Nonsteroidal anti-inflammatory drugs (NSAIDs) have been in the crosshairs for years for cardiovascular and gastrointestinal risks. Physicians now have a clearer vision of the target, thanks to a meta-analysis published online May 30 in The Lancet. The findings may help in the management of patients with painful conditions.
Colin Baigent, MD, of Oxford University in the U.K., and colleagues from the Coxib and traditional NSAID Trialists Collaboration focused the meta-analysis on randomized clinical trials in an effort to eliminate selection biases that potentially muddled observational studies on NSAIDs. Their goal was to characterize and quantify cardiovascular and gastrointestinal risks of specific NSAIDs in various patient populations.
Using Medline and EMBASE searches up to 2009 plus data from published and unpublished randomized trials up to 2011, they identified 280 placebo-controlled trials (124,513 participants and 68,342 person-years) and 474 trials that compared two different NSAIDs (229,296 participants and 165,456 person-years).
They found that compared with placebo, the risk of major vascular events increased by one-third for selective COX-2 inhibitors or diclofenac, primarily driven by an increased risk in major coronary events. They defined major vascular events as nonfatal MI, nonfatal stroke or vascular death and major coronary events as nonfatal MI or death from coronary disease.
Major coronary events also were increased with ibuprofen, but not major vascular events. For traditional NSAIDS, high-dose naproxen showed no increased risk of major vascular or coronary events. The risk of hospitalization for heart failure nearly doubled for naproxen and diclofenac and more than doubled for COX-2 inhibitors and ibuprofen.
COX-2 inhibitors and diclofenac were associated with a significantly increased risk in vascular death, which was increased nonsignificantly for ibuprofen and not increased with naproxen. There was no evidence of increased risk of stroke with any NSAID, but all NSAIDs increased upper gastrointestinal complications, with 2 percent being fatal.
The findings put high-dose diclofenac at similar risk for major vascular events as an average COX-2 inhibitor regimen and suggested ibuprofen might fall in that category, too. “The absolute excess risks were small but serious: compared with placebo, allocation to a coxib [COX-2 inhibitors] or diclofenac caused around three additional major vascular events per 1,000 participants per year, with one such event causing death,” Baigent et al wrote. “High-dose ibuprofen also significantly increased the risk of major coronary events, but there were many fewer relevant events in trials of coxib versus ibuprofen, so its safety (including the possible relevance of its interaction with aspirin) requires further study.”
Outcomes appeared to be similar in different types of patients across all levels of risk for major vascular events. The predicted risks of major vascular events were small for those at low risk of vascular disease, regardless of the NSAID regimen. Annually, seven to eight people at high risk of vascular disease treated with a COX-2 inhibitor or high-dose diclofenac would have a major vascular event, two of which would be fatal.
“[The meta-analysis] showed that the excess risk of both vascular and gastrointestinal events can be predicted once the baseline risks of such hazards are known, which could help clinical decision-making,” according to the authors.