Seven RCTs (48,248 patients) were included in the review. Sample size ranged from 113 to 15,603. Duration of follow-up ranged from 12 months to 43.2 months. Total Jadad scale scores were 5 (two trials), 4 (two trials) and 3 (three trials).
Compared with monotherapy, borderline statistically significant lower risks were found with combination therapy for the following outcomes: major cardiovascular events (RR 0.91, 95% CI 0.83 to 0.98; Ι²=47.7%; six trials); myocardial infarction (RR 0.86, 95% CI 0.76 to 0.97; Ι²=24.2%; seven trials); and stroke (RR 0.84, 95% CI 0.72 to 0.99; Ι²=50.6%; seven trials).
No statistically significant differences were observed between the combination therapy and monotherapy for risks of overall mortality, vascular death, non-vascular death and revascularization.
Compared with monotherapy, risk of major bleeding events was statistically significantly higher with combination therapy (RR 1.62, 95% CI 1.26 to 2.08; Ι²=65%; seven trials).
The major benefit of combination therapy for reduction of major cardiovascular events (absolute risk reduction 1.06%, 95% CI 0.23 to 1.99) did not outweigh the harm of combination therapy in relation to major bleeding events (absolute risk reduction 1.23%, 95% CI 0.52 to 2.14).
Sub-analyses: mean patient age
Trials with a mean patient age over 65 years had weak but statistically significant reductions in risk of major cardiovascular events (RR 0.90, 95% CI 0.83 to 0.98) and stroke (RR 0.73, 95% CI 0.63 to 0.84) with combination therapy, compared with aspirin alone. A statistically significantly increased risk of major bleeding events (RR 1.56, 95% CI 1.29 to 1.89) was demonstrated for combination therapy, compared with aspirin alone.
Trials with a mean patient age below 65 years had weak but statistically significant reductions in risk of myocardial infarction (RR 0.83, 95% CI 0.73 to 0.94) and stroke (RR 0.83, 95% CI 0.70 to 0.99) with combination therapy, compared with aspirin alone. A statistically significantly increased risk of major bleeding events (RR 1.33, 95% CI 1.14 to 1.56) was demonstrated for combination therapy, compared with aspirin alone.
Combination therapy was not associated with a reduction in harm of major adverse events compared with aspirin monotherapy when mean age was less than 65, follow-up was less than 24 months and the Jadad score was less than 4. Other sub-group results were reported in the paper.
Publication bias
Publication bias was statistically evident for stroke and major bleeding events. No evidence of publication bias was found for major cardiovascular events and myocardial infarction. Results remained the same following use of the trim and fill method.