High-Dose Clopidogrel Ineffective in Nonresponsive Patients


CHICAGO – Six months of high-dose clopidogrel were no better than standard-dose clopidogrel for preventing cardiovascular events in patients with high residual platelet reactivity after percutaneous coronary intervention in the GRAVITAS trial.

This large randomized study does not support the common practice of doubling the standard 75-mg/day dosing of clopidogrel as a default strategy in patients who are nonresponsive to the drug, Dr. Matthew J. Price said at the meeting.

“The high dose of clopidogrel doesn't appear to improve outcomes, so alternative treatment strategies should be tested,” according to Dr. Price, chair of GRAVITAS (Gauging Responsiveness With a VerifyNow Assay–Impact on Thrombosis and Safety) and director of the cardiac catheterization laboratory at the Scripps Clinic, La Jolla, Calif.

The GRAVITAS trial included 2,214 patients who displayed high residual platelet reactivity on the Accumetrics VerifyNow P2Y12 test 12-24 hours after undergoing elective or urgent PCI with stenting. They were randomized to 6 months of clopidogrel (Plavix) at the standard dose of 75 mg daily or to a 600-mg loading dose followed by high-dose therapy at 150 mg/day.

The primary study end point of cardiovascular death, nonfatal MI, or stent thrombosis at 6 months occurred in 2.3% of patients in each study arm. On the plus side, at least there was no significant difference in moderate to severe GUSTO (Global Use of Strategies to Open Occluded Coronary Arteries) bleeding, which occurred in 1.4% of patients on high-dose clopidogrel and 2.3% on standard-dose therapy, he noted.

High-dose therapy provided what the cardiologist deemed a “modest” but statistically significant pharmacodynamic effect in the form of an absolute 22% reduction in persistently high platelet reactivity at 30 days, compared with the 62% rate in the standard-dose arm.

Discussant Dr. Jessica L. Mega said one possible explanation for the neutral results in GRAVITAS is that high residual platelet reactivity is a risk marker but not a modifiable risk factor. It's not known yet whether that's true.

Another possibility worthy of future study is that a tailored approach to antiplatelet therapy would be beneficial in patients with high residual reactivity if an even higher dose of clopidogrel or an alternative, more potent agent were to be employed, added Dr. Mega of Brigham and Women's Hospital, Boston.

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. Dr. Mega has received clinical research grants through the TIMI Study Group from Accumetrics and other companies, and has served as a consultant to Sanofi-Aventis and Bristol-Myers Squibb.

A high dose isn't better than the standard dose, so 'alternative treatment strategies should be tested.'

Source DR. PRICE

Perhaps an even higher dose of clopidogrel, or a more powerful agent, would be beneficial for these patients.

Source DR. MEGA

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