By Michael H. Crawford, MD, Editor

SYNOPSIS: A recent study of patients who had undergone a percutaneous coronary intervention and were transitioning from dual antiplatelet therapy to monotherapy showed clopidogrel was superior to aspirin for preventing further major adverse events, including bleeding.

SOURCE: Koo BK, Kang J, Park KW, et al. Aspirin versus clopidogrel for chronic maintenance monotherapy after percutaneous coronary intervention (HOST-EXAM): An investigator-initiated, prospective, randomized, open-label, multicentre trial. Lancet 2021; May 14:S0140-6736(21)01063-1. doi: 10.1016/S0140-6736(21)01063-1. [Online ahead of print].

Current recommendations call for six to 12 months of dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI), depending on the type of stent used. Thereafter, monotherapy usually is used indefinitely. In the current era of drug-eluting stents (DES) and widespread statin use, no one has studied which drug to use for monotherapy.

Koo et al initiated a prospective, randomized, open-label, multicenter trial at 37 sites in South Korea. They enrolled 5,530 patients who were six to 18 months post-DES (second-generation in 97%) on DAPT without any intervening cardiovascular (CV) events. Patients were randomized to either aspirin 100 mg per day or clopidogrel 75 mg per day and followed up at 12 and 24 months. The primary endpoint was a composite of all-cause death, myocardial infarction, stroke, acute coronary syndrome, or an admission to hospital for a major bleeding episode. Secondary endpoints were components of the primary composite endpoint.

Follow-up was 98% complete in the 5,530 patients enrolled. Their average age was 64 years, 75% were men, and the average follow-up was 382 days. Also, 82% were on aspirin and clopidogrel before enrollment. The primary endpoint was experienced by 152 of those on clopidogrel and 207 of those on aspirin (HR, 0.73; 95% CI, 0.59-0.90; P = 0.0035). Mortality was 1.9% on clopidogrel vs. 1.3% on aspirin (P = not significant). A CV event was 3.7% on clopidogrel and 5.5% on aspirin (HR, 0.68; 95% CI, 0.52-0.87; P = 0.0028). Any significant bleeding was 2.3% on clopidogrel vs. 3.3% on aspirin (HR, 0.70; 95% CI, 0.51-0.98; P = 0.036). The Kaplan-Meier curves for the primary and secondary outcomes separated at about nine months. The results were not different in any of the subgroups analyzed. The authors concluded that clopidogrel monotherapy for chronic maintenance treatment after PCI with DES was superior to aspirin in preventing future CV events and significant bleeding.

COMMENTARY

Aspirin is an irreversible inhibitor of the cyclooxygenase pathway in platelets. It has been recommended for long-term maintenance therapy post-PCI based on older secondary prevention trials performed before the widespread use of statins and DES. The major adverse effect of aspirin is denudation of the stomach lining and upper gastrointestinal bleeding, which can be significant. Clopidogrel is an adenosine diphosphate receptor blocker and has been recommended as an alternative to aspirin for long-term maintenance therapy if the patient cannot tolerate aspirin. Recent studies of aspirin vs. clopidogrel in coronary artery disease patients with atrial fibrillation on anticoagulants have shown clopidogrel is as effective as aspirin for preventing CV events and is associated with less bleeding. Thus, raising the issue of whether clopidogrel would be as effective as aspirin in the chronic maintenance therapy of the post-PCI patient and whether it would be associated with less major bleeding is important. In the Koo et al study, the absolute benefits were in the 1% to 2% range. However, even saving a few patients from subsequent CV events or major bleeding episodes is a worthwhile goal. Now that clopidogrel is generic, cost should not be a major issue.

There was no significant difference in all-cause mortality alone, and the authors did not report CV mortality. There was a trend for lower rates of mortality on clopidogrel vs. aspirin, which might have reached significance in a larger trial with more events.

There were weaknesses to this study. It was open-label, which may have introduced biases, but a blinded committee adjudicated all events, which would minimize this effect. The fact there were fewer events than the investigators predicted may have been caused by patient selection bias. Also, the trial design requirement for an absence of events six to 18 months before study enrollment probably resulted in the randomization of more low-risk individuals. There was no genetic testing for clopidogrel metabolism differences. It is known that at least half of East Asians carry a loss of function mutation in the CYP2C19 gene, which decreases the effectiveness of clopidogrel. However, East Asians also experience fewer thrombotic events, which has been dubbed the “East Asian paradox.” Thus, this would have been interesting information, but the net clinical effect may not have been important. Also, it has been estimated about 18% of East Asians are aspirin-resistant, which further complicates interpreting the results of the Koo et al study. Finally, the follow-up period was rather short.

Considering the Koo et al study showed a significant reduction in CV events and major bleeding, I believe this study makes a strong case for substituting clopidogrel for aspirin in the long-term maintenance therapy of post-PCI patients who receive DES.