Clopidogrel superior to aspirin for long-term antiplatelet therapy after coronary stenting: Lancet

The findings come from the SMART-CHOICE 3 trial, a large, multicenter randomized clinical study conducted at 26 hospitals across South Korea, and were recently published in The Lancet, one of the world’s most influential medical journals.

Addressing an Unresolved Question in Long-Term Care After PCI

After percutaneous coronary intervention (PCI) with drug-eluting stents, patients typically receive dual antiplatelet therapy (DAPT) for a fixed period to prevent thrombotic complications. While this early treatment strategy is well established, the optimal choice of single antiplatelet therapy for long-term maintenance after completion of DAPT has remained uncertain.

Current clinical guidelines have traditionally recommended lifelong aspirin therapy in this setting. However, high-quality randomized evidence directly comparing aspirin with alternative agents, such as clopidogrel, has been limited—particularly in patients at high risk of recurrent ischemic events.

Design and Key Findings of the SMART-CHOICE 3 Trial

The SMART-CHOICE 3 trial enrolled more than 5,500 adult patients who had successfully completed a standard course of DAPT following PCI and who were considered to be at high risk for future ischemic events due to factors such as a prior myocardial infarction, diabetes requiring medication, or complex coronary artery disease.

Participants were randomly assigned to receive either clopidogrel (75 mg once daily) or aspirin (100 mg once daily) as long-term monotherapy and were followed for a median of more than two years. The primary outcome was a composite of all-cause death, myocardial infarction, or stroke.

The study showed that clopidogrel significantly reduced the risk of this composite outcome compared with aspirin. This benefit was mainly driven by a lower incidence of myocardial infarction, while rates of death and stroke were similar between the two groups. Importantly, the risk of clinically significant bleeding did not differ between patients receiving clopidogrel and those receiving aspirin.

Clinical Significance and Broader Implication

These results provide strong evidence that clopidogrel can offer superior protection against serious cardiovascular events without increasing bleeding risk in patients who require long-term antiplatelet therapy after PCI. Unlike previous studies that included broader or softer clinical endpoints, SMART-CHOICE 3 focused on hard clinical outcomes and specifically targeted patients with a high ischemic risk, strengthening the clinical relevance of its findings.

Although the study population consisted entirely of Korean patients and included relatively fewer women and patients at very high bleeding risk, the results represent a major step forward in refining long-term secondary prevention strategies after coronary stenting.

In recognition of its clinical importance, the SMART-CHOICE 3 trial was selected as a Late-Breaking Clinical Trial at the 2025 American College of Cardiology (ACC) Annual Scientific Session and was simultaneously published in The Lancet.

The investigators conclude that clopidogrel should be considered a preferred option over aspirin for long-term antiplatelet monotherapy in high-risk patients who have completed standard DAPT after PCI, potentially influencing future clinical practice and guideline recommendations.

Reference:

Choi, Ki Hong et al., Efficacy and safety of clopidogrel versus aspirin monotherapy in patients at high risk of subsequent cardiovascular event after percutaneous coronary intervention (SMART-CHOICE 3): a randomised, open-label, multicentre trial, The Lancet, DOI: 10.1016/S0140-6736(25)00449-0