Coxicity

REVIEW OF THE MAJOR TRIALS

In the Fall of 2000 two studies were published in JAMA and NEJM which purported to prove that COX-2 inhibitors had a significant GI safety advantage over their predecessors, the NSAIDs. The CLASS1 and VIGOR2 trials, for Celebrex and Vioxx respectively, were large studies carried out by the manufacturers of the drugs and reviewed by gastroenterologists.

The CLASS study, conducted by Pharmacia, consisted of two separate 12- and 15-month trials with Celebrex (celecoxib) 800 mg daily and either ibuprofen 2400mg daily or diclofenac 150mg daily. The data the reviewers saw, however, was a combined analysis of the first 6 months of the two trials.3 Other data was omitted, and the JAMA editor was not informed of the omission. When the entire data set was subsequently reviewed, the GI advantage attributed to celecoxib was found to be non-existent, and in June 2002 the FDA mandated that the claim of greater GI safety be removed from the Celebrex label. The consumer information section of the FDA website compares Celebrex to other NSAIDs in its ability to cause stomach ulcers.4 In a July 2001 letter to JAMA, Dr. James Wright, a clinical pharmacologist at the University of British Columbia, suggested that the complete data from the CLASS study indicated that celecoxib may actually cause worse side effects than either diclofenac or ibuprofen.5

In the 15-month VIGOR study, conducted by Merck and reviewed by the NEJM, Vioxx (rofecoxib) produced fewer perforations, ulcerations and bleeds (PUBs) than did naproxen. However, the FDA maintained that fewer PUBs was not necessarily indicative of fewer GI complications. Merck also failed to reveal that the rofecoxib subjects in the study had a much greater incidence of cardiovascular side effects, which were possibly due to COX-2 inhibitors having pro-thrombotic properties. The patients in the VIGOR study were not permitted to take low-dose aspirin as subjects in the CLASS trials were. As early as 1999 the FDA was concerned about “excess deaths and cardiovascular events experienced in Group A (Vioxx) as compared to Group B (naproxen).”6 In March 2002, five cases of aseptic meningitis in patients on Vioxx were reported.7 In April 2002 the FDA required that a warning of cardiovascular risks be placed on the label.8

As a result of these disturbing revelations involving selective reporting of pharmaceutical data, the 11 editors of the International Committee of Medical Journal Editors have issued new requirements for publication acceptance of research funded by interested parties.

SAFETY CONSIDERATIONS WHEN USING COX-2s WITH WARFARIN

Neither of these large studies included patients who were taking warfarin (Coumadin), or patients who had a history of GI disease. There is no supporting evidence for improved GI safety of either Vioxx or Celebrex when used with warfarin. However, there are many post-marketing surveillance reports of significantly elevated INRs and bleeding episodes when either of these agents are administered with warfarin. A memorandum from the FDA written shortly after these medications were approved cited 73 US deaths attributed to celecoxib and rofecoxib. These patients were generally considered to be high-risk patients “because of past medical history, a recent major systemic medical event, or concomitant therapy with aspirin or another antiplatelet drug, corticosteroids, warfarin, or another NSAID.”9


1 Silverstein FE, Faich G, Goldstein JL, et al. Gastronintestinal toxicity with celecoxib vs nonsteroidal antiinflammatory drugs for osteoarthritis and rheumatoid arthritis. The CLASS study: a randomized controlled trial. JAMA 2000; 284:1247-1255.

2 Bombardier C, Laine L, Reicin A, et al, for the VIGOR study group. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. N Engl J Med. 2000; 343:1520-1528.

3 Wright, JM, Perry TL, Basset KL, Chambers GK. Reporting of 6-month vs 12-month data in a clinical trial of celecoxib. JAMA 2001; 286:2398-2400.

4 FDA Celebrex Consumer Information Sheet. Revised November 11th, 2002. http://www.fda.gov/cder/consumerinfo/druginfo/celebrex.htm Accessibility verified May 17th, 2004.

5 Okie S. Missing data on Celebrex: Full Study Altered Picture of Drug. Washington Post, August 5th 2001; p. A11.

6 Targum, S.L. Consultation NDA 21-042, S-007: Review of cardiovascular safety database. FDA CDER Memorandum, February 1st, 2001. http://www.fda.gov/ohrms/dockets/ac/01/briefing/3677b2_06_cardio.doc Accessibility verified May 17th, 2004.
7 Bonnel, R.A., et. al. Aseptic Meningitis Associated With Rocfecoxib. Archives of Internal Medicine 2002;162:713-715. http://archinte.ama-assn.org/cgi/content/abstract/162/6/713 Accessibility verified May 17th, 2004.
8 FDA Talk Paper T02-18. April 11th , 2002. http://www.fda.gov/bbs/topics/ANSWERS/2002/ANS01145.html Accessibility verified May 17th, 2004.
9 Weaver, J. OPDRA Postmarketing Safety Review. FDA CDER Memorandum, December 29th, 2000; p. 1. http://www.fda.gov/ohrms/dockets/ac/01/briefing/3677b1_09_gi2.doc Accessibility verified May 17th, 2004.

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