title: 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.
abstract: 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.
authors.affiliation: Institute of Digestive Disease, Chinese University of Hong Kong, Shatin, Hong Kong SAR, China. fklchan@cuhk.edu.hk
authors.forename: Francis Ka Leung
authors.initials: FK
authors.lastname: Chan
authors.forename: Vincent Wai Sun
authors.initials: VW
authors.lastname: Wong
authors.forename: Bing Yee
authors.initials: BY
authors.lastname: Suen
authors.forename: Justin Che Yuen
authors.initials: JC
authors.lastname: Wu
authors.forename: Jessica Yuet Ling
authors.initials: JY
authors.lastname: Ching
authors.forename: Lawrence Cheung Tsui
authors.initials: LC
authors.lastname: Hung
authors.forename: Aric Josun
authors.initials: AJ
authors.lastname: Hui
authors.forename: Vincent King Sun
authors.initials: VK
authors.lastname: Leung
authors.forename: Vivian Wing Yan
authors.initials: VW
authors.lastname: Lee
authors.forename: Larry Hin
authors.initials: LH
authors.lastname: Lai
authors.forename: Grace Lai Hung
authors.initials: GL
authors.lastname: Wong
authors.forename: Dorothy Kai Lai
authors.initials: DK
authors.lastname: Chow
authors.forename: Ka Fa
authors.initials: KF
authors.lastname: To
authors.forename: Wai Keung
authors.initials: WK
authors.lastname: Leung
authors.forename: Philip Wai Yan
authors.initials: PW
authors.lastname: Chiu
authors.forename: Yuk Tong
authors.initials: YT
authors.lastname: Lee
authors.forename: James Yun Wong
authors.initials: JY
authors.lastname: Lau
authors.forename: Henry Lik Yuen
authors.initials: HL
authors.lastname: Chan
authors.forename: Enders Kwok Wai
authors.initials: EK
authors.lastname: Ng
authors.forename: Joseph Jao Yiu
authors.initials: JJ
authors.lastname: Sung
mesh_terms: 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
chemical_list: 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