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October 4, 2006

COX-2 Inhibitors, Other NSAIDs, and Cardiovascular Risk: The Seduction of Common Sense

Author Affiliations

Editor's Note: Dr Graham is an employee of the US Food and Drug Administration. This editorial was written by Dr Graham as an officially approved outside activity in his private capacity and not as a Food and Drug Administration employee. His contact information is publicly available at http://directory.psc.gov/employee.htm and is as follows: David J. Graham, MD, MPH, Office of Surveillance and Epidemiology, Food and Drug Administration, 10903 New Hampshire Ave, WO22, Room 4314, Silver Spring, MD 20993 (david.graham1@fda.hhs.gov).


Published online September 12, 2006 (doi:10.1001/jama.296.13.jed60058).

JAMA. 2006;296(13):1653-1656. doi:10.1001/jama.296.13.jed60058

 . . . (A) long habit of not thinking a thing wrong, gives it a superficial appearance of being right, and raises at first a formidable outcry in defence of custom. But the tumult soon subsides. Time makes more converts than reason.—Thomas Paine, Common Sense, 1776

The concept was appealing in its simplicity. Traditional nonsteroidal anti-inflammatory drugs (NSAIDs) inhibited both isoforms of the enzyme cyclooxygenase responsible for the first step in the conversion of arachidonic acid into a variety of prostaglandins, thromboxanes, and leukotrienes throughout the body.1 The anti-inflammatory and pain-relieving effects of NSAIDs resulted from inhibition of prostaglandin synthesis mediated by cyclooxygenase 2 (COX-2) at the site of tissue injury, while gastrointestinal tract complications were due to inhibition of prostaglandin synthesis mediated by cyclooxygenase 1 (COX-1) in the gastrointestinal mucosa. The allure of COX-2 inhibitors was the prospect of treating pain without gastrointestinal toxicity.1 Celecoxib and rofecoxib were the first of these new agents to gain approval and, with heavy promotion and direct-to-consumer advertising, quickly became the most widely prescribed NSAIDs in the United States.