Physicians' Academy for Cardiovascular Education

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


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.’


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