Best Long-Term Antiplatelet Monotherapy Post-PCI

By Michael H. Crawford, MD

Synopsis: In a multicenter, randomized, open-label trial of clopidogrel vs. aspirin monotherapy in patients post-percutaneous coronary intervention (PCI) who had been on dual antiplatelet therapy for the recommended period, those randomized to clopidogrel showed fewer major cardiovascular or cerebral events over a two-year follow-up period than those on aspirin without an increase in bleeding events.

Source: Choi KH, Park YH, Lee JY, 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. Lancet. 2025;405(10486):1252-1263.

After a coronary artery stent-specific time of dual antiplatelet therapy (DAPT), aspirin monotherapy is recommended indefinitely by practice guidelines, yet there is little evidence to support this practice. Thus, Choi et al conducted a multicenter, prospective, randomized, open-label trial of clopidogrel vs. aspirin monotherapy after the specified DAPT period at 26 centers in South Korea (SMART-CHOICE).

Adults were enrolled in the study after a successful percutaneous coronary intervention (PCI) with a drug-eluting stent (DES). The DAPT period was 12 months in patients with PCI for acute myocardial infarction (MI) and six months for other coronary events. The average time post-PCI to enrollment was 17 months. Patients taking oral anticoagulants or DAPT indefinitely for other reasons were excluded. Those enrolled were randomized 1:1 to clopidogrel 75 mg/day or aspirin 100 mg/day. Clinical follow-up visits were conducted at six and 12 months post-enrollment and yearly thereafter. A subgroup of 731 patients agreed to genetic testing for the CYP2C19 gene that regulates conversion of clopidogrel to the active form.

The primary outcome was major adverse cardiac or cerebral events (MACCE), which included all-cause death, MI, and stroke. Secondary endpoints included the components of the primary endpoint, major bleeding, cardiovascular death, target vessel revascularization, and gastrointestinal (GI) bleeding or erosions. Data analysis was by intention to treat, and an independent blinded data monitoring and safety board adjudicated all outcome events.

Between 2020 and 2023, 5,506 patients were randomized (median age 65 years; 18% women), of whom 46% had PCI for MI. Over the median follow-up time of 2.3 years, the primary outcome occurred in 4.4% of the clopidogrel group and 6.6% of the aspirin group (hazard ratio [HR], 0.71; 95% confidence interval [CI], 0.54-0.93; P = 0.013), with a number needed to treat of 45. All-cause mortality was 2.4% in the clopidogrel group vs. 4.0% in the aspirin group (HR, 0.71; 95% CI, 0.49-1.02). MI occurred in 1.0% vs. 2.2% (HR, 0.54; 95% CI, 0.33-0.90), respectively, and strokes occurred in 1.3% of both groups. Major bleeding occurred in 1.6% vs. 1.3%, which was not statistically significant (HR, 1.00; 95% CI, 0.58-1.73), but GI events occurred in 2.8% vs. 4.9% (HR, 0.65; 95% CI, 0.47-0.90). No patient subgroup in a sensitivity analysis favored aspirin.

The results were not different in the genetic testing subgroup between those with the genes for normal vs. poor metabolism of clopidogrel to the active form. The authors concluded that patients post-PCI at high risk of an ischemic event after the standard DAPT treatment time who were transitioned to clopidogrel, compared to aspirin monotherapy, had significantly fewer MACCE with clopidogrel without an increase in bleeding.

Commentary

The guidelines recommending indefinite aspirin monotherapy after the stent-specific DAPT period are largely based on a meta-analysis of smaller trials in largely low-risk individuals. The STOPDAPT-2 trial showed that clopidogrel was numerically (but not significantly) superior to aspirin for reducing adverse clinical events without any difference in bleeding. The HOST-EXAM trial showed that clopidogrel monotherapy compared to aspirin decreased net major adverse clinical events, but not all patients were high-risk and there was a low incidence of MI and death. Thus, SMART-CHOICE is of interest because it enrolled patients at high ischemic risk for adverse events post-PCI. Also, SMART-CHOICE chose hard ischemic endpoints (death, MI, stroke) and showed that clopidogrel monotherapy significantly reduced these hard endpoints compared to aspirin.

The results were mainly driven by a reduction in MI. Although the rates of death and stroke were reduced, they were not statistically significant alone. Major bleeding also was not significantly different, but it is noteworthy that 30% of the patients in both groups were taking proton pump inhibitors.

There are limitations to consider. SMART-CHOICE was open-label, but there was a blinded clinical event committee. Also, the event rate was half of what was expected, which raises concerns about a type I error. In addition, there were few patients at high bleeding risk, only 18% were women, and there were no non-Koreans. Finally, the use of oral anticoagulants was not prohibited nor assessed during the trial.

In summary, SMART-CHOICE supports previous studies that have shown that clopidogrel monotherapy is preferred to aspirin for the long-term management of patients at high risk of an ischemic event after the stent-specific DAPT time period is over.

Michael H. Crawford, MD, is Professor Emeritus of Medicine and Consulting Cardiologist, UCSF Health, San Francisco.