Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used for the treatment of chronic arthritic diseases such as osteoarthritis and rheumatoid arthritis (RA). Conventional NSAIDs nonspecifically inhibit both cyclooxy-genase-1 (COX-1) and cyclooxygenase-2 (COX-2) isoforms. Anti-inflammatory and analgesic benefits of NSAIDs result from the inhibition of COX-2, whereas the increased rates of gastrointestinal (GI) complications are attributed to the inhibition of the COX-1 iso-form. It is important to note, however, that both COX-1 and COX-2 have important homeostatic physiologic functions. Recently, the FDA required amendments to the rofecoxib package insert to reflect the enhanced cardiovascular risk associated with the use of this agent. (1,2)
The selectivity for COX-1 isoforms differs among the NSAIDs. In addition, the selectivity can differ in response to the assay used. In several in vitro assays, rofecoxib has been shown to be the most selective COX-2 inhibitor agent, compared with other NSAIDs approved for the treatment of chronic arthritis. The half-life of rofecoxib is approximately 17 hours, with no clinical evidence of accumulation. Rofecoxib is primarily metabolized through the liver, and the metabolites are excreted in the urine. For the treatment of arthritis, the recommended dose is 12.5 mg daily to a maximum recommended dose of 25 mg/day. (2)
The safety and efficacy of rofecoxib for the treatment of RA were studied in a multicenter, double-blind, randomized trial.(2) The safety of rofecoxib was compared to that of naproxen in 8,076 patients with RA. Patients were ?50 years old (or ?40 years old if receiving long-term glucocorticoid therapy) and were expected to require chronic NSAID therapy for ?1 year. Patients were excluded if medical history was significant for renal impairments, if they had a recent history of stroke or myocardial infarction (MI), and/or if they had a positive test for fecal occult blood. Patients taking aspirin, ticlopi-dine, or an anticoagulant were not allowed in the study. The overall findings confirmed that GI complications (gastric or duodenal ulcer, perforation, obstruction, or GI bleeding) were significantly lower in the rofecoxib group (0.52% vs 1.22%, P < .01).
Rofecoxib administration, however, was associated with an increased risk of cardiac toxicity and hypertension (P< .01), and higher rates of serious thromboembolic cardiovascular events, compared with traditional NSAIDs. The overall incidence of vascular thrombotic events was 1.8% in the rofecoxib group and 0.6% in the naproxen group (P < .002). MI occurred in 0.5% of the patients randomized to rofecoxib and in 0.1% of those treated with naproxen (P < .01).(2) Until further study can indicate the safety of rofe-coxib in patients at risk for cardiovascular complications, caution should be employed when rofecoxib is used for the treatment of arthritis. (2)
COX-2 selective agents should be considered in patients at risk for GI complications (the elderly, patients with a history of peptic ulcer disease or GI complications, those on multiple and high doses of NSAIDs, etc). However, clinicians should avoid the use of rofecoxib in patients with ischemic heart disease.
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One study linked multiple pregnancies to an increased risk of developing atrial fibrillation later in life, and another investigated the association between premature delivery and cardiovascular disease.
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