COX-2 inhibitors may be a better bet than the older NSAIDs

Although they have come in for a tremendous amount of criticism over the past year, the selective COX-2 inhibitors may turn out to be a better bet overall than the older nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) for many patients, argue two UK researchers In a detailed review of both science and the clinical data in the January 1, 2006 issue of Nature Reviews Drug Discovery, they comment that further analysis may eventually lead to the conclusion that COX-2-selective drugs carry a similar risk to NSAIDs when it comes to cardiovascular events but that they have a lower gastrointestinal risk. If this does transpire, “we would be back to where the COX-2 field started – the possibility of newer drugs with improved overall safety.”

In fact, the evidence so far suggests that the cardiovascular risks are very similar for selective COX-2 inhibitors and nonselective NSAIDs, lead author Prof Tim Warner (William Harvey Research Institute, London, UK) tells rheumawire. There’s been a lot of focus on selectivity and on how the newer drugs differ from the older drugs, and “as scientists we’ve been very interested in this, but with regard to clinical use, COX-2 selectivity in a test-tube is much less important. In the way these drugs are used, it must be realized that once in the body, they all inhibit the COX-2 enzyme,” he says. “If, as many people hold, it is the inhibition of the COX-2 enzyme that underlies the cardiovascular risk, then there wouldn’t be much difference in this adverse effect between the selective COX-2 inhibitors and the nonselective NSAIDs, because they all inhibit the COX-2 enzyme.” In the review, Warner and his coauthor Dr Jane Mitchell (Royal Brompton Hospital, London, UK), suggest that the newer drugs would be more accurately described as being “COX-1 sparing” rather than COX-2 selective and speculate that it is this COX-1 sparing that underlines the crucial differences between the two groups of drugs. They also argue against the use of the term “coxib,” which has been loosely used for these newer agents, pointing out that this is neither a chemical nor pharmacological class. “Overall, we should remember that COX-2-selective inhibitors are members of the NSAID class, and all produce their therapeutic effects through the common mechanism of inhibiting COX-2,” the authors write. “I think that many people haven’t really got this point,” Warner comments to rheumawire. “People seem to think that the selective COX-2 inhibitors are doing something different, but in fact the difference between them and traditional NSAIDs doesn’t lie in what the newer drugs do, it lies in what they don’t do.” He believes that general physicians would have a better understanding of these drugs if they had been called COX-1 sparing and recalls that his group did suggest this name quite early on in the development of these products in a letter to the Lancet, but it “wasn’t early enough, as the other name had already been widely used.” The review also notes that recent regulatory announcements made on this class of compounds have highlighted the fact that the cardiovascular risks associated with selective COX-2 inhibitors appear to be similar to those associated also with the nonselective NSAIDS. In the US, the FDA concluded that the available data are best interpreted as being consistent with a class effect of an increased risk of serious adverse CV events for both and ruled that all these drugs should carry a boxed warning. European and Canadian regulators have also reached similar conclusions, the review notes. It also points out that Health Canada’s expert panel voted overwhelmingly in July 2005 that the benefits of rofecoxib outweigh its potential cardiovascular harm (although by this time, the drug was already off the market). (Source: 1)Mitchell JA and Warner TD. COX isoforms in the cardiovascular system: understanding the activities of nonsteroidal anti-inflammatory drugs. Nat Rev Drug Discov 2006; 5:75-86. Rheumawire: Zosia Chustecka: Joint and Bone: January 2006.)