HOST-EXAM: Clopidogrel Monotherapy Non-Inferior to Aspirin at 10 Years

Following PCI with DES, dual antiplatelet therapy (DAPT) is typically prescribed for a defined period, after which monotherapy is initiated. Aspirin has historically been the standard long-term monotherapy. However, concerns regarding its gastrointestinal bleeding risk and the potential for residual thrombotic events have prompted investigation into alternative strategies. The HOST-EXAM trial aimed to compare the long-term efficacy and safety of clopidogrel monotherapy versus aspirin monotherapy in patients with stable CAD who had undergone PCI with DES and completed 6-18 months of DAPT.¹

Coronary artery disease (CAD) remains a leading cause of morbidity and mortality worldwide. Percutaneous coronary intervention (PCI) with drug-eluting stents (DES) has revolutionized the management of CAD, significantly reducing restenosis rates compared to bare-metal stents. However, stent thrombosis, a rare but often fatal complication, and other atherothrombotic events necessitate ongoing antiplatelet therapy. DAPT, typically consisting of aspirin and a P2Y12 inhibitor, is crucial in the initial phase post-PCI to prevent these events. The optimal duration of DAPT and the choice of subsequent monotherapy have been subjects of extensive research and clinical debate, balancing the prevention of ischemic events against the risk of bleeding. Aspirin, by irreversibly inhibiting cyclooxygenase-1 (COX-1), reduces thromboxane A2 production, thereby inhibiting platelet aggregation. Clopidogrel, a thienopyridine, selectively and irreversibly inhibits the P2Y12 ADP receptor on platelets, preventing ADP-induced platelet activation and aggregation. Both mechanisms are vital in preventing thrombotic events, but their safety profiles, particularly regarding bleeding, differ.

The Trial Design and Findings

The HOST-EXAM trial was a prospective, multicenter, randomized, open-label, non-inferiority trial that enrolled 5,436 patients from 37 centers in South Korea. Patients with stable CAD who had undergone successful PCI with DES and completed 6-18 months of DAPT without major adverse events were randomized 1:1 to receive either clopidogrel (75 mg once daily) or aspirin (100 mg once daily). The primary endpoint was a composite of all-cause death, non-fatal myocardial infarction, stroke, readmission due to acute coronary syndrome, or definite/probable stent thrombosis. The initial follow-up period was 24 months.¹

Patient eligibility criteria included age 20 years or older, successful PCI with DES for stable CAD (including stable angina, silent ischemia, or prior myocardial infarction), and completion of 6 to 18 months of DAPT without experiencing major adverse cardiac or cerebrovascular events (MACCE) or major bleeding. Exclusion criteria included acute myocardial infarction within 30 days, cardiogenic shock, severe heart failure, significant valvular heart disease, severe renal or hepatic dysfunction, active bleeding, or a history of hemorrhagic stroke. The randomization process was performed using a web-based system, ensuring allocation concealment. Adherence to the assigned antiplatelet regimen was monitored through patient interviews and review of prescription records at follow-up visits. The trial's non-inferiority margin for the primary endpoint was a hazard ratio of 1.25, meaning clopidogrel would be considered non-inferior if its upper 95% confidence interval for the hazard ratio did not exceed 1.25 compared to aspirin. This design allowed for a robust comparison of the two monotherapy strategies.

The 10-year follow-up data, presented at ACC.26, extended the observation period significantly, providing robust long-term insights. At 10 years, clopidogrel monotherapy demonstrated a 26% lower risk of the primary composite endpoint compared to aspirin monotherapy (Hazard Ratio [HR] 0.74, 95% Confidence Interval [CI] 0.65-0.84, p<0.001). This finding established the non-inferiority of clopidogrel and further suggested superiority for the primary endpoint.²

Breaking down the composite endpoint, clopidogrel significantly reduced the risk of myocardial infarction (HR 0.70, 95% CI 0.56-0.88, p=0.002) and stent thrombosis (HR 0.57, 95% CI 0.38-0.86, p=0.007) compared to aspirin. There was no significant difference in the rates of all-cause death or stroke between the two groups.²

Regarding safety outcomes, clopidogrel monotherapy was associated with a 34% lower risk of major bleeding (HR 0.66, 95% CI 0.50-0.87, p=0.003) and a 42% lower risk of gastrointestinal bleeding (HR 0.58, 95% CI 0.40-0.84, p=0.004) compared to aspirin. This reduction in bleeding events contributed to the overall favorable safety profile of clopidogrel.²

The trial's strengths include its large sample size and extended follow-up duration, providing long-term evidence in a real-world setting. A limitation is that the study population was predominantly Asian, which may limit generalizability to other ethnic groups, given known differences in drug metabolism and genetic predispositions to bleeding or thrombotic events. Furthermore, the open-label design, while pragmatic, introduces potential for bias, though objective endpoints like death and myocardial infarction are less susceptible. The trial did not include other P2Y12 inhibitors, such as ticagrelor or prasugrel, which are also used in CAD management. The generalizability of these findings to patients with acute coronary syndromes or those requiring longer DAPT durations also warrants further investigation. Future research could explore the cost-effectiveness of clopidogrel monotherapy in different healthcare systems and patient populations, as well as investigate the role of genetic testing for clopidogrel metabolism in guiding personalized antiplatelet strategies.^1,2