Rofecoxib for rheumatoid arthritis

  • Review
  • Intervention




Editor's note: The anti-inflammatory drug rofecoxib (Vioxx) was withdrawn from the market at the end of September 2004 after it was shown that long-term use (greater than 18 months) could increase the risk of heart attack and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

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).

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.




Rofecoxib (Vioxx) 因長期使用(大於18個月)可能增加發生心血管疾病及中風的風險,於2004年9月30日宣全球回收。更多的資訊在 類風濕性關節炎一種系統性自體免疫疾病,主要表現是關節滑液膜及韌帶發炎的疾病。


評估rofecoxib (Vioxx)在治療類風濕性關節炎的療效與副作用。


搜尋包括MEDLINE, EMBASE, Cochrane Database of Systematic Reviews, Cochrane Controlled Trials Register, National Research Register, NHS Economic Evaluation Database, Health Technology Assessment database (直到2000年12月),同時手動搜尋所選文章之參考文獻。National Institute for Clinical Excellence(NICE)機構亦聯絡默克公司提供其有關使用環氧合?抑制劑治療關節炎之資料。


所有隨機對照試驗及控制對照研究,比較rofecoxib與安慰劑對照組或另一種治療,對類風濕性關節炎的療效與毒性。 OMERACT結果指標亦用來評估療效和毒性。




2篇隨機對照試驗符合選入條件。1個隨機對照試驗比較多種rofecoxib劑量與安慰劑,並評估療效與安全性。第2個隨機對照試驗比較rofecoxib與naproxen之安全性,所以沒有包含建議的類風關節炎的評估療效。整體而言,接受25毫克 (82/ 171 = 48%) 或 0毫克(86/161 = 53% ofecoxib比接受安慰劑 (58/168 = 35%),有統計學上較高的ACR 20反應人數之(相對風險分別為1.39 信賴區間CI: 1.07−, 1.80 與1.5 信賴區間CI: 1.20 – 1.99),但25mg或50mg並無顯著差異。Rofecoxib與安慰劑之安全性相似。rofecoxib每日50毫克與 naproxen 早晚500毫克療效相當,但胃腸之穿孔、潰瘍、出血、或阻塞之副作用方面,rofecoxib潰瘍及出血方面比naproxen風險小(相對風險0.46, 95% 信賴區間CI, 0.34 to 0.63)。比起naproxen而言,rofecoxib有較高的風險產生心血管事件(45/4047 = 1.1% vs. 19/4029 = 0.47%),相對風險2.36 信賴區間C .38 to 4.02。且非致死的心肌梗塞 (18/404 0 .44% 比上4/4029 = 0.1%),相對風險4.48, 95% 信賴區間CI, 1.52 to 13.23。


Rofecoxib治療類風濕性關節炎比安慰劑有療效,相對亦安全。rofecoxib與 aproxen比較療效相當,但潰瘍及出血方面比naproxen風險小,然心肌梗塞相對風險增加但是確切的影響及病生理關係仍然不明,Rofecoxib在2004年9月時被主動全球回收,目前沒有處方及臨床使用的疑慮,當考慮使用非類固醇類抗發炎藥物時,其毒性是因人而異,與劑量、不同的作用機轉、吸收、代謝相關。對於選擇性Cox2的益處與風險仍存在許多問題,除非對於Cox系統的複雜機轉有更全面的瞭解才能解決這個問題。。



此翻譯計畫由臺灣國家衛生研究院(National Health Research Institutes, Taiwan)統籌。


編者按:在2004年9月底,因長期使用(大於 18個月)會增加心臟病發作和中風的風險使得抗炎藥rofecoxib (Vioxx) 從市場上召回。更多信息可在www.vioxx.com取得。 是否rofecoxib可治療類風濕關節炎和其安全性如何呢?要回答這個問題,科學家從Cochrane肌肉骨骼組取得並分析了兩個高品質的研究。這些研究包括了8700位類風濕關節炎(RA)患者,大約 80%是婦女。大多數人服用每天一次25或50毫克的Rofecoxib超過 8週或9個月。這些研究提供了我們至今日最好的證據。 什麼是Rofecoxib(Vioxx)?Rofecoxib(Vioxx)通常被稱為 ‘COX II抑製劑’ ,是一種新的非類固醇消炎止痛藥(NSAIDs)用於減輕類風濕關節炎的疼痛和發炎。其他NSAIDs,如naproxen (Naprosyn)也用於類似病症,但被提出警告,可能會引起下列嚴重副作用,如消化道潰瘍,出血和甚至嚴重的穿孔。Rofecoxib被認為在腸胃道作用比其他NSAIDs安全,但更加昂貴。Rofecoxib在2004年9月底被退出市場。一項研究顯示,比起服用糖丸,服用Rofecoxib來預防罹患結腸癌的病患有更多的心臟病發作和中風。 它是如何產生效果?研究表明,比起服用‘糖丸’或安慰劑,越多的類風濕關節炎患者服用Rofecoxib 8週可緩解症狀。事實上,病患呈現了在疼痛和關節腫脹數目20%的改善,另加上至少五分之三的其他評估有20%的改善,如疼痛的報告,他們描述疾病活動的程度,做日常活動的能力,身體檢查的血液學結果。有人還發現,使用25毫克的Rofecoxib超過八週的效果同50毫克。研究還表明,Rofecoxib使用超過 個月可和naproxen效果一樣好。 安全性如何呢?比起使用naproxen的人,使用Rofecoxib9個月的人有較少的潰瘍和出血。但比起安慰劑,更多的人因為副作用而停止服用Rofecoxib。 9個月的研究表明,Rofecoxib和naproxen引起了同樣數量的腎損傷,但Rofecoxib引起更多心臟問題,例如心血管疾病。心臟問題的原因至今仍不清楚。 什麼是底線?Rofecoxib在50毫克(這是推薦劑量的2倍)的效果等同 1克的naproxen,所以減輕疼痛和類風濕性關節炎的發炎。使用9個月在胃部安全性比naproxen好,但目前尚不能確定它是否長期也能安全使用。心臟問題,如心血管疾病,比起使用naproxen者,服用50毫克Rofecoxi 個月的人更常發生,因此建議有較多心臟問題風險的人需謹慎使用。更多的研究需要進行來測試Rofecoxib的成本效益和長遠影響

Plain language summary

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.