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Vioxx and Cardiac Risk

Researchers, led by an FDA official, have assessed in more detail the cardiac risk associated with use of the now-withdrawn COX-2 inhibitor Vioxx (rofecoxib). They analyzed data from 1.4 million patients enrolled in a California HMO who had filled at least one nonsteroidal anti-inflammatory drug (NSAID) prescription from 1999 through 2001, including for COX-2 selective NSAIDs (rofecoxib and celecoxib) and nonselective NSAIDs.

During 2.3 million person-years of follow-up, there were 8143 cases of acute MI or sudden cardiac death, each matched with four controls who had not experienced these events. Current NSAID use was defined as overlap between the prescription period and the index date, and remote use as a prescription that ended more than 60 days before that date.

The lowest cardiac risk associated with current use (compared with remote use) was for celecoxib (adjusted odds ratio, 0.84; a nonsignificant difference). When current use of celecoxib was used as the reference (AOR, 1.00), cardiac risk was significantly higher with current use of rofecoxib (AOR, 1.59) and naproxen (AOR, 1.36), with a borderline significant risk for ibuprofen (AOR, 1.26). Notably, the risk associated with rofecoxib varied by dose: AORs were 1.47 for 25 mg/day and 3.58 for >25 mg/day. The mean duration of rofecoxib use before an index event was about 3.7 months.

Comment: These nested case-control data point to cardiac risk associated with the highly selective COX-2 inhibitor rofecoxib, and they suggest that risk varies by dose and begins soon after treatment initiation. Naproxen (a nonselective NSAID) did not have the protective effect shown in previous studies, and celecoxib (which is moderately selective for COX-2) was not associated with increased risk. However, a recent adenoma-prevention trial was halted when increased cardiovascular risk surfaced among patients treated with celecoxib, compared with placebo recipients (Journal Watch Cardiology Apr 1 2005). Basic research suggests that the degree of COX-2 selectivity might explain the variation in risk among NSAIDs, but more study is needed, including of newer coxib drugs. An editorialist notes that even available clinical-trial evidence is not sufficiently enlightening, because patients with established vascular disease, who have the most potential cardiac vulnerability, have often been excluded from trials of newer coxibs (e.g., Journal Watch Cardiology Nov 5 2004). For several Journal Watch Cardiology reviews of studies on COX-2 inhibitors and other NSAIDs, see our April 1, 2005, web update.

— Beat J. Meyer, MD

Published in Journal Watch Cardiology December 30, 2005

Citation(s):

Graham DJ et al. Risk of acute myocardial infarction and sudden cardiac death in patients treated with cyclo-oxygenase 2 selective and non-selective non-steroidal anti-inflammatory drugs: Nested case-control study. Lancet 2005 Feb 5; 365:475-81.

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Maxwell SRJ and Webb DJ. COX-2 selective inhibitors — Important lessons learned. Lancet 2005 Feb 5; 365:449-51.

• Medline abstract (Free)