Halted trials: Celecoxib tied to rise in CV risk

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 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 200mg or 400mg twice daily or 400mg 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.

Reporting on the composite results at the annual Digestive Disease Week, 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.

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 mg/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.

An asterisk to overall conclusion was the issue of the 400-mg, 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.

Questioned about a possible mechanism, doctor noted that celecoxib has a relatively short half-life, leaving hours during the day when vessels and stroma would not expose 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. Said adenomas were reduced by 36% and advanced adenomatous by 51% among patients in the trials taking celecoxib, compared with those who received placebo. The additional adenoma-reduction benefit of aspirin in conjunction with celecoxib was minimal.

Once the celecoxib trials ended, an independent safety committee led by Harvard University Boston, Mass., analyzed the data. Prevention summarized the conclusions of that panel. That investigation was sponsored by the National Cancer Institute, with no financial contribution from the drug’s manufacturer.