GRAVITAS Finds High Dose of Clopidogrel Is No Better Than Standard Dose for High-Risk DES Patients

November 16, 2010—Compared to the standard dose, a high dose of clopidogrel (Plavix, Bristol-Myers Squibb/Sanofi Pharmaceuticals Partnership, New York, NY) did not reduce the incidence of death, myocardial infarction, and in-stent restenosis in certain high-risk patients who had drug-eluting stents implanted, according to late-breaking clinical trial results reported at the American Heart Association's (AHA) Scientific Sessions 2010.

According to the AHA, earlier studies have shown that clopidogrel works well in some patients who have undergone percutaneous coronary interventions with drug-eluting stent implantation. However, other patients have high residual platelet reactivity despite taking the anticlotting medication.

The purpose of the GRAVITAS (Gauging Responsiveness With a VerifyNow Assay-Impact on Thrombosis and Safety) trial was to determine if high-dose clopidogrel reduces cardiovascular events in patients with high residual platelet reactivity as determined by the VerifyNow P2Y₁₂ platelet function test (Accumetrics, San Diego, CA).

“Those [patients] with high residual platelet reactivity have a higher risk of major cardiovascular events after procedures to implant stents,” noted Matthew J. Price, MD, principal investigator of GRAVITAS.

In GRAVITAS, the investigators administered a loading dose followed by a high maintenance dose of clopidogrel—double the standard maintenance dose—to patients whose platelet function test showed that they had high residual platelet reactivity.

“The high dose of clopidogrel doesn't appear to improve outcomes, so alternative treatment strategies should be tested,” Dr. Price stated. He expects these new data to change the way cardiologists treat these patients. “Many physicians have been using a high dose of clopidogrel as a default strategy in patients who are nonresponsive to the drug. We show that this strategy is probably ineffective.”

Although the proposed regimen failed to cut the risk of dangerous events, the study showed that it did not cause additional bleeding, so the patients did not risk harm at the higher dose.

According to the AHA, the 6-month GRAVITAS trial involved approximately 80 centers in the United States and Canada. The investigators randomized 2,214 patients who had a specific platelet function test after the percutaneous coronary intervention procedure that revealed the patients had high residual platelet activity. Those patients were randomly assigned to receive either a high dose of clopidogrel (150 mg daily) or the standard dose of clopidogrel (75 mg daily) with an inactive placebo. The composite endpoint is the rate of death from cardiovascular causes, myocardial infarction, and blood clots in stents at 6 months. In patients randomized to high-dose clopidogrel, there was a 2.3% composite endpoint rate, which was identical to that in patients randomized to standard-dose clopidogrel. Further analysis of the GRAVITAS data is expected to be available in early 2011.

This trial serves as a model for future research into personalized therapy, which may reduce the need for extremely large clinical trials that include many thousands of patients, said Dr. Price. “If we can identify certain high-risk patients based upon their individual response to therapy, instead of mega trials, we can potentially find effective therapy using a much smaller trial size.”

Dr. Price concluded, “GRAVITAS is addressing the question of whether personalized, selective antiplatelet therapy may have substantial benefit when treating the highest-risk patients. Traditional trials seek the best treatment for the average patient. GRAVITAS is using a personalized approach, which seeks to identify the best treatment for a particular individual. This is a paradigm-shifting approach for evidence-based medicine.”

GRAVITAS was sponsored by Accumetrics, the manufacturer of the platelet function test. The company noted that the study also found that patients with high residual platelet reactivity, as measured by the VerifyNow P2Y₁₂ test, demonstrated almost twice the risk of ischemic events compared to patients without high residual platelet reactivity. Dr. Price commented, “The GRAVITAS findings do not support a uniform treatment strategy of high-dose clopidogrel in patients with high residual platelet reactivity based upon a single platelet function test after stent implantation. This is important as currently many physicians utilize a strategy of doubling the dose of clopidogrel the morning after the stent procedure. Alternative therapies or testing a patient multiple times to treat to a specific target of reactivity deserve consideration.”