s25ab_5

COX-2 inhibitors and the cardiovascular system

G.A. FitzGerald, Y. Cheng, S. Austin

Center for Experimental Therapeutics, University of Pennsylvania, Philadelphia, Pennsylvania, USA

ABSTRACT
Cyclooxygenase-2 selective inhibitors (coxibs) represent a new class of non steroidal anti-inflammatory drugs that exhibit preference for inhibition of cyclooxygenase-2 (COX-2), the COX isoform thought to account largely for prostanoid formation in inflammation.
We review the divergent incidence of cardiovascular events derived from the two large clinical trials of coxibs, the Vioxx¨ Gastrointestinal Outcomes Research Trial (VIGOR) and the Celecoxib Long-term Arthritis Safety Study (CLASS), in the context of current understanding of relevant clinical and basic pharmacology.
The incidence of cardiovascular events was higher in patients receiving rofecoxib than in those receiving naproxen in VIGOR and did not differ between the groups in CLASS. By contrast, while the primary gastrointestinal (GI) endpoint comparison favored rofecoxib in VIGOR, no significant difference in the incidence of the primary GI endpoint was evident between celecoxib and two NSAID comparators not attained in CLASS.
The cardiovascular results in VIGOR may have resulted from chance, a cardioprotective effect of naproxen, or suppression of prostacyclin but not thromboxane on rofecoxib. Differences in cardiovascular outcome between the two trials may also have resulted either from chance, or from aspects of the trial design (such as the use of aspirin by roughly one-fifth of the participants in CLASS), or from differences in the COX-2 selectivity or other pharmacology of the coxibs.
Individuals who warrant low-dose aspirin for cardioprotection may have less likelihood of a GI event if they combine aspirin with rofecoxib, rather than a traditional NSAID. However, evidence addressing directly this hypothesis is currently unavailable. On the other hand, coxib consumption alone does not currently warrant initiation of a cardioprotective regimen, such as low-dose aspirin.

Key words
Cyclooxygenase inhibitors, prostacyclin, thromboxane, cardiovascular.

Supported by grants HL62250, HL57847 and MO1R00040 from the National Institutes of Health. Professor FitzGerald is the Robinette Foundation Professor of Cardiovascular Medicine.
Please address correspondence and reprint requests to: Professor Garret A. FitzGerald, University of Pennsylvania School of Medicine, Department of Pharmacology, 153 Johnson Pavilion, Philadelphia, PA 19104-6084, USA.
E-mail: garret@spirit.gcrc.upenn.edu