Published online before print March 31, 2008, doi: 10.1161/CIRCULATIONAHA.108.764530
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
(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
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.
CLINICAL PERSPECTIVE
Related Article:
-
Clinical Summaries
Circulation 2008 117: 2041.[Extract] [Full Text]
This article has been cited by other articles:
 |
|
 |
|
  G. Rimon, R. S. Sidhu, D. A. Lauver, J. Y. Lee, N. P. Sharma, C. Yuan, R. A. Frieler, R. C. Trievel, B. R. Lucchesi, and W. L. Smith Coxibs interfere with the action of aspirin by binding tightly to one monomer of cyclooxygenase-1 PNAS, December 1, 2009; (2009) 0909765106v1. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. D. Kekatpure, J. O. Boyle, X. K. Zhou, A. J. Duffield-Lillico, N. D. Gross, N. Y. Lee, K. Subbaramaiah, J. D. Morrow, G. Milne, S. M. Lippman, et al. Elevated Levels of Urinary Prostaglandin E Metabolite Indicate a Poor Prognosis in Ever Smoker Head and Neck Squamous Cell Carcinoma Patients Cancer Prevention Research, November 1, 2009; 2(11): 957 - 965. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. I. Neugut Aspirin as Adjuvant Therapy for Colorectal Cancer: A Promising New Twist for an Old Drug JAMA, August 12, 2009; 302(6): 688 - 689. [Full Text] [PDF]
|
|
|
|
 |
|
 S. M. Lippman and E. T. Hawk Cancer Prevention: From 1727 to Milestones of the Past 100 Years Cancer Res., July 1, 2009; 69(13): 5269 - 5284. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. M. Lippman Cancer Prevention Research: Back to the Future Cancer Prevention Research, June 1, 2009; 2(6): 503 - 513. [Full Text] [PDF]
|
|
|
|
 |
|
 F. Seta, A. D. Chung, P. V. Turner, J. D. Mewburn, Y. Yu, and C. D. Funk Renal and cardiovascular characterization of COX-2 knockdown mice Am J Physiol Regulatory Integrative Comp Physiol, June 1, 2009; 296(6): R1751 - R1760. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. T. Nicholson, B. Vaa, C. Hesse, J. H. Eisenach, and M. J. Joyner Aging Is Associated With Reduced Prostacyclin-Mediated Dilation in the Human Forearm Hypertension, June 1, 2009; 53(6): 973 - 978. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. J. Duffield-Lillico, J. O. Boyle, X. K. Zhou, A. Ghosh, G. S. Butala, K. Subbaramaiah, R. A. Newman, J. D. Morrow, G. L. Milne, and A. J. Dannenberg Levels of Prostaglandin E Metabolite and Leukotriene E4 Are Increased in the Urine of Smokers: Evidence that Celecoxib Shunts Arachidonic Acid into the 5-Lipoxygenase Pathway Cancer Prevention Research, April 1, 2009; 2(4): 322 - 329. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. N. DuBois New, Long-term Insights from the Adenoma Prevention with Celecoxib Trial on a Promising but Troubled Class of Drugs Cancer Prevention Research, April 1, 2009; 2(4): 285 - 287. [Full Text] [PDF]
|
|
|
|
|
|
J. A. Zell, D. Pelot, W.-P. Chen, C. E. McLaren, E. W. Gerner, and F. L. Meyskens Risk of Cardiovascular Events in a Randomized Placebo-Controlled, Double-Blind Trial of Difluoromethylornithine plus Sulindac for the Prevention of Sporadic Colorectal Adenomas Cancer Prevention Research, March 1, 2009; 2(3): 209 - 212. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. M. Bertagnolli, A. G. Zauber, and S. Solomon Prostaglandin Inhibition and Cardiovascular Risk: Maybe Timing Really Is Everything Cancer Prevention Research, March 1, 2009; 2(3): 195 - 196. [Full Text] [PDF]
|
|
|
|
 |
|
 R B. Haynes and L. Hart Evidence in context: one person's poison is another's acceptable risk Evid. Based Med., February 1, 2009; 14(1): 5 - 5. [Full Text] [PDF]
|
|
|
|
 |
|
 C. Patrono and C. Baigent Low-Dose Aspirin, Coxibs, and other NSAIDS: A Clinical Mosaic Emerges Mol. Interv., February 1, 2009; 9(1): 31 - 39. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. J. Warner, R. A. Weideman, K. C. Kelly, E. S. Brilakis, S. Banerjee, F. Cunningham, W. V. Harford, S. Kazi, B. B. Little, and B. Cryer The Risk of Acute Myocardial Infarction with Etodolac Is not Increased Compared to Naproxen: A Historical Cohort Analysis of a Generic COX-2 Selective Inhibitor Journal of Cardiovascular Pharmacology and Therapeutics, December 1, 2008; 13(4): 252 - 260. [Abstract] [PDF]
|
|
|
|
 |
|
 L. A. Garcia Rodriguez, S. Tacconelli, and P. Patrignani Role of Dose Potency in the Prediction of Risk of Myocardial Infarction Associated With Nonsteroidal Anti-Inflammatory Drugs in the General Population J. Am. Coll. Cardiol., November 11, 2008; 52(20): 1628 - 1636. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. L Meinert, B. K Martin, L. D McCaffrey, and J. C. Breitner Do we need to adjudicate major clinical events? Clinical Trials, October 1, 2008; 5(5): 557 - 557. [PDF]
|
|
|
|
|
|
C. B. Granger, N. L. Stockbridge, V. G. Vogel, and S. R. Cummings Response to letter of Meinert et al Clinical Trials, October 1, 2008; 5(5): 558 - 558. [PDF]
|
|
|
|
|
|
E. Szabo Assessing Efficacy in Early-Phase Cancer Prevention Trials: The Case of Oral Premalignancy Cancer Prevention Research, October 1, 2008; 1(5): 312 - 315. [Full Text] [PDF]
|
|
|
|
 |
|
 J. Lenzer Truly independent research? BMJ, August 21, 2008; 337(aug21_1): a1332 - a1332. [Full Text]
|
|