Some anti-inflammatories are safer than others.GettyA huge review of studies on pain relievers has found that a widely-used medicine may confer cardiovascular risks as serious as those found with Vioxx, an arthritis medicine that was withdrawn from the market two years ago.
Diclofenac, an older non-steroidal anti-inflammatory drug (NSAID), has been on the market for decades and is one of the most-widely prescribed anti-inflammatories in the world — especially in Europe. At commonly prescribed doses, it was found to increase the risk of cardiovascular events — primarily heart attack and sudden death — by 40%.
The good news from the study is that there are alternatives. "European consumers would be better off switching [from diclofenac] to naproxen," says David Graham, a safety official at the US Food and Drug Administration, who authored an editorial1 accompanying the published review. Naproxen was found to neither increase nor decrease cardiac risk.
The meta-analysis, published online today by the Journal of the American Medical Association, looked at 23 studies involving some 1.6 million people2. The studies were not gold-standard clinical trials, but the review's huge scope lends it weight, says Graham. "It looked at all NSAIDs across the board, at all available evidence for those NSAIDs. In that regard, it's unprecedented and in my view becomes authoritative."
Not everyone agrees. "Our view is that this meta-analysis is incomplete and the findings have not been critically analyzed," says John Gilardi, a spokesperson for Novartis in Basel, Switzerland. Novartis markets diclofenac under the trade name Voltaren. "Other epidemiological data does not indicate an increased cardiovascular risk of diclofenac versus other non-steroidal anti-inflammatory drugs, or NSAIDs," he says.
The study authors — Patricia McGettigan of the University of Newcastle in New South Wales, Australia, and David Henry of Newcastle Mater Hospital in Waratah, New South Wales — call for a review of the regulatory status of diclofenac, which is marketed as a generic drug and also under the trade names Voltaren, Cataflam, Solaraze and Arthrotec.
Dodgy outlier
The JAMA review looked at both standard NSAIDs and at a newer class of drugs hoped to cause fewer side-effects.
Standard NSAIDS, such as ibuprofen or naproxen, work to relieve pain by blocking one form of the cyclooxygenase enzyme — cox-2 — at sites of tissue injury. But because they also work on another form, cox-1, which is found in the gut, they also often damage the gastrointestinal tract. A new generation of drugs, selective for cox-2 alone, were created with the hope of easing pain without damaging the gut.
Vioxx (rofecoxib) is one of these drugs. But Vioxx was withdrawn from the market after studies showed that it substantially increased the risk of heart attack and other serious cardiovascular events. The new JAMA study confirms these earlier findings, showing that the risk is dose-related (more than doubling at high doses), begins immediately and is elevated in the first month of use.
But Vioxx may be unique in its class in the extent to which it causes these side-effects. Steve Nissen, a cardiologist at the Cleveland Clinic who is running a separate trial that includes Celebrex (a chemical cousin of Vioxx and a common cox-2 inhibitor), says that the JAMA study hints that Vioxx is an outlier. "It looks like it's really a problem with one or two drugs but not all of them," he says. This opens the possibility that other such NSAIDs will be safe, even if Vioxx is not.
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The study suggests that Celebrex (celecoxib) is not harmful to the heart at the commonly used dose of 200 mg, but seems to be unsafe at doses of 400 mg or more.
For the future, researchers are aiming to find a class of anti-inflammatories that will both be kind to the stomach and to the heart. Research released by the Proceedings of the National Acadamy of Sciences this week shows promising news of a drug target, found in a mouse model, that slows the development of atherosclerosis. This might help a new class of 'super NSAIDs' not only steer clear of heart disease risk but work to reduce it.
In the meantime, the JAMA study may cause problems for Merck. The company is currently using diclofenac as a comparison drug in a trial of Arcoxia, a next-generation cox-2 inhibitor developed to succeed Vioxx for arthritis patients. Merck spokesperson Christopher Loder says that the company stands by their choice of diclofenac for this trial.
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