Low-dose aspirin is currently recommended as monotherapy to reduce atherosclerotic events in patients with chronic coronary disease (CCD). To explore the effects of other antiplatelet agents, researchers in South Korea performed SMART-CHOICE 3, a randomized, open-label study that compared clopidogrel 75 mg daily to aspirin 100 mg daily in 5506 high-risk CCD patients who had completed standard dual antiplatelet therapy after PCI. Over a median follow-up of 2.3 years, the primary outcome, a composite of death from any cause, myocardial infarction, or stroke, occurred in 4.4% of the clopidogrel group and 6.6% of the aspirin group (hazard ratio 0.71 [95% CI 0.54-0.93]; p=0.013). There was no significant difference in bleeding risk. 

These findings align with a previous 2021 study, HOST-EXAM (N=5438), which similarly found clopidogrel monotherapy superior to aspirin for preventing a composite of CVD events in South Korean patients (5.7% vs 7.7%, p=0.003). Despite these results favoring clopidogrel, the 2023 AHA CCD guidelines, published after HOST-EXAM but before SMART-CHOICE 3, still recommend aspirin as first-line therapy. The authors cite weaknesses in HOST-EXAM, including its open-label design, homogenous South Korean population (high CYP2C19 loss-of-function allele prevalence), and low event rate, as reasons for sticking with aspirin. Until updated guidelines are published, it is unclear if SMART-CHOICE 3 will change this position.

• SMART-CHOICE 3 - Clopidogrel vs Aspirin in High-risk CCD Patients, Lancet (2025)
• HOST-EXAM - Clopidogrel vs Aspirin for CCD after PCI and 6 - 18 Months of DAPT, Lancet (2021)
• AHA 2023 CCD recommendations