Serious GI Toxicity With The Heart Drug Clopidogrel (PLAVIX)

Research published in the January 20, 2005 New England Journal of Medicine found “an astonishingly high rate of bleeding ulcers” in patients taking clopidogrel (PLAVIX) compared to patients taking plain aspirin plus the antiulcer/heartburn drug esomeprazole (NEXIUM). In the study, 13 patients (8.6%) experienced renewed ulcer bleeding during the one year duration of the study compared to only one (0.7%) of those taking aspirin plus esomeprazole. This is a 12-fold difference in bleeding.

Clopidogrel, like aspirin, is used to prevent recurrent heart attacks and strokes.

The assumption had long been that clopidogrel is safer on the stomach than aspirin. In fact, The American College of Cardiology — American Heart Association guidelines recommend the use of clopidogrel in some patients who are unable to take aspirin because of gastrointestinal (GI) intolerance.

Previously, we recommended that clopidogrel only be used in patients who could not tolerate aspirin because of ulcers caused by aspirin or severe allergies to aspirin (see Worst Pills, Best Pills News November 1999 and January 2005). The results of this study require us to change our recommendation for clopidogrel because no safety advantage was found for the drug over aspirin plus esomeprazole in ulcer bleeding. The only role that appears to be left for clopidogrel is in patients who have a severe allergy to aspirin.

The New England Journal of Medicine study was conducted to answer the question as to whether clopidogrel is a proper alternative to aspirin plus an antiulcer/heartburn drug, in this case esomeprazole, for patients at high risk of developing an ulcer.

The study was a randomized controlled trial, a design that is considered the scientific “gold standard” for comparing medical treatments. The patients eligible for the study had to have developed a bleeding ulcer while taking less than 325 milligrams of aspirin per day. A total of 320 patients at high risk of developing ulcers with aspirin were randomly selected to receive either clopidogrel plus an esomeprazole placebo or low dose aspirin, 80 milligrams, plus 20 milligrams of esomeprazole.

There were other troubling results from the study. Three patients taking clopidogrel experienced bleeding outside of the GI tract: two had intracranial hemorrhage and one had severe bleeding into the urine (hematuria) requiring blood transfusions.

Overall, of the 12 patients who died during the study, eight were receiving clopidogrel. Of these eight, one died of a heart attack, one from an intracranial hemorrhage, one from heart failure, three from infection, and two from uncertain causes. There were four deaths in the aspirin plus esomeprazole group. Of these four patients one died of a heart attack, one from diminished blood flow to the brain (cerebrovascular insufficiency), one from kidney failure, and one from uncertain causes.

The authors of the study concluded:

In summary, among patients with a history of aspirin-induced ulcer bleeding, aspirin plus esomeprazole was superior to clopidogrel for the prevention of recurrent bleeding. Our observations do not support the current recommendation that clopidogrel be used for patients who have major gastrointestinal intolerance of aspirin.

Esomeprazole, a member of the proton pump inhibitor (PPI) family of drugs, was selected by the authors of the study out of convenience rather than any unique therapeutic property of this drug. Esomeprazole is a DO NOT USE drug only because it is a much more expensive form of omeprazole (PRILOSEC), which is now available as a generic and over-the-counter without a prescription (see Worst Pills, Best Pills News November 2001). The other PPIs currently on the market are lansoprazole (PREVACID), pantoprazole (PROTONIX), and rabeprazole (ACIPHEX).

The amount of money spent on clopidogrel has been phenomenal. In 2003, more than 13.2 million prescriptions were dispensed in U.S. pharmacies with retail sales exceeding $1.7 billion.

A one-month supply of clopidogrel, 30 tablets of 75 milligrams, retail for $114.99 at a popular Internet pharmacy. A one-month supply of low dose aspirin can cost as little $1.50. If the cost of a one-month supply of over-the-counter omeprazole, which is the same as esomeprazole, is added to the cost of the aspirin, one month’s worth of treatment would be $21.51. This is a savings of $93.48 per month or $1,121.76 per year.

Switching from clopidogrel to aspirin plus a PPI such as over-the-counter omeprazole allows you to cut your drug bill without adversely effecting the quality of your healthcare.

What You Can Do

If you are now taking clopidogrel and do not have a severe allergy to aspirin, contact your doctor and discuss switching from clopidogrel to low dose aspirin plus a PPI.