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Double-Dose Clopidogrel (Plavix) Does Not Reduce Heart Attack or Stent Thrombosis for Angioplasty Patients with High Platelet Reactivity

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Double dose of Plavix not effective in some patients    

March 15, 2011 -- When does one plus one equal one? In the case of angioplasty or stent patients who are at high risk for adverse events, such as stent thrombosis, a new study concludes that a double dose of clopidogrel (Plavix) "did not reduce the incidence of death from cardiovascular causes, nonfatal myocardial infarction, or stent thrombosis." The GRAVITAS study, first presented last November at the American Heart Association's Annual Scientific Sessions, is now published in the current Journal of the American Medical Association (JAMA).

Clopidogrel After Stenting
One problem that can occur after a stent is placed in a coronary artery is stent thrombosis: the platelets in the blood react to the foreign object and begin to form a blood clot, or thrombosis, acutely blocking the artery. This blockage can result in a heart attack -- fatal in almost half of these cases. In order to prevent stent thrombosis from occurring, stent patients are given two antiplatelet drugs, usually clopidogrel (Plavix) and aspirin. For bare metal stents (BMS), the guidelines now recommend six months; for drug-eluting stents (DES) it's a year or more, if the patient does not suffer any bleeding complications which is a side-effect of any antiplatelet medication.

Dual antiplatelet therapy (DAPT) has been very successful in reducing the incidence of stent thrombosis and other adverse events post-Percutaneous Coronary Intervention (PCI), but the challenge has been in the group of patients who have elevated levels of platelet reactivity -- and who, according to current thought, are therefore at higher risk for thrombosis.

Using a platelet reactivity test, called VerifyNow (made by San Diego-based Accumetrics), Dr. Matthew J. Price of Scripps Translational Science Institute and his colleagues identified 2,214 patients at 83 North American centers between July 2008 and April 2010 who were found to have high on-treatment reactivity, measured 12-24 hours after PCI. (The study's acronym GRAVITAS stands for Gauging Responsiveness with A VerifyNow assay -- Impact on Thrombosis And Safety.) These patients were randomized 50/50 to standard antiplatelet therapy (75 mg of clopidogrel) and higher double-dose levels (600 mg initial dose followed by 150 mg daily). All patients also received aspirin.

The hypothesis was that personalizing therapy, based on the VerifyNow test, and utilizing greater levels of antiplatelet medication in certain patients would reduce the incidence of death from cardiovascular causes. However, at six months the rates of death were identical: 2.3% in both patient groups. Even at 30 days, the difference in regular vs. double dose clopidogrel was insignificant: 1.6% vs. 1.9%. The authors concluded:

"The results of GRAVITAS do not support a uniform treatment strategy of high dose clopidogrel in patients with high on-treatment reactivity identified by a single platelet function test after PCI. Alternative treatment strategies incorporating platelet function testing merit further investigation."

Attempting to determine the optimal therapy for patients with high platelet reactivity is an important goal, because this patient population is not small: 41% of all the patients screened for GRAVITAS (2,214 out of 5,429) were in that group.

Possible Factors at Play: Low Event Rates
In an accompanying editorial, Paul A. Gurbel, MD and Udaya S. Tantry, PhD of Sinai Hospital in Baltimore, noted several factors that may have contributed to the trial's failure to show any difference. One was the possibility that the cutpoint for determining high reactivity may have been too high (230 platelet reactivity units or PRUs), and that a lower cutpoint would have revealed a greater differential.

But a significant problem in GRAVITAS was the very low event rate (only 25 events in each cohort), making it necessary for the treatment to be "super-effective" in order to show a difference in 2,214 patients. Stent thrombosis rates alone were only 0.5% (5 patients with double dose) and 0.7% (8 patients with standard dose). Although this was obviously good news for the patients in the study, when the trial originally was designed, it was assumed that the rates of adverse events and death would be higher. Dr. Gurbel pointed out that the elimination of periprocedural MI as an adverse event may have contributed to this low event, but he also opined that:

"It also may just be that interventionalists are better than they were years ago. The procedures are faster, flow is maintained fairly well in each procedure, and the concomitant therapies that these patients get, statins, good blood pressure control and, if you look at the frequency of patients who were stable, there was like 60% of the patients had stable angina -- it was in general a fairly low risk group of patients."

Dr. Price also told Angioplasty.Org that another reason might have been that 73% of the patients were treated with the newer second generation drug-eluting stents (XIENCE/PROMUS and Endeavor) which probably contributed to better outcomes, as well. So the excellence in procedural skills and the improvement in the stents themselves may have been a factor in GRAVITAS not showing a difference.

A further factor may be that clopidogrel has a "threshold effect": that more concentration of the drug doesn't have any impact. However, platelet reactivity, as measured by the VerifyNow assay, was significantly reduced at six months in many of the patients who received the double-dose, yet there was no change in the clinical outcomes -- which might offer a hypothesis that, as Dr. Gurbel noted in his editorial:

"...would suggest that high on-treatment platelet reactivity identified early after stenting is only a marker of risk and that the level of risk cannot be modified by intensification of antiplatelet therapy."

Indeed, even in the patients who were found to have normal platelet reactivity, the event rates, while numerically lower, did not achieve statistical significance over the highly reactive patients.

Take-Away Message for Clinical Practice
Left with the message that increasing clopidogrel in this population of "low responders" is not effective, cardiologists are left with many questions. Some feel, as does Dr. Gurbel, that an alternative antiplatelet agent like prasugrel (Effient) should be utilized in those patients at high risk for thrombosis. And there are several trials now underway or in the near future that will test prasugrel in highly reactive patients.

Further analyses of the GRAVITAS patient cohorts are ongoing; one such substudy of patients who had genotype testing, in addition to the VerifyNow phenotype test, will be presented at the upcoming American College of Cardiology meeting as a late-breaking trial. (For more information on genotype testing, read our exclusive interview with Dr. Eric Topol, also of Scripps.)

When asked by Angioplasty.Org how they currently manage their patients, in light of the results from GRAVITAS, Drs. Price and Gurbel responded, as follows:

"One takeaway from GRAVITAS is that patients with low reactivity do really well. I think, if you have a patient, either elective or ACS, if the PRUs are low, then the likelihood of them having an event is very small.

"But I look at the whole patient. Platelet reactivity does not exist in a vacuum. So I look at other risk factors for thrombotic events, be it stent length or diabetes, and then decide how best to treat that patient. I think that platelet reactivity can help guide how aggressive we should be with antiplatelet therapy."

    Matthew J. Price, MD
Matthew J. Price, MD
Scripps Translational
Science Institute

Paul A. Gurbel, MD
Paul A. Gurbel, MD
Sinal Hospital of Baltimore
    "High platelet reactivity entails a risk. Particularly those patients in the highest quartile for on-treatment platelet reactivity. Particularly if they have high predictors of stent thrombosis, such as implantation of multiple stents, overlapping stents, long vessel segments stented, bifurcation stenting, poor left ventricular function -- all those anatomic features would make me want to personalize the therapy in those patients. And also co-morbid factors such as diabetes, history of congestive heart failure, prior stent thrombosis, prior myocardial infarction -- any patient who's proven that they can form a thrombus would be a high risk patient. And I don't think any clinical trial result's going to really alter my thinking about that.

When asked, what his treatment strategy in these high risk patients would be, Dr. Gurbel answered, "Prasugrel."


Reported by Burt Cohen, March 15, 2011