Chronic treatment with high doses of some NSAIDs might be associated with a small increased risk of thrombotic events, such as myocardial infarction or stroke, a review performed by the European Medicines Agency (EMEA) concluded. However, NSAIDs’ overall risk-benefit balance “remains favourable” when used according to the product information.

The associated ‘Dear Doctor’ letter from the Commission on Human Medicines (CHM) highlights that the risk with diclofenac may be similar to some coxibs and underscores the hazards of co-prescribing antiplatelet drugs with NSAIDs.

The EMEA and CHM kept coxibs and NSAIDs under review since links emerged in 2000 between rofecoxib (Vioxx) and serious cardiovascular thrombotic events. A 2005 review concluded that there were inadequate data to update prescribing advice for non-selective NSAIDs. However, studies linking non-selective NSAIDs and cardiovascular thrombotic events continued to emerge.

In the new review, the EMEA concluded that a direct link between some NSAIDs and a small increased risk of thrombotic events “cannot be excluded”, especially when used for long periods at high doses. For example, a Dear Doctor letter from the CHM informing clinicians of the review’s conclusions, comments that at high doses (e.g. 2400 mg daily) ibuprofen may be associated with a small thrombotic risk. However, at low doses (e.g. 1200 mg or below dalily) the “epidemiological data do not suggest an increased risk of myocardial infarction.” The letter adds that further studies need to define the thrombotic safety of other NSAIDs.

The Dear Doctor letter also comments that, based on the MEDAL (Multinational Etoricoxib and Diclofenac Arthritis Long-term) study, diclofenac (particularly 150 mg daily) “may have a small thrombotic risk, similar to that of licensed doses of etoricoxib, and possibly other coxibs.” On the other hand, naproxen seems to be associated with a lower thrombotic risk than coxibs. However, the Dr Doctor letter adds; “some increase in risk cannot be excluded on the basis of available evidence.” Once again, the CHM suggest that further studies need to establish naproxen’s risk profile.

The letter suggests prescribing the lowest effective dose for the shortest time necessary to control symptoms and reviewing long-term treatment periodically. Doctors should choose the treatment based on the safety profiles of each NSAID or coxib and each patient’s gastrointestinal, cardiovascular and other risk factors. Furthermore, the letter notes, “Concomitant aspirin (and possibly other antiplatelet drugs) greatly increase the gastrointestinal risks of NSAIDs and severely reduce any gastrointestinal safety advantages of coxibs. Aspirin should only be co-prescribed if absolutely necessary.”

This isn’t the end of the story. The EMEA is currently discussing the procedure to update NSAIDs’ product information. Meanwhile, the CHM is establishing “a cross-specialty expert group” to consider the risks and benefits of anti-inflammatory and analgesic drugs and to update advice as new evidence emerges.

Mark Greener