Prasugrel overcomes high on-clopidogrel platelet reactivity post-stenting more effectively than high-dose (150-mg) clopidogrel: the importance of CYP2C19*2 genotyping.

OBJECTIVES: The primary aim of the study was to determine the antiplatelet effects of prasugrel versus high-dose clopidogrel in patients with high on-treatment platelet reactivity (HTPR) after percutaneous coronary intervention (PCI) and, secondarily, their relation to cytochrome (CYP) 2C19*2 carriage.

BACKGROUND: High on-treatment platelet reactivity after clopidogrel administration after PCI is linked to the loss-of-function CYP2C19*2 allele and accompanied by an increased risk of adverse events.

METHODS: We performed a prospective, randomized, single-blind, crossover study of platelet inhibition by prasugrel 10 mg/day versus high-dose 150 mg/day clopidogrel in 71 (of 210 screened; 33.8%) post-PCI patients with HTPR. Platelet function was assessed by the VerifyNow assay (Accumetrics, San Diego, California), and real-time polymerase chain reaction genotyping was performed for CYP2C19*2 carriage.

RESULTS: The primary endpoint of platelet reactivity (measured in platelet reactivity units) at the end of the 2 treatment periods was lower after prasugrel compared with clopidogrel (least-squares estimates 129.4, 95% confidence interval [CI]: 111.1 to 147.7 versus 201.7, 95% CI: 183.2 to 220.2; p < 0.001). The least-squares mean difference between the 2 treatments was -122.9 (95% CI: -166.7 to -79.2, p < 0.001), and -47.5 (95% CI: -79.5 to -15.4, p = 0.004), in carriers and noncarriers of at least 1 mutant allele, respectively. The HTPR rates were lower for prasugrel than for clopidogrel, in all patients (7.5% vs. 35.8%, p < 0.001), in carriers (5.3% vs. 47.4%, p = 0.007), and in noncarriers (8.8% vs. 29.4%, p = 0.005), respectively.

CONCLUSIONS: In patients with HTPR after PCI, prasugrel is more effective compared with high clopidogrel in reducing platelet reactivity, particularly in CYP2C19*2 carriers. Genotyping guidance might be helpful only in case an increased clopidogrel maintenance dose is considered. (Prasugrel Versus High Dose Clopidogrel in Clopidogrel Resistant Patients Post Percutaneous Coronary Intervention (PCI); NCT01109784).