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Association of Aspirin Use for Primary Prevention With Cardiovascular Events and Bleeding EventsA Systematic Review and Meta-analysis

Educational Objective
To review the benefits and risks of aspirin for primary prevention of cardiovascular events.
1 Credit CME
Key Points

Question  What is the association of aspirin use with cardiovascular events and bleeding events in individuals without cardiovascular disease?

Findings  In this meta-analysis of 13 trials with 164 225 participants without cardiovascular disease, aspirin use was associated with a lower risk of cardiovascular events, defined as cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke (hazard ratio [HR], 0.89; absolute risk reduction, 0.41%) and an increased risk of major bleeding (HR, 1.43; absolute risk increase, 0.47%).

Meaning  In individuals without cardiovascular disease, the use of aspirin was associated with a lower risk of cardiovascular events and an increased risk of major bleeding.

Abstract

Importance  The role for aspirin in cardiovascular primary prevention remains controversial, with potential benefits limited by an increased bleeding risk.

Objective  To assess the association of aspirin use for primary prevention with cardiovascular events and bleeding.

Data Sources  PubMed and Embase were searched on Cochrane Library Central Register of Controlled Trials from the earliest available date through November 1, 2018.

Study Selection  Randomized clinical trials enrolling at least 1000 participants with no known cardiovascular disease and a follow-up of at least 12 months were included. Included studies compared aspirin use with no aspirin (placebo or no treatment).

Data Extraction and Synthesis  Data were screened and extracted independently by both investigators. Bayesian and frequentist meta-analyses were performed.

Main Outcomes and Measures  The primary cardiovascular outcome was a composite of cardiovascular mortality, nonfatal myocardial infarction, and nonfatal stroke. The primary bleeding outcome was any major bleeding (defined by the individual studies).

Results  A total of 13 trials randomizing 164 225 participants with 1 050 511 participant-years of follow-up were included. The median age of trial participants was 62 years (range, 53-74), 77 501 (47%) were men, 30 361 (19%) had diabetes, and the median baseline risk of the primary cardiovascular outcome was 10.2% (range, 2.6%-30.9%). Aspirin use was associated with significant reductions in the composite cardiovascular outcome compared with no aspirin (60.2 per 10 000 participant-years with aspirin and 65.2 per 10 000 participant-years with no aspirin) (hazard ratio [HR], 0.89 [95% credible interval, 0.84-0.94]; absolute risk reduction, 0.41% [95% CI, 0.23%-0.59%]; number needed to treat, 241). Aspirin use was associated with an increased risk of major bleeding events compared with no aspirin (23.1 per 10 000 participant-years with aspirin and 16.4 per 10 000 participant-years with no aspirin) (HR, 1.43 [95% credible interval, 1.30-1.56]; absolute risk increase, 0.47% [95% CI, 0.34%-0.62%]; number needed to harm, 210).

Conclusions and Relevance  The use of aspirin in individuals without cardiovascular disease was associated with a lower risk of cardiovascular events and an increased risk of major bleeding. This information may inform discussions with patients about aspirin for primary prevention of cardiovascular events and bleeding.

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Article Information

Corresponding Author: Sean L. Zheng, BM, BCh, MA, MRCP, Department of Cardiology, King’s College Hospital NHS Foundation Trust, Denmark Hill, London SE5 9RS, United Kingdom (sean.zheng@nhs.net).

Accepted for Publication: December 3, 2018.

Correction: This article was corrected on June 11, 2019, to correct errors in the Results because 2 studies (the Prevention of Arterial Disease and Diabetes Trial and the Thrombosis Prevention Trial) that were identified in the search and included in the meta-analysis were unintentionally omitted from the analysis for the primary composite cardiovascular outcome. The Results have been corrected and now include these studies in all other outcome analyses.

Author Contributions: Dr Zheng and Mr Roddick had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Dr Zheng and Mr Roddick conducted and are responsible for the data analysis. Dr Zheng and Mr Roddick take full responsibility as first authors.

Concept and design; acquisition, analysis, or interpretation of data; drafting of the manuscript; critical revision of the manuscript for important intellectual content; statistical analysis; and administrative, technical, or material support: Both authors.

Supervision: Zheng.

Conflict of Interest Disclosures: The authors have no conflicts of interest to disclose.

References
1.
Wall  HK, Ritchey  MD, Gillespie  C, Omura  JD, Jamal  A, George  MG.  Vital signs: prevalence of key cardiovascular disease risk factors for million hearts 2022 - United States, 2011-2016.  MMWR Morb Mortal Wkly Rep. 2018;67(35):983-991. doi:10.15585/mmwr.mm6735a4PubMedGoogle ScholarCrossref
2.
Wright  JS, Wall  HK, Ritchey  MD.  Million Hearts 2022: small steps are needed for cardiovascular disease prevention.  JAMA. 2018;320(18):1857-1858. doi:10.1001/jama.2018.13326PubMedGoogle ScholarCrossref
3.
Ritchey  MD, Wall  HK, Owens  PL, Wright  JS.  Vital signs: state-level variation in nonfatal and fatal cardiovascular events targeted for prevention by Million Hearts 2022.  MMWR Morb Mortal Wkly Rep. 2018;67(35):974-982. doi:10.15585/mmwr.mm6735a3PubMedGoogle ScholarCrossref
4.
Antithrombotic Trialists’ (ATT) Collaboration, Baigent  C, Blackwell  L,  et al.  Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials.  Lancet. 2009;373(9678):1849-1860. doi:10.1016/S0140-6736(09)60503-1PubMedGoogle ScholarCrossref
5.
ASCEND Study Collaborative Group, Bowman  L, Mafham  M.  Effects of aspirin for primary prevention in persons with diabetes mellitus.  N Engl J Med. 2018;18(16):1529-1539. doi:10.1056/NEJMoa1804988Google Scholar
6.
Gaziano  JM, Brotons  C, Coppolecchia  R,  et al.  Use of aspirin to reduce risk of initial vascular events in patients at moderate risk of cardiovascular disease (ARRIVE): a randomised, double-blind, placebo-controlled trial.  Lancet. 2018;392(10152):1036-1046. doi:10.1016/S0140-6736(18)31924-XPubMedGoogle ScholarCrossref
7.
Whitlock  EP, Burda  BU, Williams  SB, Guirguis-Blake  JM, Evans  CV.  Bleeding risks with aspirin use for primary prevention in adults: a systematic review for the U.S. Preventive Services Task Force.  Ann Intern Med. 2016;164(12):826-835. doi:10.7326/M15-2112PubMedGoogle ScholarCrossref
8.
Piepoli  MF, Hoes  AW, Agewall  S,  et al.  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).  Eur Heart J. 2016;37(29):2315-2381. doi:10.1093/eurheartj/ehw106PubMedGoogle ScholarCrossref
9.
Guirguis-Blake  JM, Evans  CV, Senger  CA, O’Connor  EA, Whitlock  EP.  Aspirin for the primary prevention of cardiovascular events: a systematic evidence review for the U.S. Preventive Services Task Force.  Ann Intern Med. 2016;164(12):804-813. doi:10.7326/M15-2113PubMedGoogle ScholarCrossref
10.
Van’t Hof  JR, Duval  S, Walts  A, Kopecky  SL, Luepker  RV, Hirsch  AT.  Contemporary primary prevention aspirin use by cardiovascular disease risk: impact of US Preventive Services Task Force recommendations, 2007-2015: a serial, cross-sectional study.  J Am Heart Assoc. 2017;6(10):e006328. doi:10.1161/JAHA.117.006328PubMedGoogle Scholar
11.
Moher  D, Liberati  A, Tetzlaff  J, Altman  DG, PRISMA Group.  Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.  BMJ. 2009;339:b2535. doi:10.1136/bmj.b2535PubMedGoogle ScholarCrossref
12.
Egger  M, Davey Smith  G, Schneider  M, Minder  C.  Bias in meta-analysis detected by a simple, graphical test.  BMJ. 1997;315(7109):629-634. doi:10.1136/bmj.315.7109.629PubMedGoogle ScholarCrossref
13.
Rothwell  PM, Fowkes  FGR, Belch  JFF, Ogawa  H, Warlow  CP, Meade  TW.  Effect of daily aspirin on long-term risk of death due to cancer: analysis of individual patient data from randomised trials.  Lancet. 2011;377(9759):31-41. doi:10.1016/S0140-6736(10)62110-1PubMedGoogle ScholarCrossref
14.
Chubak  J, Whitlock  EP, Williams  SB,  et al.  Aspirin for the prevention of cancer incidence and mortality: systematic evidence reviews for the U.S. Preventive Services Task Force.  Ann Intern Med. 2016;164(12):814-825. doi:10.7326/M15-2117PubMedGoogle ScholarCrossref
15.
McNeil  JJ, Nelson  MR, Woods  RL,  et al Effect of aspirin on all-cause mortality in the healthy elderly.  N Engl J Med. 2018;379(16):1519-1528. doi:10.1056/NEJMoa1803955Google ScholarCrossref
16.
Dias  S, Sutton  AJ, Ades  AE, Welton  NJ.  Evidence synthesis for decision making 2: a generalized linear modeling framework for pairwise and network meta-analysis of randomized controlled trials.  Med Decis Making. 2013;33(5):607-617. doi:10.1177/0272989X12458724PubMedGoogle ScholarCrossref
17.
Zheng  SL, Roddick  AJ, Aghar-Jaffar  R,  et al.  Association between use of sodium-glucose cotransporter 2 inhibitors, glucagon-like peptide 1 agonists, and dipeptidyl peptidase 4 inhibitors with all-cause mortality in patients with type 2 diabetes: a systematic review and meta-analysis.  JAMA. 2018;319(15):1580-1591. doi:10.1001/jama.2018.3024PubMedGoogle ScholarCrossref
18.
McNeil  JJ, Wolfe  R, Woods  RL,  et al Effect of aspirin on cardiovascular events and bleeding in the healthy elderly.  N Engl J Med. 2018;379(3):1509-1518. doi:10.1056/NEJMoa1805819Google ScholarCrossref
19.
Peto  R, Gray  R, Collins  R,  et al.  Randomised trial of prophylactic daily aspirin in British male doctors.  Br Med J (Clin Res Ed). 1988;296(6618):313-316. doi:10.1136/bmj.296.6618.313PubMedGoogle ScholarCrossref
20.
Steering Committee of the Physicians’ Health Study Research Group.  Final report on the aspirin component of the ongoing Physicians’ Health Study.  N Engl J Med. 1989;321(3):129-135. doi:10.1056/NEJM198907203210301PubMedGoogle ScholarCrossref
21.
Hansson  L, Zanchetti  A, Carruthers  SG,  et al.  Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial.  Lancet. 1998;351(9118):1755-1762. doi:10.1016/S0140-6736(98)04311-6PubMedGoogle ScholarCrossref
22.
 Thrombosis prevention trial: randomised trial of low-intensity oral anticoagulation with warfarin and low-dose aspirin in the primary prevention of ischaemic heart disease in men at increased risk. The Medical Research Council’s General Practice Research Framework.  Lancet. 1998;351(9098):233-241. doi:10.1016/S0140-6736(97)11475-1PubMedGoogle ScholarCrossref
23.
de Gaetano  G, Collaborative Group of the Primary Prevention Project.  Low-dose aspirin and vitamin E in people at cardiovascular risk: a randomised trial in general practice.  Lancet. 2001;357(9250):89-95. doi:10.1016/S0140-6736(00)03539-XPubMedGoogle ScholarCrossref
24.
Ridker  PM, Cook  NR, Lee  I-M,  et al.  A randomized trial of low-dose aspirin in the primary prevention of cardiovascular disease in women.  N Engl J Med. 2005;352(13):1293-1304. doi:10.1056/NEJMoa050613PubMedGoogle ScholarCrossref
25.
Belch  J, MacCuish  A, Campbell  I,  et al.  The prevention of progression of arterial disease and diabetes (POPADAD) trial: factorial randomised placebo controlled trial of aspirin and antioxidants in patients with diabetes and asymptomatic peripheral arterial disease.  BMJ. 2008;337:a1840. doi:10.1136/bmj.a1840PubMedGoogle ScholarCrossref
26.
Ikeda  Y, Shimada  K, Teramoto  T,  et al.  Low-dose aspirin for primary prevention of cardiovascular events in Japanese patients 60 years or older with atherosclerotic risk factors: a randomized clinical trial.  JAMA. 2014;312(23):2510-2520. doi:10.1001/jama.2014.15690PubMedGoogle ScholarCrossref
27.
Fowkes  FGR, Price  JF, Stewart  MCW,  et al.  Aspirin for prevention of cardiovascular events in a general population screened for a low ankle brachial index: a randomized controlled trial.  JAMA. 2010;303(9):841-848. doi:10.1001/jama.2010.221PubMedGoogle ScholarCrossref
28.
Ogawa  H, Nakayama  M, Morimoto  T,  et al.  Low-dose aspirin for primary prevention of atherosclerotic events in patients with type 2 diabetes: a randomized controlled trial.  JAMA. 2008;300(18):2134-2141. doi:10.1001/jama.2008.623PubMedGoogle ScholarCrossref
29.
Okada  S, Morimoto  T, Ogawa  H,  et al.  Effect of aspirin on cancer chemoprevention in Japanese patients with type 2 diabetes: 10-year observational follow-up of a randomized controlled trial.  Diabetes Care. 2018;41(8):1757-1764. doi:10.2337/dc18-0368PubMedGoogle ScholarCrossref
30.
Yokoyama  K, Ishizuka  N, Uemura  N,  et al.  Effects of daily aspirin on cancer incidence and mortality in the elderly Japanese.  Res Pract Thromb Haemost. 2018;2(2):274-281. doi:10.1002/rth2.12097PubMedGoogle ScholarCrossref
31.
Cook  NR, Lee  I-M, Gaziano  JM,  et al.  Low-dose aspirin in the primary prevention of cancer: the Women’s Health Study: a randomized controlled trial.  JAMA. 2005;294(1):47-55. doi:10.1001/jama.294.1.47PubMedGoogle ScholarCrossref
32.
Rana  JS, Tabada  GH, Solomon  MD,  et al.  Accuracy of the atherosclerotic cardiovascular risk equation in a large contemporary, multiethnic population.  J Am Coll Cardiol. 2016;67(18):2118-2130. doi:10.1016/j.jacc.2016.02.055PubMedGoogle ScholarCrossref
33.
Allan  GM, Nouri  F, Korownyk  C, Kolber  MR, Vandermeer  B, McCormack  J.  Agreement among cardiovascular disease risk calculators.  Circulation. 2013;127(19):1948-1956. doi:10.1161/CIRCULATIONAHA.112.000412PubMedGoogle ScholarCrossref
34.
Li  L, Geraghty  OC, Mehta  Z, Rothwell  PM, Oxford Vascular Study.  Age-specific risks, severity, time course, and outcome of bleeding on long-term antiplatelet treatment after vascular events: a population-based cohort study.  Lancet. 2017;390(10093):490-499. doi:10.1016/S0140-6736(17)30770-5PubMedGoogle ScholarCrossref
35.
Zheng  SL, Chan  FT, Maclean  E, Jayakumar  S, Nabeebaccus  AA.  Reporting trends of randomised controlled trials in heart failure with preserved ejection fraction: a systematic review.  Open Heart. 2016;3(2):e000449. doi:10.1136/openhrt-2016-000449PubMedGoogle ScholarCrossref
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