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J R Soc Med. 2004 December; 97(12): 609.
PMCID: PMC1079689

Coxibs and serious adverse cardiovascular events: a class-effect?

Selective cyclo-oxygenase-2 (COX-2) inhibitors, sometimes referred to as 'coxibs', are widely prescribed by hospital doctors and general practitioners for arthritic pain. Their gastrointestinal tolerability is believed to be superior to that of 'non-selective' non-steroidal anti-inflammatory drugs (NSAIDs) such as naproxen and diclofenac. Since the US Food and Drug Administration (FDA) approved the use of rofecoxib (Vioxx) in May 1999, 83 million prescriptions have been issued worldwide. However, on 30 September 2004, rofecoxib was voluntarily withdrawn by Merck Sharp & Dohme because of an increased relative risk of serious cardiovascular events seen after 18 months' use in the APPROVe (Adenomatous Polyp Prevention On Vioxx) trial. The APPROVe trial was initiated because of two previous studies1,2 indicating that daily aspirin had protective effects against colorectal adenomas.

The finding of increased risk of cardiovascular events in relation to rofecoxib did not come as a complete surprise. Such an effect was evident in the Vioxx Gastrointestinal Outcomes Research (VIGOR)3 study, the results of which were reported almost 4 years ago. Results for the first 6 months from a similarly large trial of another selective COX-2 inhibitor, the Celecoxib Long-term Arthritis Safety Study (CLASS),4 suggested that celecoxib had a better gastrointestinal toxicity profile than diclofenac or ibuprofen but results for the 12 month period, made available on the FDA website,5 do not entirely support this conclusion. The discrepancy generated criticism of the way the CLASS data were initially reported.6 Moreover, although celecoxib was not associated with a higher risk of serious cardiac sequelae than diclofenac or ibuprofen over the whole duration of the trial, the data do not exclude the possibility of lesser effects related to cardiac ischaemia.

When an unexpected drug effect is observed, whether adverse or beneficial, the possibility of a 'class-effect' has to be considered. So, might adverse cardiovascular effects be expected with COX-2 agents other than rofecoxib? This question will need to be addressed with complete transparency in future studies of COX-2 inhibitors— especially with the advent of agents such as valdecoxib (Bextra), the successor drug of celecoxib, and etoricoxib (Arcoxia), planned successor of the withdrawn rofecoxib. Meanwhile, for the purposes of alleviating arthritic pain at least, COX-2 inhibitors have lost some of their attraction compared with the older NSAIDs such as diclofenac in combination with a proton pump inhibitor (omepraxole).7


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3. Bombardier C, Laine L, Reicin A, et al. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. N Engl J Med 2000;343: 1520-8 [PubMed]
4. Silverstein FE, Faich G, Goldstein JL, et al. Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis: the CLASS study: a randomized controlled trial. Celecoxib Long-term Arthritis Safety Study. JAMA 2000;284: 1247-55 [PubMed]
5. Witter J. Medical Officer review []
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7. Chan FK, Hung LC, Suen BY, et al. Celecoxib versus diclofenac and omeprazole in reducing the risk of recurrent ulcer bleeding in patients with arthritis. N Engl J Med 2002;347: 2104-10 [PubMed]

Articles from Journal of the Royal Society of Medicine are provided here courtesy of Royal Society of Medicine Press