Cardiovascular thrombotic events in arthritis trials of the cyclooxygenase-2 inhibitor celecoxib*


      To determine whether the cyclooxygenase-2 (COX-2) inhibitor celecoxib affects cardiovascular thrombotic risk, we analyzed the incidence of cardiovascular events for celecoxib, placebo, and nonsteroidal anti-inflammatory drugs (NSAIDs) in the entire controlled, arthritis clinical trial database for celecoxib. The primary analysis used the Antiplatelet Trialists’ Collaboration end points, which include: (1) cardiovascular, hemorrhagic, and unknown deaths, (2) nonfatal myocardial infarction, and (3) nonfatal stroke. Other secondary thrombotic events were also examined. Separate analyses were performed for all patients and for those not taking aspirin. Data from all controlled, completed arthritis trials of ≥4 weeks duration, including 13 new drug application studies and 2 large post-marketing trials (CLASS and SUCCESS) were included for analyses. Patients were randomized to celecoxib at doses from 100 to 400 mg twice daily (18,942 patients; 5,668.2 patient-years of exposure), diclofenac 50 to 75 mg twice daily, ibuprofen 800 mg thrice daily, naproxen 500 mg twice daily (combined NSAID exposure of 11,143 patients; 3,612.2 patient-years), or placebo (1,794 subjects; 199.9 subject-years). Data from a long-term uncontrolled trial with 5,209 patients (6,950 patients-years) treated with celecoxib were included in a supplemental analysis. The entire 15-trial database was searched for possible serious thrombotic events as well as to identify all deaths. For these patients, detailed clinical data were obtained and reviewed by 2 of the investigators (WBW and JSB), who were independently and blinded to exposure, to classify the event as primary, secondary, or neither. All analyses were done using the intent-to-treat population, and time-to-event analyses were performed using per-patient data. To examine heterogeneity of results among studies, tests of interaction were performed using the Cox model. Incidences of the primary and secondary events were not significantly different between the celecoxib and placebo groups, nor for the celecoxib group compared with the NSAIDs group, regardless of aspirin use and NSAID type. The relative risks comparing celecoxib with the NSAIDs for the primary events were 1.06 (95% confidence interval 0.70 to 1.61, p = 0.79) for all patients, and 0.86 (95% confidence interval 0.48 to 1.56, p = 0.62) for the subgroup not taking aspirin. Similarly, for secondary cardiovascular end points, all relative risks were ≤1 for celecoxib compared with either placebo or NSAIDs. These comparative analyses demonstrate no evidence of increased risk of cardiovascular thrombotic events associated with celecoxib compared with either conventional NSAIDs or placebo.
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        • Silverstein F.E.
        • Faich G.
        • Goldstein J.L.
        • Simon L.S.
        • Pincus T.
        • Whelton A.
        • Makuch R.
        • Eisen G.
        • Agrawal N.M.
        • Stenson W.F.
        • et al.
        Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis—The CLASS study.
        JAMA. 2000; 284: 1247-1255
        • Bombardier C.
        • Laine L.
        • Reicin A.
        • Shapiro D.
        • Burgos-Vargas R.
        • Davis B.
        • Day R.
        • Ferraz M.B.
        • Hawkey C.J.
        • Hochberg M.C.
        • Kvien T.K.
        • Schnitzer T.J.
        Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis.
        N Engl J Med. 2000; 343: 1520-1528
        • McAdam B.F.
        • Catella L.F.
        • Mardini I.A.
        • Kapoor S.
        • Lawson J.A.
        • FitzGerald G.A.
        Systemic biosynthesis of prostacyclin by cyclooxygenase (COX)-2.
        Proc Natl Acad Sci USA. 1999; 96: 272-277
        • Catella-Lawson F.
        • McAdam B.
        • Morrison B.W.
        • Kapoor S.
        • Kujubu D.
        • Antes L.
        • Lasseter K.C.
        • Quan H.
        • Gertz B.J.
        • FitzGerald G.A.
        Effects of specific inhibition of cyclooxygenase-2 on sodium balance, hemodynamics, and vasoactive eicosanoids.
        J Pharmacol Exp Ther. 1999; 289: 735-741
        • Cheng Y.
        • Austin S.C.
        • Rocca B.
        • Koller B.H.
        • Coffman T.M.
        • Grosser T.
        • Lawson J.A.
        • FitzGerald G.A.
        Role of prostacyclin in the cardiovascular response of thromboxane A2.
        Science. 2002; 296: 539-541
        • Boers M.
        NSAIDs and selective COX-2 inhibitors.
        Lancet. 2001; 357: 1222-1223
        • Mukherjee D.
        • Nissen S.E.
        • Topol E.J.
        Risk of cardiovascular events associated with selective COX-2 inhibitors.
        JAMA. 2001; 286: 954-959
        • Konstam M.A.
        • Weir M.R.
        • Reicin A.
        • Shapiro D.
        • Sperling R.S.
        • Barr E.
        • Gertz B.J.
        Cardiovascular thrombotic events in controlled, clinical trials of rofecoxib.
        Circulation. 2001; 104: R15-R23
        • Antiplatelet Trialists Collaboration
        Collaborative overview of randomized trials of antiplatelet therapy. I.
        BMJ. 1994; 308: 81-106
        • Hennekens C.H.
        • Dyken M.L.
        • Fuster V.
        Aspirin as a therapeutic agent in cardiovascular disease.
        Circulation. 1997; 96: 2751-2753
        • Mantel N.
        Evaluation of survival data and two new rank order statistics arising in its considerations.
        Cancer Chemo Reports. 1966; 50: 163-170
        • Kaplan E.J.
        • Meier P.
        Nonparametric estimation from incomplete observation.
        J Am Statistical Assoc. 1958; 53: 457-481
        • Cox D.R.
        Regression models and life tables.
        J Royal Statistical Soc. 1972; 34 (with discussion): 187-220
        • Chen Y.T.
        • Makuch R.W.
        Use of meta-analysis to evaluate medical questions of interest.
        Drug Inform J. 1999; 33: 1161-1171
        • White W.B.
        • Faich G.
        • Whelton A.
        • Murath C.
        • Ridge N.J.
        • Verberg K.M.
        • Geis G.S.
        • Lefkowith J.B.
        Comparison of thromboembolic events in patients treated with celecoxib, a cyclooxygenase-2 specific inhibitor, versus ibuprofen or diclofenac.
        Am J Cardiol. 2002; 89: 425-430
      1. Targum, S. Division of Cardio-Renal Drug Products Consultation on NDA 21–042 S-007. Available at: Accessed July 8, 2003

        • Hennan J.K.
        • Huang J.
        • Barrett T.
        Effects of selective cyclooxygenase-2 inhibition on vascular responses and thrombosis in canine coronary arteries.
        Circulation. 2001; 104: 820-825
        • Green K.
        • Drvota V.
        • Vesterqvist O.
        Pronounced reduction of in vivo prostacyclin synthesis in humans by acetaminophen (paracetamol).
        Prostaglandins. 1989; 37: 311-315
        • Koki A.T.
        • Leahy K.M.
        Potential utility of COX-2 inhibitors in chemoprevention and chemotherapy.
        Expert Opin Invest Drugs. 1999; 8: 1623-1638
        • Reilly I.A.
        • FitzGerald G.A.
        Inhibition of thromboxane formation in vivo and ex vivo.
        Blood. 1987; 69: 180-186
        • Ross R.
        N Engl J Med. 1999; 340: 115-126
        • Catella-Lawson F.
        • Reilly M.P.
        • Kapoor S.C.
        • Cucciara A.J.
        • DeMarco S.
        • Tournier B.
        • Vyas S.N.
        • Fitzgerald G.A.
        Cycloxygenase inhibitors and the antiplatelet effects of aspirin.
        N Engl J Med. 2001; 345: 1809-1817

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