Clopidogrel better than aspirin for secondary prevention of CAD, finds meta-analysis

By Rebecca Jenkins

Long-term clopidogrel monotherapy provides better protection against major cardiovascular events in patients with coronary artery disease (CAD) compared with aspirin, without an increase in bleeding, a large meta-analysis finds.

Previous evidence on the comparative efficacy and safety of the two antiplatelet strategies had been inconsistent and limited by insufficient statistical power of individual trials and heterogeneity across trial design, researchers wrote in The Lancet.

In light of newer evidence, they conducted a systematic literature review and identified seven randomised trials comparing single antiplatelet treatment with clopidogrel against aspirin in patients with established CAD, who had discontinued or never started dual antiplatelet therapy.

Of the 28,982 patients included in the trials, most had undergone percutaneous coronary intervention or had acute coronary syndrome, researchers noted.

In a patient-level meta-analysis, the data showed that at 5.5 years major adverse cardiovascular or cerebrovascular events were less common in patients randomised to clopidogrel than in patients assigned to aspirin, driven primarily by lower rates of myocardial infarction and stroke.

There were 929 events (2.61 per 100 patient-years) in the clopidogrel group versus 1062 events in patients randomised to aspirin (2.99 per 100 patient-years), resulting in a hazard ratio of 0.86. Mortality and major bleeding events did not differ between the two groups, researchers noted.

In addition, treatment effects were consistent across prespecified subgroups, including individuals with clinical features associated with poor responsiveness to clopidogrel.

‘These results support a preference for clopidogrel over aspirin for chronic antiplatelet monotherapy for patients with stable CAD,’ the study authors wrote.

‘The widespread availability, generic formulation, and affordability of clopidogrel further supports its potential for extensive adoption in clinical practice.’

Commenting on the findings, Professor David Brieger, Interventional Cardiologist and Head of Cardiology at Concord Repatriation General Hospital, Sydney, said in recent years several small studies had suggested clopidogrel might be more effective than aspirin in this setting.

‘The trials have not all been consistent, however, and there has always been a nagging concern that clopidogrel resistance, present in 30 to 50% of patients, limits its efficacy,’ he told Medicine Today.

Strengths of this latest paper included the number of patients, the patient-level data acquired and the robust statistical methodology.

‘Furthermore, this study suggested that even in patients with clinical characteristics associated with clopidogrel resistance, outcomes were not worse than in comparable patients receiving aspirin, which is reassuring.’

Professor Brieger said clinical practice was already moving towards a preference for P2Y12 antagonist drugs over aspirin for this patient group.

‘The recent Australian guidelines gave a strong recommendation of P2Y12 antagonist drugs over aspirin in this setting, while grading the evidence supporting this recommendation as "moderate",’ Professor Brieger said.

‘This analysis may nudge the strength of evidence towards "strong", particularly for clopidogrel which is the only P2Y12 drug reimbursed by the PBS when used as monotherapy.’

Although not commented on in this analysis, Professor Brieger noted that clopidogrel was known to increase surgical bleeding rates relative to aspirin.

‘To guard against this, we recommend that patients undergoing elective surgery in whom ceasing an antiplatelet agent is undesirable (e.g. previous stents), clopidogrel be replaced by  low-dose aspirin five days before surgery,’ he said.

Lancet 2025; https://doi.org/10.1016/ S0140-6736(25)01562-4.