By Michael H. Crawford, MD
Professor of Medicine, Lucy Stern Chair in Cardiology, University of California, San Francisco
SYNOPSIS: The five-year follow-up of patients randomized to clopidogrel vs. aspirin monotherapy beyond one year after percutaneous coronary intervention has shown that clopidogrel is noninferior, but not superior, to aspirin for preventing the combined endpoint of adverse cardiovascular or major bleeding events.
SOURCE: Watanabe H, Morimoto T, Natsuaki M, et al. Clopidogrel vs aspirin monotherapy beyond 1 year after percutaneous coronary intervention. J Am Coll Card 2024;83:17-31.
Aspirin monotherapy currently is recommended for antiplatelet therapy beyond one year after percutaneous coronary interventions (PCIs). The Short and Optimal Duration of Dual Antiplatelet Therapy 2 (STOPDAPT-2) trial demonstrated that one month of DAPT after PCI followed by clopidogrel monotherapy for up to one year reduced bleeding events without an increase in cardiovascular (CV) events compared to 12 months of DAPT. However, there is a paucity of data on long-term antiplatelet monotherapy after DAPT cessation.
The STOPDAPT-2 protocol called for continued clopidogrel monotherapy in the one-month DAPT group and a shift to aspirin monotherapy in the 12-month DAPT group beyond one year. The Watanabe study presents the five-year follow-up data comparing clopidogrel to aspirin monotherapy beyond one year. STOPDAPT-2 was a prospective, multicenter, open-label, adjudicator-blinded, randomized trial in Japan in patients post-PCI with cobalt-chromium everolimus-eluting stents. The clopidogrel dose was 75 mg/day and aspirin was 81 mg/day to 200 mg/day at the site investigators’ discretion.
The primary endpoint was net adverse clinical events, which were a composite of CV outcomes and bleeding outcomes. CV events and bleeding were individual secondary outcomes. In addition, newly diagnosed gastrointestinal (GI) cancer was a secondary outcome. The primary analysis was made in the intention-to-treat population except for those who discontinued the study for nonmedical reasons.
The study population of 3,045 patients was collected in 2016-2017 from 89 centers. By five years, there were 1,498 patients in the clopidogrel group and 1,507 patients in the aspirin group in the intention-to-treat analysis (mean age 69 years, 22% women, 38% acute coronary syndrome at baseline). More than 80% of patients in both groups maintained their assigned monotherapy at five years.
Clopidogrel monotherapy was noninferior but not superior to aspirin for the primary endpoint (12% vs. 14%, respectively; hazard ratio [HR], 0.85; 95% confidence interval [CI], 0.70-1.05; P noninferiority > 0.001, P superiority = 0.13). Clopidogrel monotherapy was superior for CV outcomes (9% vs. 11%; HR, 0.77; 95% CI, 0.67-0.97; P = 0.03), but not for major bleeding (4% vs. 5%; HR, 0.89; 95% CI, 0.64-1.25; P = 0.51).
There was no difference in the incidence of GI malignancies between the two groups. The authors concluded that clopidogrel monotherapy had a borderline ischemic benefit beyond one year compared to aspirin monotherapy, but no significant major bleeding advantage.
COMMENTARY
Recent studies have shown that one to three months of DAPT with the latest generation of stents followed by P2Y12 inhibitor monotherapy for up to one year results in less bleeding with no increase in ischemic events. However, antiplatelet monotherapy after PCI is recommended indefinitely, especially with clopidogrel, since it has fewer adverse intestinal mucosal effects compared to aspirin and potentially a lower risk of bleeding. However, there are several concerns about the long-term use of clopidogrel in post-PCI patients.
First, genetic polymorphisms in CYP2C19 may lead to variable responses to clopidogrel, especially in people of East Asian descent. Second, clopidogrel is more expensive than aspirin. Third, long-term aspirin use, but not clopidogrel use, has been shown to reduce GI cancers. Accordingly, most guidelines still recommend aspirin for long-term antiplatelet monotherapy. Thus, this long-term extension of the Japanese STOPDAPT-2 study is of interest.
Watanabe and colleagues show that clopidogrel monotherapy is noninferior but not superior to aspirin monotherapy for preventing net clinical events (ischemic and bleeding) one to five years post-PCI. Also, the authors show that clopidogrel monotherapy is numerically but not significantly superior to aspirin for preventing major ischemic events without any difference in major bleeding. A sensitivity analysis of those adherent to therapy at one year showed clopidogrel was superior to aspirin for preventing ischemic events, which was driven largely by a 39% decrease in acute myocardial infarction. Finally, there was no difference in the rate of cancer or non-CV death between the two groups.
There are weaknesses to the Watanabe study. Very few bleeding events occurred, which suggests that this was a low bleeding risk cohort. This may be explained partially by the observation that 79% of their patients also were taking proton pump inhibitors. Although adherence to the assigned study drugs was reported to be > 80% in both groups, adherence was higher in the clopidogrel group at one year. The structure of the trial resulted in the clopidogrel group receiving DAPT for one month and the aspirin group receiving DAPT for 12 months.
In addition, intracoronary imaging was used in almost all the patients, which may have improved the outcomes in general and, thus, the results may not be widely applicable. Finally, it was a study of exclusively Japanese individuals who are known to have a higher incidence of CYP2C19 polymorphisms. Given these considerations, the authors postulated that clopidogrel might be an attractive alternative to aspirin for the beyond one-year management of post-PCI patients.
