CMAJ • October 11, 2005; 173 (8). doi:10.1503/cmaj.1050143.
© 2005 CMA Media Inc. or its licensors
All editorial matter in CMAJ represents the opinions of the authors and not necessarily those of the Canadian Medical Association.
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Letters
Correspondance

Coxibs and cardiovascular risk

Syed A.H. Zaidi

Department of Pharmacology, University of Oxford, Oxford, UK

Jill Cotter and Eric Wooltorton1 indicated that COX-2 inhibitors appear to increase the risk of cardiovascular adverse events in a dose-related fashion. The CLASS and VIGOR clinical trials of COX-2 inhibitor(s) suggested that both celecoxib and rofecoxib can increase the risk of cardiovascular events.2 The VIGOR trial compared rofecoxib with the NSAID naproxen in patients with rheumatoid arthritis3 and indicated a 5-fold increase in the relative risk of developing serious cardiovascular events between the rofecoxib group and the naproxen group.

Clinical data have shown that expression of COX-2 is upregulated by inducible nitric oxide synthase (iNOS) that might play a protective role in the cardiovascular system.4 However, the COX-2 enzyme might be exerting detrimental effects elsewhere, because analysis of protein extracts from normal arteries has revealed constitutive COX-1 only, but atheromatous lesions contained both COX-1 and COX-2 protein.5 Some studies suggest that prostanoids and nitric oxide may have proatherosclerotic effects6 resulting from the formation of peroxynitrite species in the affected vessels, possibly involving "cross talk" between the COX-2, iNOS and other enzyme systems, which may generate oxidants including dihydrogen trioxide and even ozone from singlet oxygen and water in atheromatous plaques.7

Well-planned basic research is essential to show whether COX-2 activity is beneficial or harmful for the cardiovascular system in different sites or in cardiovascular disease and to exploit the benefits of COX-2 inhibitor therapy.

Footnotes

Competing interests: None declared.


References

  1. Cotter J, Wooltorton E. New restrictions on celecoxib (Celebrex) use and the withdrawal of valdecoxib (Bextra). CMAJ 2005;172(10):1299.[Free Full Text]
  2. Mukherjee D, Nissen SE, Topol EJ. Risk of cardiovascular events associated with selective COX-2 inhibitors [review]. JAMA 2001;286(8):954-9. [Summary for patients in: Can Fam Physician 2002;48:1449-51.] [Abstract/Free Full Text]
  3. Bombardier C, Laine L, Reicin A, Shapiro D, Burgos-Vargas R, Davis B, et al; VIGOR Study Group. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. VIGOR Study Group. N Engl J Med 2000343(21):1520-8, 2 p following 1528.
  4. Bolli R, Shinmura K, Tang XL, Kodani E, Xuan YT, Guo Y, et al. Discovery of a new function of cyclooxygenase (COX)-2: COX-2 is a cardioprotective protein that alleviates ischemia/reperfusion injury and mediates the late phase of preconditioning. Cardiovasc Res 2002;55(3):506-19.[Abstract/Free Full Text]
  5. Schonbeck U, Sukhova GK, Graber P, Coulter S, Libby P. Augmented expression of cyclooxygenase-2 in human atherosclerotic lesions. Am J Pathol 1999;155(4):1281-91.[Abstract/Free Full Text]
  6. Baker CS, Hall RJ, Evans TJ, Pomerance A, Maclouf J, Creminon C, et al. Cyclooxygenase-2 is widely expressed in atherosclerotic lesions affecting native and transplanted human coronary arteries and colocalizes with inducible nitric oxide synthase and nitrotyrosine particularly in macrophages. Arterioscler Thromb Vasc Biol 1999;19(3):646-55.[Abstract/Free Full Text]
  7. Wentworth P Jr, Nieva J, Takeuchi C, Galve R, Wentworth AD, Dilley RB, et al. Evidence for ozone formation in human atherosclerotic arteries. Science 2003;302(5647):1053-6.[Abstract/Free Full Text]




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