To the Editor: Solomon et al., for the Adenoma Prevention withCelecoxib (APC) Study Investigators (March 17 issue),1 reportedan increase in cardiovascular events associated with the useof celecoxib, and two accompanying editorials2,3 supported theconclusion of a class effect for cyclooxygenase-2 (COX-2) inhibitors.Although abundant and concordant data from both randomized trialsand observational studies show that the use of rofecoxib isassociated with cardiovascular risk, the literature concerningthe risk with the use of celecoxib is more heterogeneous. Numerousobservational studies4,5,6,7,8 have failed to identify an increasedrisk with celecoxib. Moreover, among randomized trials of celecoxibwith a minimum of 12 months of follow-up, the totality of theevidence of an increased cardiovascular risk is again far fromconclusive (Figure 1). Caution in prescribing any COX-2 inhibitor,including celecoxib, is mandatory, but publication of the resultsof the APC trial without insistence on a more thorough discussionof other, similar trials may present a biased picture. Althoughan increased cardiovascular risk associated with the use ofcelecoxib is certainly possible, particularly in the incompletelystudied high-risk population, this risk has not been establishedwith the conviction implied in the Journal.
Figure 1. Risk of Cardiovascular Events Associated with the Use of Celecoxib, Placebo, or Traditional Nonsteroidal Antiinflammatory Drugs (NSAIDs) in Trials with Follow-up of at Least 12 Months.
Open circles and the black square denote hazard ratios, and horizontal lines 95 percent confidence intervals (CI). Data are from the Food and Drug Administration hearings of February 16 to 18, 2005 (www.fda.gov/ohrms/dockets/ac/05/minutes/2005-4090M1_Final.htm, accessed June 2, 2005), with the exception of the Alzheimer's Disease Antiinflammatory Prevention Trial (ADAPT) data, which are based on an extrapolation from newspaper articles. CAESAR denotes Canada, Australia, Europe, South Africa trial; IQ5-97-02-001 Double-Blind, Randomized, Placebo-Controlled, Comparative Study of Celecoxib for the Inhibition of Progression of Alzheimer's Disease; CLASS Celecoxib Long Term Arthritis Safety Study trial, APC Adenoma Prevention with Celecoxib study; and PreSAP Prevention of Spontaneous Adenomatous Polyps trial.
James M. Brophy, M.D., Ph.D. McGill University Health Center Montreal, QC H3A 1A1, Canada james.brophy{at}mcgill.ca
References
Solomon DS, McMurray JJV, Pfeffer MA, et al. Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention. N Engl J Med 2005;352:1071-1080. [Free Full Text]
Drazen JM. COX-2 inhibitors -- a lesson in unexpected problems. N Engl J Med 2005;352:1131-1132. [Free Full Text]
Psaty BM, Furberg CD. COX-2 inhibitors -- lessons in drug safety. N Engl J Med 2005;352:1133-1135. [Free Full Text]
Graham DJ, Campen D, Hui R, et al. Risk of acute myocardial infarction and sudden cardiac death in patients treated with cyclo-oxygenase 2 selective and non-selective non-steroidal anti-inflammatory drugs: nested case-control study. Lancet 2005;365:475-481. [Web of Science][Medline]
Levesque LE, Brophy JM, Zhang B. The risk for myocardial infarction with cyclooxygenase-2 inhibitors: a population study of elderly adults. Ann Intern Med 2005;142:481-489. [Free Full Text]
Shaya FT, Blume SW, Blanchette CM, Weir MR, Mullins CD. Selective cyclooxygenase-2 inhibition and cardiovascular effects: an observational study of a Medicaid population. Arch Intern Med 2005;165:181-186. [Free Full Text]
Solomon DH, Schneeweiss S, Glynn RJ, et al. Relationship between selective cyclooxygenase-2 inhibitors and acute myocardial infarction in older adults. Circulation 2004;109:2068-2073. [Free Full Text]
Ray WA, Stein CM, Hall K, Daugherty JR, Griffin MR. Non-steroidal anti-inflammatory drugs and risk of serious coronary heart disease: an observational cohort study. Lancet 2002;359:118-123. [CrossRef][Web of Science][Medline]
The authors reply: Most data on the cardiovascular risk associatedwith celecoxib have come from observational studies or short-termrandomized trials. Discrepant findings between observationalstudies and randomized trials1,2,3 underscore the potentiallimitations of observational data. A modest "signal" of harmmay also be obscured by misclassification of end points thatare not carefully adjudicated. The heterogeneity of the trialsanalyzed by Dr. Brophy — including differences in studydesign, populations, length of follow-up, dosing, and ascertainmentof outcomes — makes interpretation of these results challenging.Only three studies cited by Dr. Brophy were placebo-controlled— APC, PreSAP, and IQ5-97-02-001 — and all showedhazard ratios above 1 (the data presented for PreSAP were preliminary).The conclusions of our study were tempered by the small numberof events and wide confidence intervals; however, the internalconsistency of the data — increased hazards for all cardiovascularend points and a dose–response relationship — alongwith similar findings from trials of other drugs in this classsupport our conclusions. Moreover, a consistent safety concernshould not require the same degree of statistical convictionas a proof of benefit.
Scott D. Solomon, M.D. Brigham and Women's Hospital Boston, MA 02115 ssolomon{at}rics.bwh.harvard.edu
Janet Wittes, Ph.D. Statistics Collaborative Washington, DC 20036
John McMurray, M.D. Western Infirmary Glasgow G11 6NT, Scotland
for the APC Study Cardiovascular Safety Committee and Investigators
References
Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial. JAMA 2002;288:321-333. [Free Full Text]
Smigel K. Beta carotene fails to prevent cancer in two major studies; CARET intervention stopped. J Natl Cancer Inst 1996;88:145-145. [Free Full Text]
Lonn E, Bosch J, Yusuf S, et al. Effects of long-term vitamin E supplementation on cardiovascular events and cancer: a randomized controlled trial. JAMA 2005;293:1338-1347. [Free Full Text]
The editorialists reply: We agree that the literature concerningcelecoxib is heterogeneous. One source of the heterogeneityis discrepancies in the numbers of events reported for celecoxibacross various versions of the same trial. For instance, theoriginal CLASS trial publication included only the first sixmonths of events.1 Brophy's figure lists 46 and 48 events forone year; but the report by White and colleagues lists 49 and52 events.2 In the Alzheimer's study (IQ5-97-02-001), celecoxibis weakly associated with an increase in cardiovascular risk(odds ratio, 1.65; 95 percent confidence interval, 0.56 to 7.46),but the unpublished report indicates that "a statistically significantdifference favoring placebo in adverse events was observed forcertain cardiovascular-risk–related body system terms."3Events in some but not all of the trials were adjudicated byindependent committees. Brophy's analysis pools two differentcomparison groups, users of nonsteroidal antiinflammatory drugsand placebo groups. Timely publication and full reporting ofevents would have enabled physicians and scientists to adequatelyassess the risks associated with celecoxib.
Bruce M. Psaty, M.D., Ph.D. University of Washington Seattle, WA 98101-1448
Curt D. Furberg, M.D., Ph.D. Wake Forest University Winston-Salem,NC 27106
References
Silverstein FE, Faich G, Goldstein JL, et al. Gastrointestinal toxicity with celecoxib vs nonsteroidal antiinflammatory drugs for osteoarthritis and rheumatoid arthritis: the CLASS study: a randomized controlled trial. JAMA 2000;284:1247-1255. [Free Full Text]
White WB, Faich G, Whelton A, et al. Comparison of thromboembolic events in patients treated with celecoxib, a cyclooxygenase-2 specific inhibitor, versus ibuprofen or diclofenac. Am J Cardiol 2002;89:425-430. [CrossRef][Web of Science][Medline]
Pfizer. A double-blind, randomized, placebo-controlled, comparative study of celecoxib (SC-58635) for the inhibition of progression of Alzheimer's disease: protocol IQ5-97-02-001. (Accessed June 2, 2005, at http://www.clinicalstudyresults.org/documents/company-study_76_0.pdf.)
Schug, S. A., Joshi, G. P., Camu, F., Pan, S., Cheung, R.
(2009). Cardiovascular Safety of the Cyclooxygenase-2 Selective Inhibitors Parecoxib and Valdecoxib in the Postoperative Setting: An Analysis of Integrated Data. Anesth. Analg.
108: 299-307
[Abstract][Full Text]
Levesque, L. E., Brophy, J. M., Zhang, B.
(2006). Time variations in the risk of myocardial infarction among elderly users of COX-2 inhibitors. CMAJ
174: 1563-1569
[Abstract][Full Text]
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