ExpressionofConcern: Bombardier et al., "Comparison of Upper Gastrointestinal Toxicity of Rofecoxib and Naproxen in Patients with Rheumatoid Arthritis," N Engl J Med 2000;343:1520-8.
Gregory D. Curfman, M.D., Stephen Morrissey, Ph.D., and Jeffrey M. Drazen, M.D.
We have recently obtained information regarding inaccuraciesin data in the report of the VIGOR (Vioxx Gastrointestinal OutcomesResearch) study by Bombardier et al.1 that raise concern aboutcertain conclusions in the article.
The VIGOR study was designed primarily to compare gastrointestinalevents in patients with rheumatoid arthritis randomly assignedto treatment with rofecoxib (Vioxx) or naproxen (Naprosyn),but data on cardiovascular events were also monitored. Threemyocardial infarctions, all in the rofecoxib group, were notincluded in the data submitted to the Journal. The editors firstbecame aware of the additional myocardial infarctions in 2001when updated data were made public by the Food and Drug Administration.
Until the end of November 2005, we believed that these werelate events that were not known to the authors in time to beincluded in the article published in the Journal on November23, 2000. It now appears, however, from a memorandum dated July5, 2000, that was obtained by subpoena in the Vioxx litigationand made available to the Journal, that at least two of theauthors knew about the three additional myocardial infarctionsat least two weeks before the authors submitted the first oftwo revisions and 4 1/2 months before publication of the article.Given this memorandum, it appears that there was ample timeto include the data on these three additional infarctions inthe article.
The fact that these three myocardial infarctions were not includedmade certain calculations and conclusions in the article incorrect.Although only summary percentages, not actual numbers of myocardialinfarctions, were included in the Journal article, the followingtables display the numerical data without (Table 1) and with(Table 2) the three myocardial infarctions.
Table 2. Data on Myocardial Infarctions Including the Three Events.
Lack of inclusion of the three events resulted in an understatementof the difference in risk of myocardial infarction between therofecoxib and naproxen groups (presented in the article as areduction in the risk with naproxen but shown here as an increasein the risk with rofecoxib). It also resulted in the misleadingconclusion that there was a difference in the risk of myocardialinfarction between the aspirin indicated and aspirin not indicatedgroups.
In addition, the memorandum of July 5, 2000, contained otherdata on cardiovascular adverse events that we believe wouldhave been relevant to the article. We determined from a computerdiskette that some of these data were deleted from the VIGORmanuscript two days before it was initially submitted to theJournal on May 18, 2000.
Taken together, these inaccuracies and deletions call into questionthe integrity of the data on adverse cardiovascular events inthis article. We have asked the authors to submit a correctionto the Journal.
Source Information
This editorial was published on December 8, 2005, at www.nejm.org.
References
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;343:1520-1528. [Free Full Text]
Response to ExpressionofConcern Regarding VIGOR Study
Bombardier C., Laine L., Burgos-Vargas R., Davis B., Day R., Ferraz M. B., Hawkey C. J., Hochberg M. C., Kvien T. K., Schnitzer T. J., Weaver A., Reicin A., Shapiro D.
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N Engl J Med 2006;
354:1196-1199, Mar 16, 2006;
published at www.nejm.org on Feb 22, 2006 (10.1056/NEJMc066096).
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