Clopidogrel versus aspirin for secondary prevention of coronary artery disease stratified by age: an individual patient data meta-analysis of 28,982 patients from 7 randomized trials
D Giacoppo, F Gragnano, H Watanabe, K H Choi, T Kimura, J Kang, H S Kim, K W Park, A A Pettersen, M Woodward, D Bhatt, D Angiolillo, R Mehran, J Y Hahn, M ValgimigliAbstract
Background
Aspirin monotherapy is currently recommended as the standard antiplatelet monotherapy for the secondary prevention of ischemic events in patients with established coronary artery disease (CAD). Emerging evidence suggests that, compared with aspirin, clopidogrel is associated with a lower incidence of ischemic events at long-term follow-up, without a concomitant increase in the risk of bleeding. However, it remains unclear whether these effects depend on patient age.
Purpose
To provide an assessment of the comparative efficacy and safety of clopidogrel versus aspirin monotherapy in patients with established CAD according to patient age.
Methods
The study represents a prespecified subanalysis of an individual patient data meta-analysis of 7 randomized trials in which patients were stratified according to a prespecified age cut off of 65 years. The main analysis was performed using semi-parametric shared log-normal frailty models (one-stage analysis), including a random intercept to account for differences in the baseline hazard across trials, and a random slope to account for between-trial differences in treatment effects. Secondary analyses included analyses by multivariable frailty models (multivariable one-stage analysis) and two-stage analyses. The primary efficacy endpoint was a composite of major adverse cardiovascular or cerebrovascular events (MACCE) including cardiovascular death, myocardial infarction, or stroke, assessed at the maximum available follow-up of 5.5 years. The primary safety endpoint was major bleeding at the same follow-up duration.
Results
A total of 13,980 patients (48.2%) were included in the ≤65 years group (median age: 57 years) and 15,002 patients (51.8%) were included in the >65 years group (median age: 74 years). Baseline characteristics were overall well balanced between treatment groups. At 5.5 years, the significant reduction in MACCE associated with clopidogrel monotherapy over aspirin monotherapy was consistent between age subgroups (≤65 years: hazard ratio [HR] 0.82, 95% confidence interval [CI] 0.70-0.96; >65 years: HR 0.87, 95% CI 0.76-1.00), with no significant interaction (Pint=0.577). The results remained unchanged after multivariable adjustment. At 5.5 years, the absence of significant differences in major bleeding between clopidogrel and aspirin monotherapies was consistent between age subgroups (≤65 years: HR 1.03, 95% CI 0.62-1.72; >65 years: HR 0.91, 95% CI 0.72-1.14), with no significant interaction (Pint=0.). The results remained unchanged after multivariable adjustment. The two-stage analysis yielded consistent results for both MACCE and major bleeding. The effects were also consistent across all the secondary endpoints, regardless of the type of analysis.
Conclusion
Clopidogrel monotherapy is associated with a significant reduction in MACCE without a concomitant increase in major bleeding regardless of the patient age.MACCE