COX-2 selective inhibitors cardiac toxicity: getting to the heart of the matter.

On September 30, 2004, Merck and Co. voluntary withdrew rofecoxib (Vioxx) from the market due to increased risk of cardiovascular events associated with the drug. This raised some issues. It is unclear whether the cardiac toxicities associated with rofecoxib isare due to its high COX-2 selectivity. Rofecoxib is the most specific COX-2 inhibitor among the first generation of the class, i.e., negligible COX-1 inhibitory effect. In addition to the gastrointestinal side effects, COX-1 inhibition is known to offer cardioprotection. This is one of the main present indications of aspirin-like drugs. It is plausible that the COX-2 inhibition is associated with altered homeostasis that is compensated with the cardioprotection effect of COX-1 inhibition that patients receive either through the less COX-2 selectivity of other NSAIDs or through co-administration of low dose aspirin. In addition, the cardiac toxicity of rofecoxib could be due to its unique chemical structure, its pharmacokinetics and tissue distribution, and/or the presence of toxic metabolites. Nevertheless, one cannot ignore the public need for NSAIDs with less gastrointestinal side effects than the traditional drugs. However, based on some available indirect evidence, and unless more clear-cut data become available, the use of highly COX-2 selective NSAIDs without the use of a suitable COX-1 inhibitor, (e.g., low dose aspirin) may be best avoided. This may be particularly relevant to the chronic use of these drugs.