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Non-steroidal anti-inflammatory drugs (NSAIDs) are a chemically heterogeneous group of agents to treat symptoms of acute pain and chronic inflammatory and degenerative joint diseases, such as rheumatoid arthritis (RA) and osteoarthritis (OA).1 They act mostly through the inhibition of cyclooxygenase-2 (COX-2)-dependent prostanoids. They comprise traditional (t) NSAIDs and NSAIDs selective for COX-2, named cyclooxygenase-2 inhibitors, developed to reduce the gastrointestinal (GI) toxicity of tNSAIDs, which is dependent, at least in part, on the inhibition of COX-1.
Placebo-controlled trials have established that cyclooxygenase-2 inhibitors (rofecoxib, valdecoxib and celecoxib) confer a small but absolute increase in the incidence of thrombotic vascular events.2 An overview of data derived from trials with cyclooxygenase-2 inhibitors suggests that myocardial infarction (MI) predominates over stroke.3 The cardiovascular (CV) hazard associated with the use of cyclooxygenase-2 inhibitors led to the voluntary withdrawal from the United States (US) and European Union (EU) markets of rofecoxib and valdecoxib, in 2004 and 2005 respectively. Recently, the Food and Drug Administration (FDA) has formally rejected manufacturer application for approval of another cyclooxygenase-2 inhibitor, etoricoxib, as a prescription pain reliever. The FDA decision was influenced by the results of safety analyses from the MEDAL (Multinational Etoricoxib vs Diclofenac Arthritis Long Term) Program, a pooling from three randomised, double-blind clinical trials: the MEDAL study and the EDGE and EDGE II studies.4 The authors reported that etoricoxib (60 or 90 mg daily, mean duration of therapy 18 months) and the tNSAID diclofenac (150 mg/d, ie, 50 mg three times daily or 75 mg twice daily) administered to OA or RA patients have comparable rates, constant over time, of thrombotic CV events. However, the increase in heart failure, hypertension, and oedema shown with etoricoxib and the fact that the cyclooxygenase-2 inhibitor did not reduce complicated peptic ulcer attenuated the safety benefit of …