New Questions About Plavix

Plavix (clopidogrel) is an important anti-platelet drug that is used extensively in cardiology to help prevent blood clotting (thrombosis) in the coronary arteries. Plavix is most often used after acute heart attacks and other forms of Acute Coronary Syndrome, when the risk of clotting is high, and after the placement of stents to prevent stent thrombosis. Plavix is the second most-prescribed drug in the United States.

The results of recent studies have now caused a major conundrum among cardiologists and other experts regarding their use of Plavix. Two common risk factors have emerged that appear to significantly reduce the effectiveness of Plavix. Patients exposed to either of these risk factors, when treated with Plavix, appear to have a significantly higher risk of coronary artery thrombosis than patients treated with Plavix who do not have the risk factors.

The first risk factor is a genetic variant (i.e., having one of the CYP2C19 alleles). Unfortunately this is a common variant. It occurs in in 30% of individuals of European ancestry, 40% of African ancestry, and greater than 50% of Asian ancestry.

The second risk factor is the use of a proton-pump inhibitor (PPI) to reduce stomach acid. (Plavix often causes heartburn symptoms, so PPIs have been prescribed commonly in people taking this drug.) PPIs available by prescription include omeprazole (Prilosec, Zegerid), lansoprazole (Prevacid), pantoprazole (Protonix), rabeprazole (Aciphex), and esomeprazole (Nexium). Prilosec is also sold over-the-counter for heartburn.

Plavix is a "pro-drug." That is, before it can be used by the body, the drug needs to be metabolized to its active form. Both the genetic variant and the PPIs appear to interfere with the activation of Plavix, thus reducing its effectiveness.

The FDA has expressed concern about these new findings, and is working with the makers of Plavix (Sanofi-Aventis and Bristol-Myers Squibb) to gather as much information as they can, so that formal recommendations can be made to doctors and patients about the use of Plavix.

In the meantime, people taking Plavix should talk to their doctors about these new findings. They should also avoid taking PPIs. Some doctors will want their patients taking Plavix to have genetic testing.

If your doctor is talking to you about elective (i.e., non-emergency) stent placement, you may want to discuss the possibility of having genetic testing before agreeing to the procedure. Plavix is needed to help prevent clotting of the stent, and knowing whether Plavix is likely to be fully useful in your case may be important in deciding whether to have the procedure done.

_Sources:

Collet JP, Hulot JS, Pena A, et al. Cytochrome P450 2C19 polymorphism in young patients treated with clopidogrel after myocardial infarction: a cohort study. Lancet 2008; DOI:10.1016/S0140-6736(08)61845-0.

Simon T, Verstuyft C, Mary-Krause M, et al. Genetic determinants of response to clopidogrel and cardiovascular events. N Engl J Med 2009; DOI 10.1056/NEJMoa0808227.

FDA. Early Communication about an Ongoing Safety Review of clopidogrel bisulfate (marketed as Plavix). available at: http://www.fda.gov/cder/drug/early_comm/clopidogrel_bisulfate.htm