Clopidogrel Bests Aspirin Monotherapy After PCI Across Risk Strata

Among secondary-prevention patients who are event free for 6 to 18 months after PCI, clopidogrel seems to be superior to aspirin monotherapy over the next 2 years regardless of the patient’s baseline clinical risk or relative ischemic and bleeding risks, according to a post hoc analysis of the HOST-EXAM trial.

The original study, as reported by TCTMD, opened the door to the broader idea of using clopidogrel monotherapy over the usual aspirin for this patient population by showing consistent benefit with the former for thrombotic and bleeding events through 24 months of follow-up.

This analysis, published in the October 17, 2023, issue of the Journal of the American College of Cardiology, further stratified patients by both the DAPT score and the Thrombolysis In Myocardial Infarction Risk Score for Secondary Prevention (TRS 2°P; the sum of age ≥ 75 years, diabetes, hypertension, current smoking, peripheral artery disease, stroke, CABG, heart failure, and renal dysfunction).

“Taken together, favorable clinical outcomes of clopidogrel over aspirin monotherapy can be expected in high clinical, ischemic, or bleeding risk patients,” write Seokhun Yang, MD (Seoul National University College of Medicine, Republic of Korea), and colleagues.

“It is very important that we maximize our efforts to prevent recurrent events in this patient population,” said Arman Qamar, MD (NorthShore University Health System, Chicago, IL), who commented on the study for TCTMD. “The traditional approach has been aspirin, and we have thought that that is the gold standard, but aspirin has its own . . . limitations,” including GI bleeding and sometimes unpredictable results, he added.

While the findings of HOST-EXAM can only truly be applied to an East Asian population, as well as to a lower-risk cohort without any events before 6 months, Qamar said, “having an alternative [to aspirin] is great.”

Post Hoc Analysis Findings

For the study, Yang and colleagues included 5,403 patients from HOST-EXAM (median age 64 years; 74.7% male) who were randomized to clopidogrel 75 mg once daily or aspirin 100 mg once daily. They were stratified by risk using both the DAPT and TRS 2°P scores. The primary composite endpoint was the same as the original trial: all-cause death, nonfatal MI, stroke, readmission because of ACS, and major bleeding (BARC type ≥ 3) at 2 years after randomization.

Overall, the primary composite endpoint was lower with clopidogrel than aspirin monotherapy (HR 0.73; 95% CI 0.59-0.90). This result was consistent for all risk groups.

Primary Endpoint by Patient Risk: Clopidogrel vs Aspirin Monotherapy

Notably, as the TRS 2°P score increased, so did the rates of the primary composite endpoint, thrombotic composite endpoint (cardiac death, MI, ischemic stroke, readmission because of ACS, and definite or probable stent thrombosis), and major bleeding. Similarly, the DAPT score directly correlated with the incidence of MI but was indirectly related to the rate of major bleeding.

In an email, co-author Kyung Woo Park, MD, PhD (Seoul National University College of Medicine), told TCTMD the researchers were “pleasantly surprised” by the fact that clopidogrel seemed to be beneficial across all high-risk subgroups.

“Our findings suggest that clopidogrel monotherapy can be a preferable choice over aspirin monotherapy for secondary prevention after PCI, irrespective of the patients' risk profile,” he said. “Clinicians might consider these results when making therapeutic decisions for the choice of antiplatelet agents following DAPT, especially for high-risk patients.”

A Tailored Approach

In an accompanying editorial, Luis Ortega-Paz, MD, PhD (University of Florida College of

Medicine, Jacksonville), and colleagues write that the “results are consistent with prior studies showing that high bleeding risk (HBR) patients benefit from aspirin-free strategies, and clopidogrel monotherapy reduces thrombotic events compared with aspirin monotherapy.”

But they note several caveats they say must be considered when applying the findings to practice. First, it’s notable that the study, as well as others, show no difference in mortality between the two drugs. Next, they highlight that the significant reduction in the thrombotic composite endpoint seen with clopidogrel was driven not by MI but by fewer ACS readmissions, which is not considered a “hard” endpoint.

The editorialists also point out that while clopidogrel was linked to fewer strokes than aspirin, these were mostly of the spontaneous hemorrhagic variety. “Although the pathophysiology of this finding is unclear, it is in line with prior investigations and should promote further research to better identify patients at risk to favor safer therapeutic strategies,” they write.

Additionally, patients classified as high ischemic risk by the TRS 2°P score did not see a reduction in ischemic events but instead only a decrease in major bleeding, Ortega-Paz and colleagues say, a finding that “denotes the complex interactions between high bleeding and ischemic features and underlines the importance of scores that evaluate the trade-off between bleeding and ischemic risk.”

Importantly, they write, these data are in contrast with those published in an individual participant-level meta-analysis earlier this year. In that study, patients with high bleeding risk did not see a significant reduction in the primary endpoint with a P2Y12 inhibitor versus aspirin monotherapy.

“The reasons for these mixed results are unclear,” the editorialists say, suggesting they are likely related to the fact that HOST-EXAM only included clopidogrel, not other P2Y12 inhibitors, and that it only included East Asians, a population “known to have more bleeding events but fewer thromboembolic events.”

However, they note, these findings are consistent with those of CAPRIE, which three decades ago showed superiority of clopidogrel over aspirin monotherapy in patients with stable atherosclerotic disease.

Qamar commended the researchers for “using more of a personalized approach; that is what our goal should be. Our goal should be tailoring antiplatelet or antithrombotic therapy based on the patient's bleeding and thrombotic risk.”

While the results are “hypothesis generating” at this time, he said, they “do not say that aspirin should be replaced with clopidogrel, but certainly say that it's [overall] a very good alternative, especially for patients who are at a high bleeding risk or those having severe side effects.”

Qamar called for similar trials to be done, especially in European and American populations, and also for trials looking at alternative options depending on patients’ risk profiles including prolonged DAPT or even a regimen of low-dose rivaroxaban as was studied in COMPASS.