What Does Clopidogrel's Black Box Warning Mean for Neurologists?

Mark J. Alberts, MD


August 04, 2010

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Hello. My name is Dr. Mark Alberts, Professor of Neurology at Northwestern University, and Director of the Stroke Program at Northwestern Memorial Hospital. Welcome to this Medscape stroke update. Today I wanted to talk to you briefly about the new FDA [US Food and Drug Administration] black box warning related to Plavix®, or clopidogrel.1] As many of you are aware, several months ago, the FDA issued this black box warning which focused on the fact that clopidogrel or Plavix® needs to be metabolized into its active metabolites and that certain polymorphisms in the cytochrome 2P-C19 gene, or enzyme system that metabolizes Plavix®, could reduce the metabolism of Plavix® to its active metabolites.

Based on this warning, and based on concerns from several studies, almost all of which were relatively small, and almost all of which focused exclusively on patients with acute coronary syndromes -- or PCI [percutaneous coronary intervention] for coronary disease -- it was found that patients who were poor metabolizers tended not to respond quite as well to Plavix® and had a higher risk for cardiovascular events.

What does this mean for neurologists and for treating patients with stroke or cerebrovascular disease? Well, the bottom line is that it is very uncertain what this means, because the vast majority of these data, if not all of them, are based on patients with active heart disease, many of whom underwent cardiac interventions.

The FDA black box warning talks about using loading doses of Plavix®, which are not FDA-approved for stroke, or perhaps higher maintenance doses of Plavix®, which again, are not FDA-approved for stroke. There was a recent expert consensus statement published in Circulation by David Holmes and colleagues,[2] published online June 28th of this year. Holmes and his colleagues looked at all of the available data and their bottom line in terms of interpreting the FDA black box warning is that they were very unsure what this all means. They were not sure that this calls for a mandate in terms of changing therapy, and they were not even sure whether all patients should be tested for their genetic background. There were concerns about the cost of the genetic testing, who is going to pay for it, and about the ultimate outcomes, for which there are very few data.

The bottom line, in my opinion, is that this remains a very important avenue of research. Its applicability to patients with stroke or cerebrovascular disease is very uncertain at this time. In many cases, we don't know how to do this genetic testing, or who to send it to, or who is going to pay for it. But again, this line of research is very important and I think we should stay tuned as more data come forth to see if this is really of relevance in terms of changing therapies for our patients. Thank you very much.


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