People at high risk for recurrent cardiac events following percutaneous coronary intervention (PCI), a procedure to open blocked arteries, experienced significantly better outcomes with clopidogrel rather than aspirin as their long-term antiplatelet therapy, according to research presented at the American College of Cardiology’s Annual Scientific Session (ACC.25).

After a median follow-up of over two years, patients taking clopidogrel were 29% less likely than those taking aspirin to experience the trial’s primary composite endpoint of all-cause death, heart attack or stroke. There was no difference seen in the rate of major bleeding. Researchers said a reduction in heart attacks was the main driver of the benefits seen with clopidogrel, a drug that prevents dangerous blood clots by inhibiting the P2Y12 receptor on platelets.

“In our study, clopidogrel beat aspirin as a lifelong maintenance monotherapy after standard-duration dual antiplatelet therapy,” said Joo-Yong Hahn, MD, an interventional cardiologist at Samsung Medical Center in Seoul, South Korea, and the study’s senior author. “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. Current ACC/AHA clinical guidelines recommend that patients should take both aspirin and a P2Y12 inhibitor such as clopidogrel (a strategy known as dual antiplatelet therapy, or DAPT) for six months to a year following PCI, then continue taking aspirin alone for the rest of their lives.

The new study sought to determine whether some higher-risk patients might benefit from continuing to take clopidogrel, a more potent antiplatelet medication, instead of aspirin following DAPT.

The trial, called SMART-CHOICE 3, enrolled 5,506 patients who underwent PCI at 26 sites in South Korea. All participants had either a prior heart attack, medication-treated diabetes or complex coronary artery lesions, putting them at high risk for future ischemic events. Eighteen percent of participants were women.

Following DAPT, half of the participants were randomly assigned to take clopidogrel alone and half took aspirin alone. After a median of 2.3 years, 4.4% of those taking clopidogrel and 6.6% of those taking aspirin experienced the composite primary endpoint. This difference was attributed primarily to a significant reduction in the rate of heart attacks, which occurred in 1% of those taking clopidogrel and 2.2% of those taking aspirin. There was also a strong tendency in the rate of all-cause death in favor of clopidogrel but no significant difference in the rate of strokes between the two groups.

The results also revealed no significant difference between groups in the rate of major bleeding events.

“In general, the more potent antiplatelet therapy increases bleeding risk, but in our study, clopidogrel reduced the ischemic endpoints compared to aspirin but without increased risk of bleeding, so it’s a very ideal result,” Hahn said.

Hahn said that the results are also in line with a previous study, the HOST-EXAM trial, that had a different endpoint and did not exclusively focus on high-risk patients, strengthening the evidence in favor of clopidogrel as a safe and effective drug for preventing recurrent ischemic events. However, since clopidogrel is more expensive than aspirin, at least in certain countries including South Korea, and likely comparable with aspirin in terms of efficacy in lower-risk patients, he said that the use of clopidogrel monotherapy following DAPT after PCI is likely to be most relevant in the case of high-risk patients.

One limitation of the study is that patients and clinicians were aware of which medication participants were assigned to take, but researchers said that this open label design was unlikely to have influenced the outcomes that were included in the primary endpoint. In addition, the trial was only conducted at hospitals in South Korea, so additional research would be needed to confirm that the results are generalizable in a more diverse population. However, Hahn said that overall, the medical practices surrounding PCI and follow-up care are similar in South Korea and other developed countries.

The researchers plan to further analyze the results to assess whether subgroups of patients with specific cardiovascular and metabolic conditions saw any difference in the rate of adverse outcomes.

The study was funded by the Korean pharmaceutical company Dong-A ST Co, Ltd.

This study was simultaneously published online in the Lancet at the time of presentation.

ACC.25 will take place March 29-31, 2025, in Chicago, bringing together cardiologists and cardiovascular specialists from around the world to share the newest discoveries in treatment and prevention. Follow @ACCinTouch, @ACCMediaCenter and #ACC25 for the latest news from the meeting.

The American College of Cardiology (ACC) is the global leader in transforming cardiovascular care and improving heart health for all. As the preeminent source of professional medical education for the entire cardiovascular care team since 1949, ACC credentials cardiovascular professionals in over 140 countries who meet stringent qualifications and leads in the formation of health policy, standards and guidelines. Through its world-renowned family of JACC Journals, NCDR registries, ACC Accreditation Services, global network of Member Sections, CardioSmart patient resources and more, the College is committed to ensuring a world where science, knowledge and innovation optimize patient care and outcomes. Learn more at ACC.org.