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Arthritis Current Topics in Arthritis

COX-2 Inhibitors and Cardiovascular Risk

When the prescription pain reliever Vioxx was pulled from the market in 2004 because it was found to increase risk of heart attack and stroke, many doctors and patients wondered about the safety of similar drugs.

They soon began to get answers. In December, just weeks after drugmaker Merck stopped selling Vioxx, Pfizer announced study results linking its painkiller Celebrex to an increased risk of heart attacks.

That same day, doctors from the Vanderbilt University School of Medicine raised questions about the safety of Bextra, Pfizer’s sister drug to Celebrex, in a letter to The New England Journal of Medicine. Bextra had recently been found to raise the risk of heart problems in people who have undergone bypass surgery. The drug was finally pulled from the market in April 2005.

Celebrex, Vioxx and Bextra are part of a class of drugs called COX-2 inhibitors, which are newer forms of non-steroidal anti-inflammatory drugs (NSAIDs). COX-2s became an appealing option for people with arthritis, as well as those with acute and menstrual pain, because they are less likely to cause the gastrointestinal problems associated with regular use of older, over-the-counter NSAIDs, such as aspirin, ibuprofen and naproxen.

Traditional NSAIDs block both forms of an enzyme called cyclooxygenase, or COX, in order to reduce pain and inflammation. But because a form of the enzyme called COX-1 also protects the stomach, COX-2 inhibitors were developed to block more of COX-2 than COX-1. These drugs seemed to be a good solution for pain management with fewer side effects.

Then came the flood of news reports that Vioxx, Celebrex and Bextra may all carry cardiovascular risks.

In the case of Celebrex, the only one of the three still on the market, the news arose from a National Cancer Institute (NCI) sponsored trial where patients were randomly assigned to receive either Celebrex or a placebo.

The researchers found that participants who took 400 milligrams (mg) of Celebrex twice daily had more than three times the risk of heart attack as those on placebo. Participants taking 200 mg twice daily had a two-fold increase in heart attack risk. The NCI has since stopped the trial, which followed participants for almost three years on average.

Another long-term cancer prevention study did not find a higher risk of heart attack in participants taking Celebrex at 400 mg daily. Celebrex is approved for the treatment of arthritis and pain at recommended doses of 100 mg to 200 mg daily.

Following the withdrawal of Vioxx and Bextra from the market, Pfizer has placed the following warning on Celebrex’s label:

Important Information: CELEBREX may increase the chance of a heart attack or stroke that can lead to death. It should not be used right before or after certain heart surgeries. Serious skin reactions or stomach problems such as bleeding can occur without warning and may cause death.

Certain physicians, though, have been calling for studies to examine the heart attack and stroke risks of all COX-2 inhibitors for years. Dr. Debabrata Mukherjee, a cardiologist at Gill Heart Institute at the University of Kentucky in Lexington, was the co-author of a review published in 2001 in the Journal of the American Medical Association (JAMA) that called for such trials.

"I think we were behind the eight ball on this," Mukherjee said. "If the initial reports of cardiovascular problems were taken seriously, we could have seen these results in 2002 instead of 2004. But I'm glad the studies are being done now."

Dr. A. Mark Fendrick, a professor of medicine and health management and policy at the University of Michigan Medical School in Ann Arbor, says that new research has serious implications for patients and recommends that people "go back to the future" and take a traditional anti-inflammatory drug, such as ibuprofen, for pain relief.

"A large number of patients taking COX-2 inhibitors will do just fine with the older, traditional anti-inflammatory drugs," he said. "Those with gastrointestinal problems could use an older drug with a proton pump inhibitor such as Prilosec, Nexium or Prevacid to protect their stomachs."