Advertisement

2016 European Guidelines on cardiovascular disease prevention in clinical practice

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

      Keywords

      Abbreviations and acronyms

      ABI
      ankle–brachial (blood pressure) index
      ABPM
      ambulatory blood pressure monitoring
      ACCORD
      Action to Control Cardiovascular Risk in Diabetes
      ACE-I
      angiotensin-converting enzyme inhibitor
      ACS
      acute coronary syndromes
      ADVANCE
      Action in Diabetes and Vascular disease: PreterAx and Diamicron MR Controlled Evaluation
      AF
      atrial fibrillation
      AMI
      acute myocardial infarction
      apoA1
      apolipoprotein A1
      apoB
      apolipoprotein B
      ARB
      angiotensin receptor blocker
      BEUC
      Bureau Européen des Unions de Consummateurs
      BMI
      body mass index (weight (kg)/height (m2))
      BP
      blood pressure
      CAC
      coronary artery calcium
      CAD
      coronary artery disease
      CAPRIE
      Clopidogrel versus Aspirin in Patients at Risk for Ischaemic Events
      CARDS
      Collaborative Atorvastatin Diabetes Study
      CHANCE
      Clopidogrel in High-risk patients with Acute Non-disabling Cerebrovascular Events
      CHARISMA
      Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilisation, Management, and Avoidance
      CI
      confidence interval
      CKD
      chronic kidney disease
      CR
      cardiac rehabilitation
      CT
      computed tomography
      CTT
      Cholesterol Treatment Trialists’ Collaboration
      CURE
      Clopidogrel vs. Placebo in Patients with ACS without ST-segment elevation
      CV
      cardiovascular
      CVD
      cardiovascular disease
      DALYs
      disability-adjusted life years
      DASH
      Dietary Approaches to Stop Hypertension
      DBP
      diastolic blood pressure
      DCCT
      Diabetes Control and Complications Trial
      DHA
      docosahexaenoic acid
      DM
      diabetes mellitus
      DPP-4
      dipeptidyl peptidase-4
      eGFR
      estimated glomerular filtration rate
      ECDA
      European Chronic Disease Alliance
      ECG
      electrocardiogram
      ED
      erectile dysfunction
      EHN
      European Heart Network
      EMA
      European Medicines Agency
      EPA
      eicosapentaenoic acid
      EPIC
      European Prospective Investigation into Cancer and Nutrition
      EPODE
      Ensemble Prévenons l’Obésité des Enfants
      ESC
      European Society of Cardiology
      EU
      European Union
      FDA
      Food and Drug Administration (USA)
      FDC
      fixed dose combination
      FH
      familial hypercholesterolaemia
      GLP-1
      glucagon-like peptide 1
      GP
      general practitioner
      GOSPEL
      Global Secondary Prevention Strategies to Limit Event Recurrence After Myocardial Infarction
      HbA1c
      glycated haemoglobin
      HBPM
      home blood pressure measurements
      HDL-C
      high-density lipoprotein cholesterol
      HF
      heart failure
      HF-ACTION
      Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training
      HOPE
      Heart Outcomes Prevention Evaluation
      HPS
      Heart Protection Study
      HRQoL
      health-related quality of life
      HR
      heart rate
      hsCRP
      high-sensitivity C-reactive protein
      HYVET
      Hypertension in the Very Elderly Trial
      ICD
      International Classification of Diseases
      IMT
      intima–media thickness
      INVEST
      International Verapamil-Trandolapril Study
      LDL-C
      low-density lipoprotein cholesterol
      Lp(a)
      lipoprotein(a)
      LV
      left ventricle/left ventricular
      LVH
      left ventricular hypertrophy
      MET
      metabolic equivalent
      MHO
      metabolically healthy overweight/obesity
      MI
      myocardial infarction
      MUFA
      monounsaturated fatty acids
      NGO
      non-governmental organization
      NHS
      National Health Service (UK)
      NICE
      National Institute for Health and Care Excellence
      NNT
      number needed to treat
      NRI
      net reclassification index
      NRT
      nicotine replacement therapy
      OASIS
      Organization to Assess Strategies in Acute Ischemic Syndromes
      ONTARGET
      ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial
      OSAS
      obstructive sleep apnoea syndrome
      OR
      odds ratio
      PA
      physical activity
      PAD
      peripheral artery disease
      PLATO
      Ticagrelor vs. Clopidogrel in Patients with ACS with and without ST-segment elevation
      PCOS
      polycystic ovary syndrome
      PCSK9
      proprotein convertase subtilisin/kexin type 9
      PROactive
      Prospective Pioglitazone Clinical Trial in Macrovascular Events
      PROGRESS
      Perindopril Protection Against Recurrent Stroke Study
      PROCAM
      Prospective Cardiovascular Munster Study
      PWV
      pulse wave velocity
      RA
      rheumatoid arthritis
      RCT
      randomized controlled trial
      RESPONSE
      Randomised Evaluation of Secondary Prevention by Outpatient Nurse Specialists
      RM
      repetition maximum
      ROS
      reactive oxygen species
      RPE
      rating of perceived exertion
      RR
      relative risk
      SAVOR-TIMI 53
      Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus –Trombolysis in Myocardial Infarction
      SBP
      systolic blood pressure
      SGLT2
      sodium-glucose co-transporter 2
      SNP
      single nucleotide polymorphism
      SCORE
      Systematic Coronary Risk Estimation
      SPARCL
      Stroke Prevention by Aggressive Reduction in Cholesterol Levels
      TIA
      transient ischaemic attack
      TRITON
      Prasugrel vs. Clopidogrel in Patients with ACS
      UKPDS
      United Kingdom Prospective Diabetes Study
      VADT
      Veterans Affairs Diabetes Trial
      VALUE
      Valsartan Antihypertensive Long-Term Use Evaluation
      VLDL
      very low-density lipoprotein
      VO2
      oxygen uptake
      WHO
      World Health Organization
      Tabled 1Classes of recommendations
      Table thumbnail fx1
      Tabled 1Level of evidence
      Table thumbnail fx2

      1. What is cardiovascular disease prevention?

      1.1 Definition and rationale

      Cardiovascular disease (CVD) prevention is defined as a coordinated set of actions, at the population level or targeted at an individual, that are aimed at eliminating or minimizing the impact of CVDs and their related disabilities.

      A Dictionary of Epidemiology. 4th ed. New York: Oxford University Press.

      CVD remains a leading cause of morbidity and mortality, despite improvements in outcomes. Age-adjusted coronary artery disease (CAD) mortality has declined since the 1980s, particularly in high-income regions.
      • Moran A.E.
      • Forouzanfar M.H.
      • Roth G.A.
      • Mensah G.A.
      • Ezzati M.
      • Murray C.J.
      • Naghavi M.
      Temporal trends in ischemic heart disease mortality in 21 world regions, 1980 to 2010: the Global Burden of Disease 2010 study.
      CAD rates are now less than half what they were in the early 1980s in many countries in Europe, due to preventive measures including the success of smoking legislation. However, inequalities between countries persist and many risk factors, particularly obesity
      • Finucane M.M.
      • Stevens G.A.
      • Cowan M.J.
      • Danaei G.
      • Lin J.K.
      • Paciorek C.J.
      • Singh G.M.
      • Gutierrez H.R.
      • Lu Y.
      • Bahalim A.N.
      • Farzadfar F.
      • Riley L.M.
      • Ezzati M.
      National, regional, and global trends in body-mass index since 1980: systematic analysis of health examination surveys and epidemiological studies with 960 country-years and 9.1 million participants.
      and diabetes mellitus (DM),
      • Danaei G.
      • Finucane M.M.
      • Lu Y.
      • Singh G.M.
      • Cowan M.J.
      • Paciorek C.J.
      • Lin J.K.
      • Farzadfar F.
      • Khang Y.H.
      • Stevens G.A.
      • Rao M.
      • Ali M.K.
      • Riley L.M.
      • Robinson C.A.
      • Ezzati M.
      National, regional, and global trends in fasting plasma glucose and diabetes prevalence since 1980: systematic analysis of health examination surveys and epidemiological studies with 370 country-years and 2.7 million participants.
      have been increasing substantially. If prevention was practised as instructed it would markedly reduce the prevalence would markedly reduce the of CVD. It is thus not only prevailing risk factors that are of concern, but poor implementation of preventive measures as well.
      • Kotseva K.
      • Wood D.
      • De Backer G.
      • De Bacquer D.
      • Pyorala K.
      • Reiner Z.
      • Keil U.
      • EUROASPIRE III,
      Management of cardiovascular risk factors in asymptomatic high-risk patients in general practice: cross-sectional survey in 12 European countries.
      • Kotseva K.
      • Wood D.
      • De Bacquer D.
      • De Backer G.
      • Ryden L.
      • Jennings C.
      • Gyberg V.
      • Amouyel P.
      • Bruthans J.
      • Castro Conde A.
      • Cifkova R.
      • Deckers J.W.
      • De Sutter J.
      • Dilic M.
      • Dolzhenko M.
      • Erglis A.
      • Fras Z.
      • Gaita D.
      • Gotcheva N.
      • Goudevenos J.
      • Heuschmann P.
      • Laucevicius A.
      • Lehto S.
      • Lovic D.
      • Milicic D.
      • Moore D.
      • Nicolaides E.
      • Oganov R.
      • Pajak A.
      • Pogosova N.
      • Reiner Z.
      • Stagmo M.
      • Stork S.
      • Tokgozoglu L.
      • Vulic D.
      EUROASPIRE IV: a European Society of Cardiology survey on the lifestyle, risk factor and therapeutic management of coronary patients from 24 European countries.
      Prevention should be delivered (i) at the general population level by promoting healthy lifestyle behaviour
      • Cooney M.T.
      • Dudina A.
      • Whincup P.
      • Capewell S.
      • Menotti A.
      • Jousilahti P.
      • Njolstad I.
      • Oganov R.
      • Thomsen T.
      • Tverdal A.
      • Wedel H.
      • Wilhelmsen L.
      • Graham I.
      Re-evaluating the Rose approach: comparative benefits of the population and high-risk preventive strategies.
      and (ii) at the individual level, i.e. in those subjects at moderate to high risk of CVD or patients with established CVD, by tackling unhealthy lifestyles (e.g. poor-quality diet, physical inactivity, smoking) and by optimising risk factors. Prevention is effective: the elimination of health risk behaviours would make it possible to prevent at least 80% of CVDs and even 40% of cancers.
      • Liu K.
      • Daviglus M.L.
      • Loria C.M.
      • Colangelo L.A.
      • Spring B.
      • Moller A.C.
      • Lloyd-Jones D.M.
      Healthy lifestyle through young adulthood and the presence of low cardiovascular disease risk profile in middle age: the Coronary Artery Risk Development in (Young) Adults (CARDIA) study.

      NICE Public Health Guidance 25. Prevention of Cardiovascular Disease. http://www.nice.org.uk/guidance/PH25.

      1.2 Development of the 6th Joint Task Force guidelines

      The present guidelines represent an evidence-based consensus of the 6th European Joint Task Force involving 10 professional societies.
      By appraising the current evidence and identifying remaining knowledge gaps in managing CVD prevention, the Task Force formulated recommendations to guide actions to prevent CVD in clinical practice. The Task Force followed the quality criteria for development of guidelines, which can be found at http://www.escardio.org/Guidelines-&-Education/Clinical-Practice-Guidelines/Guidelines-development/Writing-ESC-Guidelines. For simplification and in keeping with other European Society of Cardiology (ESC) guidelines, the ESC grading system based on classes of recommendation and levels of evidence has been maintained, recognising that this may be less suitable to measure the impact of prevention strategies, particularly those related to behavioural issues and population-based interventions.
      This document has been developed to support healthcare professionals communicating with individuals about their cardiovascular (CV) risk and the benefits of a healthy lifestyle and early modification of their CV risk. In addition, the guidelines provide tools for healthcare professionals to promote population-based strategies and integrate these into national or regional prevention frameworks and to translate these in locally delivered healthcare services, in line with the recommendations of the World Health Organization (WHO) global status report on non-communicable diseases 2010.
      • World Health Organization
      Global status report on non-communicable diseases.
      As in the present guidelines, the model presented in the previous document from the Fifth European Joint Task Force
      • Perk J.
      • De Backer G.
      • Gohlke H.
      • Graham I.
      • Reiner Z.
      • Verschuren M.
      • Albus C.
      • Benlian P.
      • Boysen G.
      • Cifkova R.
      • Deaton C.
      • Ebrahim S.
      • Fisher M.
      • Germano G.
      • Hobbs R.
      • Hoes A.
      • Karadeniz S.
      • Mezzani A.
      • Prescott E.
      • Ryden L.
      • Scherer M.
      • Syvanne M.
      • Scholte op Reimer W.J.
      • Vrints C.
      • Wood D.
      • Zamorano J.L.
      • Zannad F.
      European Guidelines on cardiovascular disease prevention in clinical practice (version 2012): the Fifth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of nine societies and by invited experts).
      has been structured around four core questions: (i) What is CVD prevention? (ii) Who will benefit from prevention? (iii) How to intervene? (iv) Where to intervene?
      Compared with the previous guidelines, greater emphasis has been placed on a population-based approach, on disease-specific interventions and on female-specific conditions, younger individuals and ethnic minorities. Due to space restrictions for the paper version, the chapter on disease-specific intervention is on the web, together with a few tables and figures for more detail see web addenda.
      A lifetime approach to CV risk is important since both CV risk and prevention are dynamic and continuous as patients age and/or accumulate co-morbidities. This implies that, apart from improving lifestyle and reducing risk factor levels in patients with established CVD and those at increased risk of developing CVD, healthy people of all ages should be encouraged to adopt a healthy lifestyle. Healthcare professionals play an important role in achieving this in their clinical practice.

      1.3 Cost-effectiveness of prevention

        Key messages

      • Prevention of CVD, either by implementation of lifestyle changes or use of medication, is cost effective in many scenarios, including population-based approaches and actions directed at high-risk individuals.
      • Cost-effectiveness depends on several factors, including baseline CV risk, cost of drugs or other interventions, reimbursement procedures and implementation of preventive strategies.
      Tabled 1Recommendation for cost-effective prevention of cardiovascular disease
      Table thumbnail fx3
      aClass of recommendation.bLevel of evidence.cReference(s) supporting recommendations.
      In 2009, costs related to CVD amounted to €106 billion, representing ∼9% of the total healthcare expenditure across the European Union (EU).
      • Nichols M.T.N.
      • Scarborough P.
      • Rayner P.
      Thus, CVD represents a considerable economic burden to society and effective preventive measures are necessary. There is consensus in favour of an approach combining strategies to improve CV health across the population at large from childhood onward, with specific actions to improve CV health in individuals at increased risk of CVD or with established CVD.
      Most studies assessing the cost-effectiveness of CVD prevention combine evidence from clinical research with simulation approaches, while cost-effectiveness data from randomized controlled trials (RCTs) are relatively scarce.
      • McConnachie A.
      • Walker A.
      • Robertson M.
      • Marchbank L.
      • Peacock J.
      • Packard C.J.
      • Cobbe S.M.
      • Ford I.
      Long-term impact on healthcare resource utilization of statin treatment, and its cost effectiveness in the primary prevention of cardiovascular disease: a record linkage study.
      • Mistry H.
      • Morris S.
      • Dyer M.
      • Kotseva K.
      • Wood D.
      • Buxton M.
      Cost-effectiveness of a European preventive cardiology programme in primary care: a Markov modelling approach.
      Cost-effectiveness strongly depends on parameters such as the target population’s age, the overall population risk of CVD and the cost of interventions. Hence, results obtained in one country may not be valid in another. Furthermore, changes such as the introduction of generic drugs can considerably change cost-effectiveness.
      • Plans-Rubio P.
      The cost effectiveness of statin therapies in Spain in 2010, after the introduction of generics and reference prices.
      According to the WHO, policy and environmental changes could reduce CVD in all countries for less than US$1/person/year.
      • World Health Organization
      Scaling up action agains noncommunicable diseases: how much will it cost?.
      A report from the National Institute for Health and Care Excellence (NICE) estimated that a UK national programme reducing population CV risk by 1% would prevent 25 000 CVD cases and generate savings of €40 million/year. CAD mortality rates could be halved by only modest risk factor reductions and it has been suggested that eight dietary priorities alone could halve CVD death.
      • Collins M.
      • Mason H.
      • O’Flaherty M.
      • Guzman-Castillo M.
      • Critchley J.
      • Capewell S.
      An economic evaluation of salt reduction policies to reduce coronary heart disease in England: a policy modeling study.
      In the last three decades, more than half of the reduction in CV mortality has been attributed to changes in risk factor levels in the population, primarily the reduction in cholesterol and blood pressure (BP) levels and smoking. This favourable trend is partly offset by an increase in other risk factors, mainly obesity and type 2 DM.
      • Mason H.
      • Shoaibi A.
      • Ghandour R.
      • O’Flaherty M.
      • Capewell S.
      • Khatib R.
      • Jabr S.
      • Unal B.
      • Sozmen K.
      • Arfa C.
      • Aissi W.
      • Ben Romdhane H.
      • Fouad F.
      • Al-Ali R.
      • Husseini A.
      • MedCHAMPS project team
      A cost effectiveness analysis of salt reduction policies to reduce coronary heart disease in four Eastern Mediterranean countries.
      • O’Keeffe C.
      • Kabir Z.
      • O’Flaherty M.
      • Walton J.
      • Capewell S.
      • Perry I.J.
      Modelling the impact of specific food policy options on coronary heart disease and stroke deaths in Ireland.
      Aging of the population also increases CVD events.
      • Roth G.A.
      • Forouzanfar M.H.
      • Moran A.E.
      • Barber R.
      • Nguyen G.
      • Feigin V.L.
      • Naghavi M.
      • Mensah G.A.
      • Murray C.J.
      Demographic and epidemiologic drivers of global cardiovascular mortality.
      Several population interventions have efficiently modified the lifestyle of individuals. For example, increased awareness of how healthy lifestyles prevent CVD has helped to reduce smoking and cholesterol levels. Lifestyle interventions act on several CV risk factors and should be applied prior to or in conjunction with drug therapies. Also, legislation aimed at decreasing salt and the trans fatty acid content of foods and smoking habits is cost effective in preventing CVD.
      • Cobiac L.J.
      • Magnus A.
      • Lim S.
      • Barendregt J.J.
      • Carter R.
      • Vos T.
      Which interventions offer best value for money in primary prevention of cardiovascular disease?.
      • Collins M.
      • Mason H.
      • O’Flaherty M.
      • Guzman-Castillo M.
      • Critchley J.
      • Capewell S.
      An economic evaluation of salt reduction policies to reduce coronary heart disease in England: a policy modeling study.
      • Mason H.
      • Shoaibi A.
      • Ghandour R.
      • O’Flaherty M.
      • Capewell S.
      • Khatib R.
      • Jabr S.
      • Unal B.
      • Sozmen K.
      • Arfa C.
      • Aissi W.
      • Ben Romdhane H.
      • Fouad F.
      • Al-Ali R.
      • Husseini A.
      • MedCHAMPS project team
      A cost effectiveness analysis of salt reduction policies to reduce coronary heart disease in four Eastern Mediterranean countries.
      Cholesterol lowering using statins
      • McConnachie A.
      • Walker A.
      • Robertson M.
      • Marchbank L.
      • Peacock J.
      • Packard C.J.
      • Cobbe S.M.
      • Ford I.
      Long-term impact on healthcare resource utilization of statin treatment, and its cost effectiveness in the primary prevention of cardiovascular disease: a record linkage study.
      • Mistry H.
      • Morris S.
      • Dyer M.
      • Kotseva K.
      • Wood D.
      • Buxton M.
      Cost-effectiveness of a European preventive cardiology programme in primary care: a Markov modelling approach.
      and improvement in BP control are cost effective if targeted at persons with high CV risk.
      • Pereira M.
      • Azevedo A.
      • Lunet N.
      • Carreira H.
      • O’Flaherty M.
      • Capewell S.
      • Bennett K.
      Explaining the decline in coronary heart disease mortality in Portugal between 1995 and 2008.
      Importantly, a sizable portion of patients on lipid-lowering or BP-lowering drug treatment fails to take their treatment adequately or to reach therapeutic goals,
      • Banegas J.R.
      • Lopez-Garcia E.
      • Dallongeville J.
      • Guallar E.
      • Halcox J.P.
      • Borghi C.
      • Masso-Gonzalez E.L.
      • Jimenez F.J.
      • Perk J.
      • Steg P.G.
      • De Backer G.
      • Rodriguez-Artalejo F.
      Achievement of treatment goals for primary prevention of cardiovascular disease in clinical practice across Europe: the EURIKA study.
      • De Smedt D.
      • Kotseva K.
      • De Bacquer D.
      • Wood D.
      • De Backer G.
      • Dallongeville J.
      • Seppo L.
      • Pajak A.
      • Reiner Z.
      • Vanuzzo D.
      • Georgiev B.
      • Gotcheva N.
      • Annemans L.
      Cost-effectiveness of optimizing prevention in patients with coronary heart disease: the EUROASPIRE III health economics project.
      with clinical and economic consequences.

        Gap in evidence

      • Most cost-effectiveness studies rely on simulation. More data, mainly from RCTs, are needed.

      2. Who will benefit from prevention? When and how to assess risk and prioritize

      2.1 Estimation of total cardiovascular risk

      All current guidelines on the prevention of CVD in clinical practice recommend the assessment of total CVD risk since atherosclerosis is usually the product of a number of risk factors. Prevention of CVD in an individual should be adapted to his or her total CV risk: the higher the risk, the more intense the action should be.
      The importance of total risk estimation in apparently healthy people before management decisions are made is illustrated in supplementary Figure A (see web addenda) and in Table 1 derived from the high-risk Systemic Coronary Risk Estimation (SCORE) chart (http://www.escardio.org/Guidelines-&-Education/Practice-tools/ CVD-prevention-toolbox/SCORE-Risk-Charts). This shows that a person with a cholesterol level of 7 mmol/L can be at 10 times lower risk than someone with a cholesterol level of 5 mmol/L if the former is a female and the latter is a male hypertensive smoker.
      Table 1Impact of combinations of risk factors on risk
      Table thumbnail fx4
      CVD = cardiovascular disease; F = female; M = male; SBP = systolic blood pressure.
      A recent meta-analysis on CV risk reduction by treatment with BP-lowering drugs does, however, support the concept that absolute risk reduction is larger in those individuals at higher baseline risk.
      • Blood Pressure Lowering Treatment Trialists’ Collaboration
      • Sundstrom J.
      • Arima H.
      • Woodward M.
      • Jackson R.
      • Karmali K.
      • Lloyd-Jones D.
      • Baigent C.
      • Emberson J.
      • Rahimi K.
      • MacMahon S.
      • Patel A.
      • Perkovic V.
      • Turnbull F.
      • Neal B.
      Blood pressure-lowering treatment based on cardiovascular risk: a meta-analysis of individual patient data.
      This was confirmed in a further meta-analysis that also showed a greater residual risk during treatment in those at higher baseline risk, supporting earlier intervention.
      • Thomopoulos C.
      • Parati G.
      • Zanchetti A.
      Effects of blood pressure lowering on outcome incidence in hypertension: 3. Effects in patients at different levels of cardiovascular risk—overview and meta-analyses of randomized trials.
      • Thomopoulos C.
      • Parati G.
      • Zanchetti A.
      Effects of blood pressure lowering on outcome incidence in hypertension: 2. Effects at different baseline and achieved blood pressure levels—overview and meta-analyses of randomized trials.
      Although clinicians often ask for decisional thresholds to trigger intervention, this is problematic since risk is a continuum and there is no exact point above which, for example, a drug is automatically indicated nor below which lifestyle advice may not usefully be offered.
      The risk categories presented later in this section are to assist the physician in dealing with individual people. They acknowledge that although individuals at the highest levels of riskgain most from risk factor interventions, most deaths in a community come from those at lower levels of risk, simply because they are more numerous compared with high-risk individuals. Thus a strategy for individuals at high risk must be complemented by public health measures to encourage a healthy lifestyle and to reduce population levels of CV risk factors.
      It is essential for clinicians to be able to assess CV risk rapidly and with sufficient accuracy. This realization led to the development of the risk chart used in the 1994 and 1998 Guidelines. This chart, developed from a concept pioneered by Anderson,
      • Anderson K.M.
      • Odell P.M.
      • Wilson P.W.
      • Kannel W.B.
      Cardiovascular disease risk profiles.
      used age, sex, smoking status, blood cholesterol and systolic BP (SBP) to estimate the 10- year risk of a first fatal or non-fatal CAD event. There were several problems with this chart, which are outlined in the Fourth Joint European Guidelines on prevention.
      • Perk J.
      • De Backer G.
      • Gohlke H.
      • Graham I.
      • Reiner Z.
      • Verschuren M.
      • Albus C.
      • Benlian P.
      • Boysen G.
      • Cifkova R.
      • Deaton C.
      • Ebrahim S.
      • Fisher M.
      • Germano G.
      • Hobbs R.
      • Hoes A.
      • Karadeniz S.
      • Mezzani A.
      • Prescott E.
      • Ryden L.
      • Scherer M.
      • Syvanne M.
      • Scholte op Reimer W.J.
      • Vrints C.
      • Wood D.
      • Zamorano J.L.
      • Zannad F.
      European Guidelines on cardiovascular disease prevention in clinical practice (version 2012): the Fifth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of nine societies and by invited experts).
      • Graham I.
      • Atar D.
      • Borch-Johnsen K.
      • Boysen G.
      • Burell G.
      • Cifkova R.
      • Dallongeville J.
      • De Backer G.
      • Ebrahim S.
      • Gjelsvik B.
      • Herrmann-Lingen C.
      • Hoes A.
      • Humphries S.
      • Knapton M.
      • Perk J.
      • Priori S.G.
      • Pyorala K.
      • Reiner Z.
      • Ruilope L.
      • Sans-Menendez S.
      • Op Reimer W.S.
      • Weissberg P.
      • Wood D.
      • Yarnell J.
      • Zamorano J.L.
      • Walma E.
      • Fitzgerald T.
      • Cooney M.T.
      • Dudina A.
      • Vahanian A.
      • Camm J.
      • De Caterina R.
      • Dean V.
      • Dickstein K.
      • Funck-Brentano C.
      • Filippatos G.
      • Hellemans I.
      • Kristensen S.D.
      • McGregor K.
      • Sechtem U.
      • Silber S.
      • Tendera M.
      • Widimsky P.
      • Zamorano J.L.
      • Altiner A.
      • Bonora E.
      • Durrington P.N.
      • Fagard R.
      • Giampaoli S.
      • Hemingway H.
      • Hakansson J.
      • Kjeldsen S.E.
      • Larsen M.L.
      • Mancia G.
      • Manolis A.J.
      • Orth-Gomer K.
      • Pedersen T.
      • Rayner M.
      • Ryden L.
      • Sammut M.
      • Schneiderman N.
      • Stalenhoef A.F.
      • Tokgozoglu L.
      • Wiklund O.
      • Zampelas A.
      European guidelines on cardiovascular disease prevention in clinical practice: full text. Fourth Joint Task Force of the European Society of Cardiology and other societies on cardiovascular disease prevention in clinical practice (constituted by representatives of nine societies and by invited experts).
      This led to the presently recommended SCORE system, estimating an individual’s 10 year risk of fatal CVD.
      • Conroy R.M.
      • Pyorala K.
      • Fitzgerald A.P.
      • Sans S.
      • Menotti A.
      • De Backer G.
      • De Bacquer D.
      • Ducimetiere P.
      • Jousilahti P.
      • Keil U.
      • Njolstad I.
      • Oganov R.G.
      • Thomsen T.
      • Tunstall-Pedoe H.
      • Tverdal A.
      • Wedel H.
      • Whincup P.
      • Wilhelmsen L.
      • Graham I.M.
      Estimation of ten-year risk of fatal cardiovascular disease in Europe: the SCORE project.
      The SCORE charts have been developed to estimate risk in both high- and low-risk European populations; its applicability to non-Caucasian populations has not been examined.

      2.2 When to assess total cardiovascular risk?

      Tabled 1Recommendations for cardiovascular risk assessment
      Table thumbnail fx5
      BP = blood pressure; CV = cardiovascular; CVD = cardiovascular disease; DM = diabetes mellitus.aClass of recommendation.bLevel of evidence.
      Screening is the identification of unrecognized disease or, in this case, of an unknown increased risk of CVD in individuals without symptoms. CV risk assessment or screening can be done opportunistically or systematically. Opportunistic screening means without a predefined strategy, but is done when the opportunity arises [e.g. when the individual is consulting his or her general practitioner (GP) for some other reason]. Systematic screening can be done in the general population as part of a screening programme or in targeted subpopulations, such as subjects with a family history of premature CVD or familial hyperlipidaemia.
      While the ideal scenario would be for all adults to have their risk assessed, this is not practical in many societies. The decision about who to screen must be made by individual countries and will be resource dependent.
      In a meta-analysis, GP-based health checks on cholesterol, BP, body mass index (BMI) and smoking were effective in improving surrogate outcomes, especially in high-risk patients.
      • Si S.
      • Moss J.R.
      • Sullivan T.R.
      • Newton S.S.
      • Stocks N.P.
      Effectiveness of general practice-based health checks: a systematic review and meta-analysis.
      A large study of CV risk assessment in the general population found that although there were overall improvements in risk factors, there was no impact on CV outcomes at the population level.
      • Jorgensen T.
      • Jacobsen R.K.
      • Toft U.
      • Aadahl M.
      • Glumer C.
      • Pisinger C.
      Effect of screening and lifestyle counselling on incidence of ischaemic heart disease in general population: Inter99 randomised trial.
      A Cochrane review of RCTs using counselling or education to modify CV risk factors in adults from the general population, occupational groups or those with specific risk factors (i.e. DM, hypertension) concluded that risk factor improvements were modest and interventions did not reduce total or CV mortality in general populations, but reduced mortality in high-risk hypertensive and DM populations.
      • Ebrahim S.
      • Taylor F.
      • Ward K.
      • Beswick A.
      • Burke M.
      • Davey Smith G.
      Multiple risk factor interventions for primary prevention of coronary heart disease.
      Although the benefits of treating asymptomatic conditions such as hypertension, DM and dyslipidaemia on morbidity and mortality outcomes have been documented, a Cochrane review of the existing trials concluded that general health checks (including screening for these conditions) do not reduce all-cause or CV morbidity or mortality.
      • Krogsboll L.T.
      • Jorgensen K.J.
      • Gronhoj Larsen C.
      • Gotzsche P.C.
      General health checks in adults for reducing morbidity and mortality from disease.
      However, most studies were performed three to four decades ago, and thus risk factor interventions were not contemporary. Perhaps application of medical treatment in addition to the lifestyle interventions that were the core component of most trials would improve efficacy.
      Most guidelines recommend a mixture of opportunistic and systematic screening.
      • Perk J.
      • De Backer G.
      • Gohlke H.
      • Graham I.
      • Reiner Z.
      • Verschuren M.
      • Albus C.
      • Benlian P.
      • Boysen G.
      • Cifkova R.
      • Deaton C.
      • Ebrahim S.
      • Fisher M.
      • Germano G.
      • Hobbs R.
      • Hoes A.
      • Karadeniz S.
      • Mezzani A.
      • Prescott E.
      • Ryden L.
      • Scherer M.
      • Syvanne M.
      • Scholte op Reimer W.J.
      • Vrints C.
      • Wood D.
      • Zamorano J.L.
      • Zannad F.
      European Guidelines on cardiovascular disease prevention in clinical practice (version 2012): the Fifth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of nine societies and by invited experts).
      • National Institute for Health and Care Excellence
      Lipid Modification: Cardiovascular Risk Assessment and the Modification of Blood Lipids for the Primary and Secondary Prevention of Cardiovascular Disease.
      • Scottish Intercollegiate Guidelines Network
      Risk estimation and the prevention of cardiovascular disease. A national clinical guideline.
      • European Association for Cardiovascular Prevention & Rehabilitation
      • Reiner Z.
      • Catapano A.L.
      • De Backer G.
      • Graham I.
      • Taskinen M.R.
      • Wiklund O.
      • Agewall S.
      • Alegria E.
      • Chapman M.J.
      • Durrington P.
      • Erdine S.
      • Halcox J.
      • Hobbs R.
      • Kjekshus J.
      • Filardi P.P.
      • Riccardi G.
      • Storey R.F.
      • Wood D.
      ESC/EAS Guidelines for the management of dyslipidaemias: the Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) the European Atherosclerosis Society (EAS).
      Screening in people at relatively low risk of CVD is not particularly effective in reducing the risk of CV events. The costs of such screening interventions are high and these resources may be better used in people at higher CV risk or with established CVD. In many countries, GPs have a unique role in identifying individuals at risk of but without established CVD and assessing their eligibility for intervention (see section 4a.1.1). A modelling study based on the European Prospective Investigation of Cancer–Norfolk (EPIC-Norfolk) cohort data concluded that, compared with the National Health Service (NHS) national strategy to screen all adults 40–74 years of age for CV risk, inviting the 60% of the population at the highest risk according to an integrated risk score was equally effective in preventing new cases of CVD and had potential cost savings.
      • Chamnan P.
      • Simmons R.K.
      • Khaw K.T.
      • Wareham N.J.
      • Griffin S.J.
      Estimating the population impact of screening strategies for identifying and treating people at high risk of cardiovascular disease: modelling study.
      A general concern in screening, including CV risk assessment, is its potential to do harm. False positive results can cause unnecessary concern and medical treatment. Conversely, false negative results may lead to inappropriate reassurance and a lack of lifestyle changes. However, current data suggest that participating in CV screening in general does not cause worry in those who are screened.
      • Nielsen A.D.
      • Videbech P.
      • Gerke O.
      • Petersen H.
      • Jensen J.M.
      • Sand N.P.
      • Egstrup K.
      • Larsen M.L.
      • Mickley H.
      • Diederichsen A.C.
      Population screening for coronary artery calcification does not increase mental distress and the use of psychoactive medication.
      • Christensen B.
      • Engberg M.
      • Lauritzen T.
      No long-term psychological reaction to information about increased risk of coronary heart disease in general practice.
      • Lokkegaard T.
      • Andersen J.S.
      • Jacobsen R.K.
      • Badsberg J.H.
      • Jorgensen T.
      • Pisinger C.
      Psychological consequences of screening for cardiovascular risk factors in an un-selected general population: results from the Inter99 randomised intervention study.
      • Jorgensen T.
      • Ladelund S.
      • Borch-Johnsen K.
      • Pisinger C.
      • Schrader A.M.
      • Thomsen T.
      • Glumer C.
      • Ibsen H.
      • Mortensen E.L.
      Screening for risk of cardiovascular disease is not associated with mental distress: the Inter99 study.
      More research is needed on how certain subgroups, such as older people, the socially deprived and ethnic minorities, react to screening.
      Despite limited evidence, these guidelines recommend a systematic approach to CV risk assessment targeting populations likely to be at higher CV risk, such as those with a family history of premature CVD. Thus systematic CV risk assessment in men <40 years of age and women <50 years of age with no known CV risk factors is not recommended. Additionally, screening of specific groups with jobs that place other people at risk, e.g. bus drivers and pilots, may be reasonable, as is screening for CV risk factors in women before prescribing combined oral contraception, although there are no data to support the beneficial effects. Beyond this, systematic CV risk assessment in adults <40 years of age with no known CV risk factors is not recommended as a main strategy due to the low cost-effectiveness. Systematic CV assessment may be considered in adult men >40 years of age and in women >50 years of age or post-menopausal with no known CV risk factors. Risk assessment is not a one-time event; it should be repeated, for example, every 5 years.

      2.3 How to estimate total cardiovascular risk?

        Key messages

      • In apparently healthy persons, CV risk in general is the result of multiple, interacting risk factors. This is the basis for the total CV risk approach to prevention.
      • SCORE, which estimates the 10 year risk of fatal CVD, is recommended for risk assessment and can assist in making logical management decisions and may help to avoid both under- and overtreatment. Validated local risk estimation systems are useful alternatives to SCORE.
      • Individuals automatically at high to very high CV risk (Table 5) do not need the use of a risk score and require immediate attention to risk factors.
      • In younger persons, a low absolute risk may conceal a very high relative risk and use of the relative risk chart or calculation of their “risk age” may help in advising them of the need for intensive preventive efforts.
      • While women are at lower CV risk than men, their risk is deferred by ∼10 years rather than avoided.
      • The total risk approach allows flexibility; if perfection cannot be achieved with one risk factor, trying harder with others can still reduce risk.
      Tabled 1Recommendation for how to estimate cardiovascular risk
      Table thumbnail fx6
      CV = cardiovascular; DM = diabetes mellitus; SCORE = Systematic Coronary Risk Estimation.aClass of recommendation.bLevel of evidence.cReference(s) supporting recommendations.

      2.3.1 Ten-year cardiovascular risk

      Many CV risk assessment systems are available for use in apparently healthy individuals (Table 2), including Framingham,
      • RBSr D’Agostino
      • Vasan R.S.
      • Pencina M.J.
      • Wolf P.A.
      • Cobain M.
      • Massaro J.M.
      • Kannel W.B.
      General cardiovascular risk profile for use in primary care: the Framingham Heart Study.
      SCORE,
      • Conroy R.M.
      • Pyorala K.
      • Fitzgerald A.P.
      • Sans S.
      • Menotti A.
      • De Backer G.
      • De Bacquer D.
      • Ducimetiere P.
      • Jousilahti P.
      • Keil U.
      • Njolstad I.
      • Oganov R.G.
      • Thomsen T.
      • Tunstall-Pedoe H.
      • Tverdal A.
      • Wedel H.
      • Whincup P.
      • Wilhelmsen L.
      • Graham I.M.
      Estimation of ten-year risk of fatal cardiovascular disease in Europe: the SCORE project.
      ASSIGN (CV risk estimation model from the Scottish Intercollegiate Guidelines Network),
      • Woodward M.
      • Brindle P.
      • Tunstall-Pedoe H.
      Adding social deprivation and family history to cardiovascular risk assessment: the ASSIGN score from the Scottish Heart Health Extended Cohort (SHHEC).
      Q-Risk,
      • Hippisley-Cox J.
      • Coupland C.
      • Vinogradova Y.
      • Robson J.
      • May M.
      • Brindle P.
      Derivation and validation of QRISK, a new cardiovascular disease risk score for the United Kingdom: prospective open cohort study.
      • Hippisley-Cox J.
      • Coupland C.
      • Vinogradova Y.
      • Robson J.
      • Minhas R.
      • Sheikh A.
      • Brindle P.
      Predicting cardiovascular risk in England and Wales: prospective derivation and validation of QRISK2.
      PROCAM (Prospective Cardiovascular Munster Study),
      • Assmann G.
      • Cullen P.
      • Schulte H.
      Simple scoring scheme for calculating the risk of acute coronary events based on the 10-year follow-up of the prospective cardiovascular Munster (PROCAM) study.
      CUORE,
      • Giampaoli S.
      CUORE: a sustainable cardiovascular disease prevention strategy.
      the Pooled Cohort equations,
      • Goff Jr., D.C.
      • Lloyd-Jones D.M.
      • Bennett G.
      • Coady S.
      • RBSr D’Agostino
      • Gibbons R.
      • Greenland P.
      • Lackland D.T.
      • Levy D.
      • O’Donnell C.J.
      • Robinson J.G.
      • Schwartz J.S.
      • Shero S.T.
      • Smith Jr., S.C.
      • Sorlie P.
      • Stone N.J.
      • Wilson P.W.
      2013 ACC/AHA guideline on the assessment of cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.
      Arriba
      • Krones T.
      • Keller H.
      • Sonnichsen A.
      • Sadowski E.M.
      • Baum E.
      • Wegscheider K.
      • Rochon J.
      • Donner-Banzhoff N.
      Absolute cardiovascular disease risk and shared decision making in primary care: a randomized controlled trial.
      and Globorisk.
      • Hajifathalian K.
      • Ueda P.
      • Lu Y.
      • Woodward M.
      • Ahmadvand A.
      • Aguilar-Salinas C.A.
      • Azizi F.
      • Cifkova R.
      • Di Cesare M.
      • Eriksen L.
      • Farzadfar F.
      • Ikeda N.
      • Khalili D.
      • Khang Y.H.
      • Lanska V.
      • Leon-Munoz L.
      • Magliano D.
      • Msyamboza K.P.
      • Oh K.
      • Rodriguez-Artalejo F.
      • Rojas-Martinez R.
      • Shaw J.E.
      • Stevens G.A.
      • Tolstrup J.
      • Zhou B.
      • Salomon J.A.
      • Ezzati M.
      • Danaei G.
      A novel risk score to predict cardiovascular disease risk in national populations (Globorisk): a pooled analysis of prospective cohorts and health examination surveys.
      In practice, most risk estimation systems perform rather similarly when applied to populations recognizably comparable to those from which the risk estimation system was derived. Since 2003, the European Guidelines on CVD prevention in clinical practice recommend use of the SCORE system, because it is based on large, representative European cohort datasets. The SCORE risk function has been externally validated.
      • Aktas M.K.
      • Ozduran V.
      • Pothier C.E.
      • Lang R.
      • Lauer M.S.
      Global risk scores and exercise testing for predicting all-cause mortality in a preventive medicine program.
      Table 2Current cardiovascular disease risk estimation systems for use in apparently healthy persons, updated from
      • Cooney M.T.
      • Dudina A.
      • D’Agostino R.
      • Graham I.M.
      Cardiovascular risk-estimation systems in primary prevention: do they differ? Do they make a difference? Can we see the future?.
      • Cooney M.T.
      • Dudina A.L.
      • Graham I.M.
      Value and limitations of existing scores for the assessment of cardiovascular risk: a review for clinicians.
      Table thumbnail fx7a
      ACC = American College of Cardiology; AHA = American Heart Association; ARIC = Atherosclerosis Risk in Communities; ATP = Adult Treatment Panel; BMI = body mass index; BP = blood pressure; CAD = coronary artery disease; CARDIA = Coronary Artery Risk Development in Young Adults; CHS = Cardiovascular Health Study; CVD = cardiovascular disease; DM = diabetes mellitus; HDL-C = high-density lipoprotein cholesterol; J BS = Joint British Societies; LDL-C = low-density lipoprotein cholesterol; NCEP = National Cholesterol Education Program; NICE = National Institute for Health and Care Excellence; no. cigs = number of cigarettes; PROCAM = Prospective Cardiovascular Munster Study; SBP = systolic blood pressure; SIGN = Scottish Intercollegiate Guidelines Network; SHHEC = Scottish Heart Health Extended Cohort.
      Table 3 lists the advantages of the SCORE risk charts.
      Table 3Advantages and limitations in using the SCORE risk charts
      Table thumbnail fx8
      CVD = cardiovascular disease; SCORE = Systematic Coronary Risk Estimation.
      The SCORE system estimates the 10 year risk of a first fatal atherosclerotic event. All International Classification of Diseases (ICD) codes that could reasonably be assumed to be atherosclerotic are included, including CAD, stroke and aneurysm of the abdominal aorta. Traditionally most systems estimated CAD risk only; however, more recently a number of risk estimation systems have changed to estimate the risk of all CVDs.
      • RBSr D’Agostino
      • Vasan R.S.
      • Pencina M.J.
      • Wolf P.A.
      • Cobain M.
      • Massaro J.M.
      • Kannel W.B.
      General cardiovascular risk profile for use in primary care: the Framingham Heart Study.
      • Hippisley-Cox J.
      • Coupland C.
      • Vinogradova Y.
      • Robson J.
      • Minhas R.
      • Sheikh A.
      • Brindle P.
      Predicting cardiovascular risk in England and Wales: prospective derivation and validation of QRISK2.
      • Goff Jr., D.C.
      • Lloyd-Jones D.M.
      • Bennett G.
      • Coady S.
      • RBSr D’Agostino
      • Gibbons R.
      • Greenland P.
      • Lackland D.T.
      • Levy D.
      • O’Donnell C.J.
      • Robinson J.G.
      • Schwartz J.S.
      • Shero S.T.
      • Smith Jr., S.C.
      • Sorlie P.
      • Stone N.J.
      • Wilson P.W.
      2013 ACC/AHA guideline on the assessment of cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.
      • Board J.B.S.
      Joint British Societies’ consensus recommendations for the prevention of cardiovascular disease (JBS3).
      The choice of CV mortality rather than total (fatal plus non-fatal) events was deliberate, although not universally popular. Non-fatal event rates are critically dependent upon definitions and the methods used in their ascertainment. Critically, the use of mortality allows recalibration to allow for time trends in CV mortality. Any risk estimation system will overpredict in countries in which mortality has fallen and underpredict in those in which it has risen. Recalibration to allow for secular changes can be undertaken if good quality, up-to-date mortality and risk factor prevalence data are available. Data quality does not permit this for non-fatal events. For these reasons, the CV mortality charts were produced and have been recalibrated for a number of European countries.
      Naturally, the risk of total fatal and non-fatal events is higher, and clinicians frequently ask for this to be quantified. The SCORE data indicate that the total CV event risk is about three times higher than the risk of fatal CVD for men, so that a SCORE risk of fatal CVD of 5% translates into a fatal plus non-fatal CV risk of ∼15%; the multiplier is about four in women and somewhat lower than three in older persons, in whom a first event is more likely to be fatal.
      • van Dis I.
      • Geleijnse J.M.
      • Boer J.M.
      • Kromhout D.
      • Boshuizen H.
      • Grobbee D.E.
      • van der Schouw Y.T.
      • Verschuren W.M.
      Effect of including nonfatal events in cardiovascular risk estimation, illustrated with data from The Netherlands.
      As noted in the introduction, thresholds to trigger certain interventions are problematic since risk is a continuum and there is no threshold at which, for example, a drug is automatically indicated. Obviously, decisions on whether treatment is initiated should also be based on patient preferences.
      A particular problem relates to young people with high levels of risk factors, where a low absolute risk may conceal a very high relative risk requiring intensive lifestyle advice. Several approaches to communicating about risk to younger people are presented below (refer also to section 2.5.1). These include use of the relative risk chart or ’risk age’ or ’lifetime risk’. The aim is to communicate that lifestyle changes can reduce the relative risk substantially as well as reduce the increase in risk that occurs with ageing.
      Another problem relates to older people. In some age categories, the vast majority, especially of men, will have estimated CV death risks exceeding the 5–10% level, based on age (and gender) only, even when other CV risk factor levels are low. This could lead to excessive use of drugs in the elderly. This issue is dealt with later (see section 2.3.5). It should be noted that RCT evidence to guide drug treatments in older persons is limited (refer to section 2.5.2).
      The role of high-density lipoprotein cholesterol (HDL-C) in risk estimation has been systematically re-examined using the SCORE database.
      • Pyorala K.
      • De Backer G.
      • Graham I.
      • Poole-Wilson P.
      • Wood D.
      Prevention of coronary heart disease in clinical practice. Recommendations of the Task Force of the European Society of Cardiology, European Atherosclerosis Society and European Society of Hypertension.
      • Cooney M.T.
      • Dudina A.
      • De Bacquer D.
      • Fitzgerald A.
      • Conroy R.
      • Sans S.
      • Menotti A.
      • De Backer G.
      • Jousilahti P.
      • Keil U.
      • Thomsen T.
      • Whincup P.
      • Graham I.
      How much does HDL cholesterol add to risk estimation? A report from the SCORE Investigators.
      • Cooney M.T.
      • Dudina A.
      • De Bacquer D.
      • Wilhelmsen L.
      • Sans S.
      • Menotti A.
      • De Backer G.
      • Jousilahti P.
      • Keil U.
      • Thomsen T.
      • Whincup P.
      • Graham I.M.
      HDL cholesterol protects against cardiovascular disease in both genders, at all ages and at all levels of risk.
      Overall HDL-C has a modest but useful effect in redefining risk estimation,
      • Cooney M.T.
      • Dudina A.
      • De Bacquer D.
      • Fitzgerald A.
      • Conroy R.
      • Sans S.
      • Menotti A.
      • De Backer G.
      • Jousilahti P.
      • Keil U.
      • Thomsen T.
      • Whincup P.
      • Graham I.
      How much does HDL cholesterol add to risk estimation? A report from the SCORE Investigators.
      • Cooney M.T.
      • Dudina A.
      • De Bacquer D.
      • Wilhelmsen L.
      • Sans S.
      • Menotti A.
      • De Backer G.
      • Jousilahti P.
      • Keil U.
      • Thomsen T.
      • Whincup P.
      • Graham I.M.
      HDL cholesterol protects against cardiovascular disease in both genders, at all ages and at all levels of risk.
      but this may not be seen in some low-risk populations.
      • Mortensen M.B.
      • Afzal S.
      • Nordestgaard B.G.
      • Falk E.
      The high-density lipoprotein-adjusted SCORE model worsens SCORE-based risk classification in a contemporary population of 30,824 Europeans: the Copenhagen General Population Study.
      Assessing HDL-C is particularly important at levels of risk just below the threshold for intensive risk modification of 5%, where many of these subjects will qualify for intensive advice if their HDL-C is low.
      • Cooney M.T.
      • Dudina A.
      • De Bacquer D.
      • Fitzgerald A.
      • Conroy R.
      • Sans S.
      • Menotti A.
      • De Backer G.
      • Jousilahti P.
      • Keil U.
      • Thomsen T.
      • Whincup P.
      • Graham I.
      How much does HDL cholesterol add to risk estimation? A report from the SCORE Investigators.
      SCORE charts incorporating HDL-C are illustrated in supplementary Figures B-I (see web addenda). In these charts, HDL-C is used categorically. The electronic version of SCORE, HeartScore (http://www.HeartScore.org), has been modified to take HDL-C into account on a continuous basis and is therefore more accurate.
      The role of a plasma triglyceride as a predictor of CVD has been debated for many years. Fasting triglycerides relate to risk in univariable analyses, but the effect is attenuated by adjustment for other factors, especially HDL-C.
      • Emerging Risk Factors Collaboration
      • Di Angelantonio E.
      • Sarwar N.
      • Perry P.
      • Kaptoge S.
      • Ray K.K.
      • Thompson A.
      • Wood A.M.
      • Lewington S.
      • Sattar N.
      • Packard C.J.
      • Collins R.
      • Thompson S.G.
      • Danesh J.
      Major ipids, apolipoproteins,and risk of vascular disease.
      Dealing with the impact of additional risk factors such as body weight, family history and newer risk markers is difficult within the constraint of a paper chart. It should be stressed, however, that although many other risk factors have been identified, their contribution is generally very modest to both absolute CV risk estimations and in terms of reclassification of an individual to another risk category
      • Wilson P.W.
      • Pencina M.
      • Jacques P.
      • Selhub J.
      • D’Agostino RSr O’Donnell CJ.
      C-reactive protein and reclassification of cardiovascular risk in the Framingham Heart Study.
      Table 4.
      Table 4Examples of risk modifiers that are likely to have reclassification potential (see following sections for
      Table thumbnail fx9
      ABI = ankle-brachial blood pressure index; BMI = body mass index; CVD = cardiovascular disease; CT = computed tomography.
      The SCORE risk charts are shown in Figure 1, Figure 2, Figure 3, Figure 4, including a chart of relative risks (Figure 3). Instructions on their use follow.
      Figure thumbnail gr1
      Figure 1SCORE chart: 10-year risk of fatal cardiovascular disease in populations of countries at high cardiovascular risk based on the following risk factors: age, sex, smoking, systolic blood pressure, total cholesterol. CVD = cardiovascular disease; SCORE = Systematic Coronary Risk Estimation.
      Figure thumbnail gr2
      Figure 2SCORE chart: 10-year risk of fatal cardiovascular disease in populations of countries at low cardiovascular risk based on the following risk factors: age, sex, smoking, systolic blood pressure, total cholesterol. CVD = cardiovascular disease; SCORE = Systematic Coronary Risk Estimation.
      Figure thumbnail gr3
      Figure 3Relative risk chart, derived from SCORE Conversion of cholesterol mmol/L → mg/dL: 8 = 310; 7 = 270; 6 = 230; 5 = 190; 4 = 155.
      Figure thumbnail gr4
      Figure 4SCORE chart (for use in high-risk European countries) illustrating how the approximate risk age can be read off the chart. SCORE = Systematic Coronary Risk Estimation.
      Please note that Figure 3 shows relative not absolute risk. Thus a person in the top right-hand box, with multiple CV risk factors, has a risk that is 12 times greater than a person in the bottom left with normal risk factor levels. This may be helpful when advising a young person with a low absolute but high relative risk of the need for lifestyle change.

      2.3.2 Cardiovascular risk age

      The risk age of a person with several CV risk factors is the age of a person of the same gender with the same level of risk but with ideal levels of risk factors. Thus a 40-year-old with high levels of some risk factors may have the risk age of a 60-year-old (Figure 4), because the risk equals that of a 60-year-old with ideal risk factor levels (i.e. nonsmoking, total cholesterol of 4 mmol/L and BP of 120 mmHg).
      • Cooney M.T.
      • Vartiainen E.
      • Laatikainen T.
      • De Bacquer D.
      • McGorrian C.
      • Dudina A.
      • Graham I.
      Cardiovascular risk age: concepts and practicalities.
      Risk age is an intuitive and easily understood way of illustrating the likely reduction in life expectancy that a young person with a low absolute but high relative risk of CVD will be exposed to if preventive measures are not adopted.
      • Cooney M.T.
      • Vartiainen E.
      • Laatikainen T.
      • De Bacquer D.
      • McGorrian C.
      • Dudina A.
      • Graham I.
      Cardiovascular risk age: concepts and practicalities.
      Table A showing different risk factor combinations is included in the web addenda to provide a more accurate estimation of risk ages. Risk age is also automatically calculated as part of the latest revision of HeartScore.
      Risk age has been shown to be independent of the CV endpoint used,
      • Cooney M.T.
      • Vartiainen E.
      • Laatikainen T.
      • De Bacquer D.
      • McGorrian C.
      • Dudina A.
      • Graham I.
      Cardiovascular risk age: concepts and practicalities.
      which bypasses the dilemma of whether to use a risk estimation system based on CV mortality or on total CV events. Risk age can be used in any population regardless of baseline risk and secular changes in mortality, and therefore avoids the need for recalibration.
      • Cuende J.I.
      • Cuende N.
      • Calaveras-Lagartos J.
      How to calculate vascular age with the SCORE project scales: a new method of cardiovascular risk evaluation.
      At present, risk age is recommended to help communicate about risk, especially to younger people with a low absolute risk but a high relative risk.

      2.3.3 Lifetime vs. 10-year cardiovascular risk estimation

      Conventional CV risk prediction schemes estimate the 10 year risk of CV events. Lifetime CV risk prediction models identify high-risk individuals both in the short and long term. Such models account for predicted risk in the context of competing risks from other diseases over the remaining expected lifespan of an individual.
      Notably, 10 year risk identifies individuals who are most likely to benefit from drug therapy in the near term. Drug treatment starts to work quite rapidly, and drug treatment can be largely informed by short-term risk, such as 10 year risk. One problem with short-term risk is that it is mostly governed by age and consequently few younger individuals, in particular women, reach treatment thresholds. It has therefore been argued that lifetime risk estimation may enhance risk communication, particularly among younger individuals and women.
      Evidence for the role of lifetime risk in treatment decisions is lacking. Sufficient data for robust lifetime risk estimations, as well as meaningful risk categorization thresholds, are also lacking. Providing lifetime CV risk estimates for some groups at high risk of mortality due to competing non-CVD causes can be difficult to interpret. Importantly, evidence of the benefits of lifelong preventive therapy (e.g. BP- or lipid-lowering drugs) in younger individuals with low short-term but higher lifetime risks is lacking. For these reasons, we do not recommend that risk stratification for treatment decisions be based on lifetime risk. However, like risk age and relative risk, it may be a useful tool in communicating about risk to individuals with high risk factor levels but who are at a low 10 year absolute risk of CV events, such as some younger people. Whatever approach is used, if absolute risk is low, a high relative risk or risk age signals the need for active lifestyle advice and awareness that drug treatment may need consideration as the person ages. Both risk age and lifetime risk are closer to relative than absolute risk, and none provides an evidence base for drug treatment decisions.

      2.3.4 Low-risk, high-risk and very-high-risk countries

      The countries considered here are those with national cardiology societies that belong to the ESC, both European and non-European.

      2.3.4.1 What are low-risk countries?

      The fact that CVD mortality has declined in many European countries means that more now fall into the low-risk category. While any cut-off point is arbitrary and open to debate, in these guidelines the cut-off points for calling a country ’low risk’ are based on age-adjusted 2012 CVD mortality rates in those 45-74 years of age (<225/100 000 in men and < 175/100 000 in women).

      World Health Organisation. WHO Global Health Repository. Cardiovascular diseases, deaths per 100 000. Data by country. http://apps.who.int/gho/data/node.main.A865CARDIOVASCULAR?lang=en.

      Thus the following countries are defined as low risk: Andorra, Austria, Belgium, Cyprus, Denmark, Finland, France, Germany, Greece, Iceland, Ireland, Israel, Italy, Luxembourg, Malta, Monaco,The Netherlands, Norway, Portugal, San Marino, Slovenia, Spain, Sweden, Switzerland and the United Kingdom.

      2.3.4.2 What are high-risk and very-high-risk countries?

      High-risk countries are Bosnia and Herzegovina, Croatia, Czech Republic, Estonia, Hungary, Lithuania, Montenegro, Morocco, Poland, Romania, Serbia, Slovakia, Tunisia and Turkey.
      Very-high-risk countries present levels of risk that are more than double that of low-risk countries (i.e. CVD mortality >450/100 000 for men and >350/100 000 for women). Additionally, the male:female ratio is smaller than in low-risk countries, suggesting a major problem for women. The very high-risk countries are Albania, Algeria, Armenia, Azerbaijan, Belarus, Bulgaria, Egypt, Georgia, Kazakhstan, Kyrgyzstan, Latvia, former Yugoslav Republic of Macedonia, Moldova, Russian Federation, Syrian Arab Republic, Tajikistan, Turkmenistan, Ukraine and Uzbekistan.

      2.3.5 How to use the risk estimation charts

      • The SCORE charts are used in apparently healthy people, not for those with established CVD or at very high risk or high risk for other reasons [e.g. DM (see section 3a.8) or chronic kidney disease (CKD; see section 2.4.5.1)], who need intensive risk advice anyway.
      • Use of the low-risk chart is recommended for the countries listed above. Use of the high-risk chart is recommended for all other European and Mediterranean countries, taking into account that the high-risk charts may underestimate the risk in very-high-risk countries (see above). Note that several countries have undertaken national recalibrations to allow for time trends in mortality and risk factor distributions. Such charts are likely to better represent risk levels.
      • To estimate a person’s 10 year risk of CV death, find the table for their gender, smoking status and (nearest) age. Within the table, find the cell nearest to the person’s BP and total cholesterol. Risk estimates will need to be adjusted upwards as the person approaches the next age category.
      While no threshold is universally applicable, the intensity of advice should increase with increasing risk. The effect of interventions on the absolute probability of developing a CV event increases with an increasing baseline risk; that is, the number of individuals needed to treat (NNT) to prevent one event decreases with increasing risk.
      - Low- to moderate-risk persons (calculated SCORE <5%): should be offered lifestyle advice to maintain their low- to moderate-risk status.
      High-risk persons (calculated SCORE ≥5% and <10%): qualify for intensive lifestyle advice and may be candidates for drug treatment.
      Very-high-risk persons (calculated SCORE ≥10%): drug treatment is more frequently required. In persons >60 years of age, these thresholds should be interpreted more leniently, because their age-specific risk is normally around these levels, even when other CV risk factor levels are ’normal’. In particular, uncritical initiation of drug treatments of all elderly with risks greater than the 10% threshold should be discouraged.
      Use of the risk charts should be qualified by knowledge of the following aspects:
      • The charts assist in risk estimation but must be interpreted in light of the clinician’s knowledge and experience and in view of the factors that may modify the calculated risk (see below).
      • Relative risks may be high in young persons, even if 10 year absolute risks are low, because events usually occur later in life. The relative risk chart or estimating risk age may be helpful in identifying and counselling such persons.
      • The lower risk in women is explained by the fact that risk is deferred by 10 years—the risk of a 60-year-old woman is similar to that of a 50-year-old man. Ultimately, more women than men die of CVD.
      • The charts may be used to give some indication of the effects of reducing risk factors, given that there will be a time lag before risk reduces and that the results of RCTs in general give better estimates of the benefits of interventions. Those who stop smoking generally halve their risk.

      2.3.6 Modifiers of calculated total cardiovascular risk

      Apart from the conventional major CV risk factors included in the risk charts, there are other risk factors that could be relevant for assessing total CVD risk. The Task Force recommends additional risk factor assessment if such a risk factor improves risk classification [e.g. by calculation of a net reclassification index (NRI)] and if the assessment is feasible in daily practice. In general, reclassification is of most value when the individual’s risk lies close to a decisional threshold, such as a SCORE risk of 5%. In very-high-risk or very-low-risk situations, the impact of additional risk factors is unlikely to alter management decisions. While the presence of risk modifiers may move an individual’s estimated risk upward, absence of these modifiers should lead to lowering an individual’s estimated risk.
      Table 4 lists examples of factors that fulfil the aforementioned criteria. Several other factors that are frequently discussed in the literature, but may not have the ability to reclassify subjects, are discussed in subsequent paragraphs. Also discussed further in this section are the roles of ethnicity and of specific conditions or diseases that may be associated with a higher than calculated risk, such as CKD, autoimmune diseases, etc. The way modifiers are related to CV risk may be very different. Social deprivation and being overweight, for example, are important as ’causes of the causes’ of CVD, in that they may be associated with higher levels of conventional risk factors. Family history may reflect a shared environment, genetic factors or both. Markers such as computed tomography (CT) calcium scoring are indicators of disease rather than risk factors for future disease.

      2.3.7 Risk categories: priorities

      Individuals at highest risk gain most from preventive efforts, and this guides the priorities, which are detailed in Table 5.
      Table 5Risk categories
      Table thumbnail fx10
      ACS = acute coronary syndrome; AMI = acute myocardial infarction; BP = blood pressure; CKD = chronic kidney disease; DM = diabetes mellitus; GFR = glomerular filtration rate; PAD = peripheral artery disease; SCORE = systematic coronary risk estimation; TIA = transient ischaemic attack.

      2.3.8 Risk factor targets

      Risk factor goals and target levels for important CV risk factors are presented in Table 6.
      Table 6Risk factor goals and target levels for important cardiovascular risk factors
      Table thumbnail fx11
      BMI = body mass index; HbAlc = glycated haemoglobin; HDL-C = high-densitylipoprotein cholesterol; LDL-C = low density lipoprotein cholesterol.aBlood pressure <140/90 mmHg is the general target. The target can be higher in frail elderly, or lower in most patients with DM (see chapter 3.a.8) and in some (very) high-risk patients without DM who can tolerate multiple blood pressure lowering drugs (see chapter 3.a.9).bNon-HDL-C is a reasonable and practical alternative target because it does not require fasting. Non HDL-C secondary targets of <2.6, <3.3 and <3.8 mmol/L (<100, <130 and <145 mg/dL) are recommended for very high, high and low to moderate risk subjects, respectively. See section 3a.7.10 for more details.cA view was expressed that primary care physicians might prefer a single general LDL-C goal of 2.6 mmol/L (100 mg/dL). While accepting the simplicity of this approach and that it could be useful in some settings, there is better scientific support for the three targets matched to level of risk.dThis is the general recommendation for those at very high-risk. It should be noted that the evidence for patients with CKD is less strong.

      2.3.9 Conclusions

      Estimation of total CV risk remains a crucial part of the present guidelines. The priorities (risk categories) defined in this section are for clinical use and reflect the fact that those at highest risk of a CVD event gain most from preventive measures. This approach should complement public actions to reduce community risk factor levels and promote a healthy lifestyle. The principles of risk estimation and the definition of priorities reflect an attempt to make complex issues simple and accessible. Their very simplicity makes them vulnerable to criticism. Above all, they must be interpreted in light of the physician’s detailed knowledge of his/her patient and in light of local guidance and conditions.

        Gaps in evidence

      • There are no recent RCTs of a total risk approach to risk assessment or risk management.
      • The young, women, older people and ethnic minorities continue to be underrepresented in clinical trials.
      • A systematic comparison of current international guidelines is needed to define areas of agreement and the reasons for discrepancies.

      2.4 Other risk markers

      2.4.1 Family history/(epi)genetics

        Key messages

      • Family history of premature CVD in first-degree relatives, before 55 years of age in men and 65 years of age in women, increases the risk of CVD.
      • Several genetic markers are associated with an increased risk of CVD, but their use in clinical practice is not recommended.
      Tabled 1Recommendations for assessment of family history/(epi)genetics
      Table thumbnail fx12
      CVD = cardiovascular disease.aClass of recommendation.bLevel of evidence.cReference(s) supporting recommendations.

      2.4.1.1 Family history

      Familial history of premature CVD is a crude but simple indicator of the risk of developing CVD, reflecting both the genetic trait and the environment shared among household members.
      • Banerjee A.
      A review of family history of cardiovascular disease: risk factor and research tool.
      A positive family history of premature CV death is associated with an increased risk of early and lifetime CVD.
      • Bachmann J.M.
      • Willis B.L.
      • Ayers C.R.
      • Khera A.
      • Berry J.D.
      Association between family history and coronary heart disease death across long-term follow-up in men: the Cooper Center Longitudinal Study.
      In the few studies that simultaneously assessed and reported the effects of family history and genetic scores, family history remained significantly associated with the incidence of CVD after adjusting for the genetic scores.
      • Tikkanen E.
      • Havulinna A.S.
      • Palotie A.
      • Salomaa V.
      • Ripatti S.
      Genetic risk prediction and a 2-stage risk screening strategy for coronary heart disease.
      • Ripatti S.
      • Tikkanen E.
      • Orho-Melander M.
      • Havulinna A.S.
      • Silander K.
      • Sharma A.
      • Guiducci C.
      • Perola M.
      • Jula A.
      • Sinisalo J.
      • Lokki M.L.
      • Nieminen M.S.
      • Melander O.
      • Salomaa V.
      • Peltonen L.
      • Kathiresan S.
      A multilocus genetic risk score for coronary heart disease: case-control and prospective cohort analyses.
      Limited data exist regarding the ability of family history to improve the prediction of CVD beyond conventional CV risk factors.
      • Sivapalaratnam S.
      • Boekholdt S.M.
      • Trip M.D.
      • Sandhu M.S.
      • Luben R.
      • Kastelein J.J.
      • Wareham N.J.
      • Khaw K.T.
      Family history of premature coronary heart disease and risk prediction in the EPIC-Norfolk prospective population study.
      • Veronesi G.
      • Gianfagna F.
      • Giampaoli S.
      • Chambless L.E.
      • Mancia G.
      • Cesana G.
      • Ferrario M.M.
      Improving long-term prediction of first cardiovascular event: the contribution of family history of coronary heart disease and social status.
      • Yeboah J.
      • McClelland R.L.
      • Polonsky T.S.
      • Burke G.L.
      • Sibley C.T.
      • O’Leary D.
      • Carr J.J.
      • Goff D.C.
      • Greenland P.
      • Herrington D.M.
      Comparison of novel risk markers for improvement in cardiovascular risk assessment in intermediate-risk individuals.
      One possible explanation is the varying definitions of family history applied
      • Hughes M.F.
      • Saarela O.
      • Stritzke J.
      • Kee F.
      • Silander K.
      • Klopp N.
      • Kontto J.
      • Karvanen J.
      • Willenborg C.
      • Salomaa V.
      • Virtamo J.
      • Amouyel P.
      • Arveiler D.
      • Ferrieres J.
      • Wiklund P.G.
      • Baumert J.
      • Thorand B.
      • Diemert P.
      • Tregouet D.A.
      • Hengstenberg C.
      • Peters A.
      • Evans A.
      • Koenig W.
      • Erdmann J.
      • Samani N.J.
      • Kuulasmaa K.
      • Schunkert H.
      Genetic markers enhance coronary risk prediction in men: the MORGAM prospective cohorts.
      and that conventional CV risk factors can partly explain the impact of family history.
      A family history of premature CVD is simple, inexpensive information that should be part of the CV risk assessment in all subjects. Family history can be a risk modifier to optimal management after the calculated risk using SCORE lies near a decisional threshold: a positive family history would favour more intensive interventions, while a negative family history would translate into less intensive treatment.
      • Sivapalaratnam S.
      • Boekholdt S.M.
      • Trip M.D.
      • Sandhu M.S.
      • Luben R.
      • Kastelein J.J.
      • Wareham N.J.
      • Khaw K.T.
      Family history of premature coronary heart disease and risk prediction in the EPIC-Norfolk prospective population study.

      2.4.1.2 Genetic markers

      Genetic screening and counselling is effective in some conditions, such as familial hypercholesterolaemia (FH) (see section 3a.7.9). This paragraph will focus on genetic screening for high CV risk in the general population.
      Several recent genome-wide association studies have identified candidate genes associated with CVD. Since the effect of each genetic polymorphism is small, most studies have used genetic scores to summarize the genetic component. There is a lack of consensus regarding which genes and their corresponding single nucleotide polymorphisms (SNPs) should be included in agenetic risk score and which method should be used to calculate the genetic score.
      The association of genetic scores with incident CVD has been prospectively studied, adjusting for the main CV risk factors, and most studies have found a significant association, with the relative risks varying between 1.02 and 1.49 per increase in one score unit.
      • Sivapalaratnam S.
      • Boekholdt S.M.
      • Trip M.D.
      • Sandhu M.S.
      • Luben R.
      • Kastelein J.J.
      • Wareham N.J.
      • Khaw K.T.
      Family history of premature coronary heart disease and risk prediction in the EPIC-Norfolk prospective population study.
      The ability of genetic scores to predict CV events beyond traditional CV risk factors (i.e. defined by the NRI) was found in about half of the studies. The NRI is a statistical measure quantifying the usefulness of adding new variables to a risk prediction equation.
      • Sivapalaratnam S.
      • Boekholdt S.M.
      • Trip M.D.
      • Sandhu M.S.
      • Luben R.
      • Kastelein J.J.
      • Wareham N.J.
      • Khaw K.T.
      Family history of premature coronary heart disease and risk prediction in the EPIC-Norfolk prospective population study.
      The biggest improvements in the NRI were observed in participants at intermediate risk, while little or no improvement was observed in participants at high risk.
      • Tikkanen E.
      • Havulinna A.S.
      • Palotie A.
      • Salomaa V.
      • Ripatti S.
      Genetic risk prediction and a 2-stage risk screening strategy for coronary heart disease.
      • Ganna A.
      • Magnusson P.K.
      • Pedersen N.L.
      • de Faire U.
      • Reilly M.
      • Arnlov J.
      • Sundstrom J.
      • Hamsten A.
      • Ingelsson E.
      Multilocus genetic risk scores for coronary heart disease prediction.
      One study estimated that one additional CAD event for every 318 people screened at intermediate risk could be prevented by measuring the CAD-specific genetic score in addition to established risk factors.
      • Ganna A.
      • Magnusson P.K.
      • Pedersen N.L.
      • de Faire U.
      • Reilly M.
      • Arnlov J.
      • Sundstrom J.
      • Hamsten A.
      • Ingelsson E.
      Multilocus genetic risk scores for coronary heart disease prediction.
      Importantly, since the frequency of polymorphisms might differ, the results may vary between populations.
      • Ripatti S.
      • Tikkanen E.
      • Orho-Melander M.
      • Havulinna A.S.
      • Silander K.
      • Sharma A.
      • Guiducci C.
      • Perola M.
      • Jula A.
      • Sinisalo J.
      • Lokki M.L.
      • Nieminen M.S.
      • Melander O.
      • Salomaa V.
      • Peltonen L.
      • Kathiresan S.
      A multilocus genetic risk score for coronary heart disease: case-control and prospective cohort analyses.
      • Brautbar A.
      • Pompeii L.A.
      • Dehghan A.
      • Ngwa J.S.
      • Nambi V.
      • Virani S.S.
      • Rivadeneira F.
      • Uitterlinden A.G.
      • Hofman A.
      • Witteman J.C.
      • Pencina M.J.
      • Folsom A.R.
      • Cupples L.A.
      • Ballantyne C.M.
      • Boerwinkle E.
      A genetic risk score based on direct associations with coronary heart disease improves coronary heart disease risk prediction in the Atherosclerosis Risk in Communities (ARIC), but not in the Rotterdam and Framingham Offspring,.
      • Bressler J.
      • Folsom A.R.
      • Couper D.J.
      • Volcik K.A.
      • Boerwinkle E.
      Genetic variants identified in a European genome-wide association study that were found to predict incident coronary heart disease in the atherosclerosis risk in communities study.
      Recently, a genetic risk score based on 27 genetic variants enabled the identification of subjects at increased risk of CAD, who would benefit the most from statin therapy, even after adjustment for family history.
      • Mega J.L.
      • Stitziel N.O.
      • Smith J.G.
      • Chasman D.I.
      • Caulfield M.J.
      • Devlin J.J.
      • Nordio F.
      • Hyde C.L.
      • Cannon C.P.
      • Sacks F.M.
      • Poulter N.R.
      • Sever P.S.
      • Ridker P.M.
      • Braunwald E.
      • Melander O.
      • Kathiresan S.
      • Sabatine M.S.
      Genetic risk, coronary heart disease events, and the clinical benefit of statin therapy: an analysis of primary and secondary prevention trials.
      Still, it is likely that some reported associations might be due to chance,
      • Floyd C.N.
      • Mustafa A.
      • Ferro A.
      The PlA1/A2 polymorphism of glycoprotein IIIa as a risk factor for myocardial infarction: a meta-analysis.
      and replication studies are needed to confirm positive findings.
      Currently, many commercial tests are available, allowing an almost complete assessment of an individual’s genome, and strong pressure is being applied to use this information to predict genetic risk and to make genetic testing a routine measure.
      • Singleton A.
      • Erby L.H.
      • Foisie K.V.
      • Kaphingst K.A.
      Informed choice in direct-to-consumer genetic testing (DTCGT) websites: a content analysis of benefits, risks, and limitations.
      Given the lack of agreement regarding which genetic markers should be included, how genetic risk scores should be calculated and uncertainties about improvement in CV risk prediction, the use of genetic markers for the prediction of CVD is not recommended.

      2.4.1.3 Epigenetics

      Epigenetics studies the chemical changes in DNA that affect gene expression. Methylation of genes related to CV risk factors is associated with variation in CV risk factor levels,
      • Guay S.P.
      • Brisson D.
      • Lamarche B.
      • Marceau P.
      • Vohl M.C.
      • Gaudet D.
      • Bouchard L.
      DNA methylation variations at CETP and LPL gene promoter loci: new molecular biomarkers associated with blood lipid profile variability.
      • Wang X.
      • Falkner B.
      • Zhu H.
      • Shi H.
      • Su S.
      • Xu X.
      • Sharma A.K.
      • Dong Y.
      • Treiber F.
      • Gutin B.
      • Harshfield G.
      • Snieder H.
      A genome-wide methylation study on essential hypertension in young African American males.
      and lower DNA methylation levels are associated with an increased risk of CAD or stroke.
      • Baccarelli A.
      • Wright R.
      • Bollati V.
      • Litonjua A.
      • Zanobetti A.
      • Tarantini L.
      • Sparrow D.
      • Vokonas P.
      • Schwartz J.
      Ischemic heart disease and stroke in relation to blood DNA methylation.
      No information exists, however, regarding the effect of epigenetic markers in improving CVD risk prediction beyond conventional risk factors. Thus, epigenetic screening of CVD is not recommended.

        Gaps in evidence

      • The impact of adding family history to the current SCORE risk equation should be assessed.
      • Future studies should assess the power of different genetic risk scores to improve CVD risk prediction in several different populations, the number of events prevented and the cost-effectiveness of including genetic data in the risk assessment.

      2.4.2 Psychosocial risk factors

        Key messages

      • Low socio-economic status, lack of social support, stress at work and in family life, hostility, depression, anxiety and other mental disorders contribute to the risk of developing CVD and a worse prognosis of CVD, with the absence of these items being associated with a lower risk of developing CVD and a better prognosis of CVD.
      • Psychosocial risk factors act as barriers to treatment adherence and efforts to improve lifestyle, as well as to promoting health in patients and populations.
      Tabled 1Recommendation for assessment of psychosocial risk factors
      Table thumbnail fx13
      aClass of recommendation.bLevel of evidence.cReference(s) supporting recommendations.
      Low socio-economic status, defined as low educational level, low income, holding a low-status job or living in a poor residential area, confer an increased risk of CAD; the relative risk (RR) of CAD mortality risk is 1.3–2.0.
      • Albert M.A.
      • Glynn R.J.
      • Buring J.
      • Ridker P.M.
      Impact of traditional and novel risk factors on the relationship between socioeconomic status and incident cardiovascular events.
      • Alter D.A.
      • Franklin B.
      • Ko D.T.
      • Austin P.C.
      • Lee D.S.
      • Oh P.I.
      • Stukel T.A.
      • Tu J.V.
      Socioeconomic status, functional recovery, and long-term mortality among patients surviving acute myocardial infarction.
      Compared with the Framingham risk score, adding social deprivation to CV risk assessment was able to reduce unattributed risk substantially.
      • Woodward M.
      • Brindle P.
      • Tunstall-Pedoe H.
      Adding social deprivation and family history to cardiovascular risk assessment: the ASSIGN score from the Scottish Heart Health Extended Cohort (SHHEC).
      People who are isolated or disconnected from others are at increased risk of developing and dying prematurely from CAD. Similarly, a lack of social support increases CAD risk and worsens the prognosis of CAD.
      • Barth J.
      • Schneider S.
      • von Kanel R.
      Lack of social support in the etiology and the prognosis of coronary heart disease: a systematic review and meta-analysis.
      Acute mental stressors may act as triggers of acute coronary syndrome (ACS). These stressors include exposure to natural catastrophes, as well as personal stressors (e.g. defeat or other serious life events) resulting in acute strong negative emotions (e.g. outbursts of anger or grief).
      • Nawrot T.S.
      • Perez L.
      • Kunzli N.
      • Munters E.
      • Nemery B.
      Public health importance of triggers of myocardial infarction: a comparative risk assessment.
      After the death of a significant person, the incidence rate of acute myocardial infarction (AMI) is elevated 21-fold during the first 24 hours, declining steadily during the subsequent days.
      • Mostofsky E.
      • Penner E.A.
      • Mittleman M.A.
      Outbursts of anger as a trigger of acute cardiovascular events: a systematic review and meta-analysis.
      Chronic stress at work (e.g. long working hours, extensive overtime work, high psychological demands, unfairness and job strain) predicts premature incident CAD in men [relative risk (RR) ∼1.2–1.5].
      • Kivimaki M.
      • Nyberg S.T.
      • Batty G.D.
      • Fransson E.I.
      • Heikkila K.
      • Alfredsson L.
      • Bjorner J.B.
      • Borritz M.
      • Burr H.
      • Casini A.
      • Clays E.
      • De Bacquer D.
      • Dragano N.
      • Ferrie J.E.
      • Geuskens G.A.
      • Goldberg M.
      • Hamer M.
      • Hooftman W.E.
      • Houtman I.L.
      • Joensuu M.
      • Jokela M.
      • Kittel F.
      • Knutsson A.
      • Koskenvuo M.
      • Koskinen A.
      • Kouvonen A.
      • Kumari M.
      • Madsen I.E.
      • Marmot M.G.
      • Nielsen M.L.
      • Nordin M.
      • Oksanen T.
      • Pentti J.
      • Rugulies R.
      • Salo P.
      • Siegrist J.
      • Singh-Manoux A.
      • Suominen S.B.
      • Vaananen A.
      • Vahtera J.
      • Virtanen M.
      • Westerholm P.J.
      • Westerlund H.
      • Zins M.
      • Steptoe A.
      • Theorell T.
      Job strain as a risk factor for coronary heart disease: a collaborative meta-analysis of individual participant data.
      In addition, long-term stressful conditions in family life increase CAD risk (RR ∼2.7–4.0).
      • Eaker E.D.
      • Sullivan L.M.
      • Kelly-Hayes M.
      • D’Agostino RBSr
      • Benjamin E.J.
      Marital status, marital strain, and risk of coronary heart disease or total mortality: the Framingham Offspring Study.
      • Kivimaki M.
      • Jokela M.
      • Nyberg S.T.
      • Singh-Manoux A.
      • Fransson E.I.
      • Alfredsson L.
      • Bjorner J.B.
      • Borritz M.
      • Burr H.
      • Casini A.
      • Clays E.
      • De Bacquer D.
      • Dragano N.
      • Erbel R.
      • Geuskens G.A.
      • Hamer M.
      • Hooftman W.E.
      • Houtman I.L.
      • Jockel K.H.
      • Kittel F.
      • Knutsson A.
      • Koskenvuo M.
      • Lunau T.
      • Madsen I.E.
      • Nielsen M.L.
      • Nordin M.
      • Oksanen T.
      • Pejtersen J.H.
      • Pentti J.
      • Rugulies R.
      • Salo P.
      • Shipley M.J.
      • Siegrist J.
      • Steptoe A.
      • Suominen S.B.
      • Theorell T.
      • Vahtera J.
      • Westerholm P.J.
      • Westerlund H.
      • O’Reilly D.
      • Kumari M.
      • Batty G.D.
      • Ferrie J.E.
      • Virtanen M.
      Long working hours and risk of coronary heart disease and stroke: a systematic review and meta-analysis of published and unpublished data for 603 838 individuals.
      Clinical depression and depressive symptoms predict incident CAD (RR 1.6 and 1.9, respectively)
      • Spindler H.
      • Pedersen S.S.
      Posttraumatic stress disorder in the wake of heart disease: prevalence, risk factors, and future research directions.
      and worsen its prognosis (RR 1.6 and 2.4, respectively).
      • Pogosova N.
      • Saner H.
      • Pedersen S.S.
      • Cupples M.E.
      • McGee H.
      • Hofer S.
      • Doyle F.
      • Schmid J.P.
      • von Kanel R.
      Psychosocial aspects in cardiac rehabilitation: from theory to practice. A position paper from the Cardiac Rehabilitation Section of the European Association of Cardiovascular Prevention and Rehabilitation of the European Society of Cardiology.
      • Nawrot T.S.
      • Perez L.
      • Kunzli N.
      • Munters E.
      • Nemery B.
      Public health importance of triggers of myocardial infarction: a comparative risk assessment.
      • Spindler H.
      • Pedersen S.S.
      Posttraumatic stress disorder in the wake of heart disease: prevalence, risk factors, and future research directions.
      • Orth-Gomer K.
      • Wamala S.P.
      • Horsten M.
      • Schenck-Gustafsson K.
      • Schneiderman N.
      • Mittleman M.A.
      Marital stress worsens prognosis in women with coronary heart disease: the Stockholm Female Coronary Risk Study.
      Vital exhaustion, most likely representing somatic symptoms of depression, significantly contributed to incident CAD (population attributable risk 21.1% in women and 27.7% in men). The NRI improved significantly.
      • Schnohr P.
      • Marott J.L.
      • Kristensen T.S.
      • Gyntelberg F.
      • Gronbaek M.
      • Lange P.
      • Jensen M.T.
      • Jensen G.B.
      • Prescott E.
      Ranking of psychosocial and traditional risk factors by importance for coronary heart disease: the Copenhagen City Heart Study.
      Panic attacks also increase the risk of incident CAD (RR 4.2).
      • Smoller J.W.
      • Pollack M.H.
      • Wassertheil-Smoller S.
      • Jackson R.D.
      • Oberman A.
      • Wong N.D.
      • Sheps D.
      Panic attacks and risk of incident cardiovascular events among postmenopausal women in the Women’s Health Initiative Observational Study.
      Anxiety is an independent risk factor for incident CAD (RR 1.3),
      • Pogosova N.
      • Saner H.
      • Pedersen S.S.
      • Cupples M.E.
      • McGee H.
      • Hofer S.
      • Doyle F.
      • Schmid J.P.
      • von Kanel R.
      Psychosocial aspects in cardiac rehabilitation: from theory to practice. A position paper from the Cardiac Rehabilitation Section of the European Association of Cardiovascular Prevention and Rehabilitation of the European Society of Cardiology.
      for cardiac mortality following AMI [odds ratio (OR) 1.2]105 and cardiac events (OR 1.7).
      • Roest A.M.
      • Martens E.J.
      • Denollet J.
      • de Jonge P.
      Prognostic association of anxiety post myocardial infarction with mortality and new cardiac events: a meta-analysis.
      Meta-analyses reported a 1.5-fold risk of CVD incidence, a 1.2-fold risk of CAD and 1.7-fold risk for stroke in patients with schizophrenia,
      • Fan Z.
      • Wu Y.
      • Shen J.
      • Ji T.
      • Zhan R.
      Schizophrenia and the risk of cardiovascular diseases: a meta-analysis of thirteen cohort studies.
      and a 1.3-fold risk for incident CAD, even after adjustment for depression, in patients with post-traumatic stress disorder.
      • Edmondson D.
      • Kronish I.M.
      • Shaffer J.A.
      • Falzon L.
      • Burg M.M.
      Posttraumatic stress disorder and risk for coronary heart disease: a meta-analytic review.
      Hostility is a personality trait, characterized by extensive experience of mistrust, rage and anger and the tendency to engage in aggressive, maladaptive social relationships. A meta-analysis confirmed that anger and hostility are associated with a small but significant increased riskfor CV events in both healthy and CVD populations (RR 1.2).
      • Chida Y.
      • Steptoe A.
      The association of anger and hostility with future coronary heart disease: a meta-analytic review of prospective evidence.
      The type D (’distressed’) personality involves an enduring tendency to experience a broad spectrum of negative emotions (negative affectivity) and to inhibit self-expression in relation to others (social inhibition). The type D personality has been shown to predict poor prognosis in patients with CAD (RR 2.2).
      • Grande G.
      • Romppel M.
      • Barth J.
      Association between type D personality and prognosis in patients with cardiovascular diseases: a systematic review and meta-analysis.
      In most situations, psychosocial risk factors cluster in individuals and groups. For example, both women and men of lower socio-economic status and/or with chronic stress are more likely to be depressed, hostile and socially isolated.
      • Chandola T.
      • Britton A.
      • Brunner E.
      • Hemingway H.
      • Malik M.
      • Kumari M.
      • Badrick E.
      • Kivimaki M.
      • Marmot M.
      Work stress and coronary heart disease: what are the mechanisms?.
      The INTERHEART study has shown that a cluster of psychosocial risk factors (i.e. social deprivation, stress at work or in family life and depression) is associated with increased risk for myocardial infarction (MI) (RR 3.5 for women and 2.3 for men). The population attributable risk was 40% in women and 25% in men.
      • Yusuf S.
      • Hawken S.
      • Ounpuu S.
      • Dans T.
      • Avezum A.
      • Lanas F.
      • McQueen M.
      • Budaj A.
      • Pais P.
      • Varigos J.
      • Lisheng L.
      Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study.
      Mechanisms that link psychosocial factors to increased CV risk include unhealthy lifestyle [more frequent smoking, unhealthy food choices and less physical activity (PA)] and low adherence to behaviour change recommendations or CV medication.
      • Albert M.A.
      • Glynn R.J.
      • Buring J.
      • Ridker P.M.
      Impact of traditional and novel risk factors on the relationship between socioeconomic status and incident cardiovascular events.
      • Stringhini S.
      • Sabia S.
      • Shipley M.
      • Brunner E.
      • Nabi H.
      • Kivimaki M.
      • Singh-Manoux A.
      Association of socioeconomic position with health behaviors and mortality.
      In addition, depression and/or chronic stress are associated with alterations in autonomic function, in the hypothalamic–pituitary axis and in other endocrine markers, which affect haemostatic and inflammatory processes, endothelial function and myocardial perfusion.
      • Chandola T.
      • Britton A.
      • Brunner E.
      • Hemingway H.
      • Malik M.
      • Kumari M.
      • Badrick E.
      • Kivimaki M.
      • Marmot M.
      Work stress and coronary heart disease: what are the mechanisms?.
      Enhanced risk in patients with depression may also be due in part to adverse effects of tricyclic antidepressants.
      • Lichtman J.H.
      • Froelicher E.S.
      • Blumenthal J.A.
      • Carney R.M.
      • Doering L.V.
      • Frasure-Smith N.
      • Freedland K.E.
      • Jaffe A.S.
      • Leifheit-Limson E.C.
      • Sheps D.S.
      • Vaccarino V.
      • Wulsin L.
      Depression as a risk factor for poor prognosis among patients with acute coronary syndrome: systematic review and recommendations: a scientific statement from the American Heart Association.
      Assessment of psychosocial factors in patients and persons with CV risk factors should be considered for use as risk modifiers in CV risk prediction, especially in individuals with SCORE risks near decisional thresholds. In addition, psychosocial factors can help identify possible barriers to lifestyle changes and adherence to medication. Standardized methods are available to assess psychosocial factors in many languages and countries.
      • Albus C.
      • Jordan J.
      • Herrmann-Lingen C.
      Screening for psychosocial risk factors in patients with coronary heart disease-recommendations for clinical practice.
      Alternatively, a preliminary assessment of psychosocial factors can be made within the physicians’ clinical interview, as shown in Table 7.
      Table 7Core questions for the assessment of psychosocial risk factors in clinical practice
      Table thumbnail fx14
      No more than a minimum education according to the requirement of the country and/or a ’yes’ for one or more items indicate an increased CV risk and could be applied as a modifier of CV risk (see Chapter 2.3.6). The management of psychosocial risk factors should be addressed according to Chapter 3a.2.

        Gap in evidence

      • It remains unknown whether routine screening for psychosocial risk factors contributes to fewer future cardiac events.

      2.4.3 Circulating and urinary biomarkers

        Key messages

      • CV circulating and urinary biomarkers have either no or only limited value when added to CVD risk assessment with the SCORE system.
      • There is evidence of publication bias in the field of novel biomarkers of CV risk, leading to inflated estimates of strength of association and potential added value.
      Tabled 1Recommendation for assessment of circulating and urinary biomarkers
      Table thumbnail fx15
      aClass of recommendation.bLevel of evidence.cReference(s) supporting recommendations.
      In general, biomarkers can be classified into inflammatory (e.g. high-sensitivity C-reactive protein (hsCRP, fibrinogen), thrombotic (e.g. homocysteine, lipoprotein-associated phospholipase A2), glucose- and lipid-related markers (e.g. apolipoproteins) and organ-specific markers (e.g. renal, cardiac). However, for the purpose of overall CV risk estimation, these distinctions are generally not relevant. Also, from the perspective of risk stratification (i.e. prediction of future CV events), the question of whether a biomarker is causally related to CVD or may be a marker of preclinical disease is equally irrelevant.
      Among the most extensively studied and discussed biomarkers is hsCRP. This biomarker has shown consistency across large prospective studies as a risk factor integrating multiple metabolic and low-grade inflammatory factors, with RRs approaching those of classical CV risk factors. However, its contribution to the existing methods of CV risk assessment is probably small.
      • Emerging Risk Factors Collaboration
      • Kaptoge S.
      • Di Angelantonio E.
      • Pennells L.
      • Wood A.M.
      • White I.R.
      • Gao P.
      • Walker M.
      • Thompson A.
      • Sarwar N.
      • Caslake M.
      • Butterworth A.S.
      • Amouyel P.
      • Assmann G.
      • Bakker S.J.
      • Barr E.L.
      • Barrett-Connor E.
      • Benjamin E.J.
      • Bjorkelund C.
      • Brenner H.
      • Brunner E.
      • Clarke R.
      • Cooper J.A.
      • Cremer P.
      • Cushman M.
      • Dagenais G.R.
      • RBSr D’Agostino
      • Dankner R.
      • Davey-Smith G.
      • Deeg D.
      • Dekker J.M.
      • Engstrom G.
      • Folsom A.R.
      • Fowkes F.G.
      • Gallacher J.
      • Gaziano J.M.
      • Giampaoli S.
      • Gillum R.F.
      • Hofman A.
      • Howard B.V.
      • Ingelsson E.
      • Iso H.
      • Jorgensen T.
      • Kiechl S.
      • Kitamura A.
      • Kiyohara Y.
      • Koenig W.
      • Kromhout D.
      • Kuller L.H.
      • Lawlor D.A.
      • Meade T.W.
      • Nissinen A.
      • Nordestgaard B.G.
      • Onat A.
      • Panagiotakos D.B.
      • Psaty B.M.
      • Rodriguez B.
      • Rosengren A.
      • Salomaa V.
      • Kauhanen J.
      • Salonen J.T.
      • Shaffer J.A.
      • Shea S.
      • Ford I.
      • Stehouwer C.D.
      • Strandberg T.E.
      • Tipping R.W.
      • Tosetto A.
      • Wassertheil-Smoller S.
      • Wennberg P.
      • Westendorp R.G.
      • Whincup P.H.
      • Wilhelmsen L.
      • Woodward M.
      • Lowe G.D.
      • Wareham N.J.
      • Khaw K.T.
      • Sattar N.
      • Packard C.J.
      • Gudnason V.
      • Ridker P.M.
      • Pepys M.B.
      • Thompson S.G.
      • Danesh J.
      C-reactive protein, fibrinogen, and cardiovascular disease prediction.
      Meta-analyses and systematic reviews suggest that the vast majority of other circulating and urinary biomarkers have no or limited proven ability to improve risk classification. However, the extent to which they have been tested for their ability to add value to risk stratification varies considerably,
      • Gilstrap L.G.
      • Wang T.J.
      Biomarkers and cardiovascular risk assessment for primary prevention: an update.
      • Ioannidis J.P.
      • Tzoulaki I.
      Minimal and null predictive effects for the most popular blood biomarkers of cardiovascular disease.
      with strong evidence of reporting bias.
      • Tzoulaki I.
      • Siontis K.C.
      • Evangelou E.
      • Ioannidis J.P.
      Bias in associations of emerging biomarkers with cardiovascular disease.
      Organ-specific biomarkers may be useful to guide therapy in specific circumstances (e.g. albuminuria in hypertension or DM may predict kidney dysfunction and warrant renoprotective interventions) (see section 3a).
      If, despite these recommendations, biomarkers are used as risk modifiers, it is important to note that having an unfavourable biomarker profile may be associated with a somewhat higher risk, but also that a favourable profile is associated with a lower risk than calculated. The degree to which the calculated risk is affected by biomarkers is generally unknown, but almost universally smaller than the (adjusted) RRs reported for these biomarkers in the literature.
      • Kooter A.J.
      • Kostense P.J.
      • Groenewold J.
      • Thijs A.
      • Sattar N.
      • Smulders Y.M.
      Integrating information from novel risk factors with calculated risks: the critical impact of risk factor prevalence.
      Hence, in these patients, particularly with a moderate risk profile, only relatively small adjustments in calculated risk are justifiable, and patients who are clearly at high or low risk should not be reclassified based on biomarkers.
      • Wurtz P.
      • Havulinna A.S.
      • Soininen P.
      • Tynkkynen T.
      • Prieto-Merino D.
      • Tillin T.
      • Ghorbani A.
      • Artati A.
      • Wang Q.
      • Tiainen M.
      • Kangas A.J.
      • Kettunen J.
      • Kaikkonen J.
      • Mikkila V.
      • Jula A.
      • Kahonen M.
      • Lehtimaki T.
      • Lawlor D.A.
      • Gaunt T.R.
      • Hughes A.D.
      • Sattar N.
      • Illig T.
      • Adamski J.
      • Wang T.J.
      • Perola M.
      • Ripatti S.
      • Vasan R.S.
      • Raitakari O.T.
      • Gerszten R.E.
      • Casas J.P.
      • Chaturvedi N.
      • Ala-Korpela M.
      • Salomaa V.
      Metabolite profiling and cardiovascular event risk: a prospective study of 3 population-based cohorts.

        Gap in evidence

      • Not all potentially useful circulatory and urinary biomarkers have undergone state-of-the-art assessment of their added value in CV risk prediction on top of conventional risk factors.
      • Biomarkers may be useful in specific subgroups, but this has been addressed in only a limited number of studies.
      • The role of metabolomics as risk factors for CVD and to improve CV risk prediction beyond conventional risk factors should be further assessed.

      2.4.4 Measurement of preclinical vascular damage

        Key messages

      • Routine screening with imaging modalities to predict future CV events is generally not recommended in clinical practice.
      • Imaging methods may be considered as risk modifiers in CV risk assessment, i.e. in individuals with calculated CV risks based on the major conventional risk factors around the decisional thresholds.
      Tabled 1Recommendations for imaging methods
      Table thumbnail fx16
      ABI = ankle–brachial index; CV = cardiovascular; IMT = intima–media thickness.aClass of recommendation.bLevel of evidence.cReference(s) supporting recommendations.
      Although most CVD can be explained by traditional risk factors, there is substantial variation in the amount of atherosclerosis. Thus interest has continued in the use of non-invasive imaging techniques to improve CV risk assessment. In individuals with calculated CV risks based on the major conventional risk factors near the decisional thresholds, some imaging techniques may be considered as risk modifiers to improve risk prediction and decision making.

      2.4.4.1 Coronary artery calcium

      Coronary artery calcium (CAC) is examined through electron beam or multislice CT. Calcifications indicate late-stage subclinical coronary atherosclerosis.
      • Tinana A.
      • Mintz G.S.
      • Weissman N.J.
      Volumetric intravascular ultrasound quantification of the amount of atherosclerosis and calcium in nonstenotic arterial segments.
      Atherosclerotic coronary arteries do not necessarily always show calcifications. The extent of the calcification correlates with the extent of total coronary plaque burden.
      • Tinana A.
      • Mintz G.S.
      • Weissman N.J.
      Volumetric intravascular ultrasound quantification of the amount of atherosclerosis and calcium in nonstenotic arterial segments.
      CAC is not an indicator of the (in)stability of an atherosclerotic plaque.
      • Burke A.P.
      • Kolodgie F.D.
      • Farb A.
      • Weber D.
      • Virmani R.
      Morphological predictors of arterial remodeling in coronary atherosclerosis.
      In patients with ACS, the extent of CAC is more pronounced than in those without CAD.
      • Schmermund A.
      • Schwartz R.S.
      • Adamzik M.
      • Sangiorgi G.
      • Pfeifer E.A.
      • Rumberger J.A.
      • Burke A.P.
      • Farb A.
      • Virmani R.
      Coronary atherosclerosis in unheralded sudden coronary death under age 50: histo-pathologic comparison with ‘healthy’ subjects dying out of hospital.
      The quantification of CAC scoring is fairly consistent across studies. Most studies use the Agatston score.
      • Silber S.
      Comparison of spiral and electron beam tomography in the evaluation of coronary calcification in asymptomatic persons.
      The value of the score can be further increased if the age and sex distribution within percentiles are taken into account. A CAC score ≥300 Agatston units or ≥75th percentile for age, sex and ethnicity is considered to indicate increased CV risk.
      CAC has shown a very high negative predictive value, since an Agatston score of 0 has a negative predictive value of nearly 100% for ruling out significant coronary narrowing.
      • Haberl R.
      • Becker A.
      • Leber A.
      • Knez A.
      • Becker C.
      • Lang C.
      • Bruning R.
      • Reiser M.
      • Steinbeck G.
      Correlation of coronary calcification and angiographically documented stenoses in patients with suspected coronary artery disease: results of 1,764 patients.
      However, studies have questioned the negative predictive value of CAC because significant stenosis in the absence of CAC is possible.
      • Marwan M.
      • Ropers D.
      • Pflederer T.
      • Daniel W.G.
      • Achenbach S.
      Clinical characteristics of patients with obstructive coronary lesions in the absence of coronary calcification: an evaluation by coronary CT angiography.
      Many prospective studies have shown the association of CAC with CAD, and the Agatston score is an independent predictor of CAD.
      • Hecht H.S.
      • Superko H.R.
      Electron beam tomography and National Cholesterol Education Program guidelines in asymptomatic women.
      Importantly, including CAC may improve CV risk prediction in addition to conventional risk factors.
      • Hadamitzky M.
      • Freissmuth B.
      • Meyer T.
      • Hein F.
      • Kastrati A.
      • Martinoff S.
      • Schomig A.
      • Hausleiter J.
      Prognostic value of coronary computed tomographic angiography for prediction of cardiac events in patients with suspected coronary artery disease.
      Thus, CAC scoring may be considered in individuals with calculated SCORE risks around the 5% or 10% thresholds.
      • van Werkhoven J.M.
      • Gaemperli O.
      • Schuijf J.D.
      • Jukema J.W.
      • Kroft L.J.
      • Leschka S.
      • Alkadhi H.
      • Valenta I.
      • Pundziute G.
      • de Roos A.
      • van der Wall E.E.
      • Kaufmann P.A.
      • Bax J.J.
      Multislice computed tomography coronary angiography for risk stratification in patients with an intermediate pretest likelihood.
      • Peters S.A.
      • den Ruijter H.M.
      • Bots M.L.
      • Moons K.G.
      Improvements in risk stratification for the occurrence of cardiovascular disease by imaging subclinical atherosclerosis: a systematic review.
      Although recent studies also showed the presence of CAC in low-risk populations, the added predictive value on CV events remains to be demonstrated.
      • McDermott M.M.
      • Greenland P.
      • Liu K.
      • Guralnik J.M.
      • Celic L.
      • Criqui M.H.
      • Chan C.
      • Martin G.J.
      • Schneider J.
      • Pearce W.H.
      • Taylor L.M.
      • Clark E.
      The ankle brachial index is associated with leg function and physical activity: the Walking and Leg Circulation Study.
      • Fowkes F.G.
      • Murray G.D.
      • Newman A.B.
      • Lee R.J.
      Ankle brachial index combined with Framingham Risk Score to predict cardiovascular events and mortality: a meta-analysis.
      • Fowkes F.G.
      • Price J.F.
      • Stewart M.C.
      • Butcher I.
      • Leng G.C.
      • Pell A.C.
      • Sandercock P.A.
      • Fox K.A.
      • Lowe G.D.
      • Murray G.D.
      Aspirin for prevention of cardiovascular events in a general population screened for a low ankle brachial index: a randomized controlled trial.
      • Lorenz M.W.
      • Polak J.F.
      • Kavousi M.
      • Mathiesen E.B.
      • Volzke H.
      • Tuomainen T.P.
      • Sander D.
      • Plichart M.
      • Catapano A.L.
      • Robertson C.M.
      • Kiechl S.
      • Rundek T.
      • Desvarieux M.
      • Lind L.
      • Schmid C.
      • DasMahapatra P.
      • Gao L.
      • Ziegelbauer K.
      • Bots M.L.
      • Thompson S.G.
      Carotid intima-media thickness progression to predict cardiovascular events in the general population (the PROG-IMT collaborative project): a meta-analysis of individual participant data.
      • Tinana A.
      • Mintz G.S.
      • Weissman N.J.
      Volumetric intravascular ultrasound quantification of the amount of atherosclerosis and calcium in nonstenotic arterial segments.
      • Burke A.P.
      • Kolodgie F.D.
      • Farb A.
      • Weber D.
      • Virmani R.
      Morphological predictors of arterial remodeling in coronary atherosclerosis.
      • Schmermund A.
      • Schwartz R.S.
      • Adamzik M.
      • Sangiorgi G.
      • Pfeifer E.A.
      • Rumberger J.A.
      • Burke A.P.
      • Farb A.
      • Virmani R.
      Coronary atherosclerosis in unheralded sudden coronary death under age 50: histo-pathologic comparison with ‘healthy’ subjects dying out of hospital.
      • Silber S.
      Comparison of spiral and electron beam tomography in the evaluation of coronary calcification in asymptomatic persons.
      • Gibson A.O.
      • Blaha M.J.
      • Arnan M.K.
      • Sacco R.L.
      • Szklo M.
      • Herrington D.M.
      • Yeboah J.
      Coronary artery calcium and incident cerebrovascular events in an asymptomatic cohort. The MESA Study.
      • Fernandez-Friera L.
      • Penalvo J.L.
      • Fernandez-Ortiz A.
      • Ibanez B.
      • Lopez-Melgar B.
      • Laclaustra M.
      • Oliva B.
      • Mocoroa A.
      • Mendiguren J.
      • Martinez de Vega V.
      • Garcia L.
      • Molina J.
      • Sanchez-Gonzalez J.
      • Guzman G.
      • Alonso-Farto J.C.
      • Guallar E.
      • Civeira F.
      • Sillesen H.
      • Pocock S.
      • Ordovas J.M.
      • Sanz G.
      • Jimenez-Borreguero L.J.
      • Fuster V.
      Prevalence, vascular distribution, and multiterritorial extent of subclinical atherosclerosis in a middle-aged cohort: the PESA (Progression of Early Subclinical Atherosclerosis) study.
      • Nasir K.
      • Bittencourt M.S.
      • Blaha M.J.
      • Blankstein R.
      • Agatson A.S.
      • Rivera J.J.
      • Miemdema M.D.
      • Sibley C.T.
      • Shaw L.J.
      • Blumenthal R.S.
      • Budoff M.J.
      • Krumholz H.M.
      Implications of coronary artery calcium testing among statin candidates according to American College of Cardiology/American Heart Association cholesterol management guidelines: MESA (Multi-Ethnic Study of Atherosclerosis).
      There are concerns regarding costs and radiation exposure. For CAC scoring, the radiation exposure with properly selected techniques is +1 mSv.

      2.4.4.2 Carotid ultrasound

      Population-based studies have shown correlations between the severity of atherosclerosis in one arterial territory and the involvement of other arteries.
      • O’Leary D.H.
      • Polak J.F.
      • Kronmal R.A.
      • Manolio T.A.
      • Burke G.L.
      • Wolfson Jr., S.K.
      Carotid-artery intima and media thickness as a risk factor for myocardial infarction and stroke in older adults. Cardiovascular Health Study Collaborative Research Group.
      Therefore, early detection of arterial disease in apparently healthy individuals has focused on peripheral arteries, and in particular on the carotid arteries. Risk assessment using carotid ultrasound focuses on the measurement of the intima-media thickness (IMT) and the presence and characteristics of plaques.
      The IMT is not only a measure of early atherosclerosis, but also of smooth muscle hypertrophy/hyperplasia. There is a graded increase in CV risk with increasing IMT,
      • O’Leary D.H.
      • Polak J.F.
      • Kronmal R.A.
      • Manolio T.A.
      • Burke G.L.
      • Wolfson Jr., S.K.
      Carotid-artery intima and media thickness as a risk factor for myocardial infarction and stroke in older adults. Cardiovascular Health Study Collaborative Research Group.
      and a value >0.9 mm is considered abnormal. The risk of stroke associated with IMT is non-linear, with hazards increasing more rapidly at lower IMTs than at higher IMTs. The IMT-associated risk of cardiac events is also non-linear.
      • Chambless L.E.
      • Heiss G.
      • Folsom A.R.
      • Rosamond W.
      • Szklo M.
      • Sharrett A.R.
      • Clegg L.X.
      Association of coronary heart disease incidence with carotid arterial wall thickness and major risk factors: the Atherosclerosis Risk in Communities (ARIC) Study, 1987–1993.
      The extent of carotid IMT is an independent predictor of CVD, but seems to be more predictive in women than in men.
      The lack of standardization regarding the definition and measurement of IMT, its high variability and low intra-individual reproducibility have raised concerns. A recent meta-analysis failed to demonstrate any added value of IMT compared to the Framingham Risk Score in predicting future CVD, even in the intermediate risk group.
      • Den Ruijter H.M.
      • Peters S.A.
      • Anderson T.J.
      • Britton A.R.
      • Dekker J.M.
      • Eijkemans M.J.
      • Engstrom G.
      • Evans G.W.
      • de Graaf J.
      • Grobbee D.E.
      • Hedblad B.
      • Hofman A.
      • Holewijn S.
      • Ikeda A.
      • Kavousi M.
      • Kitagawa K.
      • Kitamura A.
      • Koffijberg H.
      • Lonn E.M.
      • Lorenz M.W.
      • Mathiesen E.B.
      • Nijpels G.
      • Okazaki S.
      • O’Leary D.H.
      • Polak J.F.
      • Price J.F.
      • Robertson C.
      • Rembold C.M.
      • Rosvall M.
      • Rundek T.
      • Salonen J.T.
      • Sitzer M.
      • Stehouwer C.D.
      • Witteman J.C.
      • Moons K.G.
      • Bots M.L.
      Common carotid intima-media thickness measurements in cardiovascular risk prediction: a meta-analysis.
      Thus, the systematic use of carotid ultrasound IMT to improve risk assessment is not recommended.
      Plaque is usually defined as the presence of a focal wall thickening that it is at least 50% greater than the surrounding vessel wall oras a focal region with an IMT measurement ≥1.5 mm that protrudes into the lumen.