Boca Raton, FL- Concerns about the cardiovascular risks of COX-2 inhibitors (coxibs) have been overestimated, while similar concerns about regular nonsteroidal anti-inflammatory drugs (NSAIDs) have been underestimated, and it appears that the both groups of drugs, with the exception of naproxen, have broadly similar cardiovascular risks, a new review suggests [1].

The review, published in the March 2008 issue of the Journal of Cardiovascular Pharmacology and Therapeutics, is written by Drs Charles Hennekens and Steven Borzak (Florida Atlantic University, Boca Raton).

They point out that the most reliable data on cardiovascular risk with these drugs comes from the comprehensive meta-analysis of the randomized trials conducted by Kearney et al [2], which suggested that coxibs are associated with a small to moderate increased risk of vascular events (RR 1.42), as are high-dose regimens of ibuprofen and diclofenac, but high-dose naproxen is not associated with such an excess.

But they add that even the meta-analyses is based on individual trials that were not designed to look at cardiovascular risk and that further large-scale randomized trials of both coxibs and NSAIDs in patients with pain from inflammatory conditions specifically focusing on cardiovascular risk are needed. Such trials would have to be very large and simple and should include use of short-acting and long-acting traditional NSAIDs, including aspirin in therapeutic doses, both with and without proton-pump inhibition, as well as acetaminophen, to allow direct comparisons of benefits on pain relief with risks on the liver and the kidney, they suggest.

"In the meanwhile, from a clinical and policy perspective, the available data suggest that for relief of pain of inflammatory arthritis, naproxen may have the best benefit-to-risk ratio on cardiovascular disease," the reviewers comment. But they add that individual clinical judgments about coxibs and NSAIDs should not just focus on cardiovascular risk but should also take into account other risks, such as gastrointestinal bleeding, and other benefits, including improved quality of life resulting from decreases in impairment from musculoskeletal pain syndromes.

Hennekens commented to heartwire: "My main concern is that there has been an overreliance on early observational studies with the coxibs that may have overestimated the cardiovascular risk. We have seen this problem again and again. It happened with the calcium blockers when observational studies suggested great harm, which was not confirmed in randomized studies." In addition, Hennekens pointed out that the initial randomized studies with rofecoxib (Vioxx, Merck) that signaled cardiovascular harm had used naproxen as a control, and as naproxen may have a beneficial effect, this could have overestimated the risk with rofecoxib. "These original studies suggested a 200% to 300% increased risk of cardiovascular events, including MI, stroke, and vascular deaths, with coxibs, but the totality of the evidence from the meta-analysis shows a much smaller risk (in the range of about a 42% increase), and this seems to be exclusively on nonfatal MI, with no apparent effect on stroke or vascular death. Regular NSAIDs also appear to have similar cardiovascular risks, except for naproxen, and it is speculated that naproxen may have a long-acting aspirin-type protective effect," he said.

Hennekens, who sat on the 2005 FDA panel that reviewed coxibs and NSAIDs, also noted that the randomized data do not suggest a difference in cardiovascular risk with rofecoxib or celecoxib (Celebrex, Pfizer), and that the FDA panel voted 31-1 to keep celecoxib on the market and 17-15 in favor of letting rofecoxib return to the market.

Hennekens says his overall message is, "Wait for the evidence and look at all the evidence before rushing to judgment." He added that there are some large randomized trials now ongoing, and a new individual patient meta-analysis of all the data so far available is also under way, which will help provide more sound information to guide decision making.

He also suggested that randomized trials should not stop once a drug is approved. "I'm not a fan of just doing one or two randomized trials to show efficacy and gain approval, then for everyone to be put on the drug to gather broader safety data. I would prefer to see longer-term randomized trials after approval. This would give us much better safety information."