Medscape 2004. © 2004 WebMD Inc.
Dec. 21, 2004 (updated Dec. 22, 2004)
Naproxen appears to be the latest of the nonsteroidal anti-inflammatory drugs (NSAIDs) that may be linked to an increase in cardiovascular events.On Monday, the National Institutes of Health (NIH) halted a large Alzheimer’s disease prevention trial involving the drug after finding that patients receiving naproxen had a 50% greater incidence of cardiovascular events. The U.S. Food and Drug Administration (FDA) also released a statement Monday advising patients taking over-the-counter products containing naproxen to take the drugs for no longer than 10 days without consulting a physician. The halted study was being sponsored by the National Institute on Aging to determine if daily use of either naproxen or celecoxib could help prevent Alzheimer’s disease. About 2,500 people who had been enrolled for as long as three years were randomly assigned to daily use of one of the two drugs or a placebo.
Seventy cardiovascular events occurred among the study participants over the course of the trial. The investigators declined to say how many occurred in people taking naproxen, but they did say the naproxen group had a 50% increase in the risk of cardiovascular events compared with those receiving placebo.
The move comes just a week after concerns were raised about celecoxib (Celebrex, made by Pfizer, Inc.). Pfizer voluntarily suspended direct-to-consumer advertising and altered their promotional materials for physician detailing on the drug in compliance with an FDA recommendation.
And in September, the prescription drug rofecoxib (Vioxx, made by Merck) was taken off the market by its manufacturer due to concerns about cardiovascular and stroke risk.
The naproxen drugs (sold as a generic and under various brand names including Aleve, made by Bayer, and Naprosyn, made by Roche) have generally been considered some of the safest of the anti-inflammatory pain relievers, and many physicians have recommended them to their patients who had been taking rofecoxib.
In 2000, at the first indication of adverse cardiovascular risk with rofecoxib, Merck suggested that the protective effects of naproxen on other patients taking part in the trial may have skewed the results.
In an interview Tuesday morning on NBC’s Today Show, FDA Acting Commissioner Lester Crawford acknowledged that the new information on naproxen and celecoxib is confusing. He said any drug taken for prolonged periods or at very high doses can cause problems.”It would be premature to say what we are going to do with either one of these drugs, Celebrex and Aleve,” he said.
In a press conference held Monday afternoon, officials with the National Institute on Aging, the NIH, and the FDA discussed the halting of the trial and the future use of NSAIDs.The study’s lead investigator, John Breitner, MD, MPH, said that safety data from the trial had been showing what he called “weak signals” indicating possible increased risks of cardiovascular events in the patients receiving naproxen. No suggestion of increased risk had been seen in the patients receiving celecoxib, however. Dr. Breitner is a professor of psychiatry and behavioral sciences at the University of Washington and if affiliated with the Veterans Affairs Medical Center, both in Seattle.
Dr. Breitner said the trial committee met on Dec. 10 and elected to continue the study but changed its decision after the cancer prevention trial involving celecoxib was halted a week later.”We found it difficult to persuade our patients to stay on Celebrex due to all of the publicity,” Dr. Breitner said. He added that it was not logical to suspend the celecoxib group of the trial and continue with the naproxen group, because their data indicated that naproxen posed a higher cardiovascular risk.
Sandra Kweder of the FDA said the halted study is the first to link naproxen to an increased cardiovascular risk, even though the drug has been on the market for almost three decades.”This is the first evidence that we have seen, despite other clinical studies, that has suggested this risk,” she said. “We agree that this is confusing. Every doctor and patient will have to have a conversation about unique risk factors which have to be taken into account in deciding which medicine to choose.”
Although the spotlight is now on naproxen, Dr. Breitner warned that there is no evidence that other over-the-counter NSAIDs are any safer in terms of cardiovascular risk. “We have no data on the other nonsteroidal drugs, so I would enter a cautionary note here that we have no knowledge that this problem, if it is a problem, is unique to naproxen. It may be a problem for all NSAIDs.
“Dallas rheumatologist Scott J. Zashin, MD, noted that the two prevention trials that raised suspicions about naproxen and celecoxib involved specific subgroups of high-risk patients taking the medications in very different ways than are recommended.
“These are limited studies, and it is not clear if the findings apply to the general population,” Dr. Zashin told Medscape. “Any time a doctor recommends a medication, whether it is over-the-counter or prescription, he or she needs to weigh the risks and benefits for the individual patient.
“Dr. Zashin, who is a spokesman for the American College of Rheumatology, said he will continue to recommend naproxen to patients who do not have strong risk factors for heart attack and stroke.
In a statement released Tuesday, the American Heart Association (AHA) also pointed out that the two prevention trials had been looking at novel uses for naproxen and celecoxib.”The AHA agrees with the FDA’s caution that patients taking naproxen for approved uses should use only the recommended dose of 220 mg twice daily or less and should restrict its use to 10 days or less,” according to the statement. “Further studies will be needed to see if this effect is seen in wider populations, and to clarify the mechanisms by which it might occur.”
Reviewed by Gary D. Vogin, MD
Salynn Boyles is a staff writer for WebMD.