COX-2 Inhibitors

Since this report was published Merck Sharp & Dohme has decided to withdraw Vioxx (rofecoxib) from the world market.

Findings by SBU Alert

Version: 1

Technology and target group

NSAIDs (non-steroidal antiinflammatory drugs) are a very widely used group of drugs. NSAIDs often alleviate mild to moderate chronic or acute pain that is common in rheumatoid arthritis (RA) and osteoarthritis (OA). NSAIDs also have various side effects, primarily symptoms in the gastrointestinal tract. These side effects lead to substantial utilization of healthcare services and consequently a considerable cost to society. Ulcers involving severe bleeding are rare but represent a serious problem, mainly in certain risk groups, eg, the elderly. Other serious side effects include impaired renal function, edema, and heart failure. Intensive international research aimed at creating NSAIDs with comparable or better positive effects but fewer side effects has led to the development of selective NSAIDs (COX-2 inhibitors). Patients who require long-term treatment for symptoms from OA, RA, or other joint diseases, and who are also at a higher risk for severe side effects, constitute the primary target group for COX-2 inhibitors.

SBU Alert began to consider COX-2 inhibitors in 1999. Publication of this report has been delayed due to uncertainty about how to interpret side effects in long-term studies. Scientific reporting of new data on the side effects of COX-2 inhibitors has led SBU Alert to report on this method relatively late in the diffusion phase. In parallel with SBUs work, the National Board of Health and Welfare developed a base for setting priorities that addresses COX-2 inhibitors. The reader is referred to a working draft of this report (available only in Swedish) [70].

Patient benefit

Several studies show that the symptom-alleviating effects of COX-2 inhibitors are similar to the effects achieved with high doses of traditional NSAIDs. This finding applies both to osteoarthritis and rheumatoid arthritis. Similar results were also achieved when COX-2 inhibitors were tested on patients with acute pain. COX-2 inhibitors have side effects similar to those reported with traditional NSAIDs, except for the ulcer rate, which is shown to be significantly lower than for the compared NSAIDs delivered at the highest recommended daily dose. The association between these endoscopic findings and serious gastrointestinal bleeding is, however, unclear. Comparisons with the generally lower clinical doses of traditional NSAIDs have not been carried out. In long-term followup, a study which compared a COX-2 inhibitor (rofecoxib) with a traditional NSAID (naproxen) showed a higher rate of thromboembolic events, especially myocardial infarction. An ongoing scientific debate aims at determining whether or not COX-2 inhibitors, as a group, increase the risk for such events, or if this is a random outcome in the study. This question is the focus of a thorough investigation by the European Agency for the Evaluation of Medical Products (EMEA), but a final determination has not yet been made.

Economic aspects

The drug cost for COX-2 inhibitors is approximately twice that for traditional NSAIDs. However, several model analyses show that health benefits can be achieved with COX-2 inhibitors at a relatively low cost. This applies to patients with high or moderate risks for gastric bleeding. Few studies have yet considered other relevant factors that influence the costs for COX-2 inhibitors. One study, which includes the estimated costs for myocardial infarction, shows that the method is not a cost-effective treatment option except in carefully selected patient groups at high risk for gastric bleeding.

Scientific evidence

There is good* scientific documentation on the short-term effects of COX-2 inhibitors. However, the long-term effects of treatment, mainly as regards the occurrence of side effects, have yet to be adequately documented. There is moderate* scientific evidence about cost effectiveness. However, the results are inconsistent, and followup studies are needed.

*This assessment by SBU Alert uses a 4-point scale to grade the quality and evidence of the scientific documentation. The grades indicate: (1) good, (2) moderate, (3) poor, or (4) no scientific evidence on the subject.

This summary is based on a report prepared at SBU in collaboration with Assoc. Prof. Ellen Vinge, Lund University Hospital. It has been reviewed by Ingemar Andersson, MD, Centralsjukhuset, Kristianstad, Prof. Stefan Lohmander, Lund University Hospital and Assoc. Prof. Per Nilsson, Medical Products Agency.

The complete report is available only in Swedish.

Alert is a joint effort by the Swedish Council on Technology Assessment in Health Care (SBU), the Medical Products Agency, the National Board of Health and Welfare, and the Federation of Swedish County Councils.

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