The Debate Over Clopidogrel Continues

In December a new study created quite a stir in the already-volatile clopidogrel research community. Clopidogrel (trade names Plavix®) is a commonly prescribed anti-clotting drug. It is inactive in the body until a protein encoded by the gene CYP2C19 converts the drug to its active form. Some people are able to make this conversion more quickly and effectively than others, partially due to genetic mutations in the CYP2C19 gene. How this ability to process clopidogrel impacts a patient’s risk of heart attack and other cardiac events, however, is unclear. Are slow metabolizers (those who can not convert clopidogrel to the active form very well) at higher risk for cardiac events than fast metabolizers?

Many researchers and physicians, based upon the results of recent studies, believe that slow metabolizers of clopidogrel do, in fact, receive less protective benefit from the drug. The evidence for an association between CYP2C19 genotype and cardiac events was perceived to be so strong that, in March of 2010, the FDA added a boxed warning on the drug labeling for clopidogrel asserting that slow metabolizers of the drug may need “alternative treatments” to avoid heart attacks and other cardiovascular events. Others, however, are less convinced that being able to process clopidogrel quickly actually translates to improved protection against cardiac events. After the FDA released their boxed warning, the American College of Cardiology and the American Heart Association published a report maintaining that routine genetic testing for CYP2C19 mutations for the purpose of clopidogrel dosing was not justified by the current research.

Last month Dr. Michael Holmes and a team of researchers from the University College London published a study in the Journal of the American Medical Association stating that although CYP2C19 genotypes affect how quickly one processes clopidogrel, it does not actually affect one’s risk of cardiovascular events. After analyzing results from 32 previously published studies relating clopidogrel and CYP2C19 genotype, they determined that there was likely no true association.

Of particular note to Holmes and his colleagues was the fact that the studies reporting the strongest associations between CYP2C19 metabolizer status and cardiovascular outcomes were also the smallest, perhaps reflecting the tendency for small research groups to publish only positive findings (publication bias). The type of study also seemed to matter — the preferred, but less common case-control studies were less likely to show an association than the treatment-only studies. The researchers concluded that there is likely no statistically significant association between CYP2C19 genotype and cardiovascular events, although they briefly concede that the specific complication of stent thrombosis might be a “possible exception.”

Some scientists, such as Dr. Steven Nissen, have applauded this new meta-analysis. In Dr. Nissen’s editorial “Pharmacogenomics and Clopidogrel: Irrational Exuberance?”, he calls the analysis results “compelling.” Other experts in the field, however, were less enthusiastic about the new study. Dr. Eric Topol, the director of Scripps Translational Science Institute, responded with a rebuttal in his blog, criticizing the study for failing to correctly account for type of treatment and for including patients for whom the benefit of clopidogrel is not well established.

Dr. Topol argues that clopidogrel is useful for preventing clotting in patients who have been treated with stents, and that this is one of the primary uses of the drug. Dr. Topol criticizes the authors for downplaying the association between CYP2C19 genotype and stent thrombosis and their failure to highlight the importance of CYP2C19 genotyping for stent-treated patients. In the study’s combined analysis, both stent-treated patients and patients treated by other means (for whom the benefit of clopidogrel is less established) were included. If clopidogrel does not significantly lower the risk of cardiac events in non-stent patients, then the non-stent patients included in the analysis would make it difficult to observe an association between genotype and cardiac events. Dr. Topol called the failure to control for treatment type a “critical flaw” in the analysis and asserted that the study was “remarkably misleading.”

Certainly, the last word in the clopidogrel debate has not yet been spoken. This study and the ongoing discussion, however, illustrate many of the challenging issues surrounding pharmacogenetic research. Publication bias, inadequate scientific controls, and the difficulty in translating genetic discoveries into clinical outcomes are all obstacles we will need to hurdle to realize the benefits of personalized medicine.

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