Prognostic implications of responsiveness to aspirin and a P2Y12 inhibitor after drug-eluting stent implantation in patients with acute coronary syndrome

Background High platelet reactivity (HPR) is significantly associated with recurrent ischemic events in patients with acute coronary syndrome (ACS). However, the combined prognostic implications of HPR to aspirin and to a P2Y12 inhibitor—and their differential impact on early vs. late clinical events after drug-eluting stent (DES) implantation—remain uncertain. Purpose To investigate the prognostic impact of HPR to aspirin and P2Y12 inhibitors on early and late clinical outcomes after DES implantation in patients with ACS. Methods From the nationwide PTRG-DES consortium, we analyzed 3,848 patients with ACS who were discharged on dual antiplatelet therapy (DAPT) and underwent platelet function testing (VerifyNow®) for aspirin and clopidogrel. HPR on aspirin (HAPR) was defined as ≥ 414 ARU (aspirin reaction unit), and HPR on clopidogrel (HCPR) as ≥ 252 PRU (P2Y12 reaction unit), according to prior reports. Patients were stratified into four phenotypes: NAPR–NCPR (37.8%), NAPR–HCPR (8.8%), HAPR–NCPR (28.5%), and HAPR–HCPR (24.9%). Major adverse cardiac and cerebrovascular events (MACCE; composite of all-cause death, myocardial infarction, stent thrombosis, or stroke) and major bleeding (BARC type 3–5) were assessed through 1 year. Multivariable Cox regression and 90-day landmark analyses were performed. Results ARU and PRU showed a moderate correlation (r = 0.318, P < 0.001). Higher PRU (per 10-unit increase) was independently associated with HAPR (adjusted OR [ORadj], 1.09; 95% CI, 1.08–1.10; P < 0.001), and higher ARU (per 10-unit increase) was independently associated with HCPR (ORadj, 1.05; 95% CI, 1.04–1.07; P < 0.001). At 1-year, HAPR-HCPR demonstrated an additive association with MACCE (log-rank P = 0.006), but not with major bleeding (log-rank P = 0.122). The HAPR–HCPR group had the highest MACCE risk compared with both the NAPR–NCPR (adjusted HR [HRadj], 1.82; 95% CI, 1.14–2.91; P = 0.013) and HAPR–NCPR (HRadj, 1.66; 95% CI, 1.03–2.70; P = 0.040). In landmark analysis, the prognostic impact of the HAPR–HCPR phenotype was more pronounced for thrombotic events within the first 90 days after PCI (HRadj of 2.44, 3.01, and 6.06 for MACCE, myocardial infarction, and stent thrombosis, respectively, vs. NAPR–NCPR), whereas these associations were substantially attenuated beyond 90 days. Conclusions In patients with ACS undergoing DES implantation, responsiveness to aspirin and a P2Y12 inhibitor demonstrated an additive association with thrombotic risk, particularly during the early post-PCI period. These findings support a time-dependent effect of dual platelet hyporesponsiveness on ischemic outcomes.Figure 1Figure 2