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Clopidogrel Monotherapy Shows Stronger Benefit Than Aspirin in Females After PCI
In a prespecified sex-stratified analysis of a large randomised trial, clopidogrel monotherapy reduced the composite risk of all-cause death, myocardial infarction, or stroke by approximately 55% compared with aspirin in females (adjusted HR 0.45, 95% CI 0.24–0.85), whereas no statistically significant reduction was observed in males (adjusted HR 0.77, 95% CI 0.56–1.07). The directional consistency of benefit across both sexes, combined with a non-significant interaction test, means the apparent difference in effect size between females and males cannot be interpreted as a confirmed differential response to treatment.
What Was Studied
This analysis examined whether the relative benefit of clopidogrel monotherapy over aspirin monotherapy — measured by the composite of all-cause death, myocardial infarction, or stroke — differs according to patient sex in a high-risk post-PCI population. The question is clinically relevant because antiplatelet monotherapy choices following the standard dual antiplatelet period are consequential, and it remains unclear whether sex should influence that selection.
How It Was Studied
This was a prespecified substudy of the SMART-CHOICE 3 randomised controlled trial, conducted in South Korea. Patients enrolled were at high risk of recurrent ischaemic events and had already completed their standard-duration dual antiplatelet therapy following percutaneous coronary intervention. They were then randomly assigned to receive either clopidogrel or aspirin as ongoing monotherapy. The total analysed population comprised 5,506 patients, of whom 1,002 were female and 4,504 were male, reflecting a marked sex imbalance in enrolment that has implications for the statistical power of subgroup comparisons.
What Was Observed
- Among females, clopidogrel monotherapy was associated with an approximately 55% lower risk of the primary composite endpoint compared with aspirin — event rates of 4.3% versus 9.4% respectively (adjusted HR 0.45, 95% CI 0.24–0.85; p=0.014). This represents a statistically significant and numerically large treatment effect in the female subgroup.
- Among males, clopidogrel was associated with a directionally similar but smaller and statistically non-significant reduction in the primary endpoint compared with aspirin — event rates of 4.4% versus 6.0% (adjusted HR 0.77, 95% CI 0.56–1.07; p=0.116). The confidence interval crosses 1.0, indicating that a null or marginally adverse effect cannot be excluded in males on the basis of this analysis alone.
- Overall, the incidence of the primary composite endpoint was numerically higher in females than in males (6.7% vs 5.2%), though after adjustment this difference was not statistically significant (adjusted HR 0.89, 95% CI 0.62–1.28; p=0.537), suggesting that baseline risk profile differences between sexes did not translate into a statistically detectable gap in outcomes.
- The formal test for interaction between sex and treatment assignment was non-significant (p for interaction = 0.288), meaning the data do not statistically support the conclusion that clopidogrel’s effect genuinely differs between females and males.
Why This Matters
The optimal antiplatelet monotherapy strategy after PCI in high-risk patients remains an open clinical question, and sex-specific evidence to guide those decisions has been limited. This analysis is notable for being a prespecified substudy with a defined primary composite endpoint, lending it greater credibility than post-hoc subgroup reports. The findings suggest that clopidogrel may offer directionally consistent — and possibly greater — absolute benefit in females, providing a hypothesis that could inform the design of future trials specifically powered to assess sex-differentiated antiplatelet strategies in this setting.
How to Read This Result
Although the point estimate for clopidogrel versus aspirin in females is striking, the wide confidence interval (95% CI 0.24–0.85) and small female subgroup (n=1,002) substantially limit precision, and the non-significant interaction test means the observed sex difference in effect size may reflect chance rather than a true biological or clinical distinction between sexes.
Limitations
The abstract does not explicitly report study limitations.