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Centre for Anesthesia & Analgesia, Departments of Anesthesia and Pharmacology & Therapeutics, The University of British Columbia, Vancouver, B.C., Canada
To the Editor:
In their review article, McCrory and Lindahl state that "although ...animal data suggest that COX-2 inhibition may worsen myocardial performance in the presence of ischemia, there now is evidence that COX-2 inhibition reduces atherosclerosis." (1) The authors conclude their review by suggesting that "...selective COX-2 inhibitors...may represent a safer alternative to nonselective NSAIDs in the treatment of postoperative pain." However, no data is available from large randomized controlled trials to conclusively demonstrate that COX-2 inhibitors, administered for postoperative analgesia or other indications, produce a reduction in cardiovascular or overall serious adverse events in humans. McCrory and Lindahl do not include in their article the recent evidence from two large and widely discussed trials with over 16,000 patients that show the contrary. Analysis of the safety data of the CLASS trial [celecoxib compared to non-COX-2 selective NSAIDs, 8059 patients (2); complete data set not included in the original publication but published later by the Food and Drug Administration (3)] showed that celecoxib had no advantage over non-selective NSAIDs in terms of either cardiovascular events or overall safety. In the VIGOR trial [rofecoxib vs. naproxen, 8076 patients (4)], patients treated with rofecoxib had a relative risk of 2.36 (95% confidence interval [CI], 1.38–4.02; P= 0.002) to encounter a thrombotic cardiovascular adverse event, and a relative risk of 1.19 (95% CI, 1.04–1.38; P= 0.016) to experience a serious adverse event [complete safety data published by the Food and Drug Administration (5)]. The potential of COX-2 inhibitors to increase cardiovascular risk has subsequently been subject of review in the literature (6,7) . On the basis of the best evidence available to date, it would seem reasonable to treat claims that COX-2 inhibitors are safer agents for postoperative analgesia than non-COX-2 selective NSAIDs with caution.
References
Department of Anesthesiology and Intensive Care, Karolinska Hospital, Stockholm, Sweden
In Response:
We thank Dr. Schwarz for his interest in our review and appreciate the opportunity to respond. This article focuses on the use of Cox-2 inhibition for postoperative analgesia. The main concerns continue to be upper gastrointestinal, renal and hemostatic complications. The theoretical potential for cardiovascular (CVS) complications is well recognized, and has been reported in patients with Raynaud’s phenomena (1).
However the prevalence of this complication in a postoperative population taking a short course of a COX-2 inhibitor as part of their analgesic regime remains to be elucidated. The most common complication of NSAIDs remains upper GI and there is a wealth of data supporting the superiority of selective COX-2 inhibition over NSAIDs (2–5) . Although VIGOR did show an increased rate of CVS events this was not a prespecified endpoint of the study. It is recognized that post hoc analysis is fraught with difficulty. It also must be remembered that patients with Rheumatoid Arthritis, as recruited in the VIGOR study, have a higher risk of myocardial infarction (6). In fact one of Dr. Schwarz’s quoted studies, FDA 085 (N=1042) showed that 1 CVS event occurred in the rofecoxib group, while 2 events occurred in the nabumetone group. There are issues regarding the differing responses between short-term use of a drug and long-term continuous usage. VIGOR and CLASS were both long-term use studies.
There is no prospective randomized controlled data on cardiovascular safety for short-term COX-2 inhibition in the postoperative period (7). Thus we feel that there is data supporting the preferential use of COX-2 inhibition over conventional NSAIDs from the gastrointestinal and hemostatic perspectives. There is growing evidence of superior tolerability in the asthmatic population, thus leaving the renal issues as the major contraindication to their use (8). Therefore it is reasonable to conclude, based on current data, that COX-2 inhibition may be a safer alternative to NSAIDs for postoperative analgesia.
References
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