Prasugrel Bests Double-Dose Clopidogrel in Clopidogrel Nonresponders



CHICAGO – Patients with high platelet reactivity on standard-dose clopidogrel in conjunction with a drug-eluting stent for stable coronary disease obtain markedly greater platelet inhibition by switching to prasugrel at 10 mg/day than by doubling the clopidogrel dose to 150 mg/day, according to the Italian RESET trial.

This was a central finding in RESET. Another key finding was that high platelet reactivity on standard maintenance-dose clopidogrel was a common occurrence, affecting 23% of the 180 patients screened for the study, Dr. Gennaro Sardella, professor of cardiology at the University of Rome, reported at the annual meeting of the American College of Cardiology.

Thirty-two nonresponders to clopidogrel at 75 mg/day participated in the crossover portion of the study. They were randomized to 15 days of prasugrel at the standard dose of 10 mg/day or to clopidogrel at 150 mg/day, then underwent platelet activity testing using the Multiplate P2Y12 assay. Next came crossover to 15 days on the opposite therapy, followed by repeat platelet activity testing.

Twenty-eight percent of subjects were poor responders to double-dose clopidogrel as defined by high platelet reactivity, with an area under the curve in excess of 450/minute. In contrast, none of the subjects displayed high platelet reactivity while on prasugrel.

Moreover, inhibition of platelet aggregation was significantly greater during prasugrel therapy: 50% compared with 9% during double-dose clopidogrel therapy, the cardiologist continued.

Fourteen subjects were hetero- or homozygous for the allelic variant of CYP2C19 previously linked to high platelet reactivity in patients on clopidogrel. These were the patients who experienced high platelet reactivity on clopidogrel at 150 mg/day. Noncarriers had a similarly low level of platelet reactivity whether on prasugrel or clopidogrel.

An area under the curve greater than 600/minute on the Multiplate assay had 75% sensitivity and 72% specificity for the presence of genetic variation of the CYP2C19 allele. This is a novel observation which, if confirmed in larger studies, might obviate the need for genotyping of clopidogrel candidates, according to Dr. Sardella.

Session cochair Dr. George D. Dangas noted that while RESET and other small studies show that variants in CYP2C19 are related to clopidogrel responsiveness, a large meta-analysis by investigators at University College London found no significant association between genotype and cardiovascular events. The meta-analysis (JAMA 2011;306:2704-14) included more than 42,000 patients in 32 studies with 3,545 cardiovascular events, observed Dr. Dangas, professor of medicine at Mount Sinai School of Medicine, New York.

Dr. Sardella reported having no financial disclosures. Dr. Dangas serves as a consultant to Johnson & Johnson and Astra-Zeneca.

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