Effect of celecoxib on cardiovascular events and blood pressure in two trials for the prevention of colorectal adenomas.
BACKGROUND
Cyclooxygenase-2 (COX-2) inhibitors have been shown to reduce colorectal adenomas but have been associated with increased cardiovascular risk.


RESULTS
The Adenoma Prevention With Celecoxib (APC) trial studied celecoxib 200 mg twice daily and 400 mg twice daily and the Prevention of Spontaneous Adenomatous Polyps (PreSAP) trial used 400 mg once daily totest the efficacy and safety of celecoxib against placebo in reducing colorectal adenoma recurrence after polypectomy. An independent safety committee for both studies adjudicated and categorized serious cardiovascular events and then combined individual patient data from these long-term trials to improve the estimate of the cardiovascular risk and blood pressure changes associated with celecoxib compared with placebo. For adjudicated cardiovascular events, 77% and 54% in APC and PreSAP, respectively, had 37 months of follow-up. For APC and PreSAP combined, 83 patients experienced cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or heart failure. The hazard ratio for this prespecified composite end point was 2.6 (95% confidence interval [CI], 1.1 to 6.1) in patients taking 200 mg twice daily, 3.4 (95% CI, 1.5 to 7.9) in patients taking 400 mg twice daily in APC, and 1.3 (95% CI, 0.6 to 2.6) in patients taking 400 mg once daily in PreSAP (P for heterogeneity = 0.13 comparing the combined doses in APC with the dose in PreSAP). The overall hazard ratio for this composite end point was 1.9 (95% CI, 1.1 to 3.1). Both dose groups in APC showed significant systolic blood pressure elevations at 1 and 3 years (200 mg twice daily: 1 year, 2.0 mm Hg; 3 years,2.6 mm Hg; 400 mg twice daily: 1 year, 2.9 mm Hg; 3 years, 5.2 mm Hg); however, the 400 mg once daily group inPreSAP did not (P0.0001 between studies).


CONCLUSIONS
Celecoxib at 200 or 400 mg twice daily or 400 mg once daily showed a nearly 2-fold-increased cardiovascular risk. The trend for a dose-related increase in cardiovascular events and blood pressure raises the possibility that lower doses or other dose intervals may be associated with less cardiovascular risk.
Solomon
Scott D
SD
Cardiovascular Division, Brigham and Women's Hospital, Boston, Mass 02115, USA. ssolomon@rics.bwh.harvard.edu
Pfeffer
Marc A
MA
McMurray
John J V
JJ
Fowler
Rob
R
Finn
Peter
P
Levin
Bernard
B
Eagle
Craig
C
Hawk
Ernest
E
Lechuga
Mariajosé
M
Zauber
Ann G
AG
Bertagnolli
Monica M
MM
Arber
Nadir
N
Wittes
Janet
J
D000236:Adenoma / Q000453:epidemiology / Q000517:prevention & control*; D000368:Aged; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D001794:Blood Pressure / Q000187:drug effects*; D002318:Cardiovascular Diseases / Q000139:chemically induced / Q000401:mortality; D002320:Cardiovascular Physiological Phenomena; D000068579:Celecoxib; D015179:Colorectal Neoplasms / Q000453:epidemiology / Q000517:prevention & control*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010919:Placebos; D011720:Pyrazoles / Q000627:therapeutic use*; D018570:Risk Assessment; D012449:Safety; D013449:Sulfonamides / Q000627:therapeutic use*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D010919:Placebos; D011720:Pyrazoles; D013449:Sulfonamides; D000068579:Celecoxib