Rofecoxib for rheumatoid arthritis

Editor's note: The anti-inflammatory drug rofecoxib (Vioxx) was withdrawn from the market at the end of September 2004 after it was shown that long-term use (greater than 18 months) could increase the risk of heart attack and stroke. Further information is available at

Does rofecoxib work to treat rheumatoid arthritis and how safe is it?
To answer this question, scientists working with the Cochrane Musculoskeletal Group found and analyzed two high quality studies. These studies include over 8700 people with rheumatoid arthritis (RA) and about 80% were women. Most people received 25 or 50 mg of rofecoxib once a day over 8 weeks or 9 months. These studies provide the best evidence we have today.

What is rofecoxib (Vioxx)?
Rofecoxib (Vioxx) is often referred to as a 'COX II inhibitor' and is one of the new non-steroidal anti-inflammatory drugs (NSAIDs) prescribed to decrease pain and inflammation in rheumatoid arthritis. Other NSAIDS, such as naproxen (Naprosyn) are also prescribed but they come with warnings that they may cause digestive side effects such as ulcers, bleeds and perforations that can be serious. Rofecoxib is thought to be safer on the stomach than other NSAIDS but can be more expensive.

Rofecoxib was taken off the market at the end of September 2004. A study had shown that people taking rofecoxib to prevent colon cancer had more heart attacks and strokes than people taking a sugar pill.

How well does it work?
The studies show that more people with RA who took rofecoxib for 8 weeks had relief from their symptoms than people who took a 'sugar pill' or placebo. In fact, people showed a 20% improvement in the number of tender and swollen joints plus a 20% improvement in at least three out of five other measures such as the level of pain they reported, the level of disease activity they described, their ability to do everyday activities, their physical check-up and their results on blood tests.

It was also found that 25 mg of rofecoxib worked just as well as 50 mg over 8 weeks.

The studies also show that rofecoxib worked just as well as naproxen over 9 months.

How safe is it?
Fewer people taking rofecoxib for 9 months had ulcers and bleeds than people who took naproxen. But more people stopped taking rofecoxib than placebo because of its side effects.

The 9 month study showed that rofecoxib and naproxen caused a similar number of kidney difficulties, but that rofecoxib caused more heart problems such as heart attacks. The reason for the heart problems is not clear at this time.

What is the bottom line?

Rofecoxib at 50 mg (which is two times the recommended dose) works just as well as 1 gram of naproxen to reduce pain and inflammation in RA. It is safer on the stomach than naproxen for 9 months, but it is uncertain whether it is safer in the long term.

Heart problems, such as heart attacks occurred in more people taking 50 mg of rofecoxib for 9 months than people taking naproxen and therefore caution is recommended for people who have a greater risk of heart problems.

More studies need to be done to test the cost-effectiveness and the long term effects of rofecoxib.

Authors' conclusions: 

In patients with RA, rofecoxib demonstrates a greater degree of efficacy than placebo, while having a comparable safety profile. Rofecoxib demonstrates a similar degree of efficacy as naproxen, but with a significantly lower rate of ulceration and gastrointestinal bleeding. Rofecoxib was associated with a greater risk for MI, but the exact significance and pathophysiology of this possible relationship is unclear.

Rofecoxib was voluntarily withdrawn from global markets in October 2004. It cannot therefore be prescribed and therefore there are no implications for practice concerning its use. None the less when considering which NSAID to use, it must be borne in mind that the toxicity of NSAIDs is variable amongst patients and drugs and it tends to be dose related and associated with variation in the mode of action, absorption, distribution and metabolism.There remains a number of questions over both the benefits and risks associated with Cox II selective agents and further work is ongoing. It is likely that this issue will not be resolved until research has enabled a fuller understanding of the complex mechanism by which the Cox system operates.

Read the full abstract...

Editor's note: The anti-inflammatory drug rofecoxib (Vioxx) was withdrawn from the market at the end of September 2004 after it was shown that long-term use (greater than 18 months) could increase the risk of heart attack and stroke. Further information is available at

Rheumatoid arthritis (RA) is a systemic auto-immune disorder, in which the synovial lining of many joints and tendon sheaths are persistently inflamed.


To assess the efficacy and toxicity of rofecoxib for treating RA.

Search strategy: 

We searched the following electronic databases up to December 2000: MEDLINE, EMBASE, Cochrane Database of Systematic Reviews, Cochrane Controlled Trials Register, National Research Register, NHS Economic Evaluation Database, Health Technology Assessment database. The bibliographies of retrieved papers were scanned for additional references. The manufacturers of rofecoxib, MSD, were also approached by the UK National Institute for Clinical Excellence to submit additional evidence to inform it's appraisal on the use of cyclo-oxygenase inhibitors for arthritis.

Selection criteria: 

We included randomised controlled trials of parallel group design evaluating the efficacy and/or toxicity of rofecoxib in RA, both placebo based and comparative trials were eligible. Relevant outcome criteria had to be available to evaluate efficacy and/or toxicity, such as the OMERACT outcomes.

Data collection and analysis: 

Data were abstracted independently by two reviewers and the results were compared for the degree of agreement. A validated tool (Jadad 1996) was used to score the quality of the randomised controlled trials. The planned analysis was to pool, where appropriate, continuous outcome measures using mean or standardized mean differences, and dichotomous outcome measures using relative risk ratios.

Main results: 

Two randomised controlled trials evaluating rofecoxib for the treatment of RA were identified and met the inclusion criteria. One compared rofecoxib to placebo and was designed to assess the safety and efficacy of several doses of rofecoxib. The second trial compared rofecoxib to naproxen and was primarily designed to assess the safety of rofecoxib so did not include all the recommended RA efficacy measures. The overall number of ACR 20 responders who had received 25mg (82/ 171 = 48%) or 50mg (86/161 = 53%) was statistically significantly more than those receiving placebo (58/168 = 35% ) (RR 1.39 CI: 1.07, 1.80 and RR 1.55 CI: 1.20, 1.99 respectively) with no statistically significant differences between the 25 and 50 mg doses. The safety profile of rofecoxib was similar to that of placebo. In the comparative trial, rofecoxib at a dosage of 50 mg/day demonstrated similar efficacy to naproxen at a dosage of 500 mg twice daily. However, the combined rate of clinically significant complicated gastro-intestinal events (GI) (perforations, ulcers, bleeds, or obstructions) was lower with rofecoxib than with naproxen (RR 0.46, 95% CI, 0.34 to 0.63) due to a reduction in the number of ulcers and bleeds. Compared to patients taking naproxen, patients taking rofecoxib had a greater risk of having any cardiovascular event (45/4047 = 1.1% vs 19/4029 =0.47%) (RR 2.36 CI 1.38 to 4.02) and had greater risk of having a non-fatal myocardial infarction (MI) (18/4047 =0 .44% and 4/4029 =0.1%) (RR 4.48, 95% CI, 1.52 to 13.23).