Recent clinical trial data presented at the American College of Cardiology's Annual Scientific Session 2025 demonstrated that clopidogrel monotherapy may provide better outcomes compared with aspirin alone following dual antiplatelet therapy in high-risk patients who have undergone percutaneous coronary intervention.
In the SMART-CHOICE 3 trial, simulatensouly published in The Lancet, researchers found that patients receiving clopidogrel experienced a 29% reduction in the composite primary endpoint of all-cause mortality, myocardial infarction, or stroke compared with those receiving aspirin, with no statistically significant difference in major bleeding events between the two groups.
"In our study, clopidogrel beat aspirin as a lifelong maintenance monotherapy after standard-duration dual antiplatelet therapy," said senior study author Joo-Yong Hahn, MD, an interventional cardiologist at Samsung Medical Center in Seoul, South Korea, in a companion press release from the American College of Cardiology (ACC). "Based on these results, I hope that guidelines will address clopidogrel monotherapy as comparable to aspirin monotherapy or as preferred to aspirin monotherapy for patients at high risk of recurrent ischemic events."
Clopidogrel and aspirin are both antiplatelet medications that interfere with the clotting activity of platelets, but they act through different mechanisms. Clopidogrel works by inhibiting the P2Y12 receptor on platelets, preventing dangerous blood clots.
The reduction in myocardial infarction rates was identified as the primary driver of benefit, occurring in 1% of patients receiving clopidogrel vs 2.2% of those taking aspirin. There was also a noted trend toward reduced all-cause mortality in the clopidogrel group, though no statistically significant difference in stroke incidence was observed between the treatment groups.
Current ACC/American Heart Association guidelines recommend dual antiplatelet therapy (aspirin plus a P2Y12 inhibitor such as clopidogrel) for 6 to 12 months following percutaneous coronary intervention (PCI), followed by lifelong aspirin monotherapy. The SMART-CHOICE 3 trial specifically investigated whether higher-risk patients might benefit from continuing the more potent antiplatelet medication, clopidogrel, instead of transitioning to aspirin.
The researchers enrolled 5,506 patients across 26 South Korean sites who had undergone PCI and had at least one high-risk feature: prior myocardial infarction, medication-treated diabetes, or complex coronary artery lesions. The cohort was 18% female.
After a median follow-up of 2.3 years, the primary endpoint occurred in 4.4% of the patients in the clopidogrel group vs 6.6% of those in the aspirin group.
"In general, the more potent antiplatelet therapy increases bleeding risk, but in our study, clopidogrel reduced the ischemic endpoints compared [with] aspirin ... without increased risk of bleeding, so it's a very ideal result," Dr. Hahn noted.
The findings aligned with the previous HOST-EXAM trial, further strengthening the evidence supporting clopidogrel as a safe and effective option for preventing recurrent ischemic events. However, given clopidogrel's higher cost compared with aspirin in certain regions, the researchers suggested that clopidogrel monotherapy following dual antiplatelet therapy may be most relevant specifically among high-risk patients.
Study limitations included its open-label design and exclusive South Korean population, though the researchers indicated that PCI and follow-up care practices were similar across developed countries. The research team plans additional subgroup analyses to determine whether specific cardiovascular or metabolic conditions influenced outcomes differentially.
The SMART-CHOICE 3 trial was funded by Dong-A ST Co, Ltd, a Korean pharmaceutical company.