FDA Now Reviewing Panel's Nod to COX-2s : Celecoxib garnered nearly unanimous support; vote was more divided on rofecoxib and valdecoxib.

The data were considered more compelling for rofecoxib. Dr. Nissen, who voted against supporting the marketing of rofecoxib, except possibly under a compassionate use program, said the evidence of risk for rofecoxib raised more concerns.

He referred to blood pressure increases and a signal for heart failure “clearly” outside those of other drugs in the class demonstrated in the Adenomatous Polyp Prevention on Vioxx trial, at a daily dose of 25 mg–effects not seen at lower doses of celecoxib.

Compared with celecoxib and rofecoxib, there is much less information on valdecoxib, with data from only two trials available. Dr. Wood said he was uncertain whether the available data supported continued marketing of valdecoxib, which has a clear risk and no evidence of GI benefit. Referring to comments made at the meeting about patient choices, he said “it seems highly improbable” that valdecoxib is safer than celecoxib, given the size of the signal in the CABG study.

The panel agreed that some type of warning should be added to the labels of the more than 20 nonselective NSAIDs approved in the United States, for which safety has not been studied in long-term, large, placebo-controlled trials like those done for the COX-2-selective drugs.

However, several panelists recommended against using the same warning for all nonselective NSAIDs, given that naproxen as a comparator in trials seemed to do better than many of the other such drugs.

But there is still more to be learned about the traditional NSAIDs' safety, cautioned Dr. Wood, professor of medicine and pharmacology at Vanderbilt University, Nashville. However, the available data suggest that “naproxen is more beneficial than some of the others,” but it is associated with GI risks, so patients using naproxen could take a proton pump inhibitor (PPI).

There are not many data on naproxen given with a PPI, but there are “certainly data in other settings” supporting this approach, he noted.

At the meeting, Garret FitzGerald, M.D., professor of cardiovascular medicine at the University of Pennsylvania, a guest speaker for the FDA, said that given the pharmacoepidemiology and the body of evidence from clinical trials, “most rational people would accept a class-based mechanism” for these drugs.

He said that in five placebo-controlled trials with three structurally distinct COX-2 inhibitors, an increase in MI and/or stroke has been documented.

Dr. Steven Abramson (left) and Dr. Steven Nissen agree that among the COX-2s, celecoxib appears to have the weakest risk for cardiovascular events. James Reinaker