Broad regulatory investigations into the COX-2 class could quickly extend to all NSAIDs.

FDA learned of cardiovascular safety concerns with Pfizer's COX-2 Celebrex (celecoxib) on the night of Dec. 16 from the National Cancer Institute. The signals stem from an analysis of two NCI-funded long-term cancer trials.

The data safety and monitoring board for the cancer trial reported that Celebrex demonstrated an increased cardiovascular risk over placebo.

The APC trial, which looked at a variety of different cancers but focused on colorectal cancer, showed a higher cardiovascular risk as dosage increased.

Patients taking 400 mg of Celebrex twice a day were 3.4 times more likely to have a cardiovascular event compared to placebo users.

A 200 mg dose of the COX-2 twice a day resulted in a 2.5 times greater risk of CV events.

An event was defined as a heart attack, stroke or cardiovascular death. The average duration of treatment for the trial was 33 months.

"While we have not seen all available data on Celebrex, these findings are similar to recent results from a study of Vioxx (rofecoxib)," Acting FDA Commissioner Lester Crawford said during a Dec. 17 conference call with reporters. "Vioxx was recently withdrawn by Merck," he observed.

PreSAP, a second cancer study that evaluated one 400 mg dose of Celebrex per day, showed no statistically significant elevated cardiovascular risk.

FDA said it has only seen preliminary data and is gathering all available information from the trials, in addition to other studies involving Celebrex.

Pfizer's other COX-2, Bextra (valdecoxib), now carries a "black box" warning for skin irritation and has exhibited a higher cardiovascular risk for patients after heart surgery. Celebrex and Bextra are the only COX-2s available in the U.S.

Although Vioxx was withdrawn from the market about one week after cardiovascular risks became known, FDA has decided not to mandate a recall of Celebrex at the current time.

"We are keeping all regulatory options open, including a black box warning," Crawford said.

"FDA advises evaluating alternative therapy," according to Crawford. "At this time, if physicians determine that continued use is appropriate for individual patients, FDA advises the use of the lowest effective dose of Celebrex."

Crawford cautioned patients against using conventional Rx and OTC therapies, however.

"Because similar long-term studies of other products in the class of nonsteroidal anti-inflammatory drugs other than COX-2 inhibitors have not been done, it is not known whether other NSAIDs pose a similar risk."

CDER Office of New Drugs Director John Jenkins echoed Crawford's comments.

Non-selective NSAIDs carry severe risks - when used chronically - of life-threatening gastrointestinal hemorrhage, Jenkins said, noting that such events occur at "a fairly significant rate."

"We do not have long-term placebo-controlled data to assess the cardiovascular risk for any of the other nonsteroidals," Jenkins emphasized.

"We have them for the COX-2s, we don't have [them] for those other agents, so we don't know whether those other agents carry a similar increased risk, or are protective or are neutral. We have an absence of information there."

Nevertheless, Rx and OTC NSAIDs could prove to be the preferred first-line therapy for arthritis sufferers while FDA determines what regulatory action to take with Celebrex.

"These clinical trial results are new," Pfizer CEO Hank McKinnell said in a statement. "The cardiovascular findings in one of the studies are unexpected and not consistent with the reported findings in the second study."

Meanwhile, key members of Congress were quick to call for an investigation into the handling of the Celebrex situation by Pfizer and FDA. House Energy & Commerce Chairman Joe Barton (R-Tex.) wrote a letter to McKinnell asking for documentation related to Celebrex. Senate Finance Committee Chairman Chuck Grassley (R-Iowa) called for an independent commission to look into the matter.

Celebrex Heart Risk Findings In Cancer Study Deals Blow To COX-2s

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