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Figure.
Venn Diagram Comparing the American College of Cardiology/American Heart Association (ACC/AHA) 2013 and European Society of Cardiology (ESC) 2012 Guideline Recommendations With Eligibility for Statin Trials
Venn Diagram Comparing the American College of Cardiology/American Heart Association (ACC/AHA) 2013 and European Society of Cardiology (ESC) 2012 Guideline Recommendations With Eligibility for Statin Trials

The Venn diagram demonstrates the overlap of treatment recommendations for ACC/AHA and ESC prevention guidelines, as well as the trial eligibility for any of 10 randomized clinical trials studying the efficacy of statins in primary prevention of cardiovascular disease in the general population. For each subgroup, atherosclerotic cardiovascular disease incidence rates (IRs) per 1000 person-years over up to 10 years of follow-up are presented in the figure.

Table 1.  
Cardiovascular Risk Factor Profiles by ACC/AHA 2013 Guideline Recommendations, ESC 2012 Guideline Recommendations, and Statin Trial Eligibilitya
Cardiovascular Risk Factor Profiles by ACC/AHA 2013 Guideline Recommendations, ESC 2012 Guideline Recommendations, and Statin Trial Eligibilitya
Table 2.  
Treatment Recommendations Based on the ACC/AHA 2013 or ESC 2012 Guidelines and Trial Eligibilitya
Treatment Recommendations Based on the ACC/AHA 2013 or ESC 2012 Guidelines and Trial Eligibilitya
Supplement.

eAppendix. Assessment of Cardiovascular Risk Factors, Study Population, Follow-up Data Collection, and Other RCTs Inclusion and Exclusion Criteria, and Methods

eReferences

eTable 1. Definitions of the Recommendation Categories for ACC/AHA 2013 and ESC 2012 Guidelines

eTable 2. Detailed List of the Inclusion and Exclusion Criteria per RCT (for Both Primary and Sensitivity Analysis)

eTable 3. Overview of Selected Clinical Trials on Statin Use for Primary Prevention of CVD (for Both Primary and Sensitivity Analysis)

eTable 4. Overall Cardiovascular Risk Factor Profiles by ACC/AHA 2013, ESC 2012 Guidelines, Trial Eligibility

eFigure 1. Statin Use at Baseline Within Subgroups of ACC/AHA 2013, ESC 2012 Guidelines, and Trial Eligibility

eFigure 2. Venn Diagram Comparing the ACC/AHA 2013, ESC 2012 Recommendations and Eligibility for 18 Statin Trials Selected in the 2013 Review by the Cochrane Collaboration on Statins for Primary Prevention of Cardiovascular Disease

eFigure 3. Venn Diagram Comparing the ACC/AHA 2013 and ESC 2012 Guideline Recommendations and Eligibility for 10 Statin Trials for Primary Prevention of Cardiovascular Disease, Excluding Statin Users at Baseline

eFigure 4. Venn Diagram Comparing the ACC/AHA 2013 and ESC 2012 Guideline Recommendations and Eligibility for 10 Statin Trials for Primary Prevention Of Cardiovascular Disease, Excluding Individuals With Type 2 Diabetes at Baseline

eFigure 5. ACC/AHA 2013 and ESC 2012 Guideline Recommendations and Trial Eligibility by Clinical Characteristics

1.
Perk  J, De Backer  G, Gohlke  H,  et al; European Association for Cardiovascular Prevention & Rehabilitation (EACPR); ESC Committee for Practice Guidelines (CPG).  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).  Eur Heart J. 2012;33(13):1635-1701.PubMedArticle
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Stone  NJ, Robinson  JG, Lichtenstein  AH,  et al; American College of Cardiology/American Heart Association Task Force on Practice Guidelines.  2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.  J Am Coll Cardiol. 2014;63(25, pt B):2889-2934.PubMedArticle
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Goff  DC  Jr, Lloyd-Jones  DM, Bennett  G,  et al; American College of Cardiology/American Heart Association Task Force on Practice Guidelines.  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.  Circulation. 2014;129(25)(suppl 2):S49-S73.PubMedArticle
4.
Mihaylova  B, Emberson  J, Blackwell  L,  et al; Cholesterol Treatment Trialists’ (CTT) Collaborators.  The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials.  Lancet. 2012;380(9841):581-590.PubMedArticle
5.
Taylor  F, Huffman  MD, Macedo  AF,  et al.  Statins for the primary prevention of cardiovascular disease.  Cochrane Database Syst Rev. 2013;1(1):CD004816.PubMed
6.
Ridker  PM.  What works and in whom? a simple, easily applied, evidence-based approach to guidelines for statin therapy.  Circ Cardiovasc Qual Outcomes. 2012;5(4):592-593.PubMedArticle
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Ridker  PM, Wilson  PWF.  A trial-based approach to statin guidelines.  JAMA. 2013;310(11):1123-1124.PubMedArticle
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Ridker  PM, Cook  NR.  Statins: new American guidelines for prevention of cardiovascular disease.  Lancet. 2013;382(9907):1762-1765.PubMedArticle
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Hofman  A, Brusselle  GGO, Darwish Murad  S,  et al.  The Rotterdam Study: 2016 objectives and design update.  Eur J Epidemiol. 2015;30(8):661-708.PubMedArticle
10.
Wieberdink  RG, Ikram  MA, Hofman  A, Koudstaal  PJ, Breteler  MM.  Trends in stroke incidence rates and stroke risk factors in Rotterdam, the Netherlands from 1990 to 2008.  Eur J Epidemiol. 2012;27(4):287-295.PubMedArticle
11.
Bos  MJ, van Rijn  MJ, Witteman  JCM, Hofman  A, Koudstaal  PJ, Breteler  MM.  Incidence and prognosis of transient neurological attacks.  JAMA. 2007;298(24):2877-2885.PubMedArticle
12.
Leening  MJG, Kavousi  M, Heeringa  J,  et al.  Methods of data collection and definitions of cardiac outcomes in the Rotterdam Study.  Eur J Epidemiol. 2012;27(3):173-185.PubMedArticle
13.
Maitland-van der Zee  AH, Klungel  OH, Stricker  BHC,  et al.  Repeated nitrate prescriptions as a potential marker for angina pectoris: a comparison with medical information from the Rotterdam Study.  Pharm World Sci. 2003;25(2):70-72.PubMedArticle
14.
Leening  MJG, Ferket  BS, Steyerberg  EW,  et al.  Sex differences in lifetime risk and first manifestation of cardiovascular disease: prospective population based cohort study.  BMJ. 2014;349:g5992.PubMedArticle
15.
Conroy  RM, Pyörälä  K, Fitzgerald  AP,  et al; SCORE Project Group.  Estimation of ten-year risk of fatal cardiovascular disease in Europe: the SCORE Project.  Eur Heart J. 2003;24(11):987-1003.PubMedArticle
16.
Brugts  JJ, Yetgin  T, Hoeks  SE,  et al.  The benefits of statins in people without established cardiovascular disease but with cardiovascular risk factors: meta-analysis of randomised controlled trials.  BMJ. 2009;338:b2376.PubMedArticle
17.
Muntner  P, Colantonio  LD, Cushman  M,  et al.  Validation of the atherosclerotic cardiovascular disease Pooled Cohort risk equations.  JAMA. 2014;311(14):1406-1415.PubMedArticle
18.
Kavousi  M, Leening  MJG, Nanchen  D,  et al.  Comparison of application of the ACC/AHA guidelines, Adult Treatment Panel III guidelines, and European Society of Cardiology guidelines for cardiovascular disease prevention in a European cohort.  JAMA. 2014;311(14):1416-1423.PubMedArticle
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Pencina  MJ, Navar-Boggan  AM, D’Agostino  RB  Sr,  et al.  Application of new cholesterol guidelines to a population-based sample.  N Engl J Med. 2014;370(15):1422-1431.PubMedArticle
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Vaucher  J, Marques-Vidal  P, Preisig  M, Waeber  G, Vollenweider  P.  Population and economic impact of the 2013 ACC/AHA guidelines compared with European guidelines to prevent cardiovascular disease.  Eur Heart J. 2014;35(15):958-959.PubMedArticle
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Ridker  PM, Rose  L, Cook  NR.  A proposal to incorporate trial data into a hybrid ACC/AHA algorithm for the allocation of statin therapy in primary prevention.  J Am Coll Cardiol. 2015;65(9):942-948.PubMedArticle
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Zipes  DP, Camm  AJ, Borggrefe  M,  et al; American College of Cardiology/American Heart Association Task Force; European Society of Cardiology Committee for Practice Guidelines; European Heart Rhythm Association and the Heart Rhythm Society.  ACC/AHA/ESC 2006 guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: executive summary: a report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Develop Guidelines for Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death) developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society.  Eur Heart J. 2006;27(17):2099-2140.PubMedArticle
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Fuster  V, Rydén  LE, Asinger  RW,  et al; American College of Cardiology; American Heart Association; European Society of Cardiology; North American Society of Pacing and Electrophysiology.  ACC/AHA/ESC guidelines for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines and Policy Conferences (Committee to develop guidelines for the management of patients with atrial fibrillation) developed in collaboration with the North American Society of Pacing and Electrophysiology.  Eur Heart J. 2001;22(20):1852-1923.PubMedArticle
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Brief Report
September 2016

Comparison of ACC/AHA and ESC Guideline Recommendations Following Trial Evidence for Statin Use in Primary Prevention of Cardiovascular DiseaseResults From the Population-Based Rotterdam Study

Author Affiliations
  • 1Department of Epidemiology, Erasmus MC–University Medical Center Rotterdam, Rotterdam, the Netherlands
  • 2Department of Preventive Medicine, Northwestern University, Chicago, Illinois
  • 3Department of Cardiology, Erasmus MC–University Medical Center Rotterdam, Rotterdam, the Netherlands
  • 4Department of Neurology, Erasmus MC–University Medical Center Rotterdam, Rotterdam, the Netherlands
  • 5Department of Radiology, Erasmus MC–University Medical Center Rotterdam, Rotterdam, the Netherlands
  • 6Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, Massachusetts
  • 7Department of Internal Medicine, Erasmus MC–University Medical Center Rotterdam, Rotterdam, the Netherlands
  • 8Inspectorate for Health Care, Utrecht, the Netherlands
JAMA Cardiol. 2016;1(6):708-713. doi:10.1001/jamacardio.2016.1577
Abstract

Importance  The American College of Cardiology/American Heart Association (ACC/AHA) and the European Society of Cardiology (ESC) guidelines both recommend lipid-lowering treatment for primary prevention based on global risk for cardiovascular disease (CVD). However, randomized clinical trials (RCTs) for statin use have included participants with specific risk-factor profiles.

Objective  To evaluate the overlap between the ACC/AHA and ESC guideline recommendations and available evidence from RCTs for statin use in primary prevention of CVD.

Design, Setting, and Participants  We calculated the 10-year risk for hard atherosclerotic CVD (ASCVD) following the ACC/AHA guideline, 10-year risk of CVD mortality following the ESC guideline, and we determined eligibility for each of 10 major RCTs for primary prevention of CVD. Conducted from July 2014 to August 2015, this study included 7279 individuals free of CVD, aged 45 to 75 years, examined between 1997 and 2008 for the Rotterdam Study, a prospective population-based cohort.

Main Outcomes and Measures  Proportions of individuals qualifying for lipid-lowering treatment per guidelines, proportions of individuals eligible for any of the 10 RCTs, overlap between these groups, and corresponding ASCVD incidence rates.

Results  Of the 7279 individuals included in the study, 58.2% were women (n = 4238) and had a mean (SD) age of 61.1 (6.9) years. The ACC/AHA guidelines would recommend statin initiation in 4284 participants (58.9%), while the ESC guidelines would in 2399 participants (33.0%) (overlapping by 95.8% with ACC/AHA). A total of 3857 participants (53.0%) met eligibility criteria for at least 1 RCT. Recommendations from both guidelines and trial evidence overlapped for 1546 participants (21.2%), who were at high risk for ASCVD (21.5 per 1000 person-years). A further 1703 participants (23.4%) would be recommended for statins by the guidelines in the absence of direct trial evidence, while 1176 (16.2%) would have been eligible for at least 1 trial without being recommended statin treatment by any guideline. Finally, 1719 participants (23.6%) would not be recommended a statin, nor would qualify for any of the trials. These individuals had low incidence of ASCVD (3.3 per 1000 person-years).

Conclusions and Relevance  Based on this European population study, ACC/AHA and ESC prevention guidelines often did not align at the individual level. However, for one-fifth of the general population, guidelines on both sides of the Atlantic recommend statin initiation, with trial data supporting the efficacy. There should be no controversy about providing optimal preventive medication to these individuals.

Introduction

Guidelines on lipid-lowering treatment for primary prevention of cardiovascular disease (CVD) are provided by the American College of Cardiology/American Heart Association (ACC/AHA) and the European Society of Cardiology (ESC).13 The recommendations for lipid-lowering treatment initiation from both guidelines are based on evidence from randomized clinical trials (RCTs) demonstrating the efficacy of statins for primary prevention of CVD.4,5 The trial evidence was translated by recommending initiation of treatment for adults with a predicted 10-year risk for CVD exceeding a given threshold.1,3 However, global-risk algorithms were never used as an enrollment criterion for RCTs. Therefore, it has been argued that risk-based allocation of statins does not fully reflect the existing evidence.6,7 The degree of overlap and discrepancy between US and European guidelines in light of available trial evidence remains unclear.7,8

We aimed to compare recommendations from the latest ACC/AHA and ESC prevention guidelines with the evidence from 10 major primary prevention RCTs for statins.

Box Section Ref ID

Key Points

  • Question How do recommendations from the US and European guidelines for statin treatment in primary prevention of cardiovascular disease compare with each other and with available trial evidence?

  • Findings Within a large population-based cohort, American College of Cardiology/American Heart Association guidelines would recommend 58.9% of the participants to initiate statin therapy vs 33.0% for European Society of Cardiology guidelines (95.8% overlap with American College of Cardiology/American Heart Association). Recommendations from both guidelines and trial evidence overlapped for 21.2% of the participants, while 23.6% did not qualify for statin treatment under any guideline or trial.

  • Meaning There should be no controversy about providing optimal preventive medication to a substantial part of the population, in whom guideline recommendations and trial evidence align.

Methods
Study Population and Setting

The study population was derived from the Rotterdam Study, a Dutch prospective population-based cohort established in 1990.9 For the present analysis conducted from July 2014 to August 2015, we included 7279 participants, aged 45 to 75 years. We excluded participants with prevalent atherosclerotic CVD, defined as myocardial infarction, coronary or other arterial revascularization procedure, stroke, transient ischemic attack, or repeated prescription of nitrates (a proxy for individuals with angina pectoris).1013

The main outcome was incident atherosclerotic cardiovascular disease (ASCVD), composed of fatal and nonfatal myocardial infarction, myocardial revascularization, coronary heart disease mortality, and nonhemorrhagic stroke.12,14

Details on the design of the Rotterdam Study, assessment of cardiovascular risk factors, and outcomes are available in the eAppendix in the Supplement. The Rotterdam Study complies with the Declaration of Helsinki and has been approved by the medical ethics committee according to the Wet Bevolkingsonderzoek: ERGO (Population Screening Act: Rotterdam Study), executed by the Ministry of Health, Welfare, and Sports of the Netherlands. All participants provided written informed consent to participate in the study and to obtain information from their treating physicians.

Guideline Recommendations

For each participant, we calculated the 10-year risk for hard ASCVD following ACC/AHA guidelines and the 10-year risk for CVD mortality following ESC guidelines. As recommended by ACC/AHA, we used sex-specific pooled cohort equations for white individuals, and for ESC guidelines, we used sex-specific Systematic Coronary Risk Evaluation (SCORE) equations for low-risk countries.15 Next, we created 3 categories following the ACC/AHA and ESC recommendations based on predicted risk thresholds (eTable 1 in the Supplement): no treatment, treatment considered, and treatment recommended. Additionally, for ACC/AHA only, we created an extra category of no recommendation, as US guidelines abstain from recommendations for individuals with heart failure and end-stage renal disease.1

Trial Eligibility

For the statin trial eligibility, we identified 10 primary prevention RCTs, reporting on all-cause mortality and CVD events, selected in the meta-analysis by Brugts and colleagues16 (eTable 2 and eTable 3 in the Supplement). Every participant was checked for eligibility criteria in each of the 10 RCTs (see the eAppendix in the Supplement for details).

The 10 randomized clinical trials included AFCAPS/TexCAPS (Force/Texas Coronary Atherosclerosis Prevention Study); ALLHAT LLT (The Lipid-Lowering Trial [LLT] Component of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial); ASCOT LLA (Prevention of Coronary and Stroke Events With Atorvastatin in Hypertensive Patients in the Anglo-Scandinavian Cardiac Outcomes Trial, The Lipid Lowering Arm); ASPEN (The Atorvastatin Study for Prevention of Coronary Heart Disease Endpoints in Non-Insulin-Dependent Diabetes Mellitus); CARDS (Collaborative Atorvastatin Diabetes Study); JUPITER (Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin); MEGA (Management of Elevated Cholesterol in the Primary Prevention Group of Adult Japanese Study Group); MRC/BHF (Heart Protection Study of Cholesterol Lowering With Simvastatin); PROSPER (The Prospective Study of Pravastatin in the Elderly at Risk); and WOSCOPS (The West of Scotland Coronary Prevention Study).

Statistical Analysis

We determined the proportions of the study population who would qualify for statin treatment under the ACC/AHA and ESC guidelines, and these were compared with trial eligibility. Further, we compared cardiovascular risk factor profiles of groups with discrepant guideline recommendations. Observed ASCVD incidence rates (IRs) are expressed per 1000 person-years over up to 10 years of follow-up.

Sensitivity analyses are provided in the Supplement, including (1) results based on 18 RCTs (including 8 trials that did not assess clinical CVD event rates) selected in the 2013 Cochrane Collaboration review on statins for primary prevention of CVD (eFigure 2),5 (2) results based on the study population free of diabetes (eFigure 3), and (3) results based on the study population not using statins at baseline (eFigure 4).

Results

The mean (SD) age of the participants was 61.1 (6.9) years, and 58.2% were women (n = 4238). Among all participants, 24.7% were current smokers (n = 1798) and 8.4% had type 2 diabetes (n = 609) (Table 1). A total of 674 participants (9.3%) used statins at baseline (eFigure 1 in the Supplement).

For the treatment-recommended category, 4284 (58.9%) and 2399 (33.0%) of the entire study population qualified for lipid-lowering therapy based on the ACC/AHA 2013 and ESC 2012 guidelines, respectively. Based on the eligibility criteria, 3857 of all participants (53.0%) would have been eligible for at the least 1 of 10 RCTs (Table 2). Among all 3857 trial eligible participants, 1 in 3 did not immediately qualify for lipid-lowering treatment under the US guidelines, and more than half did not qualify under the European guidelines. A total of 95.8% of 2399 participants qualifying for lipid-lowering treatment by the ESC also qualified under the ACC/AHA recommendations (Figure).

Although cardiovascular risk-factor profiles of treatment-recommended participants were similar for both guidelines, adults eligible by the ESC but not ACC/AHA guideline were more likely to be older, women, and have a considerably lower estimated glomerular filtration rate. Trial-eligible individuals, not qualifying for statin treatment under the US or European guidelines, were predominantly younger women, with more favorable lipid profiles when compared with the trial-ineligible individuals qualifying for statin treatment only under the US or European guidelines (Table 1; eTable 4 in the Supplement).

The ASCVD IRs for each subgroup are presented in the Figure. A high rate (21.5 per 1000 person-years) was observed among those recommended treatment by both guidelines supported by trial data, while a low rate (3.7 per 1000 person-years) was observed among trial-eligible individuals who were not recommended to initiate statins according to either of the guidelines.

Results did not materially change when the ACC/AHA and ESC recommendations were compared with the eligibility in 18 trials used in the 2013 review of the Cochrane Collaboration, nor after excluding baseline statin users or individuals with diabetes (eFigure 2, eFigure 3, and eFigure 4 in the Supplement). Increasing levels of individual cardiovascular risk factors were associated with increased likelihood of positive guideline recommendations on initiation of lipid-lowering therapy and trial eligibility (eFigure 5 in the Supplement).

Discussion

In this European population-based study of adults aged 45 to 75 years free of CVD, we observed that ESC 2012 guideline recommendations were highly (95.8%) overlapping with the ACC/AHA 2013 guidelines, yet the US guidelines recommended substantially more persons for lipid-lowering treatment (58.9%) as compared with the ESC (33.0%), which is mostly explained by the lowered treatment threshold in the US guidelines. These estimates are very much in line with results from several observational studies in this field.1721 Overall, 21.2% of adults were recommended to initiate a statin based on both guidelines supported by trial data. However, in individuals without direct RCT evidence, we noted discrepancies between the guidelines: a small group (0.8%) at very high risk (IR, 27.0 per 1000 person-years) was eligible by the ECS but not ACC/AHA guidelines (Figure). These individuals were significantly more likely to have chronic kidney disease and heart failure, which can be explained by ACC/AHA abstaining from the recommendations for individuals with heart failure and end-stage renal disease.2 On the other hand, 12.3% of the population at high risk (IR, 9.2 per 1000 person-years) was eligible by the ACC/AHA but not ESC guidelines (Figure). These discrepancies between the guidelines contribute to the ongoing discussion regarding selection of high-risk individuals and the translation of the available trial evidence into clinical practice guidelines for lipid-lowering treatment for primary prevention of CVD. For future iterations of prevention guidelines, participating experts from the ACC, AHA, ESC, and other key global organizations might consider working in unison to create a homogeneous set of recommendations as has been done before in other cardiology subspecialties.22,23

Although 16.2% of the studied population (n = 1176) would not be recommended for statin treatment by either ACC/AHA or ESC guidelines despite the availability of conclusive trial data in these individuals, we observed that such individuals had a low short-term risk for CVD (Figure). However, given that these individuals have high-risk features that qualified them for these trials, they may likely have an increased lifetime risk for CVD.24,25 Several US-based research groups have demonstrated that lowering ASCVD risk thresholds for initiating statin treatment even further would still be cost-effective, while preventing additional CVD events.26,27 Early identification and treatment of persons with elevated CVD risk factors could be considered even more cost-effective in the long run as compared with waiting to initiate treatment until absolute short-term risk is elevated.

This study had several limitations. First, 95% of the Rotterdam Study population is of European ancestry; therefore, our findings should be cautiously extrapolated to other ethnicities. Second, 9.3% of the studied population used statins; therefore, calculated ASCVD incidence rates might be disproportionally underestimated, especially in the higher-risk subgroups where statin use was most frequent (eFigure 1 in the Supplement). Finally, all population-based cohorts involving active participation are subject to the healthy volunteer effect,28 thus leading to underestimation of the proportions of individuals qualifying for lipid-lowering therapy.

Conclusions

We found that discrepancies existed between current CVD prevention guidelines on both sides of the Atlantic and available trial evidence. Yet, for 1 of 5 adults aged 45 to 75 years, the ACC/AHA 2013 guidelines, ESC 2012 guidelines, and presence of RCT evidence support statin treatment for primary prevention of CVD. Because improved patient outcomes have been demonstrated for these individuals, it should be an imperative to ensure that they are identified and are offered optimal evidence-based treatment to reduce the burden of CVD.

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Article Information

Corresponding Author: Maarten J. G. Leening, MD, PhD, Departments of Epidemiology and Cardiology, Erasmus MC–University Medical Center Rotterdam, PO Box 2040, 3000 CA Rotterdam, the Netherlands (m.leening@erasmusmc.nl).

Accepted for Publication: April 21, 2016.

Published Online: July 6, 2016. doi:10.1001/jamacardio.2016.1577.

Author Contributions: Dr Pavlović had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Pavlović, Greenland, Franco, Leening.

Acquisition, analysis, or interpretation of data: Pavlović, Deckers, Brugts, Kavousi, Dhana, Ikram, Hofman, Stricker, Franco, Leening.

Drafting of the manuscript: Pavlović.

Critical revision of the manuscript for important intellectual content: Pavlović, Greenland, Deckers, Brugts, Kavousi, Dhana, Ikram, Hofman, Stricker, Franco, Leening.

Statistical analysis: Pavlović, Leening.

Obtained funding: Ikram, Stricker, Franco.

Administrative, technical, or material support: Ikram, Leening.

Study supervision: Deckers, Brugts, Kavousi, Stricker, Franco, Leening.

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Franco works in ErasmusAGE, a center for aging research across the life course funded by Nestlé Nutrition (Nestec Ltd), Metagenics Inc, and AXA. No other disclosures were reported.

Funding/Support: The Rotterdam Study is supported by the Erasmus MC and Erasmus University Rotterdam; the Netherlands Organisation for Scientific Research; the Netherlands Organisation for Health Research and Development; the Research Institute for Diseases in the Elderly; the Netherlands Genomics Initiative; the Ministry of Education, Culture, and Science; the Ministry of Health, Welfare, and Sports; the European Commission (DG XII); and the Municipality of Rotterdam. Drs Pavlović and Dhana are supported by Erasmus Mundus Western Balkans, a project funded by the European Commission. Dr Greenland has received grants from the National Institutes of Health and the American Heart Association. Dr Leening is supported by a Prins Bernhard Cultuurfonds Fellowship and the De Drie Lichten Foundation. Dr Leening has received funding from Erasmus University Trustfonds, the American Heart Association, the Netherlands Epidemiology Society, and the European Society of Cardiology.

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Additional Contributions: The dedication, commitment, and contribution of inhabitants, general practitioners, and pharmacists of the Ommoord district to the Rotterdam Study are gratefully acknowledged.

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Ridker  PM, Wilson  PWF.  A trial-based approach to statin guidelines.  JAMA. 2013;310(11):1123-1124.PubMedArticle
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Ridker  PM, Cook  NR.  Statins: new American guidelines for prevention of cardiovascular disease.  Lancet. 2013;382(9907):1762-1765.PubMedArticle
9.
Hofman  A, Brusselle  GGO, Darwish Murad  S,  et al.  The Rotterdam Study: 2016 objectives and design update.  Eur J Epidemiol. 2015;30(8):661-708.PubMedArticle
10.
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