The A-CLOSE (A Randomized Comparison of CLOpidogrel Monotherapy Versus Extended Dual-antiplatelet Therapy Beyond 12 Months After Implantation of Drug-eluting StEnts in High-risk Lesions or Patients) trial compared clopidogrel monotherapy with extended dual antiplatelet therapy (DAPT) with clopidogrel plus aspirin in patients at high ischemic risk approximately 12 months after PCI with drug-eluting stent.¹ Patients were randomly assigned to clopidogrel monotherapy (n = 1,601) or continued DAPT (n = 1,602) for an additional 24 months. The primary endpoint was a composite of all-cause death, myocardial infarction (MI), stent thrombosis, stroke, or Bleeding Academic Research Consortium (BARC) types 2, 3, or 5 bleeding. This endpoint occurred in 5% of patients in the clopidogrel-monotherapy group and in 5.1% in the continued-DAPT group, meeting criteria for noninferiority of clopidogrel monotherapy.

The similar primary endpoint rates, however, masked opposing ischemic and bleeding event rates. Death, MI, stent thrombosis, and stroke were more frequent with clopidogrel monotherapy (3.7% vs. 1.6%; hazard ratio [HR], 2.33; 95% CI, 1.47-3.69), whereas BARC types 2, 3, or 5 bleeding were lower (1.8% vs. 4.1%; HR, 0.43; 95% CI, 0.27-0.67). These findings contrast with those of the OPT-BIRISK (Optimal antiPlatelet Therapy for high Bleeding and Ischemic RISK patients) study, in which clopidogrel monotherapy reduced bleeding and ischemic events after 9-12 months of DAPT.² Importantly, the OPT-BIRISK study encompassed patients with acute coronary syndrome at both high ischemic and high bleeding risk, whereas the A-CLOSE trial included patients at high ischemic risk without requiring increased bleeding risk.

Findings of the A-CLOSE trial suggest that aspirin withdrawal beyond 12 months after PCI may not be appropriate for all patients at high ischemic risk. The 2.3-percentage-point reduction in clinically relevant bleeding with clopidogrel monotherapy was accompanied by a 2.1-percentage-point increase in ischemic events. This situation underscores how comparing composite clinical endpoints can mask opposing treatment effects. Generalizability is limited by enrollment exclusively in South Korea and the absence of routine cytochrome P450 2C19 genotyping or platelet-function testing. Long-term antiplatelet therapy should therefore be individualized according to competing ischemic and bleeding risks.

References

1. Lee SJ, Lee YJ, Lee K, et al. Clopidogrel or dual antiplatelet therapy in high-ischemic-risk patients. N Engl J Med. Published online August 29, 2026. doi:10.1056/NEJMoa2608533
2. Li Y, Li J, Wang B, et al. Extended clopidogrel monotherapy vs DAPT in patients with acute coronary syndromes at high ischemic and bleeding risk: the OPT-BIRISK randomized clinical trial. JAMA Cardiol. 2024;9(6):523-531. doi:10.1001/jamacardio.2024.0534