GRAVITAS Trial Published in JAMA

March 16, 2011— Matthew J. Price, MD, et al have published results of the GRAVITAS (Gauging Responsiveness With a VerifyNow Assay—Impact on Thrombosis and Safety) study in the Journal of the American Medical Association (2011;305:1097–1105).

The study sought to evaluate the impact of high-dose compared with standard-dose clopidogrel (Plavix, Bristol-Myers Squibb/Sanofi Pharmaceuticals Partnership, New York, NY) on patients with high on-treatment platelet reactivity after percutaneous coronary intervention (PCI).

GRAVITAS is a randomized, double-blind, active-control trial of 2,214 patients with high on-treatment reactivity 12 to 24 hours after PCI with drug-eluting stents conducted at 83 centers in North America between July 2008 and April 2010. According to the investigators, high-platelet reactivity while receiving clopidogrel has been linked to cardiovascular events after PCI, but a treatment strategy for this issue is not well defined.

The study is sponsored by Accumetrics, Inc. (San Diego, CA), developer of the VerifyNow system used in GRAVITAS for measuring platelet reactivity to multiple antiplatelet agents. Accumetrics stated that the results refute a “one-size fits all” strategy of uniformly doubling the dose of clopidogrel over 6 months for patients with high on-treatment platelet reactivity after taking a standard dose of the commonly prescribed antiplatelet drug. The company noted that its VerifyNow system is used in various clinical settings where antiplatelet medications are prescribed to reduce the occurrence of future thrombotic events such as heart attack and stroke.

The GRAVITAS findings were presented in November 2010 at the at the American Heart Association's Scientific Sessions 2010, as reported by Cardiac Interventions Today.

“The GRAVITAS findings do not support a uniform treatment strategy for patients with high on-treatment platelet reactivity,” commented Dr. Price, the principal investigator of GRAVITAS. “Rather than prescribing a fixed, higher dose of clopidogrel based on a single post-PCI platelet function test, we need to consider alternative treatment strategies that incorporate platelet function testing, such as using more potent antiplatelet agents or repeated testing to a specific target of reactivity.”
 

As detailed in the Journal of the American Medical Association, patients in GRAVITAS were randomized to interventions using either 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. The primary endpoint was the 6-month incidence of death from cardiovascular causes, nonfatal myocardial infarction, or stent thrombosis. The key safety endpoint was severe or moderate bleeding according to the GUSTO (Global Utilization of Streptokinase and tPA for Occluded Coronary Arteries) definition. A key pharmacodynamic endpoint was the rate of persistently high on-treatment reactivity at 30 days.

The investigators reported that at 6 months, the primary endpoint had occurred in 25 of 1,109 patients (2.3%) receiving high-dose clopidogrel compared with 25 of 1,105 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).

The results show that 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, the GRAVITAS investigators concluded.