title: 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.
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.
  
  
  RESULTS
  Consecutive stable patients undergoing percutaneous coronary intervention were screened with the Multiplate Analyzer P2Y12 assay, defining 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 P2Y12 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.
  
  
  BACKGROUND
  URL: http://www.clinicaltrials.gov. Unique identifier: NCT01465828.
authors.affiliation: Departments of Cardiovascular, Respiratory, Geriatric, Anesthesiologic and Nephrologic Sciences, Umberto I Hospital, Sapienza University of Rome, Italy. rino.sardella@uniroma1.it
authors.forename: Gennaro
authors.initials: G
authors.lastname: Sardella
authors.forename: Simone
authors.initials: S
authors.lastname: Calcagno
authors.forename: Massimo
authors.initials: M
authors.lastname: Mancone
authors.forename: Raffaele
authors.initials: R
authors.lastname: Palmirotta
authors.forename: Luigi
authors.initials: L
authors.lastname: Lucisano
authors.forename: Emanuele
authors.initials: E
authors.lastname: Canali
authors.forename: Rocco Edoardo
authors.initials: RE
authors.lastname: Stio
authors.forename: Mauro
authors.initials: M
authors.lastname: Pennacchi
authors.forename: Angelo
authors.initials: A
authors.lastname: Di Roma
authors.forename: Giulia
authors.initials: G
authors.lastname: Benedetti
authors.forename: Fiorella
authors.initials: F
authors.lastname: Guadagni
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Biondi-Zoccai
authors.forename: Francesco
authors.initials: F
authors.lastname: Fedele
mesh_terms: D000368:Aged; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics* / Q000378:metabolism; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D016009:Chi-Square Distribution; D000077144:Clopidogrel; D003324:Coronary Artery Disease / Q000097:blood / Q000628:therapy*; D018592:Cross-Over Studies; D065731:Cytochrome P-450 CYP2C19; D057915:Drug Substitution; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D017202:Myocardial Ischemia / Q000097:blood / Q000209:etiology / Q000517:prevention & control*; D062645:Percutaneous Coronary Intervention / Q000009:adverse effects; D010641:Phenotype; D010879:Piperazines / Q000008:administration & dosage*; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D010979:Platelet Function Tests; D000068799:Prasugrel Hydrochloride; D011446:Prospective Studies; D058921:Purinergic P2Y Receptor Antagonists / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D058925:Receptors, Purinergic P2Y12 / Q000097:blood / Q000187:drug effects; D012384:Rome; D013876:Thiophenes / Q000008:administration & dosage*; D013988:Ticlopidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D016896:Treatment Outcome
chemical_list: C548576:P2RY12 protein, human; D010879:Piperazines; D010975:Platelet Aggregation Inhibitors; D058921:Purinergic P2Y Receptor Antagonists; D058925:Receptors, Purinergic P2Y12; D013876:Thiophenes; D000077144:Clopidogrel; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D000068799:Prasugrel Hydrochloride; D013988:Ticlopidine