Combination of a cyclo-oxygenase-2 inhibitor and a proton-pump inhibitor for prevention of recurrent ulcer bleeding in patients at very high risk: a double-blind, randomised trial.
BACKGROUND
Guidelines on pain management recommend that patients at risk of ulcers receive either a cyclo-oxygenase (COX 2) inhibitor or a non-steroidal anti-inflammatory drug (NSAID) with a proton-pump inhibitor (PPI). These two treatments have similar effectiveness, but they are insufficient for protection of patients at very high risk for ulcer bleeding. We aimed to test the hypothesis that in patients with previous ulcer bleeding induced by non-selective NSAIDs, combined treatment with the COX 2 inhibitor celecoxib and the PPI esomeprazole would be better than celecoxib alone for prevention of recurrent ulcer bleeding.


METHODS
441 consecutively presenting patients who were taking non-selective NSAIDs for arthritis were recruited to our single-centre, prospective, randomised, double-blind trial after admission to hospital with upper-gastrointestinal bleeding. Patients were enrolled after their ulcers had healed and a histological test for Helicobacter pylori was negative. All patients were given 200 mg celecoxib twice daily. 137 patients were randomly assigned to receive 20 mg esomeprazole twice daily (combined-treatment group), and 136 to receive a placebo (control group) for 12 months. The primary endpoint was recurrent ulcer bleeding during treatment or within 1 month of the end of treatment. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00365313.


RESULTS
Combination treatment was more effective than celecoxib alone for prevention of ulcer bleeding in patients at high risk. The 13-month cumulative incidence of the primary endpoint was 0% in the combined-treatment group and 12 (8.9%) in the controls (95% CI difference, 4.1 to 13.7; p=0.0004). The median follow-up was 13 months (range 0.4-13.0). Discontinuation of treatment and the incidence of adverse events were similar in the two treatment groups.


CONCLUSIONS
Patients at very high risk for recurrent ulcer bleeding who need anti-inflammatory analgesics should receive combination treatment with a COX 2 inhibitor and a PPI. Our findings should encourage guideline committees to review their recommendations for patients at very high risk of recurrent ulcer bleeding.
Chan
Francis Ka Leung
FK
Institute of Digestive Disease, Chinese University of Hong Kong, Shatin, Hong Kong SAR, China. fklchan@cuhk.edu.hk
Wong
Vincent Wai Sun
VW
Suen
Bing Yee
BY
Wu
Justin Che Yuen
JC
Ching
Jessica Yuet Ling
JY
Hung
Lawrence Cheung Tsui
LC
Hui
Aric Josun
AJ
Leung
Vincent King Sun
VK
Lee
Vivian Wing Yan
VW
Lai
Larry Hin
LH
Wong
Grace Lai Hung
GL
Chow
Dorothy Kai Lai
DK
To
Ka Fa
KF
Leung
Wai Keung
WK
Chiu
Philip Wai Yan
PW
Lee
Yuk Tong
YT
Lau
James Yun Wong
JY
Chan
Henry Lik Yuen
HL
Ng
Enders Kwok Wai
EK
Sung
Joseph Jao Yiu
JJ
D000368:Aged; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects / Q000627:therapeutic use*; D000897:Anti-Ulcer Agents / Q000009:adverse effects / Q000627:therapeutic use*; D000068579:Celecoxib; D016861:Cyclooxygenase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D064098:Esomeprazole / Q000009:adverse effects / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D008297:Male; D010003:Osteoarthritis / Q000188:drug therapy*; D010438:Peptic Ulcer Hemorrhage / Q000139:chemically induced / Q000517:prevention & control* / Q000628:therapy; D054328:Proton Pump Inhibitors; D011720:Pyrazoles / Q000009:adverse effects / Q000627:therapeutic use*; D012307:Risk Factors; D055502:Secondary Prevention; D013449:Sulfonamides / Q000009:adverse effects / Q000627:therapeutic use*; D016896:Treatment Outcome
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000897:Anti-Ulcer Agents; D016861:Cyclooxygenase Inhibitors; D054328:Proton Pump Inhibitors; D011720:Pyrazoles; D013449:Sulfonamides; D000068579:Celecoxib; D064098:Esomeprazole