Vioxx Risks

Increasing use of rofecoxib (Vioxx) and celecoxib (Celebrex), both selective inhibitors of COX-2, for treatment of arthritis has been accompanied by concerns that
they may increase the risk of thrombotic cardiovascular events.

Most older nonsteroidal anti-inflammatory drugs (NSAIDs)
decrease endothelial production of both thromboxane, which has a prothrombotic effect on platelets, and prostacyclin, which has an antithrombotic effect. The usual net effect is some inhibition of platelet function and prolongation of bleeding time. Platelet inhibition is reversible when the drug is cleared, except with aspirin, which has an antiplatelet effect for the life of the platelet, an average of about 7 days. Selective COX-2 inhibitors decrease production of prostacyclin, but not thromboxane. They could, therefore, have a prothrombotic effect (GA
FitzGerald and C Patrono, N Engl J Med 2001; 345:433).

A recent safety study raised concerns that selective COX-2 inhibitors
may increase the risk of thrombotic cardiovascular events. The Vioxx Gastrointestinal Outcomes Research (VIGOR) study randomized 8076 older rheumatoid arthritis patients (average age 58 years) to receive either 50 mg of rofecoxib daily or 500 mg of naproxen twice daily, with a median followup of 9 months (C Bombardier et al, N Engl J Med 2000; 343:1520). This dosage of rofecoxib is 2-4 times the dosage recommended for osteoarthritis. Patients with recent cardiovascular events and those taking aspirin were excluded.

Serious thrombotic cardiovascular events occurred in 45 of 4047 patients (1.11%) taking rofecoxib and in 19 of 4029 (0.47%) taking naproxen. A similar safety study of celecoxib, the Celecoxib Long-term Arthritis Safety Study (CLASS), did not exclude patients taking low-dose aspirin, and no statistically significant increase in cardiovascular events was detected with use of celecoxib 400 mg b.i.d. (4 times the dosage for osteoarthritis) compared to diclofenac (Voltaren) or ibuprofen (Motrin, and others). In general, patients taking celecoxib had about half the incidence of serious gastrointestinal events (perforation, obstruction, bleeding) as those taking diclofenac
or ibuprofen (11 of 1441 vs. 20 of 1384), but those taking aspirin as well had about the same
incidence with celecoxib (6 of 298) as with diclofenac or ibuprofen (6 of 283) (FE Silverstein et
al, JAMA 2000; 284:1247).
One recent review (D Mukherjee et al, JAMA 2001; 286:954) compared annualized myocardial
infarction (MI) rates in patients treated with COX-2 inhibitors in 4 studies (including
CLASS and VIGOR) to historical healthy controls not taking low-dose aspirin and concluded
that both celecoxib and rofecoxib increased risks for MI. Rheumatoid arthritis, which was
EDITOR: Mark Abramowicz, M.D. DEPUTY EDITOR: Gianna Zuccotti, M.D., M.P.H., Weill Medical College of Cornell University
CONSULTING EDITOR: Martin A. Rizack, M.D., Ph.D., Rockefeller University ASSOCIATE EDITORS: Donna Goodstein, Amy Faucard ASSISTANT EDITOR: Susie Wong
CONTRIBUTING EDITORS: Philip D. Hansten, Pharm. D., University of Washington; Neal H. Steigbigel, M.D., New York University School of Medicine
ADVISORY BOARD: William T. Beaver, M.D., Georgetown University School of Medicine; Jules Hirsch, M.D., Rockefeller University; James D. Kenney, M.D., Yale University
School of Medicine; Gerhard Levy, Pharm.D., State University of N.Y. at Buffalo; Gerald L. Mandell, M.D., University of Virginia School of Medicine; Hans Meinertz, M.D.,
University Hospital, Copenhagen; Dan M. Roden, M.D., Vanderbilt School of Medicine; F. Estelle R. Simons, M.D., University of Manitoba
EDITORIAL FELLOWS: Elizabeth Stephens, M.D., Oregon Health Sciences University School of Medicine; Arthur M.F. Yee, M.D., Ph.D., Cornell University Medical Center
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common among the patients in the CLASS and VIGOR studies, but not among the historical
controls, has been associated with an increased risk of cardiovascular disease (S Wållberg-
Jonsson et al, J Rheumatol 1997; 24:445). A second recent review of 23 studies found no evidence
of an excess of cardiovascular events with rofecoxib compared to various NSAIDs or
placebo (MA Konstam et al, Circulation, November 6, 2001; 104:2280).
CONCLUSION — In one study, high doses of rofecoxib taken for months were associated
with a 1.11% incidence of thrombotic cardiovascular events compared to 0.47% with naproxen.
Taking aspirin with a selective COX-2 inhibitor could protect against any possible
prothrombotic effect, but would probably also diminish the apparent advantage in gastrointestinal
safety with these drugs. Until more prospective studies with and without low-dose aspirin
are available, it would be premature to conclude that rofecoxib or celecoxib increase the
risk of thrombotic cardiovascular disease.

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100 The Medical Letter • Vol. 43 (Issue W1118A) November 12, 2001

Vioxx Lawsuit