EBQ:Omeprazole in Bleeding Peptic Ulcers

incomplete Journal Club Article

Lau JYW, et al. "Effect of Intravenous Omeprazole on Recurrent Bleeding after Endoscopic Treatment of Bleeding Peptic Ulcer". NEJM. 2000. 343(5):310-316.
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Clinical Question

Does high dose intravenous omeprazole reduce the incidence of recurrent bleeding in patients who have undergone endoscopic intervention for bleeding peptic ulcers?

Conclusion

High-dose infusion of omeprazole after endoscopic treatment of bleeding peptic ulcers substantially reduces the risk of recurrent bleeding.

Major Points

• Bleeding recurrence in 30 days was 6.7% (8 patients) in the omeprazole group, and 22.% (27 patients) in the placebo group
• In vitro studies have shown that high intragastric pH could facilitate platelet aggregation, thus preventing bleeding.<ref> Green FW Jr, Kaplan MM, Curtis LE, Levine PH. Effect of acid and pepsin on blood coagulation and platelet aggregation: a possible contrivutor prolonged gastroduodenal mucosal hemorrhage. Gastroenterology 1978;74:38-43.

Study Design

• Randomized, double-blind, placebo-controlled study
• Patients underwent endoscopy within 24 hours after admission
• Patients with actively bleeeding ulcers or ulcers with nonbleeding visible vessels were treated with local epi injection followed by thermocoagulation
• After hemostasis achieved, patients were randomly assigned in double-blind fashion to receive omeprazole or placebo. (details in interventions)
• After infusion, all patients were given 20 mg omeprazole PO daily for 8 weeks
• Primary end point was recurrent bleeding within 30 days after endoscopy
  • Bleeding was considered to have recurred if any of the following occurred: vomiting of fresh blood, shock (SBP <90 mm Hg or HR >110) with melena after stabilization, or a drop of Hb >2 g/dL within 24 hours after a transfusion to 10 g/dL
  • Patients judged to have recurrent bleeding underwent urgent endoscopy
• All patients reevaluated at eight weeks in outpatient clinic
• All investigators remained unaware of the patients' treatment assignment until the study was completed

Population

Patient Demographics

Omeprazole vs. Placebo
Male: 66.7% vs. 66.7%
Age: 64 vs. 67
Hemoglobin (g/dL): 9.4 vs. 9.5
Location of ulcer:

Stomach: 44% vs. 40%

Duodenum: 54% vs. 54%

Stoma: 2% vs. 6%

Endoscopic signs of bleeding:

Spurting hemorrhage: 12% vs. 8%

Oozing hemorrhage: 42% vs. 41%

Nonbleeding visible vessel: 32% vs. 30%

Clot with underlying vessel: 15% vs. 22%

Size of ulcer (cm): 1.2 vs. 1.1
Previous ulcer disease: 32% vs. 38%
Previous ulcer bleeding: 30% vs. 30%
Recent use of H2 antagonist or PPI: 2% vs. 2%
Risk factor of bleeding peptic ulcer:

H.pylori infection: 65% vs. 53%

Use of NSAIDs: 33% vs. 33%

Use of aspirin: 19% vs. 15%

Use of warfarin: 4% vs. 4%

Development of bleeding during hospitalization: 18% vs. 19%
Pts with coexisting illnesses: 25% vs. 30%

Inclusion Criteria

• Admitted to Prince of Wales Hospital from May 1998 to July 1999 with bleeding peptic ulcers
• >16 years
• Patients with successful endoscopic treatment of actively bleeding ulcers or ulcers with nonbleeding visible vessels

Exclusion Criteria

• Unsuccessful endoscopic treatment, requiring immediate surgery
• Ulcers with clean bases or flat pigments on endoscopy, therefore not requiring endoscopic treatment
• 10 patients excluded due to terminal cancer
• 9 patients excluded as they were moribund from concomitant illnesses

Interventions

• After endoscopic treatment, patients were randomly assigned to receive an intravenous infusion of placebo or omeprazole, given as an 80-mg bolus injection followed by a continuous infusion of 8 mg per hour for a period of 72 hours.
  • Identical-appearing vials of omeprazole and placebo were prepared by pharmacy with random numbers in blocks of 80
  • Eligible patients were given the lowest-numbered treatment package
  • Treatment was started in the recovery area of the endoscopy suite and continued in a surgical ward

Outcomes

n=240, 120 patients in each group

• End point data analyzed according to intention-to-treat principle

Primary Outcome

• Bleeding recurred within 30 days after treatment in 8 patients (6.7%) in omeprazole group, as compared with 27 (22.5%) in the placebo group.
• Hazard ratio: 3.9 (95% CI 1.7-9.0)
• Recurrent bleeding most common in first 3 days: 4.2% in omeprazole vs. 20% in placebo

Secondary Outcomes

• Mean number of units transfused after endoscopy was significant smaller in omepraole group (1.7 vs. 2.4 units, P=0.03)
  • Mean number of units transfused before treatment was similar in the groups (1.0 vs. 1.1, P=0.46)
• Significantly more patients in the omeprazole group had a hospital stay <5 days (46.7% vs. 31.7%, P=0.02)
• No significant difference in patients who underwent surgery (2.5% in omeprazole group vs. 7.5% in placebo group, P=0.14)
• No significant difference in patients who died within 30 days after endoscopy (4.2% in omeprazole group vs. 10% in placebo group, P=0.13)

Criticisms & Further Discussion

• Study intended to recruit 320 patients and to conduct four interim analysis. However, the trial was terminated after the third planned interim analysis with 240 patients because a significant different (P<0.001) between the groups.

Funding

Supported in full by a grant from the Research Grants council of the Hong Kong Special Administration Region