Aspirin in primary prevention setting: CV benefit, but higher bleeding

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

Literature - Zheng SL, Roddick AJ - JAMA 2019;321: 277-287 doi:10.1001/jama.2018.20578

Introduction and methods

The benefit of aspirin in secondary prevention of MI and stroke has been well established, however, its effect in primary prevention setting has remained inconclusive [1]. This had led to contrasting recommendations in guidelines and a decline in prescribing aspirin for primary prevention over the past 5-10 years [2-4]. The Centers for Disease Control and Prevention and the Centers for Medicare & Medicaid Services have launched the Million Hearts 2022 initiative with the aim to prevent CV events through risk factor optimization. One of their targets is to improve appropriate prescription of aspirin [5,6]. The aim of this meta-analysis was to determine the association of aspirin with CV outcomes and bleeding events in populations without known CVD.

Trials were eligible with the following criteria: a randomized controlled trial, participants without known CVD, comparison of aspirin with no aspirin, follow up ≥12 months, ≥1000 participants, information on primary and secondary CV outcomes, primary and secondary bleeding outcomes, or cancer outcomes, in English language. 13 Trials with in total 164.225 participants were included and median follow-up was 5.0 years (IQR: 4.7-6.7). 18.5% of participants had diabetes and median 10-year estimated CV event rate was 9.2%.

The primary outcome was a composite of CV death, nonfatal MI and nonfatal stroke. Secondary CV outcomes included all-cause mortality, CV-related mortality, MI, total stroke, and ischemic stroke. The primary bleeding outcome was major bleeding and secondary bleeding outcomes included intracranial bleeding and major gastrointestinal bleeding.

Main results

  • Use of aspirin was associated with a decrease in the primary outcome of CV death, nonfatal MI and nonfatal stroke compared to no aspirin (HR: 0.89, 95%CI: 0.84-0.95, ARR: 0.38%; 95%CI: 0.20-0.55%, NNT 265). Heterogeneity was low (I2 = 0%)
  • Looking at the secondary outcomes all-cause mortality and CV mortality, there were no associations with use of aspirin compared to no aspirin.
  • MI and ischemic stroke were reduced with use of aspirin compared with no aspirin (HR: 0.85, 95%CI: 0.73-0.99, ARR 0.28%; 95%CI: 0.05-0.47%, NNT 361 and HR: 0.81; 95%CI: 0.76-0.87, ARR 0.16%; 95%CI: 0.06-0.30%, NNT 540, respectively). Heterogeneity were I2=0% and 18%, respectively. There was no significant reduction in total stroke with aspirin use compared with no aspirin.
  • Use of aspirin was associated with increased major bleeding compared with no aspirin (HR: 1.43; 95%CI: 1.30-1.56, ARI0. 47%; 95%CI: 0.34-0.62%, NNH 210). Intracranial hemorrhage and major gastrointestinal bleeding were also increased with aspirin use compared with no aspirin. Heterogeneity was low (I2 range, 0%-2%).
  • In studies in which the estimated 10-year CV risk was low (<10%), use of aspirin was associated with a decrease in primary CV outcome compared with no aspirin (HR: 0.87; 95%CI: 0.79-0.95, ARR 0.34%; 95%CI: 0.14-0.52%, NNT 297), no association was found for secondary outcomes and aspirin use was associated with an increased risk of major bleeding (HR: 1.45; 95%CI: 1.28-1.63, ARI 0.40%; 95%CI: 0.25-0.57%, NNH, 249), intracranial bleeding and gastrointestinal bleeding. Heterogeneity was low (I2 range, 0%-11%).
  • Data for diabetes participants showed similar results with use of aspirin vs no aspirin: lower primary CV outcome (HR: 0.89; 95%CI: 0.80-1.00, ARR 0.65%; 95%CI: 0.10%-1.16%, NNT 153) no association for secondary outcomes and increased major bleeding (HR: 1.29; 95%CI:1.11-1.51. ARI 0.80%; 95%CI: 0.29%-1.39%, NNH 121) gastrointestinal bleeding, but not for intracranial bleeding. Heterogeneity was low to moderate (I2 range 0-23%).
  • There was no significant difference in incident cancer (HR: 1.01; 95%CI: 0.93-1.08) or cancer mortality (HR: 1.03; 95%CI: 0.96-1.11) with aspirin use compared with no aspirin.


This meta-analysis of 13 trials enrolling over 164.000 subjects without known CVD demonstrated that use of aspirin was associated with a decrease in CV outcomes, but at the cost of increased major bleeding, intracranial bleeding and gastrointestinal bleeding. Similar findings were observed looking at subgroups of subjects with low CV risk and diabetes populations.

Editorial comment

In his editorial comment, Gaziano [7] starts off with discussing why it is more difficult to do trials in a primary prevention setting. The CV event rates are much lower compared to secondary prevention studies, therefore, the study populations need to be larger and duration longer. In addition, medication adherence is more difficult in subject without disease.

He applauds the authors for a well conducted meta-analysis, using both fixed- and random-effects models. One limitation is that it is not a pooled analysis based on individual patient data, but studies in the past have shown similar findings regardless of type of meta-analysis used.

Guidelines that recommend not to use aspirin in primary prevention setting are based on similar numbers for needed to treat (265) and needed to harm (210). In contrast, the US Preventive Services Task Force recommends improving the benefit-harm ratio by estimating future risk of bleeding, understanding longevity as an indicator of the potential longer-term benefits of aspirin for colorectal cancer prevention, and by carefully discussing patient preferences regarding CV and bleeding events. This meta-analysis, including the three 2018 trials ASCEND, ASPREE and ASPIRE, leaves the estimates for CV events and bleeding with use of aspirin unchanged.

Using a personalized approach for the prescription of aspirin in patients above a certain threshold of CV risk is based on the risk estimation of future event. However, risk calculators tend to overestimate risk for population in which CV risk is declining and risk is not static. Perhaps in the future, new genetic markers or artificial intelligence approaches can help in better risk prediction. In the end when considering the risks and benefits, it should always involve a shared-decision making discussion between patient and physician.

He concludes with: ‘Aspirin remains an important medication for acute management of vascular events; for use after certain procedures; for secondary prevention; and, after careful selection of the right patients, for primary prevention.’


1. 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;373:1849-1860.

2. 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;37:2315-2381.

3. Guirguis-Blake JM, Evans CV, Senger CA, et al. Aspirin for the primary prevention of cardiovascular events: a systematic evidence review for the U.S. Preventive Services Task Force. Ann Intern Med. 2016;164:804-813.

4. 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: e006328.

5. Wright JS, Wall HK, Ritchey MD. Million Hearts 2022: small steps are needed for cardiovascular disease prevention. JAMA. 2018;320:1857-1858.

6. 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;67:974-98

7. Gaziano JM. Aspirin for primary prevention: clinical considerations in 2019. JAMA 2019; 321:253-55

Find this article online at JAMA

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