Dallas, TX - A 39-study meta-analysis including more than 41 000 patients that found no increased CV risk with celecoxib has now been published in the American Journal of Cardiology [1]. As previously reported by heartwire at the American College of Cardiology (ACC) 2006 Scientific Sessions, the analysis by Dr William B White (University of Connecticut, Farmington) and colleagues is the largest patient-level meta-analysis of celecoxib to date; however, the analysis did not include two studies of colon polyp prevention and a third trial of Alzheimer's disease prevention with celecoxib that have fueled debate over the cardiovascular side effects of the drug.

As previously reported by heartwire, the Adenoma Prevention with Celecoxib (APC) and the Prevention of Colorectal Sporadic Adenomatous Polyps (PreSAP) trials have subsequently been published [2,3]. Both suggested that use of celecoxib for up to three years reduced the risk of metachronous adenoma, but both trials also pointed to a significant increase in cardiovascular events, compared with placebo, most pronounced with the 400-mg dose twice daily in the APC trial (relative risk=3.4). The Alzheimer's Disease Antiinflammatory Prevention Trial (ADAPT) trial, also published in the past year, showed neither an increase nor decrease in cardiovascular risk, but the trial was stopped prematurely, at 23 months, due to concerns about the naproxen arm of the study [4].

Writing in the January 1, 2007 issue of the American Journal of Cardiology, White et al explain that the APC trial, the PreSAP trial, and ADAPT were ongoing and blinded at the time the analysis was done. On the basis of the studies that were included, however, "these analyses failed to demonstrate an increased CV risk with celecoxib relative to placebo and demonstrated a comparable rate of CV events with celecoxib treatment compared with nonselective NSAIDS," they write.

The analysis assessed incidence of cardiovascular events for celecoxib, placebo, and NSAIDs in a clinical-trial database for celecoxib using the defined end points of nonfatal MI, stroke, and cardiovascular death. Patient-level data were obtained from studies in arthritis, back pain, ankylosing spondylitis, and Alzheimer's disease. A three-member cardiovascular-end-point committee, blinded to treatment group and study, evaluated all events.

White et al report that CV events, whether adjudicated or nonadjudicated, were no different between celecoxib-treated patients and placebo-treated patients or between celecoxib-treated patients and NSAID-treated patients. No dose-response was seen for celecoxib and CV risk, nor did use of aspirin or presence of CV risk factors alter the primary results.

White et al point to drawbacks in their analysis, including the fact that only one small study tracked events beyond one year, and in the APC study, increased CV events were not seen until after 12 months of drug exposure.

Still, they conclude, "The results of this analysis fail to demonstrate a difference in the incidence of CV events compared with nonselective NSAIDs or compared with placebo up to one year of treatment exposure."

At the ACC meeting, after presenting the results, White told heartwire that his study "set the stage nicely" for the 20 000-patient Prospective Randomized Evaluation of Celecoxib Integrated Safety vs Ibuprofen or Naproxen (PRECISION) study, projected to be complete in three years and sponsored by Pfizer.