Key result
High platelet reactivity is linked to ~64% higher 1-year MACCE after PCI in high-bleeding-risk patients.
Why the study?
High bleeding risk patients undergoing PCI face competing ischaemic and bleeding hazards during antiplatelet therapy, and the relative prognostic value of CYP2C19 phenotype and on-treatment platelet reactivity in patients fulfilling ARC-HBR criteria remained uncertain.
Does risk stratification using on-treatment platelet reactivity and CYP2C19 phenotype predict 1-year major adverse cardiac and cerebrovascular events in high bleeding risk patients treated with clopidogrel after PCI?
Cohort (n=1,530)
Does risk stratification using on-treatment platelet reactivity and CYP2C19 phenotype predict 1-year major adverse cardiac and cerebrovascular events in high bleeding risk patients treated with clopidogrel after PCI?
In high bleeding risk patients treated with clopidogrel after PCI, on-treatment high platelet reactivity provides stronger prognostic value for 1-year ischemic events than CYP2C19 phenotype alone, without being associated with differences in major bleeding.
Background High bleeding risk (HBR) patients undergoing percutaneous coronary intervention (PCI) face competing ischaemic and bleeding hazards during antiplatelet therapy. Both CYP2C19 phenotype and on-treatment platelet reactivity are used to estimate clopidogrel response; however, their relative prognostic value in patients fulfilling Academic Research Consortium (ARC-HBR) criteria remains uncertain. Methods Among 13,160 patients in the PTRG-DES registry, 2,939 fulfilled ARC-HBR criteria. The analytic cohort comprised 1,530 HBR patients with available VerifyNow P2Y12 reaction units (PRU), CYP2C19 phenotype, and complete covariate data. High platelet reactivity (HPR) was defined as PRU ≥252. The primary ischaemic endpoint was major adverse cardiac and cerebrovascular events (MACCE), defined as the composite of all-cause death, myocardial infarction, stroke, or definite/probable stent thrombosis at 1 year. The primary analysis stratified patients into four groups by CYP2C19 phenotype (RM/NM vs. IM/PM) crossed with HPR status, comparing outcomes using Kaplan–Meier estimates and multivariable Cox regression adjusted for 21 pre-specified covariates. Results Mean age was 72.8±9.3 years; 54.6% were male. CYP2C19 distribution: RM/NM 37.5%, IM 47.0%, PM 15.6%; HPR was present in 48.1%. One-year MACCE rates differed significantly across four groups: 3.4% (RM/NM & Non-HPR), 9.4% (RM/NM & HPR), 6.2% (IM/PM & Non-HPR), and 7.6% (IM/PM & HPR) (log-rank p=0.021); major bleeding did not differ (p=0.655). On multivariable Cox regression, both RM/NM & HPR (HR 3.07, 95% CI 1.48–6.38; p=0.003) and IM/PM & HPR (HR 2.33, 95% CI 1.21–4.48; p=0.011) were independently associated with higher MACCE risk versus the reference group. In secondary models, HPR remained independently associated with MACCE (HR 1.64, 95% CI 1.07–2.52; p=0.024), whereas CYP2C19 phenotype categories were not. Conclusions In ARC-HBR patients treated with clopidogrel after PCI, on-treatment platelet reactivity provided more direct prognostic information for 1-year ischaemic events than CYP2C19 phenotype categorisation. Phenotype-guided risk stratification combining genotype with platelet function identifies clinically meaningful heterogeneity in ischaemic risk without an apparent increase in major bleeding.Clinical outcomes
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Cha et al. (2026) conducted a cohort in High bleeding risk patients undergoing percutaneous coronary intervention treated with clopidogrel (n=1,530). High platelet reactivity (PRU ≥252) stratified by CYP2C19 phenotype (RM/NM vs. IM/PM) vs. CYP2C19 RM/NM & Non-HPR (PRU <252) was evaluated on Major adverse cardiac and cerebrovascular events (MACCE: composite of all-cause death, myocardial infarction, stroke, or definite/probable stent thrombosis) at 1 year (HR 3.07, 95% CI 1.48-6.38, p=0.003). High platelet reactivity (PRU ≥252), unlike CYP2C19 phenotype alone, independently increased 1-year MACCE in high bleeding risk PCI patients (HR 1.64; 95% CI 1.07–2.52; p=0.024).
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