Taking Account of NSAID-associated Cardiovascular Risk On International Essential Drugs Lists

Patricia McGettigan1, David Henry2. 1William Harvey Research Institute, London, UK, 2Institute for Clinical Evaluative Sciences, Toronto, Canada

Background

Non-steroidal anti-inflammatory drugs (NSAIDs) are associated with increased risk of cardiovascular events including myocardial infarction and stroke. The more potent inhibitors of cyclo-oxygenase-2, for example, rofecoxib, etoricoxib, and diclofenac, appear to confer the greatest risk while naproxen appears risk-neutral. Higher risk NSAIDs should be avoided in people at high risk of cardiovascular events. Rates of cardiovascular disease are high and rising in many low and middle income countries. We studied the extent to which evidence on cardiovascular risk with NSAIDs has translated into guidance and usage in fifteen countries.

Methods

Data on the relative risk (RR) of cardiovascular events with individual NSAIDs were derived from meta-analyses of randomised trials and controlled observational studies. Listing of individual NSAIDs on Essential Medicine Lists (EMLs) was obtained from the World Health Organisation. NSAID sales or prescription data for fifteen low, middle, and high income countries were obtained from Intercontinental Medical Statistics (IMS) or national prescription pricing audit (for England).

Results

In randomised and observational studies, rofecoxib and diclofenac ranked consistently highly in terms of cardiovascular risk. Both drugs were associated with an overall risk increase of around 40% compared with non-use. Naproxen was not associated with increased risk. Diclofenac was listed on 74 national EMLs, naproxen on just 27. Rofecoxib use was not documented in any country. Diclofenac was by far the most commonly used NSAID, accounting for some 28% of total NSAID usage across the fifteen countries (median 27.8%, range 8.3% to 43.4%). This did not vary between low and high income countries. The market share of diclofenac was close to that of the next three most popular drugs combined. Naproxen had an average market share of less than 10% (median 9.4%, range 0% to 28.2%).

Conclusions

Listing of NSAIDs on international EMLs does not take account of cardiovascular risk. Diclofenac is the single most-used NSAID across fifteen low, middle and high income countries. It has an identical risk to rofecoxib, withdrawn from worldwide markets owing to cardiovascular toxicity. Diclofenac should be removed from EMLs. There are strong arguments for banning its use altogether.