Rapid Responses to:
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Rapid Responses: Rapid Responses published:
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misleading ?
- Alessandro Calderan (23 September 2002)
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Missing the point?
- Jeremy J Black (24 September 2002)
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New Cox 2 data
- David J Walker (26 September 2002)
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"Bad planning?"
- Ebbe Englev (30 September 2002)
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Celecoxib safer? Still not proven!
- Arnold G Zermansky (4 October 2002)
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On presentation and analysis
- Michael L. Jenkinson (7 October 2002)
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Assessing the risk of GI complications with NSAIDs is still problematic
- Neal Maskrey, Ruth Micklewright, Jonathan L. Underhill (9 October 2002)
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Review is more favorable than data
- Christoph Pechlaner (13 October 2002)
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Re: On presentation and analysis
- Jonathan J Deeks, Jonathan J Deeks (15 October 2002)
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Celebrex’s relative GI safety is overstated?
- Scott Metcalfe, Sean Dougherty, Wayne McNee (16 October 2002)
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A Missed Opportunity
- James M Wright (22 October 2002)
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Problems compromising the review's validity
- Peter Jüni, Rebekka Sterchi, Paul. A. Dieppe (29 October 2002)
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On presentation and analysis
- Michael L Jenkinson, Jonathan J Deeks (30 October 2002)
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Absence of evidence versus evidence of absence
- Peter Jüni, Rebekka Sterchi, Paul Dieppe (31 October 2002)
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Accolade
- Robert I. Rudolph, M.D., FACP (1 November 2002)
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Coxibs gastrointestinal safety: worth spending time on 3 months data?
- Giulio Formoso, Nicola Magrini, Anna Maria Marata, and Alessandro Liberati (9 November 2002)
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Study reports: clarification, correction and additional sources
- Jonathan J Deeks (13 November 2002)
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On eradicating publication bias, and the realities of independent reviews
- Jonathan J Deeks (15 November 2002)
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Re: On presentation and analysis
- Michael L Jenkinson (18 December 2002)
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Alessandro Calderan, General Practitioner San Donà CAP 30027-Venice - Italy
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good morning this review is very interesting but gives few light to the COX-2 cause. As authors say "there was no significant difference between celecoxib and NSAIDs in the incidence of withdrawals for all adverse events". In the discussion is stated that "rates of withdrawals due to gastrointestinal adverse events, dyspepsia and abdominal pain were 40-60% lower ..." but as well, we could say that: " rates of withdrawal due NOT to gastrointestinal adverse events, dyspepsia and abdominal pain were 40- 60% HIGHER in the celecoxib group ..." Although authors say that "This review was limited to assessing only upper gastrintestinal safety", I found misleading that in the last table "What this study adds" the fact that celecoxib has more NOT gastrointestinal adverse events than NSAIDs is left unstated. Competing interests: NONE |
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Jeremy J Black, GP Llandaff North, Cardiff CF14 2FD
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Systematic reviews are only as good as the trials included. The message "Celecoxib ... has significantly improved gastrointestinal safety and tolerability" (Abstract conclusion) carefully avoids stating the key issue regarding celecoxib - namely its safety in the longer term. The Authors reviewed nine trials to reach their conclusion, but only one was longer than 26 weeks (CLASS) and in this trial they chose to take the six month data, as opposed to the 12 month data (not published in the trial but available on the FDA website). Given that the six month data strongly (though not significantly) favoured celecoxib, and the 12 month data showed a (non-significant) much lower reduction in risk, one has to ask for a far stronger justification for this decision than that given in the review. This review may tell us a lot about the relative benefits of celecoxib in short term use, but it casts no new light on the question of longer term safety compared to "standard treatment" of (NSAID + PPI). It is this question which needs addressing before we can assume it is safer to use in patients whose requirement is measured in years not weeks. |
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David J Walker, Consultant Rheumatologist Freeman Hospital NE7 7DN
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Dear Sir, I was pleased to see the three recent articles in the BMJ. The meta- analysis (1) really confirms what those of us who have followed the story thought anyway. i.e. that these drugs are a breakthrough as far as GI side effects are concerned. I was interested that it also tended to dismiss the negative effect of aspirin seen in the CLASS study (2) for which I had not heard a plausible explanation. The Canadian study on GI haemorrhage events (3) was also interesting and confirms the concept that these drugs are safer. Whether there are genuine differences between the two coxibs or not will become apparent with time. The editorial (4) in line with previous editorials treads the usual sceptical line which I suppose is scientific rigour. Offering to save a thousand lives a year, and not short termly should be greeted with more enthusiasm. With regard to the other side effects I predict that coxibs will be found to be no more toxic than conventional NSAIDs with the possible exception of a dose related cardiovascular effect of rofecoxib. Yours sincerely, Competing interests: I have sat on advisory boards for three different coxibs. I have many patients who cannot tolerate conventional NSAIDs. 1] Efficacy, tolerability, and upper gastrointestinal safety of celecoxib for treatment of osteoarthritis and rheumatoid arthritis: systematic review of randomised controlled trials. Jonathan J Deeks, Lesley A Smith, and Matthew D Bradley BMJ 2002; 325: 619. 2] 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 3] Observational study of upper gastrointestinal haemorrhage in elderly patients given selective cyclo-oxygenase-2 inhibitors or conventional non- steroidal anti-inflammatory drugs. Muhammad Mamdani, Paula A Rochon, David N Juurlink, Alex Kopp, Geoffrey M Anderson, Gary Naglie, Peter C Austin, and Andreas Laupacis.BMJ 2002; 325: 624. 4] Efficacy and safety of COX 2 inhibitors. Roger Jones. BMJ 2002; 325: 607- 608. |
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Ebbe Englev, medical director Pharmacia AS, Overgaden Neden Vandet 7, DK-1414 Copenhagen, Denmark
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Dear Sir's. Maybe it's just a thought. Last week a systematic review article focusing on efficacy, tolerability and upper gastrointestinal safety of celecoxib was published by Deeks et al. (1). In the 1 June 2002 edtion of BMJ an editorial on selective COX-2 inhibitors by Jüni et al. (2) appeared and created massive debate. Interestingly, the Deeks article was accepted for publication two months (27 March 2002) before the Jüni editorial was published. If Deeks had been published alongside the Jüni editorial, and thus providneg a more balanced view, the debate that followed might have created more clarity. Sincerely yours, Dr. Ebbe Englev, MFPM
1: Deeks JJ et al. 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: Jüni P et al. Are selective COX 2 inhibitors superior to traditional non steroidal anti-inflammatory drugs? BMJ 2002;324:1287-1288. Competing interests: Ebbe Englev is employed at Pharmacia, the manufacturer of celecoxib. |
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Arnold G Zermansky, general practitioner; visiting senior research fellow Dib Lane Practice, 112A Dib Lane, Leeds LS8 3AY
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Deeks et al (BMJ 325: 619-623) distill evidence from 17 clinical trials to show the relative safety of celecoxib compared with "other NSAIDS". This presupposes that all NSAIDs are equal in their capacity to cause gastrointestinal harm, whilst there is good evidence (1)that they are far from equal. Of the three NSAIDs included in the trials analysed, naproxen is more than twice as harmful as ibuprofen, and diclofenac is 1.8 times as harmful. Even ibuprofen itself may be more harmful at the huge dose (2400mg daily) use by Silverstein et al (2) and this may explain why the results of Silbertein's study are at variance with those of Henry et al. in the relative harm of diclofenac and ibuprofen. The reality is that the differences between orthodox NSAIDs in their gastroinestinal safety profile are greater than the small difference between celecoxib and an assorted basket of them. Celecoxib safer? Still not proven! 1. D Henry, L Lim, L Garcia Rodriguez et al. Variability in risk of gastrointestinal complications with individual non-steroidal anti- inflammatory drugs: results of a collaborative meta-analysis. British Medical Journal 1996 312: 1563-6. 2. Silverstein FE, Faich G, Goldstein Jl, Simon LS, Pincus T, Whelton A, et al. Gastrointestinal toxicity with celecoxib vs nonsteroidal andti- inflammatory drugs for osteoartritis and rheumatoid arthritis: the CLASS study; A randomised controlled trial. Celecoxib long-term safety study. JAMA 2000; 284: 1247-55. No financial interests |
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Michael L. Jenkinson, Consultant Physician, Chair East Kent Hospitals Trust Drugs & Therapeutics Committee Queen Elizabeth Queen Mother Hospital, St Peter’s Road, Margate, Kent CT9 4AN
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Dear Sir, In their examination of the upper gastrointestinal safety of celecoxib Deeks et al [1] are to be congratulated in providing information new to the public domain but have left this reader dissatisfied with their presentation and analysis. The authors claim to be reporting on celecoxib at licensed therapeutic doses. This is incorrect in the UK. Celecoxib at a dose of 400mg bd contributed up to 535 patients to the data. Is it safe to assume that a higher dose of a drug is likely to cause more of a particular side effect? Certainly not. While adverse effects are usually dose related, the complex nature of receptor blockade or stimulation can lead to paradox. Also we now know with rofecoxib that the adverse cardiovascular side effects associated with this drug are strongly dose related [2]. You cannot have an endoscopically demonstrated ulcer if you have died of a myocardial infarction first. The inclusion of doses of celecoxib beyond the licensed range may explain the lack of overall adverse events benefit relative to other NSAIDs as shown in figure 1. What are the adverse effects that balance in incidence the higher gastrointestinal safety of celecoxib? Some may wonder why the authors did not feel it worthwhile to conclude that their presented data showed that celecoxib is not overall safer than other NSAIDs. Can the author’s assure us that re-analysis of the trial data, using data only at the licensed UK doses of celecoxib does not change the stated risk ratios significantly? I note in Fig 1 a minor error, possibly typographical, in the addition in the number of patients on celecoxib included in the meta- analysis from Simon et als 1999 paper. This is relevant in the context of the more serious errors that occurred in Fig 3 as it means all easily verifiable data presented to justify the papers main conclusions has inaccuracies. Fig 3 addresses the impact of co-administered aspirin with an NSAID. The displayed risk ratio and 95% CI are inconsistent with the numeric data reported on Study 062(N). Further the stated data would not result in the subgroup relative risks reported in the figure and reduce their significance. Either the denominators are wrong or Simon et al’s data has been missed out. This is important as this data as presented, could be used for promotional purposes to recommend that patients on aspirin and a NSAID should have their NSAID changed to celecoxib. It is a shame that no attempt is made to compare the relative risk of aspirin co-administered with placebo vs aspirin co-administered with celecoxib. Can the authors confirm if any such data was available as this would help context? The authors conclusion that NICE is wrong with its recommendation that coxibs should be withheld from aspirin users is not only overstating their own presented evidence base, but seems to based on mistakes in the presentation of that evidence base. Either NICE or the authors may be right, but I will continue to put overall patient safety first when an issue is unknown. References 1. Deeks JJ, Smith LA, Bradley MD. Efficacy, tolerability, and upper gastrointestinal safety of celcoxib for treatment of osteoarthritis and rheumatoid arthritis:systematic review of randomised controlled trials. BMJ 2002:325:619-23 2. Ray WA, Stein CM, Daugherty JR, Hall K, Arbogast PG, Griffen MR. COX-2 selective non-steroidal anti-inflammatory drugs and risk of serious coronary heart disease. Lancet 2002; 360:1071-73 Yours sincerely, Dr M. L. Jenkinson FRCP
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Neal Maskrey, Medical Director National Prescribing Centre, The Infirmary, 70 Pembroke Place, Liverpool. L69 3GF, Ruth Micklewright, Jonathan L. Underhill
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The recent systematic
review by Deeks et al[1]
was conducted to determine whether celecoxib was as effective as other NSAIDs
and if it had any benefits in terms of safety. Unfortunately, only one of the
included studies used the clinically relevant safety outcome of ulcer
complications (the CLASS study[2]),
while the other five used endoscopically detected lesions. In addition, the
systematic review only included the six-month data from the CLASS study. The
appropriateness of using this interim data, when longer-term a priori data were
already published on the FDA website, has already been the subject of
unprecedented international debate.[3]
In the same issue of
the BMJ, Mamdani et al[4]
conducted an observational study purporting to show that COX-2 selective NSAIDs
were associated with fewer GI ulcers and bleeds than standard NSAIDs. The
potential for bias within observational studies has been well documented and
large, robust RCTs, and systematic reviews of RCTs, are more reliable in
informing the evidence base. Therefore, neither of
these papers helps resolve the current difficulties in selecting which patients
stand to benefit most from taking these COX-2 selective NSAIDs agents. To try and address
this issue, we have compared the absolute risk of symptomatic ulcers and
complications from the three largest RCTs of interventions to reduce GI
toxicity with NSAIDs, namely those involving celecoxib,2 rofecoxib,[5]
and misoprostol plus standard NSAIDs[6]
(see table). Table. Rates of symptomatic ulcers plus complications in large RCTs of interventions to reduce GI toxicity with NSAIDs
The event rates for
just ulcer complications in these studies were lower still, and produce NNTs
approximately two- to five-fold higher. In the wider context, concerns remain
about increased cardiovascular risk with rofecoxib, particularly at higher
doses. As expected, the
table demonstrates that the absolute benefits of these regimens are related to
the baseline risk of the individuals included in the trial. A feasibility study
to examine the potential for the development of a risk calculator, similar to
those available for cardiovascular disease, based on individual patient data
from these three trials would be useful. Although this approach may have
inherent problems because of the low event rates, the availability of such a
tool would improve the targeting of these agents to those who would derive most
benefit. Neal Maskrey Medical Director Ruth Micklewright Associate Editor, MeReC Publications Jonathan L Underhill Manager, Training the Trainers Programme National Prescribing Centre The Infirmary 70 Pembroke Place Liverpool L69 3GF 355 words excluding table. [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;325:619-626. [2] Silverstein FE, Faich G, Goldstein JL, et al. Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis. The CLASS study: a randomized controlled trial. JAMA 2000;284:1247-55. [3] Juni P, Rutjes AWS, Dieppe PA. Are selective COX 2 inhibitors superior to traditional non steroidal anti-inflammatory drugs? Adequate analysis of the CLASS trial indicates that this may not be the case. BMJ 2002;324:1287-8. [4] Mamdani M, Rochon PA, Juurlink DN, et al. Observational study of upper gastrointestinal haemorrhage in elderly patients given selective cyclo-oxygenase-2 inhibitors or conventional non-steroidal anti-inflammatory drugs. BMJ 2002;325:624-9. [5] Bombardier C, Laine L, Reicin A, et al. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. N Engl J Med 2000;343:1520-8. [6] Silverstein FE, Graham DY, Senior JR, et al. Misoprostol reduces gastrointestinal complications in patients with rheumatoid arthritis receiving nonsteroidal anti-inflammatory drugs. A randomised, double-blind, placebo-controlled trial. Ann Intern Med 1995;123:241-9. |
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Christoph Pechlaner, Associate Professor of Medicine University Hospital, A-6020 Innsbruck
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Deeks et al.'s review 1 of celecoxib vs NSAIDs only presents relative risk reductions of adverse events, most in the range of 40 to 70 %. This contrasts with a sobering 0.7 % absolute risk reduction of eg. ulcer complications (0.76 vs 1.45 %, celecoxib vs. comparator drug in the CLASS study 2). Even more important, Deeks et al.'s review is based on disputed data. About half of the 15 187 patients were from the CLASS study 2. Study's design, outcome measures and analysis have been changed post hoc 3. These changes have been disclosed to the FDA, but not in the original publication. The changes yielded a more favorable profile of celecoxib 3. Flawed data yield flawed conclusions. No computational or analytical efforts can remedy that. 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. 2) 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: 1247-55. 3) Juni P, Rutjes AW, Dieppe PA. Are selective COX 2 inhibitors superior to traditional non steroidal anti-inflammatory drugs? BMJ 2002; 324: 1287- 8 |
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Jonathan J Deeks, Senior Medical Statistician Centre for Statistics in Medicine, Institute of Health Sciences, Old Road, Headington, Oxford OX3 7L, Jonathan J Deeks
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Dr Jenkinson raises concerns that there are errors in the figures in the paper. However, he does not substantiate his claim by specifying exactly the errors that have been made. We have double checked the data and analyses and can find no problems. We contacted him on 11th October asking him to specify the errors exactly, which he has not yet done. When we have received his reply we will undertake further checking and submit an update. |
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Scott Metcalfe, Public Health Physician Pharmaceutical Management Agency (PHARMAC), Wellington 6001, NEW ZEALAND, Sean Dougherty, Wayne McNee
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Celebrex’s relative GI safety is overstated? The editorial by Roger Jones[1] makes important points about the limitations of the meta-analysis by Jon Deeks and colleagues[2] for celecoxib. However, we also note that the Deeks meta-analysis does not account for the 12-15-month data for the CLASS study compiled by the FDA[3] [4] and cited by Peter Juni and colleagues’ critical editorial.[5] We have abstracted the 12-15 month CLASS data and applied them to the Deeks analysis, and find that these give a different picture. Firstly, the FDA’s analysis of CLASS is more complete than that published in JAMA[6], which the Juni editorial criticised for not accounting for the 12-15 month data. We believe Deeks and colleagues offer an unconvincing explanation for limiting the analysis to the six- month follow up for CLASS, insufficient to justify the post hoc changes in design, outcomes and analysis. We also believe the 12-15 month CLASS data could have been included in figure 2 of the Deeks paper for adverse GI effects, materially affecting those results. For withdrawals because of both serious upper GI events and endoscopic ulcers, the 12-15 month FDA data for CLASS showed no significant reduction in risk (relative risk (RR) 0.73 (95% CI 0.50 to 1.05)), distinct from the 39% RRR for CLASS’s 6-month data in Deeks figure 4. Combining the 12-month CLASS GI withdrawal data with the seven RCTs in Deeks fig 2, and then adjusting for the longer exposure experienced in CLASS (12-15 months, not 12 weeks) decreased the overall relative risk reduction (RRR) to 32% - somewhat less than that reported in Deeks fig 2. These results suggest that although celecoxib still caused statistically significant reductions in GI adverse events overall, these reductions were appreciably less than those suggested for the seven other RCTs by Deeks fig 2. Secondly, Deeks et al reported no statistically significant difference between low-dose aspirin and non-aspirin use for both endoscopic ulcers and for CLASS. However, using the 12-15-month data for CLASS suggests that whereas non-aspirin users had a statistically significant 42% RRR, aspirin users showed no reduction in risk (RR 1.02 (0.59 - 1.74)). The difference between the subgroups’ RRRs over the 12 months was statistically significant (p 0.03). Taken in entirety (combining both endoscopic ulcers with CLASS’s GI withdrawals+ulcers)[7], the above significant differences between subgroups persist. Including the 12-15-month CLASS data gave a non-significant 28% RRR for aspirin use, compared with a 72% RRR for non-aspirin use, the difference between RRRs being statistically significant. Extending the analysis to adjust for the greater exposure conferred by CLASS gave again a non-significant 4% RRR for aspirin users (exposure/variance-weighted RR 0.96 (0.63 - 1.46), versus 52% for non-aspirin use, p <0.01. Hence we disagree with the implication that the benefits of celecoxib extend equally to aspirin users, and agree with NICE’s current precautionary recommendation to withhold celecoxib from aspirin users. Further details of this analysis can be found on PHARMAC’s website at www.pharmac.govt.nz publications page. In summary, any results presented for celecoxib suggesting favourable GI safety need careful scrutiny. References/Endnotes [1] Jones R. Efficacy
and safety of COX 2 inhibitors. BMJ 2002;325:607-608. http://bmj.com/cgi/content/full/325/7365/607 [2] 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: 619-623 http://bmj.com/cgi/content/full/325/7365/619 [3]Witter J. Medical
officer review. www.fda.gov/ohrms/dockets/ac/01/briefing/3677b1_03_med.pdf [4] Lu HL.
Statistical reviewer briefing document for the advisory committee. www.fda.gov/ohrms/dockets/ac/01/briefing/3677b1_04_stats.doc [5] Juni P, Rutjes
AWS, Dieppe PA. Are selective COX-2 inhibitors superior to traditional
non-steroidal anti-inflammatory drugs? BMJ 2002; 324: 1287-1288. http://bmj.com/cgi/content/full/324/7349/1287 [6] 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 randomised
controlled trial. JAMA 2000; 284: 1247-1255. [7] Numbers of CLASS
withdrawals were comparatively low when compared with more sensitive GDUs found
on 12-week mandatory endoscopy in the four other RCTs. Numbers of ulcers
detected by routine endoscopy at 12 weeks reported in Deeks et al figure 5 (25%
control incidence) were considerably higher than numbers of withdrawals because
of adverse GI effects for corresponding RCTs reported in Deeks figure 2 (6%)
and in CLASS (1.6%). Hence combining the two sets of data understates ulcer
burden occurring in CLASS. |
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James M Wright, Professor University of British Columbia Vancouver, BC. Canada V6T 1Z3
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Deeks et al.[1] focused their systematic review on the gastrointestinal adverse effects of celecoxib and other non-steroidal anti -inflammatory drugs (NSAIDs), and thereby missed the opportunity to inform physicians and patients about the overall safety of celecoxib. It should be increasingly apparent that all NSAIDs particularly when taken long-term cause serious adverse events and that these events are clearly not limited to the gastrointestinal system. NSAIDs increase blood pressure, cause renal failure precipitate congestive heart failure, accelerate joint degradation, prevent fracture healing, etc. [2]. The critically important observation for patients from the CLASS and VIGOR trial data is that total serious adverse events were increased for both celecoxib and rofecoxib [2,3]. The fact that this increase was statistically significant for rofecoxib and not quite statistically significant for celecoxib should not dissuade anybody from concluding that when a patient is switched from a non-selective NSAID to a COX-2 selective NSAID, they are probably at increased risk of experiencing a serious adverse event. In other words COX-2 selective NSAIDs likely cause more harm than benefit as compared to non-selective NSAIDs. Deeks and his two co-authors, one from celecoxib’s manufacturer, certainly have access to the serious adverse event data from all the trials that they reviewed. It is an international regulatory requirement that all serious adverse events are collected and reported in clinical trials. Serious adverse events include all deaths, unscheduled hospitalizations, prolongations of hospitalization, other life-threatening events (eg. cancer diagnosis) or events leading to serious disability. Before prescribing a COX-2 selective NSAID to my patients, I want to know that the risk of total serious adverse events are decreased as compared to non-selective NSAIDs. If, in fact, the selective NSAIDs increase the risk (as appears to be the case), or even if they decrease the risk of gastrointestinal serious adverse events and this is cancelled by an equal increase in nongastrointestinal serious adverse events, I would not prescribe them. I call upon Deeks et al to provide the serious adverse event data from all the trials in their systematic review. The fact that they haven’t provided it, certainly makes me suspicious that the data do not look good for celecoxib. Competing interests: None declared. References: 1. Deeks JJ, Smith LA, Bradley MD. Efficacy, tolerability, and upper gastrointestinal safety of celecoxib for treatment of osteoarthritis and rheumatoid arthritis: a systematic review of randomized controlled trials. BMJ. 2002;325:619-623. 2. Wright JM. The double-edged sword of COX-2 selective NSAIDs. Can Med Assoc J. 2002;167 (in press). 3. Bassett K, Wright JM, Puil L, Perry TL Jr,, Heran B, Cole Carol,. Cyclooxygenase-2 inhibitor update: Journal articles fail to tell the full story. Can Fam Physician. 2002;48:1455-1460. |
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Peter Jüni, Departments of Rheumatology and Social and Preventive Medicine, University of Berne 3010 Berne, Switzerland, Rebekka Sterchi, Paul. A. Dieppe
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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. |
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Michael L Jenkinson, Chair East Kent Hospitals Trust Drugs & Therapeutics Committee Queen Elizabeth, The Queen Mother Hospital, Margate, Jonathan J Deeks
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We have had an interesting and mutually informative exchange on some of the issues raised by the recent paper one of us co-authored [1] and the other responded to [2], and are reporting that we have reached agreement on all substantive issues. Despite initial concern [2], the statistical calculations are correct. The summary statistics are consistent when analysed by alternative approaches and we both regard them as robust. The tabular presentation issues are minor and arise from, for example, justified exclusion of patients in the original trial analyses who were randomised but never received a single drug dose. We also agree on a suggestion to improve graphical display. In forest plots that display results of multiple analyses, for example, in the presentation of relative reductions in endoscopically detectable ulcers in prophylactic aspirin and non-aspirin users (Figure 3 in the printed paper, Figure 5 in the full paper) it is preferable to scale the size of the points across analyses in a standard way so that they reflect absolute weights given to each study, rather than the relative weights within each analysis. If this had been done in Figure 3/5, it would have been more notable at first glance that the number of patients exposed to prophylactic aspirin in the trials is low. It is not that any data in this figure are wrong, but that the figure may at first give a misleading impression that the data are equally distributed between aspirin and non- aspirin groups. This impression is corrected when one considers the width of the confidence intervals and sample sizes also stated in the figure. We also note that it is necessary to make assumptions when performing meta-analysis, as with most statistical analyses. Importantly, when there is variation in event rates between trials (as with the data in Figure 3/5) one must assume that the treatment effect can be expressed by a particular summary statistic which is consistent at all event rates.[3] Alternative choices of statistic do not change the direction or significance of effects for individual trials, but may lead to differences in treatment effects, observed heterogeneity and confidence intervals for the aggregated data. Reductions in rates of endoscopically detectable ulcers in participants not taking prophylactic aspirin (Figure 3/5) are heterogeneous regardless of how the data are analysed, although all 5 trials yield estimates in the direction of benefit. In such situations it is desirable to know why the trials give different estimates.[4] However, with only five data points a multitude of hypotheses can be generated that fit the data, but there is no objective way of ascertaining which is the real cause. Further studies and analysis of individual patient data may help. The use of "random effects" models for analyses displaying heterogeneity, as used in the review, ensures that the heterogeneity is quantified and some allowance made for it.[5] While the random effects model makes assumptions which are contentious and difficult to assess, in the review it has resulted in estimates of effect that are more conservative (less likely to be significant) that those obtained by using the alternative "fixed effect" model. In conclusion, we both agree that more data on the occurrence of gastrointestinal events in patients combining aspirin with a Cox-2 inhibitor is required to inform the debate as there are difficulties in knowing the importance of the observed differences in outcomes that are only surrogate measures of safety. Michael L Jenkinson Chair East Kent Hospitals Trust Drugs & Therapeutics Committee
Jonathan J Deeks Senior Medical Statistician
[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: 619-23. [2] Jenkinson ML. On presentation and analysis. BMJ Rapid Response: 7th October 2002. http://bmj.com/cgi/eletters/325/7365/619#26091 [3] Deeks JJ. Issues in the selection of a summary statistic in meta -analysis of clinical trials with binary outcomes. Statistics in Medicine 2002; 21(11): 1575-1600. [4] Thompson SG. Why sources of heterogeneity in meta-analysis should be investigated. BMJ 1994; 309: 1351-5. [5] Thompson SG, Pocock SJ. Can meta-analysis be trusted? Lancet 1991; 338:1127-30. Competing interests: None declared |
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Peter Jüni, Departments of Rheumatology, and Social and Preventive Medicine, University of Berne 3010 Berne, Switzerland, Rebekka Sterchi, Paul Dieppe
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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 |
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Robert I. Rudolph, M.D., FACP, Clinical Professor of Dermatology, University of Pennsylvania, Phila. PA 1134 Penn Avenue, Wyomissing, PA 19610 USA
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Dr. Juni's title "Absence of evidence versus evidence of absence" of Oct 31 deserves to be gilded, mounted, and displayed somewhere. It's genuinely and simply gorgeous! Competing interests: None declared |
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Giulio Formoso, Epidemiologist Center for the Evaluation of the Effectiveness of Health Care - 41100 Modena (Italy), Nicola Magrini, Anna Maria Marata, and Alessandro Liberati
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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 |
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Jonathan J Deeks, Senior Medical Statistician Centre for Statistics in Medicine, Institute of Health Sciences, Old Road, Headington, Oxford, OX3 7
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Study reports: clarification, corrections, and additional sources
Clarification of data sources The systematic review was prepared from the full company trial reports, as was stated in the paper. As the full company trial reports are not publicly available, we attempted to match them up with journal publications so that interested readers of the review could follow links to the best publicly available trial evidence. Pfizer/Pharmacia have since suggested directly to us that this may have been misleading, and that it would have been more accurate to cite the company trial reports throughout as these were used for the review and not the journal publications cited in the references. Notably, the criticisms made about CLASS study in the main relate to selective reporting in the journal publication and not problems in the trial itself (Black, Pechlaner, Metcalfe, Jüni, Formoso). It is always important to separate issues of trial quality from those of inadequate reporting. As we stated, our review was prepared from the data presented in the full company trial report, and not the JAMA publication. The criticisms relating to the company’s selective reporting in this publication do not affect our review – all data were available to us. We will respond in detail regarding our presentation of CLASS as the issues deserve detailed discussion and presentation of further data. However, we note that the CLASS trial is only included in 2 of the 17 outcomes summarised in the review. In our opinion Black, Pechlaner and Jüni are not justified in questioning the validity of the whole review based on problems they perceive with this single trial. Corrections of references During the matching process we made two minor errors, as pointed out by Jüni and also by Pfizer/Pharmacia, when matching publications with trials [2][4]. While Jüni is correct in suggesting that we have confused duplicate publications of two trials[1-4], all of our analyses are unaffected as we only have made errors with the names of publications attached to trials and not the data from the trials themselves. Each of the trials we included are distinct, and were originally identified by their FDA registered protocol numbers and not their journal publications. Further published and unpublished sources When checking these errors, we also came across new publications for two of the trials noted in the review as being unpublished [6][7]. We have also searched the FDA website, it having been brought to our attention by the BMJ editorial by Jüni, Rutjes and Dieppe. Here we have located the original licensing submission, medical, statistical and safety assessments for Celebrex which contain data from trials 20, 21, 22, 23, 41, 54, 62 and 71, as well as data on trials with shorter follow-up and for acute pain [9]. We have also found additional publicly available information about the CLASS trial, not previously cited by Jüni [10]. We would encourage those correspondents (Jenkinson, Wright, Formoso) who wanted more data than we were able to provide in our review to consult these sources. The table and reference list below should provide clarification as to the company trial numbers, names and references for the trials included in the review, and website addresses where the FDA assessments of these trials can be found.
Jonathan J Deeks Senior Medical Statistician Centre for Statistics in Medicine Institute of Health Sciences Old Road, Headington Oxford
Competing interests: see published paper |
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Jonathan J Deeks, Senior Medical Statistician Centre for Statistics in Medicine, Insitute of Health Sciences, Old Road, Headington, Oxford, OX3 7L
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On eradicating publication bias, and the realities of independent reviews Systematic reviews of drugs are plagued by publication bias. Many industry trials remain unpublished years after they are completed. Most reviewers cannot gain access to these trials, or even find out that they exist. Unless co-operation and trust between industry and systematic reviewers can be developed, full results of all trials will never become available, and reviews will be biased. We undertook this review with the requirement that the companies involved provided reports of all randomised trials that might be of relevance, and we insisted that this be backed up by a signed legal pledge. As at the point of analysis (25th May 2000) celecoxib had not been made available for evaluation outside of the company, we can reasonably claim that we included all relevant randomised evidence. We believe that this does set a new standard for reviews of pharmaceutical products, and would suggest that others involved in industry-related reviews follow our lead and take a similar approach of obtaining a "complete data pledge" to entirely eradicate the possibility of publication bias. As a result of this agreement, we obtained copies of three currently unpublished trials that recruited 3,158 participants. This constitutes 44% of the data available for the 12-week outcomes. Results of these trials are now published in the medical literature for the first time in our review. (In fact 63% of the 12-week data were unpublished when we submitted our review to the BMJ, as two additional trials were still in press). The magnitude of this political achievement in the current climate, its importance in reducing the potential for bias, and the benefits of providing access to previously unpublished trial information are issues that our correspondents appear to have overlooked. We are saddened that no one has considered it appropriate to applaud industry for taking such a large step towards increasing access to full trial information. While we as academics would like to demand that industry surrender all data and reports without condition (Jüni), in reality the process of obtaining industry data is best approached in terms of co-operation rather than hostility. In response to our request to provide all trial reports, the companies involved very reasonably insisted that they were able to check our data extraction to ensure that we were not erroneously reporting their published and unpublished trials. Hence one co-author on our review (MB) is an employee of the company, and as declared in the paper, performed duplicate data extraction and checking. The work he undertook in double checking all trial data as well as persuading the company to make all full trial reports available and sign up to the complete data pledge cannot have done anything other than increase the validity of our review. Not all industry involvement is bad, nor does it necessarily compromise independence. Correspondents have suggested that our review is flawed (Pechlaner), has serious validity problems (Jüni), does not add relevant knowledge (Formosa), and some insinuate that our review is biased through our contract with industry. We are criticised for not convincing readers that our review is thorough and that relevant results have been sought (Formosa). These comments all appear to have overlooked the significance of our achievement in obtaining a legally binding guarantee from industry that our review includes all relevant trials, and therefore can claim to be totally free from publication bias. This is a claim that only a handful of systematic reviews will ever be able to make, and is a clear marker of the level of rigour and efforts to avoid bias that we maintained when completing this review.
Jonathan J Deeks Centre for Statistics in Medicine Institute of Health Sciences Old Road, Headington Oxford OX3 7LF Competing interests: see paper |
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Michael L Jenkinson, Chair East Kent Hospitals Trust Drugs & Therapeutics Committee Queen Elizabeth, The Queen Mother Hospital
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On presentation and analysis In my original rapid response to the paper by Deeks et al [1] I commented that " This is important as this data as presented, could be used for promotional purposes to recommend that patients on aspirin and a NSAID should have their NSAID changed to celecoxib" [2]. There has been a subsequent joint letter by Deeks and myself agreeing that the graphical presentation of the data on this issue could have been improved [3]. Other correspondence has also commented on the limitations of the data set analysed by Deeks et al and that analysis of more long term data does not confirm their conclusions [4]. Today at an educational meeting in my hospital with a pharmaceutical company stand, a reprint of Deeks et al paper was available. It was offered to another doctor in my presence. The discussion between the pharmaceutical representative and the other doctor did not mention any of the reservations expressed by correspondents until I interrupted the conversation when the company representative appeared to be encouraging the co-prescription of aspirin and celecoxib. Michael L Jenkinson Chair East Kent Hospitals Trust Drugs & Therapeutics Committee Queen Elizabeth, The Queen Mother Hospital St. Peters Road, Margate, Kent CT9 4AN michael.jenkinson@ekht.nhs.uk Competing interests: None declared |
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