Differential prognostic value of platelet reactivity and CYP2C19 phenotype in high bleeding risk patients undergoing PCI: insights from the PTRG-DES Registry
J J Cha, O Kim, Y Shin, H J Joo, J H Park, S J Hong, C W YuAbstract
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