Choice of antiplatelet therapy after percutaneous coronary intervention: new evidence in patients at high risk of ischemic recurrences

The choice of long-term antiplatelet therapy after DAPT in patients undergoing percutaneous coronary intervention (PCI) remains debated. Aspirin has historically represented the antiplatelet of choice for long-term treatment after DAPT; nonetheless, recent accumulating evidence has challenged this scenario, with P2Y12-inhibitors considered as potential alternatives. The PANTHER systematic review and meta-analysis showed that P2Y12-inhibitor monotherapy was superior to aspirin in reducing the composite outcome of death, myocardial infarction and stroke; with efficacy driven primarily by reduction in myocardial infarction; notably, P2Y12-inhibitor monotherapy showed similar risk of major bleeding, and lower risk of hemorrhagic stroke compared to aspirin.(1) In the 2024 European Society of Cardiology Guidelines for the Management of Chronic Coronary Syndromes,(2) clopidogrel is proposed as a safe and effective alternative to aspirin monotherapy; in this context, the HOST-EXAM trial previously provided RCT-based evidence of a superiority of clopidogrel versus aspirin after DAPT in patients who received PCI.(3)

The recently published SMART-CHOICE 3 trial(4) was designed to provide additional insights on the efficacy and safety of clopidogrel versus aspirin, as antiplatelet monotherapy after DAPT, in patients who underwent PCI and were deemed at high risk of recurrent ischemic events (as identified by complex coronary lesions, or history of previous myocardial infarction or treated diabetes mellitus). Among the 5542 patients enrolled in the trial, clopidogrel use was associated with a lower incidence of the primary endpoint of all-cause death, myocardial infarction and stroke (3-years incidence: 4.4% vs. 6.6% in the aspirin group), without an increase in the risk of bleeding, compared to aspirin.

The results of this trial are important and expand previous evidence on the use of P2Y12-inhibitors - and particularly, clopidogrel - as an alternative to aspirin after DAPT in patients deemed at high-risk of recurrent ischemic events. Interestingly, the trial accrued a lower than expected incidence of the primary endpoint, highlighting the advancements made in the secondary prevention of coronary artery disease, beyond antiplatelet therapy. Notwithstanding this, clopidogrel still proved superiority compared to aspirin as monotherapy in patients deemed at high-risk of recurrent ischemic events. These findings further strengthen the potential evidence base for the use of P2Y12 as potential alternative to aspirin for the long-term antiplatelet treatment in patients following PCI.

Some caveats also apply: the trial was conducted in South Korea (similarly to the HOST-EXAM trial), and the applicability of these results to other, diverse cohorts need to be confirmed, considering also the potential differences in ischemic and bleeding risks in East Asian vs. other cohorts. Moreover, the representation of women was low (~19%), highlighting the outstanding need to increase female participation in cardiovascular trials - particularly in ischemic heart disease. These limitations should be taken into account when translating these results to other populations, especially when considering that prevalence of CYP2C19 loss-of-function variants (which influence response to clopidogrel) have significant geographical and ethnic-based variation.(5) In this regard, the exploratory subgroup analysis conducted in the subgroup of patients who were tested for CYP2C19 (which found similar effect on the primary composite endpoint) appears reassuring, notwithstanding the need for further validation of these findings in other populations. Finally, there were no differences in the rates of major bleeding in patients randomized to clopidogrel or aspirin; but as acknowledged by the authors, the number of patients deemed at high bleeding risk was low, as the trial was primarily focused on enrolling patients with high ischemic risk.

In conclusion, the results of the SMART-CHOICE 3 support contemporary evidence showing potential advantages of P2Y12-inhibitor-based antiplatelet monotherapy (and particularly, clopidogrel) compared to aspirin, and extend evidence of these advantages also to patients deemed at high ischemic risk. In a rapidly evolving field, this trial represents another step towards change for one of the mainstays of pharmacological treatment in cardiovascular medicine.