title: Standard- vs high-dose clopidogrel based on platelet function testing after percutaneous coronary intervention: the GRAVITAS randomized trial.
abstract: BACKGROUND
  High platelet reactivity while receiving clopidogrel has been linked to cardiovascular events after percutaneous coronary intervention (PCI), but a treatment strategy for this issue is not well defined.
  
  
  OBJECTIVE
  To evaluate the effect of high-dose compared with standard-dose clopidogrel in patients with high on-treatment platelet reactivity after PCI.
  
  
  METHODS
  Randomized, double-blind, active-control trial (Gauging Responsiveness with A VerifyNow assay-Impact on Thrombosis And Safety [GRAVITAS]) of 2214 patients with high on-treatment reactivity 12 to 24 hours after PCI with drug-eluting stents at 83 centers in North America between July 2008 and April 2010.
  
  
  METHODS
  High-dose clopidogrel (600-mg initial dose, 150 mg daily thereafter) or standard-dose clopidogrel (no additional loading dose, 75 mg daily) for 6 months.
  
  
  METHODS
  The primary end point was the 6-month incidence of death from cardiovascular causes, nonfatal myocardial infarction, or stent thrombosis. The key safety end point was severe or moderate bleeding according to the Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries (GUSTO) definition. A key pharmacodynamic end point was the rate of persistently high on-treatment reactivity at 30 days.
  
  
  RESULTS
  At 6 months, the primary end point had occurred in 25 of 1109 patients (2.3%) receiving high-dose clopidogrel compared with 25 of 1105 patients (2.3%) receiving standard-dose clopidogrel (hazard ratio [HR], 1.01; 95% confidence interval [CI], 0.58-1.76; P = .97). Severe or moderate bleeding was not increased with the high-dose regimen (15 [1.4%] vs 25 [2.3%], HR, 0.59; 95% CI, 0.31-1.11; P = .10). Compared with standard-dose clopidogrel, high-dose clopidogrel provided a 22% (95% CI, 18%-26%) absolute reduction in the rate of high on-treatment reactivity at 30 days (62%; 95% CI, 59%-65% vs 40%; 95% CI, 37%-43%; P < .001).
  
  
  CONCLUSIONS
  Among patients with high on-treatment reactivity after PCI with drug-eluting stents, the use of high-dose clopidogrel compared with standard-dose clopidogrel did not reduce the incidence of death from cardiovascular causes, nonfatal myocardial infarction, or stent thrombosis.
  
  
  BACKGROUND
  clinicaltrials.gov Identifier: NCT00645918.
authors.affiliation: Scripps Clinic, La Jolla, California, USA. price.matthew@scrippshealth.org
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Price
authors.forename: Peter B
authors.initials: PB
authors.lastname: Berger
authors.forename: Paul S
authors.initials: PS
authors.lastname: Teirstein
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Tanguay
authors.forename: Dominick J
authors.initials: DJ
authors.lastname: Angiolillo
authors.forename: Douglas
authors.initials: D
authors.lastname: Spriggs
authors.forename: Sanjeev
authors.initials: S
authors.lastname: Puri
authors.forename: Mark
authors.initials: M
authors.lastname: Robbins
authors.forename: Kirk N
authors.initials: KN
authors.lastname: Garratt
authors.forename: Olivier F
authors.initials: OF
authors.lastname: Bertrand
authors.forename: Michael E
authors.initials: ME
authors.lastname: Stillabower
authors.forename: Michael E
authors.initials: ME
authors.lastname: Stillablower
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Aragon
authors.forename: David E
authors.initials: DE
authors.lastname: Kandzari
authors.forename: Curtiss T
authors.initials: CT
authors.lastname: Stinis
authors.forename: Michael S
authors.initials: MS
authors.lastname: Lee
authors.forename: Steven V
authors.initials: SV
authors.lastname: Manoukian
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Cannon
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Schork
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Topol
mesh_terms: D000368:Aged; D015906:Angioplasty, Balloon, Coronary; D002318:Cardiovascular Diseases / Q000401:mortality; D000077144:Clopidogrel; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D054855:Drug-Eluting Stents; D005260:Female; D006470:Hemorrhage / Q000139:chemically induced / Q000453:epidemiology; D006801:Humans; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000517:prevention & control; D015539:Platelet Activation / Q000187:drug effects*; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage*; D010979:Platelet Function Tests; D011446:Prospective Studies; D012306:Risk; D013927:Thrombosis / Q000517:prevention & control; D013988:Ticlopidine / Q000008:administration & dosage / Q000031:analogs & derivatives*
chemical_list: D010975:Platelet Aggregation Inhibitors; D000077144:Clopidogrel; D013988:Ticlopidine