Compared to the standard dose, a high dose of the commonly-used drug clopidogrel (PlavixTM) did not reduce the incidence of death, heart attack or blood clots inside of stents in certain high-risk patients who have had drug-coated stents implanted to open blocked arteries, according to late-breaking clinical trial results reported at the American Heart Association's Scientific Sessions 2010.

Earlier studies have shown that the anti-clotting drug clopidogrel works well in some patients who have received a stent to prop open a blocked artery, a procedure called percutaneous coronary intervention or PCI. However, other patients have what is called "high residual platelet reactivity," meaning their blood is still prone to clotting despite taking the anti-clotting medication.

"Those with high residual platelet reactivity have a higher risk of major cardiovascular events after procedures to implant stents," said Matthew J. Price, M.D., the study's lead investigator. The main purpose of the Gauging Responsiveness With A VerifyNow Assay - Impact on Thrombosis and Safety (GRAVITAS) trial was to determine if high-dose clopidogrel reduces cardiovascular events in patients with high residual platelet reactivity as determined by the VerifyNow platelet function test.

In GRAVITAS, researchers gave a loading dose followed by a high maintenance dose of clopidogrel - double the standard maintenance dose - to those patients whose platelet function test showed they had high residual platelet reactivity.

"The high dose of clopidogrel doesn't appear to improve outcomes, so alternative treatment strategies should be tested," said Price, who is director of the Cardiac Catheterization Laboratory at the Scripps Clinic and assistant professor at the Scripps Translational Science Institute in La Jolla, Calif.

Price expects this 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," he said. "We show that this strategy is probably ineffective."

Although the proposed regimen failed to cut risk of dangerous events, the study found it didn't cause additional bleeding, so the patients didn't suffer harm at the higher dose.

The six month trial, involving about 80 centers throughout the United States and Canada, randomized 2,214 patients who had a specific platelet function test after the PCI procedure that revealed they had high residual platelet activity. Those patients were randomly assigned to either receive a high dose of clopidogrel, 150 milligrams daily, or the standard-dose of clopidogrel, 75 milligrams daily, with an inactive placebo. The composite end point (the rate of death from cardiovascular causes, of heart attacks, and of blood clots in stents) at six months in patients randomized to high-dose clopidogrel was 2.3 percent, identical to that in patients randomized to standard dose clopidogrel. Further analysis of the GRAVITAS data is expected to be available in early 2011.

Price said this trial serves as a model for future research into personalized therapy, which may one day reduce the need for extremely large clinical trials that include many thousands of patients. "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."

"GRAVITAS is addressing the question of whether personalized, selective anti-platelet therapy may have substantial benefit when treating the highest risk patients," Price said. "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."

Author disclosures are on the abstract.

The study was sponsored by Accumetrics, the maker of the platelet function test. Through an investigator-initiated grant, the makers of Plavix, Sanofi-Aventis and Bristol-Myers Squibb, provided the drug but weren't involved in the trial in any other capacity.

American Heart Association

View drug information on Plavix.

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