In this issue of our newsletter, we discuss the findings from the HOST-EXAM Extended study, a post-hoc investigation of the HOST-EXAM trial comparing the long-term use of clopidogrel versus aspirin monotherapy in high-risk percutaneous coronary intervention populations. The manuscript by Kang et al., published in JAMA Cardiology, examines outcomes stratifying patients based on high bleeding risk (HBR) and complex PCI procedures during in the chronic maintenance period. The study enrolled 3,974 patients across 37 South Korean centers who remained event-free during 6-18 months of dual antiplatelet therapy following PCI and maintained the allocated antiplatelet treatment, resulting in 866 patients (21.8%) meeting Bleeding Academic Research Consortium HBR criteria and 849 patients (21.4%) undergoing complex PCI procedures according to the ESC criteria.

Over a median follow-up of 5.9 years, clopidogrel demonstrated consistent superiority over aspirin across all risk categories. For thrombotic composite endpoints, clopidogrel provided benefit in both HBR  (0.75; 95% CI: 0.53-1.04) and non-HBR patients (0.62; 95% CI: 0.48-0.80), with no significant interaction (p=0.38). Complex PCI patients showed greater benefit from clopidogrel (HR 0.49; 95% CI: 0.32-0.77) compared to non-complex patients (HR 0.74; 95% CI: 0.59-0.92). Notably, the highest-risk subgroup combining both HBR and complex PCI features demonstrated the most pronounced benefit from clopidogrel, with a hazard ratio of 0.46 for thrombotic endpoints and an absolute risk difference of 13.8%. Bleeding risk reduction was preserved across all risk strata, contradicting concerns about increased hemorrhagic risk with clopidogrel in bleeding-prone populations.

These findings challenge traditional preferences for aspirin monotherapy during chronic maintenance post-PCI, as already suggested by previous studies and metanalyses. The benefits provided by P2Y12 inhibitors over aspirin in the specific setting of secondary prevention in patients with history of PCI (despite relevant heterogeneity in inclusion criteria and study design of the included studies) were further reiterated by a recent individual patient data metanalysis, which showed a significant reduction of myocardial infarction and any stroke without any increase in bleeding events with P2Y12 inhibitors as compared with aspirin. While current guidelines emphasize individualized antiplatelet therapy based on ischemic and bleeding risk assessment, these data suggest that clopidogrel appears superior to aspirin regardless of baseline risk profile. However, several limitations warrant consideration: the post-hoc analysis design limits causal inference, the exclusively East Asian population may restrict generalizability given pharmacogenomic differences in clopidogrel metabolism and high rate of intravascular imaging used. In addition, the study population represents stabilized patients who completed initial DAPT period without events, potentially limiting applicability to higher-risk populations. Additionally, observed bleeding rates were lower than expected based on BARC-HBR criteria, possibly reflecting incomplete risk factor capture, such as renal function and anemia.

The HOST-EXAM Extended findings represent a pivotal contribution to post-PCI antiplatelet management, suggesting that clopidogrel monotherapy may be the preferred chronic maintenance strategy regardless of bleeding risk or procedural complexity. Given the epidemiologic relevance of patients with history of PCI and the increasing prevalence of high bleeding and thrombotic risk features, the findings from this study are of outstanding relevance for daily clinical practice and should call for similar studies in Europe and other countries, to assess the consistency of the findings from the HOST-EXAM study to different geographic area and ethnicities. While further prospective validation remains necessary, these data provide compelling evidence for reconsidering current antiplatelet therapy paradigms in the stabilized post-PCI population.
Senior Comment (Assoc. Prof. Christoph B. Olivier, MD)

Guidelines recommend dual antiplatelet therapy (DAPT) following PCI, followed by aspirin monotherapy in patients after acute coronary syndrome (PMID: 37622654) and aspirin or clopidogrel (PMID: 39210710) in patients after PCI for chronic coronary syndrome. Recent evidence supports long-term clopidogrel monotherapy as an alternative to aspirin (PMID: 40902613) but the efficacy and safety according to bleeding and ischemic risk is limited.

Kang et al. (PMID: 39602157) report a post hoc analysis of the HOST-EXAM Extended trial. Patients who were event-free 6-18 months post-PCI and DAPT were randomized to clopidogrel or aspirin monotherapy. Among 3,974 patients, 21.8% were classified as high bleeding risk (HBR) and 21.4% underwent complex PCI, with a mean age of 63 years. Endpoints included a thrombotic composite (cardiovascular death, non-fatal myocardial infarction, stroke, hospitalization for acute coronary syndrome, or definite/probable stent thrombosis) and BARC 2-5 bleeding events.

As expected, patients with HBR had more bleeding events, whereas thrombotic event rates were similar between complex and non-complex PCI. This is consistent with prior evidence that elevated thrombotic risk associated with complex PCI is mainly observed during the first year post-procedure (PMID: 33541106). The treatment effect of clopidogrel compared with aspirin was consistent across HBR status and PCI-complexity. Although the P-value for interaction for PCI-complexity was not statistically significant (P=0.12), the lower hazard ratio in this subgroup suggests a potentially greater benefit. Importantly, absence of statistical significance does not imply absence of effect (PMID: 7647644).

In terms of absolute risk reduction, the group combining HBR and complex PCI appeared to benefit most, with an absolute difference of 13.8% (95%CI, 2.6-25.0) for thrombotic and 5.6% (95%CI, -4.8-16.0) for bleeding endpoints. 

Limitations of this analysis include its post hoc design, the open-label nature of the trial, and the absence of systematic assessment of platelet reactivity or CYP2C19 polymorphisms, which may vary regionally and influence outcomes.

In conclusion, Kang et al. highlight that clopidogrel monotherapy is a viable alternative to aspirin after PCI, with consistent effects across subgroups. Patients with HBR undergoing complex PCI may derive the largest absolute benefit.