Deeks et al’ systematic review (1) evaluated 12 weeks
gastrointestinal safety of coxibs by doing an original meta-analysis, and
26 weeks gastrointestinal safety by using data from the CLASS study. In
our opinion, this evaluation does not add relevant knowledge. While 26
weeks data from the CLASS study have been already (and repeatedly)
criticised (2), the need for 12 weeks data is questionable since patients
with osteoarthritis or rheumatoid arthritis, taking celecoxib for that
long, would probably keep on taking celecoxib for longer. Therefore 12-15
months data on 7968 patients published by FDA (3) (looking at the whole
study period of CLASS) are, in our opinion, more meaningful than 12 weeks
data on 2742 patients meta-analysed by the Deeks et al. FDA data clearly
demonstrates no difference in rates of complicated ulcers among celecoxib,
ibuprofen and diclofenac long-term users.

It would have been more interesting to know about short-term safety
(1-2 weeks), considering that, in real practice, coxibs are frequently
used in short courses (4) and have also been registered for acute diseases
(management of acute pain, primary dysmenorrhea). In the province of
Modena (632,000 inhabitants, Northern Italy) we found that 78% of patients
receiving coxibs were prescribed less than 60 Defined Daily Doses in the
whole 2001, suggesting a high prevalence of “acute” users. About long-term
use, the widespread concerns about coxibs’ cardiovascular safety (5) would
have deserved specific evaluations and probably an ad hoc meta-analysis,
since related data should be generally available from study investigators.

The importance of scientific studies may be questioned not only in
terms of systematic errors, but also of the relevance of the end-points
they looked at. When a research is industry-sponsored (as in this case)
concerns are more legitimate and Authors should make strong effort to
convince readers that their evaluation is thorough and that relevant
results have been sought. For the above mentioned reasons, we feel that
the paper by Deeks et al falls short of reassuring readers. Industry
independent studies and meta-analyses should be warranted to evaluate
short-term safety of coxibs and trade-offs between gastointestinal and
cardiovascular safety of these drugs in the long term.

Giulio Formoso, Epidemiologist†
Nicola Magrini, Director†
Anna Maria Marata, Head of Drug Evaluation Unit†
and Alessandro Liberati, Professor of Clinical Biostatistics‡ and
Scientific Director†

† Center for the Evaluation of the Effectiveness of Health Care,
Modena (Italy)
‡ University of Modena and Reggio Emilia (Italy)

REFERENCES

1. Deeks JJ, Smith LA, Bradley MD. Efficacy, tolerability, and upper
gastrointestinal safety of celecoxib for treatment of osteoarthritis and
rheumatoid arthritis: systematic review of randomised controlled trials.
BMJ 2002;325:619-26

2. Juni P, Rutjes AW, Dieppe PA. Are selective COX 2 inhibitors
superior to traditional non steroidal anti-inflammatory drugs? BMJ
2002;324:1287-8

3. Witter J. Medical officer review, celecoxib. Food and Drug
Administration, September 2000 (available at
http://www.fda.gov/ohrms/dockets/ac/01/briefing/3677b1_03_med.pdf -
accessed October 29, 2002)

4.Traversa G, Bianchi C, Pisetsky F, et al. New Anti-Inflammatory
Agents in General Medicine. BEN 2000.N.6 (available at
http://www.ben.iss.it/pre_2002/giugno02/1eng.htm - accessed October 29,
2002)

5. Therapeutics Letter, Issue 41, Jan 2002 (available at
www.ti.ubc.ca/pages/letter43.htm - accessed October 29, 2002)

Competing interests:  
None declared

Phil Alderson, Associate Director of the UK Cochrane Centre,
immediately spotted a problem in our rapid response [1]. We stated in the
next to last paragraph that “the best available evidence to date (…)
shows, that in the long term celecoxib is no better than diclofenac in
avoiding severe gastrointestinal complications (RR for ulcer complications
1.10 [95% CI 0.47 to 2.58]).” Naturally, we agree with Phil Alderson that
the estimate accompanied by its wide confidence intervals do not provide
evidence that celecoxib is no more beneficial than diclofenac: “absence of
evidence is not evidence of absence” [2]. In fact, the relative risk’s
wide confidence intervals are compatible with celecoxib being either
considerably better or much worse than diclofenac. Therefore, we would
like to amend our statement to “there is no evidence suggesting that in
the long term celecoxib is more beneficial than diclofenac in avoiding
severe gastrointestinal complications.”

Peter Jüni MD, Senior Research Fellow in Clinical Epidemiology
Departments of Rheumatology, and Social and Preventive Medicine,
University of Berne, 3010 Berne, Switzerland (juni@ispm.unibe.ch)

Rebekka Sterchi, Research Associate
Departments of Rheumatology and Social and Preventive Medicine, University
of Berne, 3010 Berne, Switzerland

Paul Dieppe MD, Professor of Health Services Research
MRC Health Services Research Collaboration, Department of Social Medicine,
University of Bristol, Bristol BS8 2PR

Reference List

1. Jüni P, Sterchi R, Dieppe PA. Problems compromising the review's
validity. bmj.com 2002: http://bmj.com/cgi/eletters/325/7365/619#26567
(accessed 20 October 2002).

2. Altman DG, Bland JM. Absence of evidence is not evidence of
absence. BMJ 1995;311:485.

Competing interests:  
None declared

Dear Editor

The systematic review by Deeks et al [1] suggests that the COX-2
inhibitor celecoxib has significantly improved gastrointestinal safety and
tolerability as compared with traditional non-steroidal anti-inflammatory
drugs (NSAIDS). We have several concerns regarding this review.

First, Deeks et al reported the papers by Bensen et al [2], Zhao et
al (1999) [3], Simon et al [4] and Zhao et al (2000) [5] as if they
referred to four different trials. However, the papers by Bensen et al and
Zhao et al (1999) [2;3] were merely duplicate reports of one trial, while
the papers by Simon et al and Zhao et al (2000) [4;5] reported in
duplicate on another trial. Deeks et al either included the same data more
than once or mixed up data from unpublished trials with unrelated
published papers.

Second, Deeks et al erroneously report similar relative risks (RRs)
of ulcer complications after six months observed in the two trials
included in CLASS [6]: a RR of 0.54 (95% CI 0.20 to 1.47) for Study 035
comparing celecoxib to ibuprofen, and a RR of 0.56 (95% CI 0.19 to 1.66)
for Study 102 comparing celecoxib to diclofenac. Not surprisingly, Deeks
et al’s corresponding meta-analysis showed homogeneous effects across
trials (Q=0), implying that it is perfectly reasonable to pool CLASS’ two
trials using comparator drugs of different COX-2 selectivity. However,
according to the information available on the FDA website [7;8] four
events occurred in the celecoxib group and 11 in the ibuprofen group in
Study 035, leading to a RR of 0.36 (95% CI 0.12 to 1.14), whereas seven
events occurred in the celecoxib group and nine in the diclofenac group in
Study 102, leading to a RR of 0.78 (95% CI 0.29 to 2.08) [9]. The
heterogeneity of the corresponding meta-analysis (Q=1 on 1 degree of
freedom) reflects that pooling different trials using comparator drugs of
different COX-2 selectivity may be inappropriate.

Third, Deeks et al’s justification for only considering CLASS’ six
months results, adopted from earlier invalid arguments provided by
Silverstein et al [10] and Geis et al [11], is problematic [9;12].
Admittedly, data available on the FDA website [7] suggest that there were
differences regarding patient withdrawal between celecoxib and ibuprofen
in one of CLASS’ trials (Study 035) from the beginning, indicating that
results for this trial were unreliable at all time points, including 6
months. In accordance with Deeks et al’s arguments this trial should,
therefore, have been excluded from all analyses. Contrary to Deeks et al’s
statement, data available on the FDA website [7] suggest, however, that
there were no relevant differences between celecoxib and diclofenac groups
in CLASS’ second trial (Study 102), neither for 6 months nor for the
entire follow-up duration. Unfortunately, withdrawal rates were not
reported separately for the two trials, therefore we are unable to
calculate exact RRs for withdrawal at the different time points. It is
clear, however, that the differences in treatment duration between
celecoxib and diclofenac groups reported by Deeks et al [1] merely relate
to the fact that half of the patients on celecoxib (i.e. those allocated
to celecoxib in Study 035) had a potential maximum treatment duration of
15 months, while those allocated to diclofenac in Study 102 had a
potential maximum treatment duration of only 12 months [12].

In our experience, patients suffering from osteoarthritis or
rheumatoid arthritis generally take anti-inflammatory drugs for years.
Therefore, short term results of the sort reported by Deeks et al [1] are
misleading. The best available evidence to date [9;12] shows, that on
long term celecoxib is no better than diclofenac in avoiding severe
gastrointestinal complications (RR for ulcer complications 1.10 [95% CI
0.47 to 2.58]). However, celecoxib may be about 20 times more expensive
than diclofenac.

These problems cast serious doubts on the validity of Deeks et al’s
systematic review [1]. We therefore suggest that celecoxib’s manufacturer
(Pharmacia/Pfizer) allows an industry-independent meta-analysis of all
published and unpublished randomised controlled trials by providing
unrestricted access to all available data to a team of independent
researchers.

Conflicts of interest: none

Peter Jüni MD, Senior Research Fellow in Clinical Epidemiology
Departments of Rheumatology, and Social and Preventive Medicine,
University of Berne, 3010 Berne, Switzerland (juni@ispm.unibe.ch)

Rebekka Sterchi, Research Associate
Departments of Rheumatology, and Social and Preventive Medicine,
University of Berne, 3010 Berne, Switzerland

Paul Dieppe MD, Professor of Health Services Research
MRC Health Services Research Collaboration, Department of Social Medicine,
University of Bristol, Bristol BS8 2PR

Reference List

1. Deeks JJ, Smith LA, Bradley MD. Efficacy, tolerability, and upper
gastrointestinal safety of celecoxib for treatment of osteoarthritis and
rheumatoid arthritis: systematic review of randomised controlled trials.
BMJ 2002; 325(7365):619-623.

2. Bensen WG, Fiechtner JJ, McMillen JI, Zhao WW, Yu SS, Woods EM, Hubbard
RC, Isakson PC, Verburg KM, Geis GS. Treatment of osteoarthritis with
celecoxib, a cyclooxygenase2 inhibitor: a randomized controlled trial.
Mayo Clin Proc 1999; 74:1095-1105.

3. Zhao SZ, McMillen JI, Markenson JA, Dedhiya SD, Zhao WW, Osterhaus JT,
Yu SS. Evaluation of the functional status aspects of health-related
quality of life of patients with osteoarthritis treated with celecoxib.
Pharmacotherapy 1999; 19(11):1269-1278.

4. Simon LS, Weaver AL, Graham DY, Kivitz AJ, Lipsky PE, Hubbard RC,
Isakson PC, Verburg KM, Yu SS, Zhao WW, Geis GS. Anti-inflammatory and
upper gastrointestinal effects of celecoxib in rheumatoid arthritis: a
randomized controlled trial. JAMA 1999; 282(20):1921-1928.

5. Zhao SZ, Fiechtner JJ, Tindall EA, Dedhiya SD, Zhao WW, Osterhaus JT,
Yu SS. Evaluation of health-related quality of life of rheumatoid
arthritis patients treated with celecoxib. Arthritis Care Res 2000; 13:112
-121.

6. Silverstein FE, Faich G, Goldstein JL, Simon LS, Pincus T, Whelton A,
Makuch R, Eisen G, Agrawal NM, Stenson WF, Burr AM, Zhao WW, Kent JD,
Lefkowith JB, Verburg KM, Geis GS. 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(10):1247-1255.

7. Lu HL. Statistical reviewer briefing document for the advisory
committee. Available at:
http://www.fda.gov/ohrms/dockets/ac/01/briefing/3677b1_04_stats.doc.
[Accessed December 10, 2001.]

8. Witter J. Medical officer review. Available at:
http://www.fda.gov/ohrms/dockets/ac/01/briefing/3677b1_03_med.pdf.
[Accessed December 10, 2001.]

9. Jüni P, Rutjes AW, Dieppe P. Are selective COX 2 inhibitors superior to
traditional NSAIDs? Authors' reply. BMJ 2002; 325:163-164.

10. Silverstein F, Simon L, Faich G. Reporting of 6-month vs 12-month data
in a clinical trial of celecoxib. In reply. JAMA 2001; 286:2399-2400.

11. Geis GS. Are selective COX 2 inhibitors superior to traditional
NSAIDs? Pharmacia's response to editorial. BMJ 2002; 325:161-162.

12. Jüni P, Rutjes AW, Dieppe PA. Gastrointestinal ulcer complications:
Are selective COX-2 inhibitors superior to traditional NSAIDs? Adequate
analysis of the CLASS trial indicates that this may not be the case. BMJ
2002; 324:1287-1288.