Abstract:

The long-term antiplatelet strategy for patients who have undergone percutaneous coronary intervention (PCI) continues to evolve, particularly in high-risk individuals who complete the standard duration of dual antiplatelet therapy (DAPT). Traditionally, aspirin has been central to secondary prevention regimens. However, increasing concerns regarding its gastrointestinal toxicity, bleeding risk, and pharmacodynamic variability have prompted reevaluation of its role in monotherapy, especially in light of emerging evidence favoring P2Y12 inhibitors such as clopidogrel. The SMART-CHOICE 3 trial addressed this clinical uncertainty through a large-scale, multicenter, open-label randomized trial conducted across 26 sites in South Korea. A total of 5,506 patients with previous myocardial infarction, diabetes mellitus, or complex coronary lesions who had completed DAPT after PCI were randomized to receive either clopidogrel (75 mg/day) or aspirin (100 mg/day) monotherapy. Over a median follow-up of 2.3 years, the primary composite outcome—death from any cause, myocardial infarction, or stroke—occurred significantly less frequently in the clopidogrel group (4.4%) compared to the aspirin group (6.6%) (HR 0.71; 95% CI 0.54–0.93; p=0.013). Breaking down the composite, myocardial infarction was halved in the clopidogrel arm (1.0% vs. 2.2%; HR 0.54), and all-cause mortality was numerically lower (2.4% vs. 4.0%; HR 0.71). Stroke rates were similar between groups. Notably, there was no difference in major bleeding between the two strategies (both 3.0%; HR 0.97), dispelling prior concerns regarding clopidogrel’s bleeding risk. Clopidogrel also showed a favorable safety profile with no increase in adverse events. In conclusion, clopidogrel monotherapy provides a superior net clinical benefit compared to aspirin for long-term secondary prevention following PCI, especially in high-risk patients. Its targeted mechanism of action, lower bleeding liability, and consistent performance across major trials strongly support its preferential use over aspirin in modern antiplatelet therapy. These results validate recent shifts in international guidelines advocating personalized, risk-adjusted approaches to antiplatelet therapy.

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