Most commonly used NSAID carries high cardiovascular risk

Diclofenac, one of the most cardiotoxic nonsteroidal anti-inflammatory drugs (NSAIDs), is also the most widely used, according to an analysis of usage patterns and relative risks. The results call into question whether information about relative risk is filtering down into clinical practice. The study was published online Feb. 13 in PLOS Medicine.

Patricia McGettigan of the William Harvey Research Institute and the London School of Medicine and Dentistry in the UK, and David Henry of the Institute of Clinical Evaluative Sciences in Toronto, evaluated data from meta-analyses of randomized trials to rank the relative cardiovascular risks associated with various NSAIDs. They also examined the World Health Organization’s Model List of Essential Medicines as well as the essential medicines lists (EMLs) of 100 countries that publish them.

McGettigan and Henry also examined the Intercontinental Medical Statistics Health database to obtain information on sales of NSAIDs in Australia, Bangladesh, China, Hong Kong, Indonesia, Malaysia, New Zealand, Pakistan, Philippines, Singapore, Taiwan, Thailand and Viet Nam. They obtained information on NSAID prescriptions and dispensing in England and Canada, as well.

The researchers asserted that meta-analyses were consistent in finding that the NSAIDs with the highest cardiovascular risks were rofecoxib, etoricoxib and diclofenac. Five of the six meta-analyses they reviewed characterized naproxen as risk neutral.

Most of the published EMLs listed fewer than six drugs in the class “non-opoids and nonsteroidal anti-inflammatory medicines.” The EMLs of 88 countries listed aspirin, 90 listed ibuprofen, 78 listed diclofenac, 56 listed indomethacin and 27 listed naproxen. The majority of the countries that included diclofenac on their EML did not include naproxen. Diclofenac was the most widely used NSAID.

The authors noted that studies identifying the cardiovascular risks of diclofenac first were published in 2006. They lamented that although several NSAIDs have been withdrawn from the market, diclofenac—which is as cardiotoxic as rofecoxib (which was withdrawn in 2004)—remains a popular and widely prescribed drug. In contrast, naproxen, which appears to pose the least threat of cardiovascular complications, is much less widely recommended.

“[E]vidence on the relative cardiovascular safety of this drug has failed to translate into appropriate selection for EMLs or usage,” the authors wrote.

McGettigan and Henry contended that diclofenac is not superior in terms of gastrointestinal safety, and “it has a clear cardiovascular disadvantage.” They called for the drug to be removed from EMLs and suggested that revocation of its global marketing authorizations may be appropriate.

They pointed out that their data could not assess the risk profiles of the patients taking the drugs, but the authors asserted that “the large and consistent use of high-risk NSAIDs make it very likely that those drugs are being taken by substantial numbers of individuals at high risk of serious cardiovascular events.” They also noted that they were unable to evaluate dosage or duration of treatment, but explained that these factors were unlikely to significantly change the patterns in the overall sales data.