Georgios Chalikias, University of Thessaloniki

Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most widely used of current medications usually bought over the counter. Taken singly or in combination with other classes of drug, they relieve symptoms across multiple clinical indications, including short and long term pain states and a range of musculoskeletal disorders.

Numerous meta-analyses of clinical trials as well as observational studies have highlighted the cardiovascular risks of NSAIDs. These data concluded that COX-2 inhibitors such as rofecoxib (a drug withdrawn from worldwide markets due to increased cardiovascular toxicity) and etoricoxib and the NSAID diclofenac were associated with the highest cardiovascular risk. Although the prescription dose ranges considerably for diclofenac in everyday practice, there does not appear to be a dose associated with no risk. The NSAIDs indomethacin and meloxicam had a moderately increased risk of cardiovascular toxicity. Ibubuprofen, celecoxib and naproxen had the lowest risk, with ibuprofen and celecoxib being associated with increased risk of cardiovascular toxicity when used at high doses in clinical trials. Of interest, naproxen in one meta-analysis was found to be risk-neutral at all doses whereas in another to be associated with the lowest relative cardiovascular risk. Observational studies in particular for diclofenac have reported a 40% increased risk of cardiovascular events whereas in one randomized clinical trial its use was associated with an approximately 60% increased risk of cardiovascular events.

These recent data resulted in a press-release by the European Medicines Agency (EMA) to address the recently published information on the cardiovascular safety of NSAIDs. According to this review most of the data related to the three most widely used NSAIDs – diclofenac, ibuprofen and naproxen. In relation to naproxen and ibuprofen, EMA was of the opinion that the current treatment advice adequately reflects the knowledge regarding the safety and efficacy of these medicines. For diclofenac, EMA suggested that the latest evidence appears to show a consistent but small increase in the risk of cardiovascular side effects for diclofenac compared with other NSAIDs, similar to the risks of COX-2 inhibitors. As a follow-on to this review, the Agency’s new Pharmacovigilance Risk Assessment Committee (PRAC) will now assess all available data on diclofenac (both published and unpublished) to consider the need for updated treatment advice.

References
McGettigan P, Henry D. Use of non-steroidal anti-inflammatory drugs that elevate cardiovascular risk: an examination of sales and essential medicines lists in low-, middle-, and high-income countries. PLoS Med. 2013 Feb;10(2):e1001388. doi: 10.1371/journal.pmed.1001388.
McGettigan P, Henry D. Cardiovascular risk with non-steroidal anti-inflammatory drugs: systematic review of population-based controlled observational studies. PLoS Med. 2011 Sep;8(9):e1001098. doi: 10.1371/journal.pmed.1001098.
Schjerning Olsen A, Fosbøl L, Lindhardsen J, et al. Long-term cardiovascular risk of NSAID use according to time passed after first-time myocardial infarction. A nationwide cohort study. Circulation 2012; DOI: 10.1161/?CIRCULATIONAHA.112.112607.
European Medicines Agency. European Medicines Agency finalises review of recent published data on cardiovascular safety of NSAIDs [press release]. October 19, 2012.

Cardio Debate Expert Comments

The use of NSAIDs is an underappreciated problem, since many of these agents are sold over the counter and therefore physicians are not aware of their use. Therefore, there is a strong possibility that patients with known cardiac disease frequently and for long periods of time use this class of agents. Physicians should inform patients especially those with cardiovascular diseases to refrain from the chronic use of NSAIDs, if possible. Upon indications for pain and inflammation relief in a wide range of conditions, including rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, gout, acute musculoskeletal disorders i.e. peri-arthritis, tendinitis, tenosynovitis and bursitis, and other painful conditions resulting from trauma including fractures, low back pain, sprains, strains, dislocations, orthopaedic, dental and minor surgery, published data suggest that naproxen and ibuprofen are associated with a lesser risk.