High-dose non-COX-2 NSAIDs associated with increased vascular risk

While the increased risk of vascular events associated with cyclooxygenase-2 (COX-2) inhibitors has been well established, new data are emerging that demonstrate similar risk increases associated with non-steroidal anti-inflammatory drugs (NSAIDs) that are not selective for COX-2. The data, published in the British Medical Journal (BMJ), were from a meta-analysis of published and unpublished randomized trials. The study comes more than a year after the withdrawals of the COX-2-selective NSAIDs rofecoxib and valdecoxib from the US market.

In compiling data for the meta-analysis, researchers identified prospective, randomized, controlled trials of a selective COX-2 inhibitor versus placebo, a selective COX-2 inhibitor versus a traditional NSAID, or both. Based on the hypothesis that naproxen may have aspirin-like anti-platelet effects, the researchers prospectively specified that the analyses of a selective COX-2 inhibitor versus an NSAID were to be subdivided into those involving naproxen and those involving other (non-naproxen) NSAIDs. Three sources were used for the data: the manufacturers of each of the selective COX-2 inhibitors, the FDA website ( http://www.fda.gov/), and a search of Medline and Embase from January 1966 to April 2005.

Tabular data from 138 randomized trials were used in the meta-analysis, enrolling a total of 145,373 participants. Researchers compared the incidence of serious vascular events (defined as myocardial infarction, stroke, or vascular death) associated with the various NSAIDs involved in the trials and found similar rates between COX-2- and non-COX-2-selective NSAIDs. The rate of serious vascular events was 1.0% per year for COX-2-selective NSAIDs versus 0.9% per year for traditional NSAIDs (rate ratio [RR]=1.42; 95% CI, 1.13–1.78; P=.003).

Among all the non-COX-2-selective NSAIDs, the summary rate ratio for vascular events compared with placebo was 0.92 (95% CI, 0.67–1.26) for naproxen, 1.51 (95% CI, 0.96–2.37) for ibuprofen, and 1.63 (95% CI, 1.12–2.37) for diclofenac.

The researchers pointed to the combination of both long- and short-term trials in their meta-analysis as one of the main study limitations, implying that incorporation of short-term trials would dilute the risk of adverse events observed in the long-term trials. "If, as some people have suggested, the hazard emerges only after a year or 18 months, then combining short-term and long-term trials might underestimate the effects of long-term exposure to a selective COX-2 inhibitor," the authors stated.

SOURCE Kearney PM, Baigent C, Godwin J, Halls H, Emberson JR, Patrono C. Do selective cyclo-oxygenase-2 inhibitors and traditional non-steroidal anti-inflammatory drugs increase the risk of atherothrombosis? Meta-analysis of randomized trials. BMJ. 2006;332:1302–1308.