GRAVITAS Trial Results: A Different Perspective

Mark J. Alberts, MD


January 10, 2011

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Hello, my name is Dr. Mark Alberts, Professor of Neurology at Northwestern University Medical School in Chicago, Illinois, and Director of the Stroke Program at Northwestern Memorial Hospital. Welcome to this Medscape stroke update. Today I would like to talk to you about the GRAVITAS [Gauging Responsiveness with A VerifyNow Assay-Impact on Thrombosis And Safety] study. This was a very interesting and important study presented at the American Heart Association's scientific sessions, held in Chicago in November 2010.

In GRAVITAS, the investigators took more than 5400 patients who were undergoing a percutaneous coronary intervention (PCI) for coronary artery disease. The vast majority of these patients were undergoing elective PCI. All patients received clopidogrel loading doses and standard doses of aspirin near the time of their PCI, and afterward all patients were tested for clopidogrel resistance.

The test that was used was the VerifyNow® assay (Accumetrics, Inc.; San Diego, California). If patients were believed to be clopidogrel responsive, they received the normal dose of clopidogrel and aspirin going forward (75 mg daily); however, if patients had evidence of clopidogrel resistance (approximately 2200 of the patients), they were pulled out and again randomly assigned to either standard therapy or to a clopidogrel loading dose plus 150 mg of clopidogrel daily for 6 months.

The primary endpoint was cardiovascular death, myocardial infarction (MI), and stent thrombosis. The major safety event was GUSTO [Global Use of Strategies to Open Occluded Arteries], which defined moderate or severe bleeding.

At the end of the day, what did they find? The 2 groups, whether they were randomly sampled to higher-dose clopidogrel or standard-dose, did not show any difference in the primary endpoint. For this reason, GRAVITAS was largely reported in the press as being a negative study. However, my interpretation is that this glass is half full rather than half empty, and here's why.

First, the study clearly showed that patients who had evidence of clopidogrel resistance had a higher risk for the primary endpoint than patients who were clopidogrel responsive. The second point is that patients who were treated with higher doses of clopidogrel tended to have lower P2Y12 reaction units (showing a more effective antiplatelet response) than patients who stayed on standard clopidogrel therapy.

The third very important point is that patients who had evidence of clopidogrel resistance who were randomly assigned to higher- or lower-dose clopidogrel, but who received lower-dose clopidogrel, had much worse outcomes than patients who did not have evidence of clopidogrel resistance, and stayed in their original group. In fact, the absolute increased risk of having cardiovascular death, MI, or stent thrombosis, if a patient had clopidogrel resistance and stayed on low-dose clopidogrel, was almost 1%. This did not reach statistical significance because the number of actual events was very low.

The other point to realize is that, overall, whether they got high-dose or standard-dose clopidogrel, there was no statistically significant increase in bleeding events. So what does this mean? Are we going to throw out and ignore platelet function testing and say that it has no meaning? I don't think that's the proper interpretation of the study, because we did find evidence that the results of platelet function testing predicted risk for subsequent events. The problem was more in the study design, that when patients were randomly assigned to higher-dose clopidogrel, their therapy was no longer individually titrated or adjusted to make sure that all of them -- or most of them -- had an adequate antiplatelet response.

Unlike some of the comments on this study, I don't think that this is the last chapter in this book; rather, I think it's one of the early chapters, showing us that we understand some of the issues -- but not all of them. The last issue that I want to talk about is that clopidogrel resistance was analyzed as a dichotomous variable (either you have it or you don't), and biologically, this doesn't make a whole lot of sense. It makes more sense to look at responses to clopidogrel, or even aspirin therapy on a continuum of high, medium, and low that will change from patient to patient.

More work needs to be done, but GRAVITAS is certainly an important step forward in understanding a lot of these issues. Thank you very much for tuning into this Medscape stroke update.


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