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Celecoxib nearly doubled CV risk in halted trials.

LOS ANGELES -- Celecoxib cannot be recommended to reduce colorectal cancer risk--despite its proven efficacy for that indication--until more is known about its potential cardiovascular risks, coordinators of two chemoprevention trials have concluded.

Composite data from the international Prevention of Spontaneous Adenomatous Polyps (PreSAP) study and the Adenoma Prevention with Celecoxib (APC) trial revealed nearly a twofold risk in cardiovascular events in patients taking celecoxib at doses of 200 mg or 400 mg twice daily or 400 mg once daily, compared with patients assigned to placebo in the trials.

"Celecoxib cannot currently be recommended for the prevention of sporadic adenomas until we understand more clearly its potential cardiovascular toxicity and the mechanisms that underlie this," said Dr. Bernard Levin, vice president of the division of cancer prevention at the University of Texas M.D. Anderson Cancer Center, Houston.

Reporting on the composite results at the annual Digestive Disease Week, Dr. Levin stressed that there was a low absolute number of cardiovascular deaths and nonfatal cardiovascular events in both the celecoxib and placebo groups.

"Both the APC and PreSAP studies were designed with high statistical power to assess the effect on polyp recurrence. However, the analysis of cardiac events--although it was blinded and based on prespecified outcomes--was based on few events and has limited statistical power," he said.

The 51 events among 2,289 patients taking any dose of celecoxib included cardiovascular death and nonfatal myocardial infarction, stroke, or heart failure.

The hazard ratios for increased cardiovascular events among the trials and dosages were:

* 400 rag/once daily (PreSAP): 1.3

* 200 mg/twice daily (APC): 2.6

* 400 mg/twice daily (APC): 3.4

The composite hazard ratio for both trials and all doses was 1.9, a difference that was statistically significant.

Neither concomitant aspirin use nor prior cardiovascular events produced a differentially elevated risk, although prior cardiovascular events did increase the absolute risk for a cardiovascular event during the trials, Dr. Levin reported. An asterisk to his overall conclusion was the issue of the 400mg, once-daily dose of celecoxib prescribed in the PreSAP study, which, taken on its own, did not show a statistically significant elevation in the composite end point of any fatal or nonfatal cardiovascular event.

This finding "raises the possibility" that once-daily dosing poses a lower cardiovascular risk, although more study is needed, he said.

Questioned about a possible mechanism, Dr. Levin noted that celecoxib has a relatively short half-life, leaving hours during the day when vessels and stroma would not be exposed to the drug following a once-daily dose.

The evidence for adenoma prevention was quite strong when the two celecoxib trials were prematurely halted following the September 2004 suspension of the Adenomatous Polyp Prevention on Vioxx (APPROVe) trial in response to cardiovascular concerns with that COX-2 inhibitor.

Dr. Levin reported that adenomas were reduced by 36% with celecoxib and advanced adenomas by 51% among patients in the trials taking celecoxib 400 mg once daily as compared with those who received placebo. The additional adenoma-reduction benefit of aspirin in conjunction with celecoxib was minimal, he said.

Once the celecoxib trials ended, an independent safety committee led by Dr. Scott D. Solomon of Harvard University, Cambridge, Mass., analyzed the data. Dr. Levin's presentation summarized the conclusions of that panel. That investigation was entirely sponsored by the National Cancer Institute, without any financial contribution from the drug's manufacturer, Pfizer Inc.

BY BETSY BATES

Los Angeles Bureau
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Title Annotation:Cardiovascular disease
Author:Bates, Betsy
Publication:Family Practice News
Article Type:Disease/Disorder overview
Geographic Code:1USA
Date:Jul 15, 2006
Words:569
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