Proton Pump Inhibitors increase risk of major cardiovascular event by more
than 50 percent for patients taking Plavix(R)
Study may anticipate a role for genetic testing in association with
clopidogrel prescribing

FRANKLIN LAKES, N.J., Nov. 11 /PRNewswire-FirstCall/ — Medco Health Solutions, Inc. (NYSE: MHS) today presented a study at the 2008 Scientific Sessions of the American Heart Association that showed an increased risk for major cardiovascular events in patients taking clopidogrel (the active ingredient in Plavix) and proton pump inhibitors (PPIs) together.

In the largest study of its kind to date, researchers at Medco report that PPIs inhibit the effectiveness of clopidogrel, the number two prescription drug in the world, thus increasing the risk of a major cardiac
event, such as heart attacks and strokes by 50 percent. Since PPIs mimic the effect of a variant gene, which also renders clopidogrel ineffective, this study further suggests a potential role for genetic testing.

“Considering the widespread use of these two medications, this important research adds to a growing body of evidence raising questions about their concurrent use and suggests further research is needed,” said Dr. Robert Epstein, a lead study author, chief medical officer, Medco. ”With this research in hand, we intend to open a dialogue with the major clinical organizations to advance the discussion around the guidelines that
govern the use of Plavix.”

Study details

Researchers tracked 16,690 patients who had undergone a percutaneous coronary intervention such as stent placement or balloon angioplasty, and had started taken clopidogrel as maintenance therapy. Of the patients in the study, 9,862 patients were taking clopidogrel alone; and 6,828 patients were taking clopidogrel and a PPI. Researchers tracked the two groups in the study for a 12-month period using medical and pharmacy claims data.

Results of the study were striking: researchers reported that the relative risk of a major adverse cardiovascular event was 50 percent higher, and the relative risk of a heart attack specifically was 74 percent higher, in patients taking both medications together. The incidence of a major cardiovascular event within 12 months of starting clopidogrel was 25 percent for patients taking both medications concurrently. The study was funded solely by Medco.

Genetic variability and clopidogrel:

For clopidogrel to work, it must first be converted to its active form by a liver enzyme called cytochrome P450 2C19. PPIs interfere with this enzyme reducing the amount of clopidogrel that is converted to an active form. The gene that produces this enzyme can vary such that individuals can have more or less enzyme activity, thus affecting its functionality. The way PPIs interfere with the conversion of clopidogrel to an active form may mimic this genetic variation that produces lower amounts of the enzyme, suggesting that genetic testing for this enzyme may be useful. Other studies have shown that as many as 30 percent of people worldwide are born with this particular genetic variation.

Alerting physicians to potential risk for patients

Based upon this and other research on the issue, Medco will begin alerting prescribing physicians through a range of communications via its Medco Therapeutic Resource Centers (R) and other channels so that prescribers can reconsider the risk/benefit of concurrent prescribing of clopidogrel and PPIs based on their patients individual circumstances.

Medco will also communicate its findings to various clinical organizations to encourage continued dialogue around prescribing guidelines for these two medications. Medco’s researchers plan to provide the findings
to the Food and Drug Administration (FDA) as part of their recently announced research collaboration in the area of pharmacogenomics.

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