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(Circulation. 2008;117:2104-2113.)
© 2008 American Heart Association, Inc.

Preventive Cardiology

Cardiovascular Risk of Celecoxib in 6 Randomized Placebo-Controlled Trials

The Cross Trial Safety Analysis

Scott D. Solomon, MD; Janet Wittes, PhD; Peter V. Finn, MD; Robert Fowler, MS; Jaye Viner, MD, MPH; Monica M. Bertagnolli, MD; Nadir Arber, MD; Bernard Levin, MD; Curtis L. Meinert, PhD; Barbara Martin, PhD; Joseph L. Pater, MD, MSc; Paul E. Goss, MD, PhD; Peter Lance, MD; Stefanie Obara, BS; Emily Y. Chew, MD; Jonghyeon Kim, PhD; Gretchen Arndt, MHSA; Ernest Hawk, MD, MPH, for the Cross Trial Safety Assessment Group

From the Cardiovascular Division (S.D.S., P.V.F.) and Department of Surgery (M.B.), Brigham and Women’s Hospital, Boston, Mass; Statistics Collaborative, Inc (J.W., R.F., G.A.), Washington, DC; National Cancer Institute (J.V., E.H.), Bethesda, Md; Division of Cancer Prevention and Population Sciences (B.L.), UT MD Anderson Cancer Center, Houston, Tex; Division of Epidemiology and Clinical Research (E.C.), National Eye Institute, Bethesda, Md; Johns Hopkins Medical Institutes (C.M., B.M.), Baltimore, Md; Massachusetts General Hospital (P.G.), Boston; Arizona Cancer Center (P.L., S.O.), Tucson, Ariz; EMMES Corporation (J.K.), Rockville, Md; National Cancer Institute of Canada Clinical Trials Group (J.P.), Kingston, Ontario; and Tel Aviv University (N.A.), Tel Aviv, Israel.

Correspondence to Scott D. Solomon, MD, Cardiovascular Division, Brigham and Women’s Hospital, 75 Francis St, Boston, MA 02115. E-mail ssolomon{at}rics.bwh.harvard.edu

Received January 3, 2008; accepted February 21, 2008.

Background— Observational studies and randomized trials have reported increased cardiovascular risk associated with cyclooxygenase-2 inhibitors. Prior placebo-controlled randomized studies had limited ability to assess the relationship of either celecoxib dose or pretreatment cardiovascular status to risk associated with celecoxib. Our aim was to assess the cardiovascular risk associated with celecoxib in 3 dose regimens and to assess the relationship between baseline cardiovascular risk and effect of celecoxib on cardiovascular events.

Methods and Results— We performed a patient-level pooled analysis of adjudicated data from 7950 patients in 6 placebo-controlled trials comparing celecoxib with placebo for conditions other than arthritis with a planned follow-up of at least 3 years. Patients were administered celecoxib in 3 dose regimens: 400 mg QD, 200 mg BID, or 400 mg BID. From the pooled data, we calculated a hazard ratio for all dose regimens combined and individual hazard ratios for each dose regimen and examined whether celecoxib-related risk was associated with baseline cardiovascular risk. The primary end point was the combination of cardiovascular death, myocardial infarction, stroke, heart failure, or thromboembolic event. With 16 070 patient-years of follow-up, the hazard ratio for the composite end point combining the tested doses was 1.6 (95% CI, 1.1 to 2.3). The risk, which increased with dose regimen (P=0.0005), was lowest for the 400-mg-QD dose (hazard ratio, 1.1; 95% CI, 0.6 to 2.0), intermediate for the 200-mg-BID dose (hazard ratio, 1.8; 95% CI, 1.1 to 3.1), and highest for the 400-mg-BID dose (hazard ratio, 3.1; 95% CI, 1.5 to 6.1). Patients at highest baseline risk demonstrated disproportionately greater risk of celecoxib-related adverse events (P for interaction=0.034).

Conclusions— We observed evidence of differential cardiovascular risk as a function of celecoxib dose regimen and baseline cardiovascular risk. By further clarifying the extent of celecoxib-related cardiovascular risk, these findings may help guide treatment decisions for patients who derive clinical benefit from selective cyclooxygenase-2 inhibition.

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