EBQ:Omeprazole in Bleeding Peptic Ulcers: Difference between revisions

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==Criticisms & Further Discussion==
==Criticisms & Further Discussion==
===Outcomes===
*Composite primary outcome used: included vomiting, shock with melena, or drop of Hb>2 g/dL after transfusion to 10 g/dL
**Hb of 10 g/dL no longer regarded as standard for transfusion threshold. A more conservative threshold of 7 g/dL has been shown to have overall benefit in the literature. <ref>Villanueva C. et al. "Transfusion strategies for acute upper gastrointestinal bleeding". NEJM. 2013. 368(1):11-21.</ref>
**Studied end points may not directly translate to the emergency department, as the composite outcomes do not require the patient to be clinically sick.
===Study Design===
*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.  
*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.  
*Researchers chose to exclude patients with flat pigments or clean bases seen on endoscopy, due to their low risk of recurrent bleeding <ref> Lanas A, Artal A, Blas JM, Arroyo MT, Lopez-Zaborras J, Sainz R. Effect of parenteral omeprazole and ranitidine on gastric pH and the outcome of bleeding peptic ulcer. J Clin Gastroenterol 1995;21:103-6. </ref>
*Researchers chose to exclude patients with flat pigments or clean bases seen on endoscopy, due to their low risk of recurrent bleeding <ref> Lanas A, Artal A, Blas JM, Arroyo MT, Lopez-Zaborras J, Sainz R. Effect of parenteral omeprazole and ranitidine on gastric pH and the outcome of bleeding peptic ulcer. J Clin Gastroenterol 1995;21:103-6. </ref>
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*The researchers propose that decreased intragastric pH leads to decreased re-bleeding, however this was not directly measured with pH monitoring
*The researchers propose that decreased intragastric pH leads to decreased re-bleeding, however this was not directly measured with pH monitoring
**Previous studies in white patients have shown high doses of [[omeprazole]] to neutralize intragastric pH. <ref> Labenz J, Peitz U, Leusing C, Tillenburg B, Blum AL, Borsch G. Efficacy of primed infusions with high dose ranitidine and omeprazole to maintain high intragastric pH in patients with peptic ulcer bleeding: a prospective randomised controlled study. Gut 1997;40:36-41 </ref>
**Previous studies in white patients have shown high doses of [[omeprazole]] to neutralize intragastric pH. <ref> Labenz J, Peitz U, Leusing C, Tillenburg B, Blum AL, Borsch G. Efficacy of primed infusions with high dose ranitidine and omeprazole to maintain high intragastric pH in patients with peptic ulcer bleeding: a prospective randomised controlled study. Gut 1997;40:36-41 </ref>
**Although this study specifically demonstrated the use of [[omeprazole]] after endoscopic treatment, the principle can be translated to use in the emergency department for patients with bleeding peptic ulcers.
**Although this study specifically demonstrated the use of [[omeprazole]] after endoscopic treatment, the principle can be translated to use in the emergency department for patients with bleeding peptic ulcers.
 
 


==Funding==
==Funding==

Revision as of 17:10, 28 September 2015

Under Review 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.
PubMed Full text PDF

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, with bleeding most commonly occurring in the first 3 days after treatment.
    • Hazard ratio: 3.9 (95% CI 1.7-9.0)
    • Study stopped early due to significant difference between omeprazole and placebo (P<0.001)
  • In vitro studies have shown that high intragastric pH could facilitate platelet aggregation, thus preventing bleeding.[1] While this study did not directly measure intragastric pH, it supports the idea that neutralized pH will increase platelet aggregation

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

  • Patients admitted to Prince of Wales Hospital from May 1998 to July 1999 with bleeding peptic ulcers
  • >16 years old
  • 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
  • Terminal cancer (n=10)
  • Moribund from concomitant illnesses (n=9)

Interventions

  • After endoscopic treatment, patients were randomly assigned to receive an intravenous infusion of placebo or omeprazole
    • Infusion 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 omeprazole 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)


Subgroup analysis

Criticisms & Further Discussion

Outcomes

  • Composite primary outcome used: included vomiting, shock with melena, or drop of Hb>2 g/dL after transfusion to 10 g/dL
    • Hb of 10 g/dL no longer regarded as standard for transfusion threshold. A more conservative threshold of 7 g/dL has been shown to have overall benefit in the literature. [2]
    • Studied end points may not directly translate to the emergency department, as the composite outcomes do not require the patient to be clinically sick.

Study Design

  • 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.
  • Researchers chose to exclude patients with flat pigments or clean bases seen on endoscopy, due to their low risk of recurrent bleeding [3]
    • The study likely has an overall increase in the rate of morbidity and mortality, compared to populations with any bleeding peptic ulcers
  • The researchers propose that decreased intragastric pH leads to decreased re-bleeding, however this was not directly measured with pH monitoring
    • Previous studies in white patients have shown high doses of omeprazole to neutralize intragastric pH. [4]
    • Although this study specifically demonstrated the use of omeprazole after endoscopic treatment, the principle can be translated to use in the emergency department for patients with bleeding peptic ulcers.

Funding

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

External Links

Sources

  1. 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.
  2. Villanueva C. et al. "Transfusion strategies for acute upper gastrointestinal bleeding". NEJM. 2013. 368(1):11-21.
  3. Lanas A, Artal A, Blas JM, Arroyo MT, Lopez-Zaborras J, Sainz R. Effect of parenteral omeprazole and ranitidine on gastric pH and the outcome of bleeding peptic ulcer. J Clin Gastroenterol 1995;21:103-6.
  4. Labenz J, Peitz U, Leusing C, Tillenburg B, Blum AL, Borsch G. Efficacy of primed infusions with high dose ranitidine and omeprazole to maintain high intragastric pH in patients with peptic ulcer bleeding: a prospective randomised controlled study. Gut 1997;40:36-41