More Support for Clopidogrel Platelet Response Testing

March 06, 2009

from Heartwire — a professional news service of WebMD

March 6, 2009 (Munich, Germany) — More evidence that patients with a low platelet responsiveness to clopidogrel have an increased risk of stent thrombosis has come from a new study, with the suggestion that antiplatelet therapy should be intensified in this group [1].

The study, published in the March 10, 2009 issue of the Journal of the American College of Cardiology, was conducted by a team led by Dr Dirk Sibbing (Deutsches Herzzentrum, Munich, Germany).

Sibbing commented to heartwire that several previous studies have addressed the issue of clopidogrel responsiveness and stent thrombosis, but this is the largest one and the first one to use the newly developed multiple electrode platelet aggregometry (MEA) point-of-care assay.

"Also, we used definite stent thrombosis as our end point, whereas previous studies have used definite or probable stent thrombosis. And we also looked at bleeding events, and found a trend toward an increased bleeding rate in patients who had the highest response to clopidogrel," Sibbing said.

He noted that the MEA test is relatively new. Developed by a German company, Dynabyte (Munich), it is marketed under the name Multiplate and is being used more in Europe at present than in the US. It is a point-of-care test, with results available in about 10 minutes. "This allows an easy and fast assessment of platelet function, with the possibility to decide on treatment regimens when the patient is still in the cath lab," he commented.

The other point-of-care assay available, known as VerifyNow (Accumetrics, San Diego, CA), is based on changes in light transmission in a liquid phase after ADP stimulation, whereas MEA is based on the principles of impedance aggregometry. These two tests have been shown to yield similar but not identical results.

"We can't say whether the MEA assay is better than other assays or not, but we are very happy with it, and we are convinced by the results we have seen in this study. It also works out at a reasonable cost for each test. When we started this study, we were not routinely measuring platelet responsiveness in the cath lab, but now we are measuring it with this device," Sibbing said.

An Ideal Patient Group for Prasugrel

He explained that in those patients who show a definite reduced platelet response to clopidogrel, antiplatelet treatment is intensified. At the moment, this means giving a second loading dose of clopidogrel to these patients, and if they still show a reduced platelet response, switching to ticlopidine. But in the future they will use prasugrel, which is expected to be available shortly, in this group of patients.

Sibbing said it was not possible to estimate how many patients fit into this category of low responders to clopidogrel, but he said that they see "some of these patients every week" at his center.

Sibbing said it was not the norm to do clopidogrel responsiveness testing before PCI, but it may become more popular in future, especially as there will soon be a reasonable alternative drug to use in these patients. But he added that he would like to see studies showing that intensification of treatment in the low-response patients results in a lower event rate. One such study--GRAVITAS--is under way with the VerifyNow assay. And Sibbing's group is hoping to do another such study with the MEA assay.

The current study enrolled 1608 consecutive patients who were undergoing planned drug-eluting-stent implantation. All patients received 600-mg clopidogrel, and platelet responsiveness was measured with the MEA test. Results showed that clopidogrel low responders (defined as those in the upper quintile of platelet reactivity) had a significantly higher risk of definite stent thrombosis at 30 days (the primary end point) compared with the rest of the population. There was also a strong trend toward a higher mortality in the low-responder group.

Results at 30 Days According to Platelet Response to Clopidogrel

Outcome Low responders, n=323 (%) Normal responders, n=1285 (%) Odds ratio (95% CI) p
Definite stent thrombosis 2.2 0.2 9.4 (3.1–28.4) 0.0001
Death 1.2 0.4 3.2 (0.9–11.1) 0.07
Death or stent thrombosis 3.1 0.6< 5.1 (2.2–11.6) 0.001

What About Bleeding?

The study also showed a trend toward more bleeding in the highest responders to clopidogrel (the lowest quintile of platelet reactivity in this study). They had twice as much TIMI major bleeding than the other patients (1.3% vs. 0.7%). Sibbing said it was useful to identify these patients, and while they may not be treated differently at present, it would probably be important for them not to get a more potent agent such as prasugrel.

Editorial Cautious

An accompanying editorial [2], written by a team from the Sinai Center for Thrombosis Research (Baltimore, MD), points out a couple of shortcomings of the current study--that parenteral antiplatelet therapy was not included as a possible confounder and that sufficient time for clopidogrel to have taken its complete effect might not have been allowed before measuring platelet function in all patients. The authors say that given these limitations, caution is warranted in extrapolating the results of this study to different patient populations and in guiding individualized antiplatelet therapy.

Material for platelet function analysis on the Multiplate device was provided free by Dynabyte. Sibbing received speaker fees from Dynabyte. Disclosures for the coauthors are listed in the paper.

  1. Sibbing D, Braun S, Morath T, et al. Platelet reactivity after clopidogrel treatment assessed with point-of-care analysis and early drug-eluting stent thrombosis. J Am Coll Cardiol 2009; 53:849-856.

  2. Mahla E, Antonino MJ, Tantry US, and Gurbel PA. Point-of-care platelet function analysis. Ready for prime time? J Am Coll Cardiol 2009; 53:857-859.

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