275 275.276

is it a class effect?
Mark Weatherall, Sarah Aldington, Brent Caldwell and Richard Beasley The online version of this article can be found at: can be found at:
Journal of the Royal Society of Medicine
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Table 2 Myocardial infarction data reported in the three CLASS(Celecoxib Long-term Arthritis Safety Study) publications cardiovascular data fromCOX-2 inhibitor trials—is it a The recent editorials in the New England Journal of Medicine about inaccuracies in cardiovascular data in the publication of the VIGOR (Vioxx Gastrointestinal Outcomes Research) study1,2 has prompted us to report similar inaccuracies inthe CLASS study (Celecoxib Long-term Arthritis Safety *Data taken from Table 4, page 1252{Data taken from Table 2, page 428 Study), which were identified during a systematic review of the cardiovascular effects of celecoxib.3 Like the VIGOR study, CLASS was designed primarily to compare the incidence of upper gastrointestinal adverseevents resulting from a COX-2 specific inhibitor with thoseof conventional non-steroidal anti-inflammatory drugs in CLASS there were five and eight cardiovascular deaths in (NSAIDs) in patients with arthritis. As with the VIGOR the celecoxib and NSAID groups, respectively, during the study, in CLASS there were also inconsistencies in the full 12-month study period or within the following 28 days serious adverse cardiovascular events reported in the (Table 1).6 In the subsequent 2002 American Journal of Cardiology publication of the cardiovascular events from The outcomes of CLASS have been reported in two CLASS, a total of 10 cardiovascular deaths were reported in peer-reviewed journals4,5 and in a number of documents each of the celecoxib and NSAID groups (Table 1).5 It is posted on the Food and Drug Association website, of which difficult to understand why all the cardiovascular deaths the medical officer review is the most complete.6 We have would have occurred after 6 months of treatment, and how reviewed the data from these three major publications.4–6 there could be such major discrepancies between the two In September 2000 the initial 6-month data were published complete study reports for such a definite outcome measure by Silverstein and colleagues in JAMA in which no cardiovascular deaths were reported (Table 1).4 Also in Similarly, there were inconsistencies between the three September 2000, the FDA medical officer review of sources of CLASS data in the reporting of myocardial celecoxib data supplied by GD Searle & Co, reported that infarction (Table 2). For example, in the publications of theentire CLASS data, one reported 26 myocardial infarctionsin the celecoxib group and 15 in the NSAID group5, Table 1 Mortality data reported in the three CLASS (Celecoxib Long- whereas the other reported 19 and 13 myocardial term Arthritis Safety Study) publications These findings add to the concerns previously expressed regarding the selective and partial reporting of thegastrointestinal side effects from the CLASS study and that the published CLASS study differs from the originalprotocol in primary outcomes, statistical analysis, trial Thus history appears to have repeated itself in two respects. First, in CLASS there were inconsistencies in the reporting of cardiovascular data. Of greater concern is the identification that in the two major safety studies of the most commonly used COX-2 specific inhibitors there inconsistencies in reporting of the cardiovascular events. Thus, there would seem to be a NSSAID, non-steroidal anti-inflammatory drugs; CI, confidence interval; FDA, Foodand Drug Administration systemic problem in research conduct in this field. There are considerable public health, pharmaceutical, regulatory 4 Silverstein FE, Faich G, Goldestein JL, et al. Gastrointestinal toxicity osteoarthritis and rheumatoid arthritis. The CLASS study: arandomized controlled trial. JAMA 2000;284:1247–55 5 White WB, Faich G, Whelton A, et al. Comparison of thromboembolic events in patients treated with celecoxib, acyclooxygenase-2 specific inhibitor, versus ibuprofen or diclofenac.
1Wellington School of Medicine & Health Sciences, Wellington; 6 Witter J. Celebrex capsules (celecoxib). NDA 20-998/S-009. Medical Officer 2Medical Research Institute of New Zealand, Wellington, New Zealand Review. US Department of Health and Human Services Food and Drug Correspondence to: Professor Richard Beasley Administration, 2000 [http://www.fda.gov/ohrms/dockets/ac/01/ 7 Ju¨ni P, Rutjes AWS, Dieppe PA. Are selective COX 2 inhibitors superior to traditional non steroidal anti-inflammatory drugs? BMJ 1 Curfman GD, Morrissey S, Drazen JM. Expression of concern: Bombardier et al ‘‘Comparison of upper gastrointestinal toxicity of 8 Wright JM, Perry TL, Bassett KL, Chambers GK. Reporting of 6- rofecoxib and naproxen in patients with rheumatoid arthritis’’. N Engl J month vs 12-month data in a clinical trial of celecoxib [Letter]. JAMA 2 Curfman GD, Morrissey S, Drazen JM. Expression of concern reaffirmed.
9 Berg Hrachovec J, Mora M. Reporting of 6-month vs 12-month data in [http://content.nejm.org/cgi/content/abstract/NEJMe068054] a clinical trial of celecoxib [Letter]. JAMA 2001;286:2398 3 Caldwell B, Aldington S, Weatherall M, Shirtcliffe P, Beasley R. Risk of 10 Celecoxib and the CLASS trial: data massaging by industry. Prescribe Int cardiovascular events and celecoxib: a systematic review and meta-

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