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

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 9.2% (range, 2.6%-15.9%). Aspirin use was associated with significant reductions in the composite cardiovascular outcome compared with no aspirin (57.1 per 10 000 participant-years with aspirin and 61.4 per 10 000 participant-years with no aspirin) (hazard ratio [HR], 0.89 [95% credible interval, 0.84-0.95]; absolute risk reduction, 0.38% [95% CI, 0.20%-0.55%]; number needed to treat, 265). 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.

Figure 1.. Cardiovascular and Bleeding Outcomes in All Participants

The composite cardiovascular (CV) outcome consisted of cardiovascular mortality, nonfatal myocardial infarction, and nonfatal stroke. Hazard ratios (HRs) and 95% credible interval variables (CrIs) were calculated using Bayesian meta-analysis of trial-level event counts. The absolute risk reductions and increases were calculated by multiplying the control event risk by the relative risk and 95% CIs derived by frequentist meta-analysis (eFigure 4 in Supplement 2). GI indicates gastrointestinal.

Figure 2.. Cardiovascular and Bleeding Outcomes for Studies With Patients at High and Low Risk for the Primary CV Outcome and With Diabetes

Cardiovascular and bleeding outcomes for studies in which the risk of the primary cardiovascular outcome were low and high, and in participants with diabetes. Trials were low or high risk if the 10-year cardiovascular (CV) risk for the primary CV outcome was less than 10% or greater than or equal to 10%, respectively. The composite CV outcome included CV mortality, nonfatal myocardial infarction, and nonfatal stroke. Hazard ratios (HRs) and 95% credible intervals (CrIs) were calculated using Bayesian meta-analysis of event counts. The absolute risk reductions and increases were calculated by multiplying the control event risk by the relative risk and 95% CIs derived by frequentist meta-analysis (eFigure 4 in Supplement 2). Heterogeneity was assessed using I² statistics. GI indicates gastrointestinal. ^aThe number of participants randomized to each arm in the Women's Health Study was not reported, so event counts are omitted. ^bUpper CrI: 0.997.

Figure 3.. Exploratory Cancer Outcomes

Cancer outcomes across all studies, in low and high cardiovascular risk populations, and in patients with diabetes. The absolute risk reductions and increases were calculated by multiplying the control event risk by the relative risk, and 95% CIs derived by frequentist meta-analysis (eFigure 4 in Supplement 2). Study heterogeneity was assessed using I² statistics. HR indicates hazard ratio; CrI indicates credible interval; CV indicates cardiovascular. Data for the JPAD, JPPP, and WHS trials were extracted from subsequent trial publications on cancer outcomes.^,, Data for the HOT, BDS, and PHS (cancer mortality) and the HOT, BDS, AAA, and POPADAD (incident cancer) trials were extracted from previous meta-analyses on cancer outcomes.