.1 1.2 1.4 1.5 0.5 06 0.7 0.8 0.7 0.9 1.0 1.1 0.5 0.6 0.7 0.7 140-159 n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a 100-119 1.3 1.6 1.7 1.8 0.8 1.0 1.2 1.3 1.1 1.3 1.5 1.5 0.8 1.0 1.2 1.3 120-139 1.3 1.4 1.6 1.6 0.7 0.8 1.0 1.1 0.9 1.1 1.3 1.3 0.7 0.8 1.0 1.1 45-49 160-179 1.1 1.2 1.4 1.5 0.5 0.7 0.8 0.8 0.8 0.9 1.0 1.2 0.6 0.7 0.8 0.8 100-119 n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a 160-179 1.4 1.6 1.7 1.8 0.8 1.0 1.2 1.3 1.1 1.3 1.4 1.6 0.9 1.1 1.3 1.4 140-159 1.3 1.4 1.6 1.7 0.7 0.8 1.0 1.1 0.9 1.1 1.3 1.4 0.7 0.9 1.0 1.2 40-44 120-139 1.1 1.3 1.4 1.5 0.6 0.7 0.8 0.9 0.7 0.9 1.0 1.2 0.6 0.7 0.8 0.9 100-119 n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a
Figure 15 Lifetime benefit from lowering systolic blood pressure by 10 mmHg for apparently healthy persons, based on the following risk factors: age, sex, current smoking, systolic blood pressure, non-high-density lipoprotein cholesterol. The model is currently validated for low- and moderate-risk coun- tries. The lifetime benefit is expressed as ‘years of median life expectancy free from myocardial infarction or stroke’ gained from 10 mmHg SBP lowering. The lifetime benefit is calculated by estimating lifetime CVD risk with the LIFE-CVD model multiplied by the HR (0.80) from a meta-analysis of the effect of BP lowering. For 20 mmHg SBP lowering, the average effect is almost twice as large, etc. 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/. BP = blood pressure; CVD = cardiovascular disease; ESC = European Society of Cardiology; HDL-C = high-density lipoprotein cholesterol; HR = hazard ratio; LIFE-CVD = LIFEtime-perspective CardioVascular Disease; N/A = not applicable; SBP = systolic blood pressure. ESC Guidelines 61
Table 18 Recommended office blood pressure target ranges. The first step in all groups is a reduction to systolic blood pressure <140 mmHg. The subsequent optimal goals are listed below.
Age group Office SBP treatment target ranges (mmHg) ...... Hypertension 1 DM 1 CKD 1 CAD 1 Stroke/TIA 18 2 69 years 120 130 120 130 <140 130 120 130 120 130 Lower SBP acceptable if tolerated