Cardiovascular risk of celecoxib in 6 randomized placebo-controlled trials: the cross trial safety analysis.
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.


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.
Solomon
Scott D
SD
Cardiovascular Division, Brigham and Women's Hospital, 75 Francis St, Boston, MA 02115, USA. ssolomon@rics.bwh.harvard.edu
Wittes
Janet
J
Finn
Peter V
PV
Fowler
Robert
R
Viner
Jaye
J
Bertagnolli
Monica M
MM
Arber
Nadir
N
Levin
Bernard
B
Meinert
Curtis L
CL
Martin
Barbara
B
Pater
Joseph L
JL
Goss
Paul E
PE
Lance
Peter
P
Obara
Stefanie
S
Chew
Emily Y
EY
Kim
Jonghyeon
J
Arndt
Gretchen
G
Hawk
Ernest
E
D002318:Cardiovascular Diseases / Q000453:epidemiology*; D000068579:Celecoxib; D052246:Cyclooxygenase 2 Inhibitors / Q000009:adverse effects*; D005500:Follow-Up Studies; D006801:Humans; D011720:Pyrazoles / Q000009:adverse effects*; D016032:Randomized Controlled Trials as Topic / Q000706:statistics & numerical data*; D018570:Risk Assessment; D012307:Risk Factors; D013449:Sulfonamides / Q000009:adverse effects*
D052246:Cyclooxygenase 2 Inhibitors; D011720:Pyrazoles; D013449:Sulfonamides; D000068579:Celecoxib