Diclofenac remains one of the most widely recommended and regularly used non-steroidal anti-inflammatory drugs (NSAIDs) globally, despite its known association with increased cardiovascular risk, warn researchers who argue it should be removed from Essential Medicines Lists (EMLs).
Patricia McGettigan, from Barts and The London School of Medicine and Dentistry in the UK, and David Henry, from the University of Toronto in Ontario, Canada, report in PLoS Medicine that diclofenac is included on 74 countries' EMLs, and was the most commonly used NSAID in the 15 countries they studied.
Yet the researchers point out that diclofenac is associated with around the same magnitude of cardiovascular risk as rofecoxib, which was withdrawn from markets 8 years ago owing to cardiovascular toxicity.
Using data from meta-analyses of randomized trials and controlled observational studies, they found that three drugs, rofecoxib, diclofenac, and etoricoxib, ranked the highest of all NSAIDs studied in terms of cardiovascular risk.
Relative risks for serious cardiovascular events with use of rofecoxib (versus non-use) ranged from 1.27 to 1.45, while for diclofenac they ranged from 1.38 to 1.63.
Celecoxib and ibuprofen were associated with elevated risks at higher doses, but not at those used in the community, McGettigan and Henry say, while naproxen had the lowest risk, with five of the six meta-analyses finding it risk-neutral.
According to World Health Organization (WHO) EMLs available for 100 countries, the most commonly recommended NSAIDs were aspirin (88 countries), ibuprofen (90 countries), diclofenac (74 countries), indometacin (56 countries), and naproxen (27 countries).
Importantly, "51 of the countries that listed diclofenac did not list naproxen," the authors highlight.
Moreover, diclofenac was by far the most popular NSAID in 15 countries analyzed, including England, Canada, and 13 countries across South Asian, Southeast Asian, and Asian Pacific regions - accounting for almost the same market share as the next three most popular NSAIDs (ibuprofen, mefenamic acid, and naproxen) combined.
"While the popularity of diclofenac in high-income countries is well known, to our knowledge this is the first report that highlights the risks associated with its dominant market position in low- and middle-income countries," note the researchers.
They calculate that, in China, if diclofenac was taken by 1% of the approximate 1.3 billion population annually, it would cause 14,000 additional unintended deaths.
"These deaths are preventable - lower risk NSAIDs, including naproxen and low-dose ibuprofen, are widely available and are equally efficacious," write McGettigan and Henry. Furthermore, they add: "Both are available as generics."
In an accompanying Perspective article, Srinath Reddy, from the Public Health Foundation of India, and Ambuj Roy, from the All India Institute of Medical Sciences, both in New Delhi, agree that there is "a strong case" for removing diclofenac from national EMLs.
"The dangers are especially high in countries where over-the-counter sale of diclofenac is permitted," they note.
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