A new study, which was published December 27 in the Journal of the American Medical Association (JAMA), challenged the Food and Drug Administration’s (FDA) “black box” warning for the drug while also casting doubt on the usefulness of a genetic test for taking clopidogrel (Plavix), which is marketed by Bristol-Myers Squibb Co. and Sanofi SA.
The blood-thinner Plavix is prescribed to individuals who are at risk for heart attacks and/or strokes to reduce the risk of blood clots. It is also prescribed for individuals with artificial heart valves and stents, which widen the coronary arteries. In 2010, Plavix was prescribed for approximately 40 million patients and recorded sales totaling $6.7 billion.
The genetic test’s purpose is to help determine how well patients can process the medication; thus, proponents of the drug note that it can help physicians in the determination of which benefit will benefit the most. In order to have a therapeutic effect, Plavix must be activated by enzymes within the body. A number of studies have reported that individuals with a certain variant of a gene that manufactures the CYP2C19 enzyme do not process Plavix as well as those without the variant gene; these individuals are susceptible to receiving a dose below the therapeutic level. Approximately 30% of individuals in the U.S. possess the variant gene.
In March 2010, the FDA deemed the evidence of significant merit to place its strongest warning, the black box, on the drug’s label. The label warned physicians and patients of the reduced effectiveness of the medication in patients with the CYP2C19 variant.
The studies, which prompted the FDA warning, consisted of a review of 32 published studies involving some 42,000 patients, confirmed that patients with the gene variant indeed differed in their ability to activate the drug. However, those patients did not have a substantially higher rate of heart attacks or other cardiac events, according to Michael Holmes, the primary author of the new JAMA study and a researcher in the genetic epidemiology department at University College London.
Four randomized, controlled trials did not report any linkage between the gene variant and later cardiac events. In trials where all patients received Plavix (a less-definitive study protocol) there was some evidence of benefit. However, according to the authors of the JAMA study, the effect was likely overestimated because studies with fewer patients tended to show the greatest effects.
The results suggest that “there’s insufficient evidence” to support use of genetic testing to guide Plavix use, noted Aroon Hingorani, another author and director of University College London’s Institute for Cardiovascular Science.