In a surprise announcement that cast further confusion on the safety of common painkillers, federal officials said yesterday they have found preliminary signs that a popular medication, naproxen, could increase the risk of heart disease and stroke.
The evidence is the first ever to implicate the 30-year-old drug in cardiovascular ailments.
Naproxen is sold over the counter under the brand name Aleve, as well as under a variety of proprietary labels. In prescription strength, it is sold as Naprosyn, Anaprox and Naprelan.
The link with heart attack and stroke emerged in a nationwide study testing the ability of naproxen and Celebrex, another painkiller whose safety has been called into question, to prevent Alzheimer's disease.
Investigators noticed that the rate of heart attack and stroke was 50 percent higher among those taking naproxen than it was among those taking Celebrex or a placebo.
Although another study has linked Celebrex to an increased risk of heart disease, researchers in the Alzheimer's study found no such evidence.
Nonetheless, officials with the National Institutes of Health decided late Friday to suspend use of both drugs in the study. The NIH began that night to call 2,500 volunteers who had been randomly assigned to take naproxen, Celebrex or a dummy pill.
"This action was taken to ensure the safety of study participants," said Dr. Elias Zerhouni, director of the National Institutes of Health. He said the decision "was based on appropriate evaluation of the risks and benefits."
Volunteers in the three-year trial were healthy men and women 70 and older with family histories of Alzheimer's, a brain wasting disease. Those taking naproxen received a standard 220-milligram dose.
What the data mean for the millions of people taking naproxen remained unclear.
For the time being, the FDA advised that people take no more than the amount specified on the product label or in their doctor's prescription. The label for Aleve advises people to take no more than three 220-milligram tablets over a 24-hour period.
The drug should not be taken for more than 10 days unless a physician says otherwise, said Dr. Steven Galson of the FDA.
The FDA has not taken any regulatory action against naproxen but over the next several days it will consider whether the evidence warrants limiting sales or changing the product's labeling, officials said.
"This is a very confusing situation," said Dr. Sandra Kweder, deputy director of the FDA's office of new drugs.
Confusion for patients
Kweder said the news is likely to confound patients who switched from COX-2 inhibitors - a class that includes Celebrex, Vioxx and Bextra - to naproxen on the belief they were taking a safer drug.
Merck & Co, the makers of Vioxx, pulled that drug from the market Sept. 30 after a study indicated the popular painkiller doubled the risk of heart attacks and stroke when taken for longer than 18 months.
On Friday, Pfizer disclosed evidence linking Celebrex to similar problems. Although the company decided not to withdraw the product, it did honor an FDA request to stop advertising the drug to consumers.
That same day, the New England Journal of Medicine released a letter from two researchers urging that Bextra be withdrawn because of a possible link to heart ailments.
Just as experts now question whether all COX-2 inhibitors are unsafe, Kweder acknowledged that the news about naproxen will call into question the entire class of drugs known as non-steroidal anti-inflammatories.
That class includes such popular drugs as aspirin and ibuprofen, as well as naproxen.
On Sept. 10, a committee reviewing safety data in the Alzheimer's trial presented preliminary evidence that patients on naproxen were showing an elevated rate of heart problems and stroke. Investigators decided to continue the trial for a brief time and reassess later.
"The safety data for some time has been giving weak signals that there was a possibility of increased risk for cardiovascular and cerebrovascular [problems] with naproxen," said Dr. John Breitner, principal investigator and a geriatric psychiatrist with the University of Washington in Seattle.
Heart attack, stroke
There were 70 heart attacks and strokes among the volunteers, but officials declined to spell out the number experienced by each group.
Last week, when Pfizer released the study showing Celebrex's possible link to heart disease, investigators realized they couldn't expect volunteers in their study to continue taking it.
Once that decision had been made, officials realized that the time had come to suspend use of naproxen, too.
After all, it was naproxen - not Celebrex - that was apparently causing problems in the Alzheimer's prevention trial, Breitner said.
The FDA approved Naprosyn as a prescription drug in 1976, then 18 years later approved Aleve for over-the-counter sales.
Spokesmen for Bayer, which makes Aleve, and Roche Pharmaceuticals, which makes Naprosyn, could not be reached for comment.
Word of caution
Dr. Roger Blumenthal, director of preventive cardiology at the Johns Hopkins School of Medicine, cautioned consumers not to draw sweeping conclusions from the study.
"My feeling is that many times we tend to exaggerate both what appear to be beneficial findings and what appear to be detrimental findings," Blumenthal said.
One important question, he said, is whether taking baby aspirin cancels out the increased risk from naproxen or the COX-2 inhibitors. Often missed in the debate over Vioxx, he said, was that baby aspirin virtually eliminated any increased risk among Vioxx users.
The American Heart Association recommends a daily low dose of aspirin for people who have an elevated risk of heart attack.