A new analysis of the popular blood thinner Plavix contradicts the 2010 black box warning on the label mandated by the Food and Drug Administration. The new study questions whether the FDA made the right move in requiring the most serious warning possible, which indicates that some people have a gene that may make the drug less effective.
Plavix, also called clodiprogel, is a blood thinner that prevents blood platelets from sticking together to form clots. It is a blockbuster medication, generating annual sales of over $6 billion for it’s marketers, Bristol Myers Squibb Co. and Sanofi-Aventis. In 2008, it was the world’s second-best selling drug behind Pfizer’s cholesterol drug Lipitor.
According to the FDA, for Plavix to prevent blood clots, it must first be metabolized by a particular liver enzyme. However, 2-14% of the people don’t have any copies of the genes required to metabolize the drug, and 25-40% of the population only have a single working copy of the required. On top of that, over 1/3 of patients taking Plavix are also taking stomach acid medications or antidepressants that decrease the effectiveness. So, about 50% of people aren’t getting the blood thinning effect, and this increases the risk of a heart attack or stroke by 2- to 5-fold.
In August 2009, researchers from the University of Maryland identified a gene variant found in about one-third of the population that may signal a reduced effectiveness of Plavix. This variant is known as CYP2C19.
According to the research published, people with the CYP2C19 alleles genetic variant may suffer no more cardiovascular events on Plavix than those without the gene that took the drug. However, the researchers confirmed that there was a link between the gene and Plavix effectiveness.
In March 2010, the FDA warned that people with the CYP2C19 variant have reduced functioning of a liver enzyme that is supposed to convert Plavix from its inactive form to its active form, potentially making Plavix ineffective at reducing the risk of blood clots. Therefore, the agency required Plavix to carry a black box warning, the strongest labeling warning the FDA can require.
The Journal of the American Medical Association says Plavix is a safe and effective medication for patients. The warning cautions the drug has diminished effectiveness in poor metabolizers and might lead to an increase in cardiovascular events such as heart disease or bleeding. But the new study suggests it’s time to rethink the warning.
The new research looked at 32 studies involving about 42,000 patients and found that while the ability to metabolize Plavix was affected by a special gene variant, that did not appear to translate into more heart attacks. The researchers said previous studies indicating an increased risk of Plavix heart attacks for patients with the gene variant may have been skewed by small sample sizes and selective outcome reporting. As a result, the study calls into question the FDA’s decision to place a black box warning on Plavix.
And, according to recent data presented at a November 2011 meeting of the American Heart Association in Orlando, Florida, tripling or quadrupling the amounts of Plavix given to patients with the CYP2C19 gene variant, which makes those individuals resistant to the drug, can overcome that resistance, according to The Journal of the American Medical Association.
For this particular study, researchers looked at 335 patients who had suffered a heart attack and found that they were able to overcome the inability of some patients to metabolize Plavix due to genetics with much larger doses. The method worked in all but 10% of patients with the gene variant, and resulted in no additional risk of Plavix side effects, researchers reported.