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CHICAGO -- Doubling the clopidogrel (Plavix) dose in patients with a poor response to the drug following percutaneous coronary intervention with drug-eluting stents did not improve outcomes, the randomized GRAVITAS trial showed.

The six-month rate of cardiovascular death, MI, or stent thrombosis was 2.3% with both a double dose and a standard dose of clopidogrel (HR 1.01, 95% CI 0.58 to 1.76), Matthew Price, MD, of the Scripps Clinic in La Jolla, Calif., reported at the American Heart Association meeting here.

The rate of bleeding was similar in both groups.

Cardiologists at the European Society of Cardiology meeting earlier this year said they eagerly anticipated the GRAVITAS (the Gauging Responsiveness with a VerifyNow Assay -- Impact on Thrombosis and Safety trial) findings, noting they may change clinical practice. Some clinicians have already been increasing the dose of clopidogrel in patients with residual platelet reactivity with the standard dose.

But GRAVITAS, conducted at 83 centers, does not support that strategy, Price said at a press briefing. He cautioned that the study did not assess the merits of platelet function testing, but rather looked only at one treatment option in patients found to have high platelet reactivity.

Jessica Mega, MD, MPH, of Brigham and Women's Hospital in Boston, agreed, saying that future studies should focus on different patient populations and different treatment strategies, including the use of the more powerful platelet inhibitors -- prasugrel (Effient) or the not-yet-approved ticagrelor -- or even higher doses of clopidogrel.

Elliott Antman, MD, of Harvard, who moderated the press briefing, noted that bleeding risk will become more of a consideration if the newer antiplatelets or higher doses of clopidogrel are used.

Additional strategies, such as using radial access more often in PCIs, will be needed to address the increased bleeding risk, he said.

Platelet reactivity is variable among patients on clopidogrel, both during loading and maintenance phases, partly mediated by the presence of variants of the CYP2C19 gene that impair the metabolism of the drug. Poor metabolizers have been shown to have higher rates of adverse cardiovascular events.

Although clinicians have been increasing the dose of clopidogrel in patients with poor response, that strategy had not been evaluated in a large clinical trial until now.

GRAVITAS used a point-of-care platelet function test -- the VerifyNow P2Y12 assay -- to identify patients who had undergone elective or urgent percutaneous coronary intervention (PCI) and who had residual platelet reactivity with the standard clopidogrel dose 12 to 24 hours after the procedure.

High residual reactivity was defined as a PRU (platelet reactivity unit) of at least 230.

The researchers randomized 2,214 such patients to a high-dose of clopidogrel -- an additional 600-mg loading dose followed by 150 mg daily for six months -- or a continued standard dose -- no additional loading dose and 75 mg daily.

All patients also received aspirin (81 to 162 mg daily).

The indication for PCI was stable coronary artery disease or low-risk unstable coronary artery disease in 84% of the patients. Very few patients had ST-segment elevation MI (less than 1%).

During PCI, the patients had a mean of 1.4 lesions treated with a mean of 1.7 drug-eluting stents.

Using the VerifyNow P2Y12 assay, the researchers found that post-PCI platelet reactivity was not significantly different between the two groups (P=0.98).

At both 30 days and six months, however, platelet reactivity was significantly reduced by about 40 PRU in the high-dose group (P<0.001 for both time points).

Persistently high platelet reactivity (a PRU of 230 or higher) was significantly more common in the standard-dose group at 30 days (62% versus 40%, P<0.001).

The greater platelet inhibition with the high dose, however, did not translate into improved clinical outcomes, which, according to Mega, may have resulted from a lack of statistical power to detect a difference on the primary outcome.

The study was designed assuming a 50% relative risk reduction with the higher dose, Mega said, even though trials of prasugrel and ticagrelor, which result in greater platelet inhibition than clopidogrel, reduced cardiovascular events by just 15% to 20% compared with a standard dose of clopidogrel.

Also, she said, the investigators powered the study according to an expected 5% event rate, which was twice as high as the observed rate.

But David Holmes, MD, of the Mayo Clinic, president-elect of the American College of Cardiology, said the findings may reflect a disconnect between laboratory tests and clinical outcomes that has been seen before.

He explained that antiplatelets may have multiple actions beyond their platelet inhibition effects. Also, multiple mechanisms that lead to stent thrombosis may not necessarily relate to platelet inhibition.