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Professor and Holder of the Margaret Milam McDermott Distinguished Chair in Anesthesiology, Department of Anesthesiology and Pain Management, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, paul.white{at}utsouthwestern.edu
In Response:
The letter from Babul et al. contains several questionable statements. As stated in the editorial (1), the perioperative use of parecoxib-valdecoxib over a period of 14 days in patients undergoing cardiac surgery produced some "unexpected" complications (e.g., wound infections) (2), as well as some not completely unexpected cardiovascular complications in these "at risk" patients (3). First, these adverse cardiovascular events were most likely attributable to valdecoxib, as parecoxib is a parenteral prodrug that is rapidly converted to the active cyclooxygenase (COX)-2 inhibitor (valdecoxib).
Second, although the studies used to support the New Drug Application for rofecoxib in acute pain may have contained data on "only" 741 patients, a large number of peer-reviewed publications containing postoperative outcome data have confirmed the safety and efficacy of rofecoxib in the perioperative period for patients undergoing a wide variety of noncardiac surgical procedures. In fact, rofecoxib has been safely administered to millions of patients undergoing elective surgery around the world. Given the well-known pharmacologic properties of COX-2 inhibitors (including the potential for adverse cardiovascular events in "at risk" patients), why would anyone even suggest studying rofecoxib in surgical patients at high-risk to these complications?
Although the Food and Drug Administration may have concluded that the "adverse event profile of parecoxib was generally worse than that of placebo," this statement is simply inconsistent with large-scale clinical studies involving patients undergoing noncardiac surgery. In fact, Gan et al. (4-6) found that postoperative side effects were significantly reduced in the COX-2 inhibitor group, whereas the patient’s quality of recovery was significantly improved compared with a placebo group. Other placebo-controlled studies involving both parecoxib (7,8) and valdecoxib (9,10) have confirmed that the use of these COX-2 inhibitors is associated with a reduction in postoperative side effects and an improved global evaluation by the patients.
In summary, in the two studies involving more prolonged perioperative administration of valdecoxib to cardiac surgery patients at risk for postoperative cardiovascular complications (2,3), an increased incidence of these adverse events is not really surprising given the pharmacologic profile of COX-2 inhibitors. Because clinical investigations have failed to demonstrate any increase in adverse cardiovascular complications in noncardiac surgical populations when these drugs are administered during the perioperative period, many experts would question the actions taken by the FDA and EMEA. However, as suggested in the conclusion to my Editorial (1), "other non-opioid analgesics may prove to be more cost-beneficial than the COX-2 inhibitors as part of a multimodal analgesic regimen in the future."
References
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