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Do COX-2 Inhibitors Increase Cardiovascular Risk?

Phones rang incessantly in physicians' offices several weeks ago as patients asked whether it was safe to continue taking the cyclooxygenase-2 (COX-2) inhibitors rofecoxib and celecoxib. Patients were responding to media coverage of this report from JAMA in which Cleveland Clinic researchers analyzed data from postmarketing trials.

In the first trial, investigators compared rofecoxib and naproxen in patients with rheumatoid arthritis (RA; JW Jan 1 2001, p. 2, accession number 001208001, and N Engl J Med 2000; 343:1520). Adverse cardiovascular events occurred significantly more frequently among rofecoxib recipients than among naproxen recipients (46 vs. 20 events among about 4000 patients in each group, treated for a median of 9 months). In the second trial, celecoxib, ibuprofen, and diclofenac were compared among approximately 8000 patients with RA or osteoarthritis (JW Oct 15 2000, p. 159, accession number 000922001, and JAMA 2000; 284:1247). The rate of adverse cardiovascular events did not differ significantly among the 3 groups. Finally, in 2 unpublished trials, too few patients were enrolled to allow meaningful comparisons.

Comment: Results of the rofecoxib-naproxen trial, in which patients were not permitted to take prophylactic low-dose aspirin, are the main source of concern: Naproxen has substantial antiplatelet activity, whereas COX-2 inhibitors don't inhibit platelet aggregation but may have prothrombotic properties. Thus, the increase in the cardiovascular event rate in the rofecoxib group could be explained by harmful effects of rofecoxib, by beneficial effects of naproxen, or by both. In contrast, ibuprofen and diclofenac are weaker antiplatelet agents than is naproxen, which might explain why the cardiovascular event rate did not differ among groups in the celecoxib trial. Clearly, more research is needed before we draw final conclusions. In the meantime, it may be prudent to limit use of COX-2 inhibitors in patients at high risk for cardiovascular events, particularly when alternatives are available.

— AS Brett

Published in Journal Watch General Medicine August 28, 2001

Citation(s):

Mukherjee D et al. Risk of cardiovascular events associated with selective COX-2 inhibitors. JAMA 2001 Aug 22 286 954-959.

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