Background: Cardiovascular disease (CVD) is the leading cause of death in the United States, contributing to more than a third of deaths annually.
Purpose: To systematically review evidence for the effectiveness of aspirin to prevent myocardial infarction (MI)/coronary events, stroke, cardiovascular death, and all-cause mortality in those without a history of CVD. To review evidence for harms associated with aspirin use.
Data Sources: We searched MEDLINE, PubMed, and the Cochrane Collaboration Registry of Controlled Trials to identify literature that was published between January 2008 and June 2014. We supplemented our searches with reference lists from the previous review, relevant existing systematic reviews, suggestions from experts, and Clinicaltrials.gov to identify ongoing trials.
Study Selection: Two investigators independently reviewed identified abstracts and full-text articles against a set of a priori inclusion and quality criteria.
Data Analysis: One investigator abstracted data into an evidence table and a second investigator checked these data. We conducted Mantel-Haenszel fixed effects meta-analyses to estimate the effect size of aspirin chemoprevention in preventing MI/coronary events, stroke, CVD-related death and all-cause mortality. Additionally, we conducted sensitivity analyses using Peto odds ratios. We qualitatively synthesized the harms related to major gastrointestinal (GI) bleeding, hemorrhagic stroke, and age-related macular degeneration to estimate the harms associated with aspirin use.
Results: We included 10 fair- to good-quality randomized, controlled trials (RCTs) (N=103,787) examining the effectiveness of aspirin for the primary prevention of CVD. Aspirin reduces the risk of major CVD events (total MI, total stroke, CVD mortality) by 11 percent (relative risk [RR], 0.89 [95% confidence interval (CI), 0.84 to 0.95]), which appears to be largely driven by a 20 percent reduction in nonfatal MI/coronary events (RR, 0.80 [95% CI, 0.72 to 0.88]). Aspirin’s effectiveness in reducing nonfatal MI/coronary events that were reported in trials of doses ranging from 100 mg every other day to 650 mg daily were also seen with trials using 100 mg or less daily. While primary prevention trials for doses 100 mg every other day to 650 mg daily demonstrated no reduction in stroke events with aspirin use, trials using 100 mg daily or less showed a reduction in total stroke (RR, 0.85 [95% CI, 0.76 to 0.96]). CVD mortality was unchanged with the use of aspirin in these 10 trials. All-cause mortality may be unchanged or slightly reduced with a statistically significant benefit not persistent in dose sensitivity analyses. All trials were powered for CVD composite outcomes. Increasing age being associated with greater RR reductions was the only consistent subgroup trend we identified. Trials of patients with diabetes showed no CVD benefit and trials with diabetes subgroup analyses showed no effect modification in this group. Given the paucity of data, we can draw no conclusions about treatment benefit modification based on aspirin formulation or duration. Aspirin’s CVD benefit appears to begin within the first 5 years of administration; there are limited data for longer durations. We included nine of these RCTs to examine the major GI bleeding harms, hemorrhagic stroke, and other harms associated with aspirin use. Major GI bleeding was reported variably in the nine trials, with RRs ranging from 0.50 to 8.10. An individual participant data meta-analysis reported a 50 percent increase in major GI bleeding and other extracranial bleeding (RR, 1.54 [95% CI, 1.30 to 1.82]) with aspirin use compared to controls. Seven trials reported hemorrhagic stroke as rare events (≤5% incidence) in both aspirin and control groups, making the numbers too unstable to precisely estimate the effect of aspirin on this harm. Two RCTs found no statistically significant difference in age-related macular degeneration in the aspirin group compared to controls. Both trials showed RRs of less than 1.
Conclusions: In primary prevention populations, aspirin modestly reduces nonfatal MI/coronary events and major CVD events, but also increases major GI bleeding risk. More precise real-world estimates for bleeding events, including major GI bleeding events and hemorrhagic stroke, are necessary to calculate the net benefit. At some absolute risk for 10-year CVD events, this absolute CVD benefit could potentially outweigh the bleeding risks. Models to identify these populations are needed.