Pharmacodynamic effect of switching therapy in patients with high on-treatment platelet reactivity and genotype variation with high clopidogrel dose versus prasugrel the RESET GENE trial

Gennaro Sardella, Simone Calcagno, Massimo Mancone, Raffaele Palmirotta, Luigi Lucisano, Emanuele Canali, Rocco Edoardo Stio, Mauro Pennacchi, Angelo Di Roma, Giulia Benedetti, Fiorella Guadagni, Giuseppe Biondi-Zoccai, Francesco Fedele

Research output: Contribution to journalArticlepeer-review

Abstract

Background: High on-treatment platelet reactivity (HTPR) is associated with adverse outcomes. We aim to compare the novel thienopyridine prasugrel versus double-dose clopidogrel in patients with HTPR and explore the interaction between CYP2C19 genotype and both drugs. Methods and Results: Consecutive stable patients undergoing percutaneous coronary intervention were screened with the Multiplate Analyzer P2-12 assay, defning HTPR as area under the curve >450. Those with HTPR were randomized to prasugrel (10 mg/day) or high-dose clopidogrel (150 mg/day) for 2 weeks and then crossed-over to, respectively, clopidogrel and prasugrel, repeating the P2-12 assay at the end of each cycle. Clinical follow-up (until 3 months) and CYP2C19 genotyping was performed in all patients. The primary end point was platelet reactivity after 14 days of prasugrel versus high-dose clopidogrel. Thirty-two patients were randomized to prasugrel and then high-dose clopidogrel or to high-dose clopidogrel followed by prasugrel. Prasugrel was associated with a significantly lower platelet reactivity than high-dose clopidogrel was (325.8 versus 478.5 area under the curve, P=0.028). No patient treated with prasugrel exhibited HTPR, whereas 9 (28.1%) receiving high-dose clopidogrel still had prevalence of HTPR (P=0.001). Similar findings were obtained changing cutoffs or considering platelet reactivity as a continuous variable. Genotyping showed the same efficacy between high-dose clopidogrel and prasugrel in the 18 (56.3%) CYP2C19 *2 noncarriers (HTPR in 12.5% versus 0, P=0.274), whereas it was significantly worse in the 14 (43.7%) carriers (HTPR in 43.7% versus 0, P=0.003). Conclusions: HTPR is successfully abolished by therapy with prasugrel irrespective of CYP2C19 genotype. Conversely, high-dose clopidogrel can address HTPR only in CYP2C19*2 noncarriers. Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01465828.

Original languageEnglish
Pages (from-to)698-704
Number of pages7
JournalCirculation: Cardiovascular Interventions
Volume5
Issue number5
DOIs
Publication statusPublished - Oct 2012

Keywords

  • Clopidogrel
  • Coronary artery disease
  • Platelet reactivity
  • Prasugrel

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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