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 6placebo-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.
RCT Entities:
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.
Authors: Nancy A Nussmeier; Andrew A Whelton; Mark T Brown; Richard M Langford; Andreas Hoeft; Joel L Parlow; Steven W Boyce; Kenneth M Verburg Journal: N Engl J Med Date: 2005-02-15 Impact factor: 91.245
Authors: Robert S Bresalier; Robert S Sandler; Hui Quan; James A Bolognese; Bettina Oxenius; Kevin Horgan; Christopher Lines; Robert Riddell; Dion Morton; Angel Lanas; Marvin A Konstam; John A Baron Journal: N Engl J Med Date: 2005-02-15 Impact factor: 91.245
Authors: Peter H Stone; Ahmet Umit Coskun; Yerem Yeghiazarians; Scott Kinlay; Jeffrey J Popma; Richard E Kuntz; Charles L Feldman Journal: Curr Opin Cardiol Date: 2003-11 Impact factor: 2.161
Authors: B F McAdam; F Catella-Lawson; I A Mardini; S Kapoor; J A Lawson; G A FitzGerald Journal: Proc Natl Acad Sci U S A Date: 1999-01-05 Impact factor: 11.205
Authors: Sanjeewani T Palayoor; Molykutty J-Aryankalayil; Adeola Y Makinde; David Cerna; Michael T Falduto; Scott R Magnuson; C Norman Coleman Journal: J Cardiovasc Pharmacol Date: 2012-06 Impact factor: 3.105
Authors: Gudrun Stefansdottir; Marie L De Bruin; Mirjam J Knol; Diederick E Grobbee; Hubert G M Leufkens Journal: Drug Saf Date: 2011-09-01 Impact factor: 5.606
Authors: Andrew T Chan; Ann G Zauber; Meier Hsu; Aurora Breazna; David J Hunter; Rebecca B Rosenstein; Craig J Eagle; Ernest T Hawk; Monica M Bertagnolli Journal: Gastroenterology Date: 2009-02-21 Impact factor: 22.682
Authors: Kathrin Strasser-Weippl; Michaela J Higgins; Judith-Anne W Chapman; James N Ingle; George W Sledge; George T Budd; Matthew J Ellis; Kathleen I Pritchard; Mark J Clemons; Tanja Badovinac-Crnjevic; Lei Han; Karen A Gelmon; Manuela Rabaglio; Catherine Elliott; Lois E Shepherd; Paul E Goss Journal: J Natl Cancer Inst Date: 2018-09-01 Impact factor: 13.506
Authors: Gilad Rimon; Ranjinder S Sidhu; D Adam Lauver; Jullia Y Lee; Narayan P Sharma; Chong Yuan; Ryan A Frieler; Raymond C Trievel; Benedict R Lucchesi; William L Smith Journal: Proc Natl Acad Sci U S A Date: 2009-12-01 Impact factor: 11.205