Two of the most widely used new drugs for arthritis may increase a patient's risk of heart attack and stroke and probably should not be used by people who already are at high risk for cardiovascular problems, researchers from the Cleveland Clinic report today.
More than 2 million prescriptions for the drugs Vioxx and Celebrex are expected to be written this year. The drugs' ability to relieve pain is similar to that of aspirin and other over-the-counter medicines. But unlike aspirin, they do not damage the stomach and gastrointestinal system--a major advantage for people with chronic pain that has helped lead to an expected $6 billion in sales of the two drugs this year.
But the study reported in today's issue of the Journal of the American Medical Assn. offers a cautionary note on their use. The report reviewed previous studies of the two drugs and suggests that they can increase formation of blood clots, leading to heart attacks and other cardiovascular problems.
Dr. Eric J. Topol and his colleagues note, though, that the added risk is still very small--less than 1%. Moreover, patients who take Celebrex or Vioxx routinely might be able to reduce or eliminate the risk by adding daily low doses of aspirin to their drug regimens, they said.
Topol himself takes the drugs because of an arthritic knee. They are "a great class of medicines," he said. "But if I had risk factors for heart disease, I would be more concerned right now. I would take aspirin or switch drugs until we have more concrete evidence."
The report, added co-author Dr. Steven Nissen, "reminds us once again that all drugs have both benefits and risks."
The manufacturers of the two drugs disputed the study, arguing that it is poorly designed and that it doesn't include unpublished results obtained from thousands of other patients.
When the drugs are compared directly to placebos, "we find absolutely no difference in risk" for cardiovascular disease, said Dr. Laura Demopoulos of Merck & Co., which manufactures Vioxx.
Representatives of the U.S. Food and Drug Administration took issue with Merck's assertion, however. Much of the data still need to be evaluated, they said.
"We would not agree that there is no cardiovascular risk," said Dr. Lawrence Goldkind, acting deputy director of the FDA's division of anti-inflammatory, analgesic and ophthalmic drugs. Nor would the agency say there is a risk. "We will continue to evaluate the information as more becomes available," he added.
Dr. Jack Klippel, medical director of the Arthritis Foundation, said, on balance, consumers who use the drugs should continue to do so. "We want to reassure the vast majority of people who take these drugs that they are safe and continue to represent an important advance" in arthritis treatment, he said.
But, he added, patients with known risk factors for heart disease, such as obesity, high cholesterol levels and high blood pressure, "should discuss with their doctors whether a low dose of aspirin is needed."
Vioxx and Celebrex are members of a family of drugs called Cox-2 inhibitors, which are painkillers and anti-inflammatory drugs. Their ability to relieve pain without causing stomach distress is significant in light of the fact that each year for the last decade about 100,000 Americans were hospitalized because of ulcers and other gastrointestinal problems resulting from daily use of large doses of aspirin or other painkillers.
In their review, Topol and his colleagues analyzed all of the published studies of Vioxx and Celebrex, which included about 18,000 patients. But they focused primarily on two large studies, one for each of the drugs.
The first was a study of 8,076 patients who took either Vioxx or naproxen, a drug similar to aspirin, for arthritis pain. That study concluded that patients taking Vioxx had about 2.2 times the risk of a heart attack or stroke as those taking naproxen. The absolute number of serious cardiovascular events was very small, however: only 111 in the Vioxx group.
That study left unclear whether Vioxx caused an increase in heart attacks or whether the naproxen prevented them, Topol said. Small daily doses of aspirin are known to reduce the risk of heart attacks by inhibiting the formation of blood clots. Researchers believe that naproxen acts in a similar fashion.
The second study enrolled 7,968 patients who used Celebrex or one of two other pain relievers. That study showed a slight but statistically significant increase in heart attacks among the Celebrex patients, Topol said.
Results from smaller studies were similar.
The problem with all the published studies was that the Cox-2 inhibitors were compared to naproxen, aspirin or other drugs that could reduce the rate of heart attacks.