Meta-analysis favours clopidogrel over aspirin for secondary prevention in CAD

In patients with established coronary artery disease (CAD), clopidogrel appears to provide superior protection against major adverse cardiovascular or cerebrovascular events (MACCE) without increasing the risk of bleeding when compared with aspirin, according to a meta-analysis.

Pooled data from seven randomized controlled trials involving 28,982 patients (median age 65.5 years, 78.59 percent male) showed that over the longest available follow-up of 5.5 years (median 2.3 years), the primary efficacy endpoint of MACCE—defined as a composite of cardiovascular death, myocardial infarction, or stroke—occurred less frequently among patients who received clopidogrel monotherapy than those who received aspirin monotherapy (2.61 vs 2.99 per 100 patient-years; adjusted hazard ratio [HR], 0.84, 95 percent confidence interval [CI], 0.75–0.94; p=0.0021). [Lancet 2025;doi:10.1016/S0140-6736(25)01562-4]

Major bleeding, the primary safety endpoint, did not significantly differ between the clopidogrel and aspirin groups (0.71 vs 0.77 per 100 patient-years, respectively; adjusted HR, 1.00, 95 percent CI, 0.76–1.32; p=0.99).

“Treatment effects were consistent across all prespecified subgroups, including individuals with clinical features associated with poor responsiveness to clopidogrel, as defined by the ABCD-GENE score, evaluated both individually and in combination,” the investigators said.

The incidence of net adverse cardiac or cerebrovascular events (defined as a composite of the individual components of MACCE plus major bleeding) was significantly reduced with clopidogrel monotherapy vs aspirin monotherapy (3.16 vs 3.54 per 100 patient-years; adjusted HR, 0.87, 95 percent CI, 0.79–0.96; p=0.0051).

Looking at individual components, myocardial infarction events were fewer in the clopidogrel vs aspirin group (0.99 vs 1.27 per 100 patient-years; adjusted HR, 0.75, 95 percent CI, 0.65–0.88; p=0.0003), as was that of stroke (0.73 vs 0.88 per 100 patient-years; adjusted HR, 0.84, 95 percent CI, 0.71–0.98; p=0.032). No significant between-group difference was seen for cardiovascular death (1.18 vs 1.19 per 100 patient-years; p=0.58) and all-cause death (1.96 vs 1.98 per 100 patient-years; p=0.82).

CAD population

The current patient data meta-analysis provides the most comprehensive evaluation to data of the comparative efficacy and safety of clopidogrel vs aspirin monotherapy with established CAD who had discontinued or never started dual antiplatelet therapy (DAPT). Most of these patients had undergone percutaneous coronary intervention (PCI) or had acute coronary syndrome.

The seven trials included in the meta-analysis were as follows: ASCET, CADET, CAPRIE, HOST-EXAM, STOPDAPT-2, STOPDAPT-3, and SMART-CHOICE 3.

The finding on MACCE is consistent with and extends previous analyses conducted in more heterogeneous populations, including patients with different P2Y₁₂ inhibitors, patients treated with noncoronary atherosclerotic disease, or cohorts limited to the post-PCI setting. [J Am Coll Cardiol 2023;82:89-105; Lancet 2020;395:1487-1495; BMJ 2025;389:e082561] 

“The significant anti-ischaemic benefit of clopidogrel was not offset by an increase in bleeding events,” which contrasts with findings from other studies evaluating alternative antithrombotic strategies to aspirin monotherapy, the investigators said. [EuroIntervention 2022;18:e377-e388; Eur Heart J Cardiovasc Pharmacother 2023;9:271-290; Eur Heart J Cardiovasc Pharmacother 2023;9:462-496; Nat Rev Cardiol 2022;19:117-132]

Taken together, these data suggest that clopidogrel is a better choice for long-term antiplatelet treatment in patients with established CAD, according to the investigators. “The widespread availability, generic formulation, and affordability of clopidogrel further supports its potential for extensive adoption in clinical practice.”