Patients with high on-treatment platelet reactivity after percutaneous coronary intervention who received high-dose clopidogrel fared no better in terms of cardiovascular events than did high-reactivity patients on standard-dose clopidogrel in the GRAVITAS trial.
"The results of GRAVITAS do not support a uniform treatment strategy of high-dose clopidogrel in patients with high on-treatment reactivity identified by a single platelet function test after PCI," Dr. Matthew J. Price and his coinvestigators wrote in the March 16 issue of JAMA. However, "alternative treatment strategies incorporating platelet function testing merit further investigation."
In the Gauging Responsiveness With a VerifyNow Assay – Impact on Thrombosis and Safety (GRAVITAS) trial, researchers measured platelet function with the VerifyNow P2Y12 test (Accumetrics) 12-24 hours after PCI. A greater P2Y12 reaction unit (PRU) result reflects greater P2Y12 mediated reactivity. High on-treatment reactivity was defined as 230 PRU or greater. This cutoff was chosen because it was similar to the cutoff suggested by a prior observational study.
Patients were eligible for enrollment if they had undergone PCI with at least one drug-eluting stent for the treatment of stable coronary artery disease or acute coronary syndromes. Patients with high on-treatment platelet reactivity were randomly assigned to receive either high-dose or standard-dose clopidogrel. High-dose clopidogrel was given as a total first-day dose of 600 mg followed by 150 mg daily for 6 months. Standard-dose clopidogrel involved a loading dose of placebo followed by a dose of 75 mg and placebo tablet daily.
In all, 5,429 patients from 83 sites in the United States and Canada were screened with platelet function testing. Of these, 2,214 (41%) had high on-treatment reactivity and were randomly assigned to either high-dose or standard-dose clopidogrel. An additional 586 patients without high on-treatment reactivity were selected at random and assigned to treatment with standard-dose clopidogrel (JAMA 2011;305:1097-105).
The primary efficacy end point, a composite of death from cardiovascular causes, nonfatal MI, or stent thrombosis at 6 months, was identical in both groups with high reactivity, at 25 (2.3%).
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. That occurred in 15 (1.4%) and 25 (2.3%) of patients in the high- and low-dose groups, respectively, a nonsignificant difference.
In a secondary, observational comparison of patients with and without high on-treatment reactivity treated with standard-dose clopidogrel, the rate of death from cardiovascular causes, nonfatal MI, or stent thrombosis was numerically greater in the patients with high on-treatment reactivity than in those without high on-treatment reactivity, at 25 and 8, respectively, but this difference did not reach statistical significance.
In terms of safety, intracranial hemorrhage occurred in none of the patients with high on-treatment reactivity who were randomly assigned to high-dose clopidogrel, in two patients (0.2%) with high on-treatment reactivity on standard-dose clopidogrel, and in one patient (0.2%) without high on-treatment reactivity treated with standard-dose clopidogrel. The rate of discontinuation of study drug due to severe or moderate bleeding was similar across all three groups.
The results of GRAVITAS are of particular interest because studies have shown wide interindividual variability in the platelet inhibitory response to clopidogrel and suggested a link between a poor pharmacodynamic response to cardiovascular events after PCI.
"We found that compared with the standard maintenance dose of 75 mg daily, prolonged high-dose clopidogrel therapy in a population of patients with high on-treatment reactivity after PCI provided a modest pharmacodynamic effect but did not reduce the rate of death from cardiovascular causes, nonfatal myocardial infarction, or stent thrombosis," wrote Dr. Price, director of the cardiac catheterization laboratory at the Scripps Clinic in La Jolla, Calif., and his coinvestigators.
The researchers suggested several potential mechanisms that may explain the lack of a beneficial treatment effect with high-dose clopidogrel. It may be that on-treatment platelet reactivity is simply not a modifiable risk factor for thrombosis after PCI, or that the solution is to use an agent such as prasugrel, which doesn’t require metabolic transformation to reach its active form.
But the timing of the test may also play a role. Platelet reactivity resolved in nearly 40% of patients on normal-dose clopidogrel within 30 days, suggesting that the poststenting platelet activation may be temporary in a subset of patients.
"The dynamic nature of platelet reactivity that was observed underscores the importance of understanding the effect of the timing of the measurement on the level of reactivity and its association with adverse outcomes," they observed.
The GRAVITAS trial was sponsored by Accumetrics. Dr. Price said that he serves as a consultant to the company as well as to Sanofi-Aventis and Bristol-Myers Squibb, which provided the clopidogrel used in the study. Several other authors reported significant financial relationships with a number of pharmaceutical companies.