Variability and treatment of high on-prasugrel platelet reactivity in patients with initial high on-clopidogrel platelet reactivity

Abstract

Highon-treatmentplatelet reactivity (HTPR) following clopidogrel is awell studiedphenomenonassociatedwithprognostic significancepost percutaneous coronary angioplasty (PCI). Platelet reactivity variability over time while on clopidogrel is also well appreciated [1]. Prasugrel, a newer P2Y12 inhibitor, has been shown to result in a faster, more consistent and stronger inhibition of platelet aggregation, compared to clopidogrel mainly attributed to its more efficient metabolic activation. Cases of HTPR while on prasugrel have scarcely been reported, with minimal data on its variabilityover timeandways for its treatment [2-5]. We describe our experience in patients who exhibited HTPR while on 10 mg maintenance dose of prasugrel, its variability over time and strategies to overcome. During a 15 monthperiod and in the contextof 3 randomized studies assessing the pharmacodynamic effects of prasugrel 10 mg vs clopidogrel 150 mg daily in patients with HTPR while on clopidogrel, we have performed platelet function testing using the VerifyNow (Accumetrics Inc., San Diego, CA, USA) point-of-care P2Y12 assay, as previously described [6-8]. Results are reported as P2Y12 reaction units (PRU) with a value≥235 considered as an indication of HTPR [6]. Patients with demonstration of HTPR while on prasugrel in their respective trial were invited – 6 to 12 months after the end of the trial – for a second measurement of platelet reactivity after receiving prasugrel 10 mg for at least 15 days. TheHTPR persistence between the first and the second platelet function measurement while on prasugrel was assessed. Intrasubject variability of platelet reactivity was calculated using coefficient of variation after log transformation of the existing data. Patients, with HTPR in the second measurement, were prescribed 20 mg of prasugrel daily for 15 days, when a final platelet reactivity assessment was performed. Out of 334 patients screened while on clopidogrel, 123 (36.8%) exhibited HTPR and 107 of them received prasugrel for at least 15 days. Among them, 11 (10.3%) were identified with HTPR while on prasugrel. Demographic and clinical details are presented in Table 1. A second assessment of platelet reactivity revealed that the majority (7/11) exhibited an adequate platelet inhibition (Fig. 1). Ιntrasubject variability was 63.2% (coefficient of variation). Persistence of HTPR was observed in only 4 patients, in whom increasing prasugrel to 20 mg was able to overcome HTPR in 3 of them. Only 1 patient remained nonresponsive to the 20 mg of prasugrel dose. HTPR while on prasugrel is a recently appreciated phenomenon [4,5]. When HTPR is observed in acute coronary syndrome patients 6 to 12 h following prasugrel loading, it is predictive of ischemic events at International Journal of Cardiology 154 (2012) 333–385