Use of Nonsteroidal Antiinflammatory Drugs

Clinical trial data have prompted questions about the degree to which patients and their physicians should consider an increased risk of cardiovascular or cerebrovascular events when selecting medications for pain relief. Since the 2005 publication of a Science Advisory on the use of nonsteroidal antiinflammatory drugs (NSAIDs) by the American Heart Association,1 several important events have occurred that have served as the catalyst for this update for clinicians. (1) Additional data from randomized controlled trials of cyclooxygenase (COX)-2–selective agents have been reported and summarized in meta-analyses, which has reinforced the concern about cardiovascular events with COX-2 inhibitors (coxibs; Figure 1). (2) Several reports have appeared that have identified an increased risk of cardiovascular events even with the nonselective NSAIDs, which has raised concern about the use of those agents as well (Table). (3) Regulatory authorities in several regions of the world have introduced warning statements and advisories to both healthcare professionals and the lay public about the use of various NSAIDs (Figures 2 and 3). In September 2004, Merck announced a voluntary worldwide withdrawal of Vioxx (rofecoxib) because of an increased risk of heart attack and stroke. In early December 2004, the US Food and Drug Administration (FDA) announced a “black box” warning for valdecoxib (Bextra), stating that its use in patients undergoing coronary artery bypass graft surgery is contraindicated. A week later, the National Institutes of Health (NIH) suspended the use of celecoxib (Celebrex) in the Adenoma Prevention with Celecoxib (APC) clinical trial because of increased cardiovascular events. The drug was not removed from the market, but the FDA advised physicians to consider alternative therapy or to use the smallest effective dose of Celebrex. Three days later, the NIH announced that the Alzheimer’s Disease AntiInflammatory Prevention Trial (ADAPT) showed an increase in the risk of cardiovascular events in patients given naproxen but not in those given celecoxib; the trial was halted. At the end of 2004, the FDA issued a public health advisory summarizing the agency’s recent recommendations for the use of the NSAID products Vioxx, Bextra, Celebrex, and naproxen.6 To quote from the public health advisory: