BMJ 2002;325:619-623 ( 21 September )

Papers

Efficacy, tolerability, and upper gastrointestinal safety of celecoxib for treatment of osteoarthritis and rheumatoid arthritis: systematic review of randomised controlled trials

Editorial by Jones
See also p 624

Jonathan J Deeks, senior medical statistician a, Lesley A Smith, research fellow a, Matthew D Bradley, associate director b. 

a Centre for Statistics in Medicine, Institute of Health Sciences, Headington, Oxford OX3 7LF, b Pfizer Global Research and Development, Sandwich, Kent CT13 9NJ

Correspondence to: J J Deeks jon.deeks{at}cancer.org.uk


    Abstract
Top
Abstract
Introduction
Methods
Results
Discussion
References

Objective: To determine the efficacy, gastrointestinal safety, and tolerability of celecoxib (a cyclo-oxygenase 2 (COX 2) inhibitor) used in the treatment of osteoarthritis and rheumatoid arthritis.
Design: Systematic review of randomised trials that compared at least 12 weeks' celecoxib treatment with another non-steroidal anti-inflammatory drug (NSAID) or placebo and reported efficacy, tolerability, or safety. Trials identified from manufacturer and by searching electronic databases and evaluated according to predefined inclusion and quality criteria. Data combined through meta-analysis.
Participants: 15 187 patients with osteoarthritis or rheumatoid arthritis.
Main outcome measures: Efficacy: Western Ontario and McMaster universities osteoarthritis index; American College of Rheumatology responder index and joint scores for rheumatoid arthritis. Tolerability: withdrawal rates for adverse effects. Gastrointestinal safety: incidence of ulcers, bleeds, perforations, and obstructions.
Results: Nine randomised controlled trials were included. Celecoxib and NSAIDS were equally effective for all efficacy outcomes. Compared with those taking other NSAIDs, in patients taking celecoxib the rate of withdrawals due to adverse gastrointestinal events was 46% lower (95% confidence interval 29% to 58%; NNT 35 at three months), the incidence of ulcers detectable by endoscopy was 71% lower (59% to 79%; NNT 6 at three months), and the incidence of symptoms of ulcers, perforations, bleeds, and obstructions was 39% lower (4% to 61%; NNT 208 at six months). Subgroup analysis of patients taking aspirin showed that the incidence of ulcers detected by endoscopy was reduced by 51% (14% to 72%) in those given celecoxib compared with other NSAIDs. The reduction was greater (73%, 52% to 84%) in those not taking aspirin.
Conclusion: Celecoxib is as effective as other NSAIDs for relief of symptoms of osteoarthritis and rheumatoid arthritis and has significantly improved gastrointestinal safety and tolerability.

What is already known on this topic
Long term NSAID use is associated with the development of peptic and duodenal ulcers

COX 2 specific inhibitors are claimed to cause fewer gastrointestinal complications

The National Institute for Clinical Excellence has recently recommended that COX 2 specific inhibitors are used in patients with arthritis who are at risk of gastrointestinal complications but not in those taking prophylactic aspirin

What this study adds
Systematic review of randomised trials shows that celecoxib is as effective as other NSAIDs for osteoarthritis and rheumatoid arthritis

Celecoxib has significantly improved gastrointestinal safety and tolerability compared with standard NSAIDs

An improvement in gastrointestinal safety was still evident in patients who were also taking aspirin




    Introduction
Top
Abstract
Introduction
Methods
Results
Discussion
References

Non-steroidal anti-inflammatory drugs (NSAIDs) are prescribed for the treatment of osteoarthritis and rheumatoid arthritis and provide effective relief from symptoms. However, serious gastrointestinal complications occur with their use. There are between 2000-2500 deaths annually in the United Kingdom due to use of NSAIDs. 1 2

NSAIDs control pain and inflammation by inhibiting cyclo-oxygenase 1 and 2 (COX 1 and COX 2) enzymes. Inhibition of the COX 1 enzyme is responsible for the associated gastrointestinal toxicity. Celecoxib was developed as a COX 2 specific inhibitor to provide relief without the associated gastrointestinal complications.

We conducted a systematic review of all published and unpublished trials to determine if celecoxib is as effective as other NSAIDs for the treatment of osteoarthritis and rheumatoid arthritis and if there is evidence of greater gastrointestinal tolerability and safety.


    Methods
Top
Abstract
Introduction
Methods
Results
Discussion
References

Inclusion criteria
We included randomised controlled trials if they were double blind, compared celecoxib at a licensed therapeutic dose for at least 12 weeks with placebo or another NSAID at a standard dose in patients with active rheumatoid arthritis or osteoarthritis, and reported efficacy, tolerability, or safety outcomes. In addition, to investigate safety we considered data on doses of celecoxib above those recommended for treatment. Placebo comparisons were included to demonstrate the sensitivity of efficacy outcomes and to investigate gastrointestinal toxicity.

Outcome measures
We present results of the Western Ontario and McMaster universities (WOMAC) osteoarthritis index for pain (scored 0 to 20), stiffness (scored 0 to 8), and physical function (scored 0 to 68). We used the American College of Rheumatology (ACR-20) responder index and evaluations of improvement in the numbers of painful or tender and swollen joints for trials of rheumatoid arthritis.

Drug tolerability was assessed by considering rates of withdrawal due to any adverse event at 12 weeks. Gastrointestinal safety was assessed by comparing the incidence of ulcers detected by routine endoscopy at 12 and 24 weeks and the incidence of symptomatic ulcers, perforations, bleeds, and obstructions up to 24 weeks.

Study identification
We aimed to include all randomised trials of celecoxib, regardless of whether or not they had been published. We obtained from the manufacturer reports from all industry sponsored randomised controlled trials that were completed by 25 May 2000 and that compared celecoxib with placebo or other NSAID in people with osteoarthritis and rheumatoid arthritis. We also searched Medline, Embase, and the Cochrane controlled trials register from 1998 to March 2001 using the search terms celecoxib, Celebrex, and SC-58635.

Trial quality and data abstraction
To assess the potential for bias we considered the method of randomisation, concealment of allocation, blinding of trial investigators and patients, completeness of follow up, and analysis according to intention to treat. Summary outcome data were extracted from the original company trial reports.

Data synthesis
Separate meta-analyses were undertaken for each comparison and outcome. We analysed efficacy data separately for osteoarthritis and rheumatoid arthritis. We analysed tolerability and safety data for the two diseases combined.

Dichotomous data were summarised as relative risks; continuous data were summarised as differences in means.




    Results
Top
Abstract
Introduction
Methods
Results
Discussion
References

We obtained reports of 17 trials, nine of which (15 187 patients) fulfilled the inclusion criteria.3-11 See the long version of this paper on bmj.com for full details of the studies. All nine trials were of high quality.

After 12 weeks of treatment, 56% of patients in the placebo group had dropped out due to poor efficacy or adverse events. Dropout rates in celecoxib and other NSAID groups were lower (39% on celecoxib 200 mg per day; 32% on celecoxib 400 mg per day; 39% on naproxen 1000 mg per day; 26% on diclofenac 150 mg per day).

Effectiveness of celecoxib for treatment at 12 weeks
Rheumatoid arthritis---Celecoxib provided significant improvement in all outcomes compared with placebo. 4 9 Three trials compared celecoxib with other NSAIDS (naproxen 500 mg twice daily in two trials 4 9 and diclofenac 75 mg twice daily in one7). There were no significant differences, with all drugs appearing equally effective for all outcomes. With celecoxib the ACR-20 responder rate was 4% higher (95% confidence interval -20% to 36%), 9% more (-10% to 32%) showed improvement in the number of painful or tender joints, and 2% more (-15% to 22%) showed improvement in the number of swollen joints (see also bmj.com).

Osteoarthritis---Compared with placebo celecoxib resulted in significant improvement in all components of the WOMAC scale as well as the composite WOMAC score. 3 10 11 The same three trials compared celecoxib with naproxen 500 mg twice daily in 1917 patients. There were no significant differences between celecoxib and naproxen, with both drugs appearing equally effective for all components of the WOMAC scale: pain (mean difference 0.0, -0.7 to 0.7), stiffness (0.1, -0.1 to 0.2), and physical function (0.4, -1.0 to 1.8) and the composite WOMAC score (0.4, -1.5 to 2.3) (see bmj.com).

Tolerability
Celecoxib versus placebo---Withdrawal due to adverse events occurred more often on celecoxib than on placebo, both for any adverse event (relative risk 1.49, 1.15 to 1.92) and for all gastrointestinal adverse events (1.68, 1.07 to 2.65) (fig 1). However, withdrawals due to abdominal pain, diarrhoea, dyspepsia, nausea, or vomiting were not significantly increased with celecoxib compared with placebo.



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  		Fig 1.   Withdrawals from celecoxib, placebo and NSAIDs at 12 weeks attributed to adverse effects. D=diclofenac 75 mg twice daily, I=ibuprofen 800 mg thrice daily, N=naproxen 500 mg twice daily

Celecoxib versus NSAID---There was no significant difference between celecoxib and NSAID in the incidence of withdrawals for all adverse events (fig 1). However, there was a significant decrease in the number of withdrawals due to gastrointestinal adverse events, corresponding to a number needed to treat of 35 at three months. Of the specific gastrointestinal adverse events, there were significantly fewer withdrawals due to abdominal pain and dyspepsia in the celecoxib group compared with other NSAIDs. The incidence of withdrawals due to diarrhoea, nausea, or vomiting were not significantly different between celecoxib and other NSAIDs.

Ulcers detected by endoscopy
Celecoxib versus placebo---Although there was no significant difference in the number of ulcers detected between the groups, the results were compatible with up to a threefold increase in the incidence of ulcers (1.53, 0.73 to 3.21).

Celecoxib versus NSAID---The incidence of ulcers was 71% (59% to 79%) lower in those taking celecoxib compared with other NSAIDs, corresponding to a number needed to treat of six at three months. The one study that reported ulcers detected by endoscopy at 24 weeks found a similar significant reduction, with incidence being 75% (47% to 88%) lower in those taking celecoxib.7

Ulcers, perforations, bleeds, and obstructions at 24 weeks
The CLASS study of 7968 patients investigated the incidence of serious upper gastrointestinal events (bleeds, perforations, obstructions) in those taking celecoxib (3987 given celecoxib 800 mg per day; above the recommended dose) compared with other NSAIDs (1985 took ibuprofen, 1996 took diclofenac).8 Patients were monitored and withdrawn from the trial due to adverse events, if endoscopy indicated a symptomatic ulcer, if prolonged use of an ulcer healing treatment was required, or if treatment did not control the symptoms of arthritis. Outcomes at six months were considered as the overall rates of withdrawal were more comparable after six months (40% for celecoxib, 42% for diclofenac, and 47% for ibuprofen) than at the final follow up (55%, 53% and 65%). With celecoxib the incidence of bleeds, perforations, or obstructions (n=11) was nearly half that with the other NSAIDs (n=20), but this difference was not significant (fig 2).



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  		Fig 2.   Incidence of symptomatic ulcers, perforations, bleeds, and obstructions after 24 weeks' treatment with celecoxib 400 mg twice daily, diclofenac 75 mg twice daily (D) or ibuprofen 800 mg thrice daily (I). Trial stratified into two parts as designed

Among the participants withdrawn from the trial for safety reasons, 19 patients taking celecoxib were found to have ulcers on endoscopy compared with 29 patients taking other NSAIDs. When ulcers were included within the definition of serious adverse events, the reduction of serious adverse events with celecoxib decreased to 39% (corresponding to a number needed to treat of 208 at six months) but became significant (fig 2).

Benefits of celecoxib in patients receiving low dose aspirin
Four trials compared celecoxib with other NSAIDs and showed that the incidence of ulcers detected by routine endoscopy were significantly reduced both in patients taking and not taking aspirin (up to 325 mg/day). 4-5 10 The benefit of celecoxib seemed greater in those not taking aspirin, although the difference between subgroups was not significant (P=0.18, fig 3).



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  		Fig 3.   Impact of prophylactic aspirin on incidence of ulcers detected by routine endoscopy after 12 weeks' treatment. D=diclofenac 75 mg twice daily, I=ibuprofen 800 mg thrice daily, N=naproxen 500 mg twice daily

In the CLASS study the reduction in the incidence of clinical ulcers, perforation, bleeds, and obstructions was also smaller in those taking aspirin (19% reduction, -63% to 60%) than in those not taking aspirin (50% reduction, 8% to 72%).8 This difference between the subgroups was not significant (P=0.44).




    Discussion
Top
Abstract
Introduction
Methods
Results
Discussion
References

In this review of randomised controlled trials we have shown that celecoxib is as effective as other NSAIDs for the relief from symptoms of osteoarthritis and rheumatoid arthritis. The confidence intervals around the point estimates of efficacy were reasonably narrow, which mean that it is unlikely that there were clinically important differences.

Our findings are robust and unlikely to be influenced by bias. Beyond the stated involvement of MDB, the industrial sponsors had no involvement in the review process once the protocol had been agreed. We included published and unpublished studies, and we insisted that the companies involved provided a signed legal statement confirming that they had made available data from all celecoxib trials that were completed before our inclusion date. We evaluated the impact of including unpublished studies by sensitivity analyses for main outcomes (see bmj.com); our findings and interpretation did not change. Results of further phase 4 trials (the Success trial) have recently been partially published in abstract form since we completed our search. We did not add these to our review as they are incomplete and could introduce bias.12

As we abstracted data directly from original trial reports we minimised the effects of missing data and errors in transcription. Access to individual patient data would have allowed us to investigate further any variation in treatment effect with patient characteristics.

All included trials were designed and executed to meet standards required for licensing. Although withdrawals were common, the potential biases due to unequal withdrawals act in a conservative direction.

For most analyses we did not detect any heterogeneity, which supports pooling of different doses of drugs and disease states. Each analysis comprised large numbers of patients, baseline characteristics were similar, all patients had active disease at the start of the study, and efficacy outcomes assessed were those routinely required for licensing of drugs for osteoarthritis and rheumatoid arthritis (WOMAC and ACR-20). Additional efficacy outcomes that we investigated but have not reported here showed similar patterns of benefit.

This review was limited to assessing only upper gastrointestinal safety. Recently the VIGOR (Vioxx gastrointestinal outcomes research) trial of rofecoxib has raised concerns about serious cardiovascular effects with the use of COX 2 inhibitors.13 While it is important to evaluate this concern, this was not possible here as the celecoxib trials we included did not report outcomes comparable with those assessed in VIGOR (all trials started recruitment before publication of VIGOR). This issue should be a priority for a future systematic review when adequate data on both celecoxib and rofecoxib are available.

Aspirin is commonly prescribed to prevent cardiovascular disease, and, like NSAIDs, it inhibits COX 1 thus increasing the risk of a gastrointestinal event. The present weight of evidence does not suggest that celecoxib should be withheld from aspirin users as currently recommended by the National Institute for Clinical Excellence (NICE), but further research should clarify the size of the possible reduction in efficacy in this group.

In conclusion, this meta-analysis provides strong evidence of the effectiveness of celecoxib for relief of pain and inflammatory symptoms of osteoarthritis and rheumatoid arthritis, the level of effectiveness being equivalent to that of other NSAIDs. However, the tolerability and gastrointestinal safety of celecoxib is substantially superior.

    Acknowledgments

Mark Layton (Pfizer) and Anne Hopkins (Searle) provided input into the review protocol and facilitated access to the full trial reports.

Contributors: See bmj.com

    Footnotes

Funding: Additional funding was provided to the Centre for Statistics in Medicine by Pfizer and Searle (now part of Pharmacia).

Competing interests: The review was undertaken independently at the Centre for Statistics in Medicine. LAS is employed on a fellowship funded by Pfizer. JJD has acted as a paid consultant to Pfizer and Pharmacia. MDB is an employee of Pfizer. The review was prepared as part of the submission to the UK National Institute of Clinical Excellence for appraisal of COX 2 selective inhibitors.

The full version of this article appears on bmj.com


    References
Top
Abstract
Introduction
Methods
Results
Discussion
References

1. Blower AL, Brooks A, Fenn GC, Hill A, Pearce MY, Morant S, et al. Emergency admissions for upper gastrointestinal disease and their relation to NSAID use. Aliment Pharmacol Ther 1997; 11: 283-291[CrossRef][ISI][Medline].
2. Tramer MR, Moore RA, Reynolds DJ, McQuay HJ. Quantitative estimation of rare adverse events which follow a biological progression: a new model applied to chronic NSAID use. Pain 2000; 85: 169-182[CrossRef][ISI][Medline].
3. Bensen WG, Fiechtner JJ, McMillen JI, Zhao WW, Yu SS, Woods EM, et al. Treatment of osteoarthritis with celecoxib, a cyclooxygenase-2 inhibitor: a randomized controlled trial. Mayo Clin Proc 1999; 74: 1095-1105[ISI][Medline].
4. Simon LS, Weaver AL, Graham DY, Kivitz AJ, Lipsky PE, Hubbard RC, et al. Anti-inflammatory and upper gastrointestinal effects of celecoxib in rheumatoid arthritis: a randomized controlled trial. JAMA 1999; 282: 1921-1928[Abstract/Free Full Text].
5. Study 62. Integrated clinical and statistical report for a multicenter, double blind, parallel group study comparing the incidence of gastroduodenal ulcer associated with SC-58635 200 mg with that of naproxen 500 mg BID taken for 12 weeks in patients with osteoarthritis or rheumatoid arthritis. Pharmacia: Data on file. 1997.
6. Study 071. Integrated clinical and statistical report for a multicenter, double blind, parallel group study comparing the incidence of gastroduodenal ulcer associated with SC-58635 200 mg BID with that of diclofenac 75 mg BID and ibuprofen 800 mg TID, taken for 12 weeks in patients with osteoarthritis or rheumatoid arthritis. Pharmacia: Data on file. 1998.
7. Emery P, Zeidler H, Kvien TK, Guslandi M, Naudin R, Stead H, et al. Celecoxib versus diclofenac in long-term management of rheumatoid arthritis: randomised double-blind comparison. Lancet 1999; 354: 2106-2111[CrossRef][ISI][Medline].
8. Silverstein FE, Faich G, Goldstein JL, Simon LS, Pincus T, Whelton A, et al. Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: the CLASS study: a randomized controlled trial. Celecoxib long-term arthritis safety study. JAMA 2000; 284: 1247-1255[Abstract/Free Full Text].
9. Zhao SZ, Fiechtner JI, Tindall EA, Dedhiya SD, Zhao WW, Osterhaus JT, et al. Evaluation of health-related quality of life of rheumatoid arthritis patients treated with celecoxib. Arthritis Care Res 2000; 13: 112-121.
10. Zhao SZ, McMillen JI, Markenson JA, Dedhiya SD, Zhao WW, Osterhaus JT, et al. Evaluation of the functional status aspects of health-related quality of life of patients with osteoarthritis treated with celecoxib. Pharmacotherapy 1999; 19: 1269-1278[CrossRef][ISI][Medline].
11. Study 054. Integrated clinical and statistical report for a double-blind placebo controlled, randomised comparison study of the efficacy and safety of SC-58635 50 mg, 100 mg and 200 mg BID and naproxen 500 mg BID in treating the signs and symptoms of osteoarthritis of the hip. Pharmacia: Data on file. 1997.
12. Singh G, Goldstein J, Fort J, Bello A, Boots S. Success-I in osteoarthritis (OA) trial: celecoxib has similar efficacy to the conventional NSAIDS [abstract]. J Rheumatol 2001; 28(suppl 6.3): 6[Medline].
13. Bombardier C, Laine L, Reicin A, Shapiro D, Burgos-Vargas R, Davis B, et al. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. VIGOR study group. N Engl J Med 2000; 343: 1520-1528[Abstract/Free Full Text].

(Accepted 27 March 2002)

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Rapid Responses:

Read all Rapid Responses

misleading ?
Alessandro Calderan
bmj.com, 23 Sep 2002 [Full text]
Missing the point?
Jeremy J Black
bmj.com, 24 Sep 2002 [Full text]
New Cox 2 data
David J Walker
bmj.com, 26 Sep 2002 [Full text]
"Bad planning?"
Ebbe Englev
bmj.com, 30 Sep 2002 [Full text]
Celecoxib safer? Still not proven!
Arnold G Zermansky
bmj.com, 4 Oct 2002 [Full text]
On presentation and analysis
Michael L. Jenkinson
bmj.com, 7 Oct 2002 [Full text]
Assessing the risk of GI complications with NSAIDs is still problematic
Neal Maskrey, et al.
bmj.com, 9 Oct 2002 [Full text]
Review is more favorable than data
Christoph Pechlaner
bmj.com, 13 Oct 2002 [Full text]
Re: On presentation and analysis
Jonathan J Deeks, et al.
bmj.com, 15 Oct 2002 [Full text]
Celebrex’s relative GI safety is overstated?
Scott Metcalfe, et al.
bmj.com, 16 Oct 2002 [Full text]
A Missed Opportunity
James M Wright
bmj.com, 22 Oct 2002 [Full text]
Problems compromising the review's validity
Peter Jüni, et al.
bmj.com, 29 Oct 2002 [Full text]
On presentation and analysis
Michael L Jenkinson, et al.
bmj.com, 30 Oct 2002 [Full text]
Absence of evidence versus evidence of absence
Peter Jüni, et al.
bmj.com, 31 Oct 2002 [Full text]
Accolade
Robert I. Rudolph, M.D., FACP
bmj.com, 1 Nov 2002 [Full text]
Coxibs gastrointestinal safety: worth spending time on 3 months data?
Giulio Formoso, et al.
bmj.com, 9 Nov 2002 [Full text]
Study reports: clarification, correction and additional sources
Jonathan J Deeks
bmj.com, 13 Nov 2002 [Full text]
On eradicating publication bias, and the realities of independent reviews
Jonathan J Deeks
bmj.com, 15 Nov 2002 [Full text]
Re: On presentation and analysis
Michael L Jenkinson
bmj.com, 18 Dec 2002 [Full text]

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