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Original Contribution
March 16, 2011

Standard- vs High-Dose Clopidogrel Based on Platelet Function Testing After Percutaneous Coronary Intervention: The GRAVITAS Randomized Trial

Author Affiliations

Author Affiliation: Scripps Clinic (Drs Price, Teirstein, Stinis, and Topol), Scripps Translational Science Institute (Drs Price, Teirstein, Schork, and Topol), and Scripps Research Institute (Dr Schork), La Jolla, California; Geisinger Clinic, Danville, Pennsylvania (Dr Berger); Montreal Heart Institute, Montreal, Canada (Dr Tanguay); University of Florida at Shands-Jacksonville, Jacksonville (Dr Angiolillo); Clearwater Cardiovascular Consultants, Clearwater, Florida (Dr Spriggs); Trinity Medical Center, Moline, Illinois (Dr Puri); Vanderbilt University, Nashville, Tennessee (Dr Robbins); Lenox Hill Hospital, New York, New York (Dr Garratt); Laval Hospital, Quebec City, Quebec, Canada (Dr Bertrand); Christiana Hospital, Newark, Delaware (Dr Stillabower); Sansum Clinic, Santa Barbara, California (Dr Aragon); Piedmont Heart Institute, Atlanta, Georgia (Dr Kandzari); University of California at Los Angeles (Dr Lee); Sarah Cannon Research Institute and Hospital Corporation of America, Nashville, Tennessee (Dr Manoukian); and Brigham and Women's Hospital, Boston, Massachusetts (Dr Cannon).

JAMA. 2011;305(11):1097-1105. doi:10.1001/jama.2011.290

Context 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.

Design, Setting, and Patients 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.

Interventions 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.

Main Outcome Measures 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.

Trial Registration clinicaltrials.gov Identifier: NCT00645918