Reference: Lancet 2026 Apr 11;407(10537):1439-1447; Lancet 2021 Jun 26;397(10293):2487-2496
Practice Point: Clopidogrel may be preferred over aspirin for secondary prevention of major adverse cardiovascular events (MACE) following percutaneous coronary intervention (PCI).
EBM Pearl: When trials report a composite outcome, null findings of analyzed individual components should be interpreted with caution because the study is usually not powered to detect differences in those individual components.
Following PCI, it is currently recommended that patients receive dual antiplatelet therapy combining aspirin and a P2Y12 inhibitor (such as clopidogrel) for about a year for the prevention of MACE. Following this initial intervention, patients are then switched to a long-term monotherapy for continued MACE prevention. Historically, aspirin is recommended as a lifelong single antiplatelet therapy for secondary prevention of MACE following PCI, but recent short-term trials report that clopidogrel may actually be the ideal choice. However, long-term data supporting this is lacking. That is, until a 10-year follow-up of the HOST-EXAM trial was published last month in The Lancet.
Before jumping into the long-term study, it’s important to lay the groundwork. In the initial HOST-EXAM open-label trial, adults who had a PCI with drug-eluting stents receiving 6-18 months of dual antiplatelet therapy were randomly assigned to receive either 75 mg of clopidogrel or 100 mg of aspirin and were followed for 2 years. The results demonstrated that, at 2 years, clopidogrel reduced the incidence of the primary outcome, which was a composite of all-cause death, nonfatal myocardial infarction, stroke, readmission for acute coronary syndrome, and major bleeding (Bleeding Academic Research Consortium ≥ 3), compared to aspirin (5.7% vs. 7.7%). Individual components of the composite were analyzed as secondary endpoints, along with a few other secondary outcomes. Compared to aspirin, clopidogrel reduced the incidence of major bleeding (1.2% vs. 2%), the incidence of any bleeding (2.3% vs. 3.3%), and readmission due to acute coronary syndrome (2.5% vs. 4.1%) but did not significantly reduce all-cause or cardiac mortality, nonfatal myocardial infarction, or ischemic stroke.
While not a perfect design (more on that later), these initial findings showed promising results for clopidogrel as the superior choice for antiplatelet monotherapy following PCI in a stable patient population. However, given that secondary prevention of MACE after PCI is typically a lifelong endeavor, follow-up beyond 5 years is critical to better understand the long-term impact of antiplatelet monotherapy using these medications. Thus, patients of the HOST-EXAM trial were followed for 10 years to assess the same primary composite outcome as the initial trial. These new data reveal that clopidogrel reduced the incidence of the primary composite outcome (25.4% vs. 28.5%) and the same individual components of the composite as the initial trial, confirming its long-term efficacy.
Similar to the initial results, the rate of all-cause mortality was not different between clopidogrel and aspirin (13.4% vs. 12.5%). However, it is important to note that this study was not powered to detect significant differences in the individual components of the composite outcome, only the composite itself. Therefore, it is difficult to draw firm conclusions on 2 of the most important outcomes, all-cause and cardiac mortality, because there may not have been enough included patients (or events) to do so. Moreover, the trial was open-label, meaning patients and physicians were not blinded to the treatment groups, which could further distort the otherwise promising data. That said, while ideal in theory, blinding patients and physicians for 10 years would be difficult in practice. Taken together with short-term trials, these 10-year findings strengthen the case for clopidogrel monotherapy following PCI but highlight the need for harder mortality outcomes.
For more information, see the topic Antiplatelet and Anticoagulant Drugs for Elective Percutaneous Coronary Intervention (PCI) in DynaMed.
DynaMed EBM Focus Editorial Team
This EBM Focus was written by Michael Butler, PhD, Medical Writer at DynaMed. Edited by Katharine DeGeorge, MD, MS, Executive Editor at DynaMed and Professor of Family Medicine at the University of Virginia; Alan Ehrlich, MD, FAAFP, Executive Editor at DynaMed and Associate Professor in Family Medicine at the University of Massachusetts Medical School; McKenzie Ferguson, PharmD, BCPS, Senior Clinical Writer at DynaMed; Rich Lamkin, MPH, MPAS, PA-C, Senior Clinical Writer at DynaMed; by Claire Symanski, PhD, Medical Editor and Team Lead for ENT at DynaMed; Matthew Lavoie, BA, Senior Medical Copyeditor at DynaMed; Hannah Ekeh, MA, Senior Associate Editor II at DynaMed; and Jennifer Wallace, BA, Senior Associate Editor at DynaMed.