Cardiovascular safety of rofecoxib (Vioxx):  lessons learned and unanswered questions

Langton, Paul E; Hankey, Graeme J; Eikelboom, John W

doi:10.5694/j.1326-5377.2004.tb06433.x

We need processes in place to follow up suspicions about serious adverse events

Rofecoxib and a second cyclooxygenase-2 (COX-2) inhibitor, celecoxib, were approved by the Therapeutic Goods Administration in 1999 after large phase III randomised trials showed they were as effective as “traditional” non-steroidal anti-inflammatory drugs in reducing pain and inflammation and less likely to cause gastric ulceration.1,2 Since then, COX-2 inhibitors have become one of the 10 most widely used prescription medicines in Australia, at a cost to the federal government of more than $200 million annually.3 However, uncertainty has surrounded the cardiovascular safety of rofecoxib (Vioxx; Merck Sharp & Dohme), and COX-2 inhibitors as a class, ever since an increased risk of cardiovascular events was reported among patients randomly allocated to the rofecoxib group in the VIGOR trial.1

1 Hollywood Private Hospital, Perth, WA.
2 Royal Perth Hospital, Perth, WA.

Correspondence:

Competing interests:

Dr Langton has given advice to and/or talks for a variety of pharmaceutical companies, including Pfizer and Merck Sharp & Dohme.

1. 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: 1520-1528.
2. Silverstein FE, Faich G, Goldstein JL, et al. Gastrointestinal toxicity with celecoxib vs non-steroidal anti-inflammatory drugs for osteoarthritic and rheumatoid arthritis. The CLASS study: a randomised controlled trial. JAMA 2000; 284: 1247-1255.
3. Department of Health and Ageing. Expenditure and prescriptions twelve months to 30 June 2004. Available at: www.health.gov.au/internet/wcms/publishing.nsf/Content/health-pbs-general-pubs-pbbexp-jun04.htm (accessed Oct 2004).
4. Department of Health and Ageing. Therapeutic Goods Administration. Consumer level recall of arthritis drug. Media release. Available at: www.tga.gov.au/media/2004/040930_vioxx.htm (accessed Oct 2004).
5. Lisse JR, Perlman M, Johansson G, et al. Gastrointestinal tolerability and effectiveness of rofecoxib versus naproxen in the treatment of osteoarthritis: a randomised, controlled trial. Ann Intern Med 2003; 139: 539-546.
6. Mukherjee D, Nissen SE, Topol EJ. Risk of cardiovascular events associated with selective COX-2 inhibitors. JAMA 2001; 286: 954-959.
7. Solomon DH, Schneeweiss S, Glynn RJ, et al. Relationship between selective cyclooxygenase-2 inhibitors and acute myocardial infarction in older adults. Circulation 2004; 109: 2068-2073.
8. Topol EJ, Falk GW. A coxib a day won’t keep the doctor away. Lancet 2004; 364: 639-640.
9. Hankey GJ, Eikelboom JW. Cyclooxygenase-2 inhibitors. Are they really atherothrombotic, and if not, why not? Stroke 2003; 34: 2736-2740.
10. Fitzgerald GA. COX-2 and beyond: approaches to prostaglandin inhibition in human disease. Nat Rev Drug Discov 2003; 2: 879-890.
11. Fitzgerald GA. Coxibs and cardiovascular disease. N Engl J Med 2004; 351: 1709-1710.
12. Bogaty P, Brophy JM, Noel M, et al. Impact of prolonged cyclo-oxygenase-2 inhibition on inflammatory markers and endothelial function in patients with ischemic heart disease and raised C-reactive protein. A randomised placebo-controlled study. Circulation 2004; 110: 934-939.
13. Farkouh M, Kirshner H, Harrington RA, et al, on behalf of the TARGET Study Group. Comparison of lumiracoxib with naproxen and ibuprofen in the Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET), cardiovascular outcomes: randomised controlled trial. Lancet 2004; 364: 675-684.
14. Ott E, Nussmeier NA, Duke PC, et al. Efficacy and safety of the cyclooxygenase 2 inhibitors parecoxib and valdecoxib in patients undergoing coronary artery bypass surgery. J Thorac Cardiovasc Surg 2003; 125: 1481-1492.
15. Zhang W, Jones A, Doherty M. Does paracetamol (acetaminophen) reduce the pain of osteoarthritis? A meta-analysis of randomised controlled trials. Ann Rheum Dis 2004; 63: 901-907.
16. Pollack A. A new trial of celebrex, and questions on its timing. The New York Times 2004; 19 Oct. Available at: www.nytimes.com/2004/10/19/business/19drug.html (accessed Oct 2004).

Online responses are no longer available. Please refer to our instructions for authors page for more information.