Clopidogrel (Plavix) can be compromised by common drugs for the treatment of heartburn and ulcers resulting in a roughly 50 percent increase in the combined risk of hospitalization for MI, stroke and other serious cardiovascular illnesses, according to a study presented May 6 at the Society for Cardiovascular Angiography and Interventions (SCAI) 32nd annual scientific sessions in Las Vegas.
The study focused on the effects of proton pump inhibitors (PPI) omeprazole (Prilosec from AstraZeneca), esomeprazole (Nexium from AstraZeneca), pantoprazole (Protonix from Wyeth) and lansoprazole (Prevacid from Takeda Pharmaceuticals), which together accounted for about 96 percent of PPI use in the study.
Patients who receive a drug-eluting stent benefit from taking anti-clotting medications, including thienopyridines, such as clopidogrel or ticlopidine, and aspirin, for at least one year following the procedure. Doctors often also prescribe PPIs to patients taking clopidogrel because of pre-existing stomach disease or to reduce the risk of common side effects such as nausea and gastroesophageal reflux.
Before Plavix from Bristol-Myers Squibb and Sanofi Aventis can exert its anti-clotting effects, it must be converted from its inactive, pro-drug form to an active drug by enzymes in the liver. PPIs--the sixth most commonly prescribed drug class in the U.S.--can interfere with those liver enzymes, according to the study.
"Clopidogrel should continue to be taken as prescribed, and the need for PPI therapy should be carefully evaluated to ensure that it is prescribed only when clearly indicated," said the study's principal investigator Eric J. Stanek, PharmD, senior director of research, personalized medicine research and development, Medco Health Solutions in Franklin Lakes, N.J.
For the study, researchers analyzed integrated data on pharmacy and medical claims from more than 10 million patients, including 16,690 patients taking clopidogrel for a full year following coronary stenting. Of these, 41 percent also took a PPI, on average, for more than nine months of the year. Over that 12 month period when patients took clopidogrel, investigators evaluated the risk of hospitalization for major adverse cardiovascular events (MACE), which they defined as a combination of MI, unstable angina, stroke or temporary stroke-like symptoms, repeat coronary procedures or cardiovascular death.
The overall MACE risk was 51 percent higher among patients taking any PPI. The findings were equally concerning when the effects of individual PPIs were analyzed. Omeprazole correlated with a 39 percent increased risk of MACE, esomeprazole to a 57 percent increased risk, pantoprazole to a 61 percent increased risk and lansoprazole to a 39 percent increased risk. All of the associations were highly statistically significant.
Overall, they found that the incidence of hospitalization for upper gastrointestinal bleeding was only 1.1 percent among patients taking a PPI and 0.07 percent among those not taking a PPI.
Additional research is needed to determine whether newer, less widely used PPIs such as rabeprazole (Aciphex) and dexlansoprazole (Kapidex) are also associated with increased cardiovascular risk in patients taking clopidogrel. The researchers are also interested in examining how genetic variations in the liver enzymes that activate clopidogrel might alter the impact of PPIs on clopidogrel effectiveness, the potential influence of the timing of PPI administration, the effect of alternate dosing of clopidogrel, and the comparative effectiveness of other anti-clotting medications.
This study was supported by Medco Health Solutions, and conducted in collaboration with investigators from the Indiana University School of Medicine in Indianapolis.