Intermittent vs Continuous Proton Pump Inhibitor Therapy for High-Risk Bleeding Ulcers: A Systematic Review and Meta-analysis

Authors: Hamita Sachar, MD; Keta Vaidya, MD; Loren Laine, MD

Journal: JAMA Intern Med. 2014 November; 174(11):1755–1762.

Type of Study: Systematic Review and Meta-analysis

PMID/PMCID/DOI: PMID: 25201154, PMCID: PMC4415726, DOI: 10.1001/jamainternmed.2014.4056

Quick Reference Summary

Intermittent proton pump inhibitor (PPI) therapy is noninferior to the standard bolus plus continuous-infusion PPI regimen in reducing rebleeding within 7 days in patients with high-risk bleeding ulcers. The absolute risk difference was −2.64% (95% CI: −0.28%), well below the predefined noninferiority margin of 3%.

Core Clinical Question

In patients with high-risk bleeding ulcers treated with endoscopic therapy, is intermittent proton pump inhibitor therapy noninferior to continuous proton pump inhibitor therapy in reducing ulcer rebleeding within 7 days?

Background

Disease Overview:

Ulcers are the most common cause of upper gastrointestinal (GI) bleeding.

Prior Data:

• Meta-analysis of randomized trials: High-dose continuous-infusion PPI therapy significantly decreases further bleeding, surgery, and mortality in high-risk bleeding ulcers post-endoscopic therapy.
• Meta-analysis of intermittent PPI therapy vs placebo/no therapy: Intermittent PPI therapy also significantly reduces further bleeding in high-risk bleeding ulcers post-endoscopic therapy.

Current Standard of Care:

Guidelines recommend an 80-mg intravenous bolus dose of a PPI followed by a continuous infusion of 8 mg/h for 72 hours after endoscopic therapy in patients with high-risk bleeding ulcers (active bleeding, nonbleeding visible vessels, adherent clots).

Knowledge Gaps Addressed by Study:

Whether intermittent PPI therapy is noninferior to the currently recommended bolus plus continuous-infusion PPI regimen.

Study Rationale:

Substituting intermittent PPI therapy could decrease PPI dose, costs, and resource use if it is as effective as the continuous regimen.

Methods Summary

Study Design:

Systematic review and meta-analysis of randomized controlled trials.

Setting and Time Period:

Studies published up to December 31, 2013; included US and European gastroenterology meeting abstracts from 2009 to 2013.

Population Characteristics:

Patients with endoscopically treated high-risk bleeding ulcers (active bleeding, nonbleeding visible vessels, adherent clots).

Inclusion/Exclusion Criteria:

• Included: Randomized trials comparing intermittent PPI doses vs. standard bolus plus continuous-infusion PPI regimen.
• Excluded: Patients with ulcers showing flat spots and clean bases; studies not reporting necessary statistical data.

Intervention Details:

Intermittent PPI regimens varied in dosing frequency, total dose, and route (oral vs. intravenous).

Control/Comparison Group Details:

Standard regimen of an 80-mg intravenous bolus followed by an 8-mg/h continuous infusion for 72 hours.

Primary and Secondary Outcomes:

• Primary Outcome: Rebleeding within 7 days.
• Secondary Outcomes: Rebleeding within 3 and 30 days, need for urgent intervention, mortality, red blood cell transfusion, length of hospital stay.

Statistical Analysis Approach:

• Risk Ratios (RRs) calculated using the Mantel-Haenszel method.
• Absolute Risk Differences with predefined noninferiority margin of 3%.
• Fixed-effects or random-effects models based on heterogeneity.
• Subgroup and sensitivity analyses performed.

Sample Size Calculations:

Not directly applicable as this is a meta-analysis; however, acknowledgment of required large sample sizes for future studies.

Ethics and Funding Information:

• Conflict of Interest: No other disclosures reported; one author served on a data safety monitoring board for a company manufacturing PPIs.
• Funding: Funded by grant T32 DK007017 from the National Institutes of Health (Dr. Sachar).
• Role of Sponsor: No role in study design, data collection, analysis, interpretation, manuscript preparation, or publication decision.

Detailed Results

Participant Flow and Demographics:

• Total Studies Included: 13
• Total Patients: Varied per outcome but primary analysis included 1,346 patients.

Primary Outcome Results:

• Rebleeding within 7 Days:
  • Risk Ratio (RR): 0.72
  • 1-sided 95% CI Upper Boundary: 0.97
  • Absolute Risk Difference: −2.64% (95% CI Upper Boundary: −0.28%)
  • Statistical Significance: Noninferior (95% CI well below 3% margin)

Effect Sizes and Confidence Intervals:

• Rebleeding within 7 Days: RR 0.72 (95% CI: not crossing the noninferiority margin)
• Rebleeding within 3 Days: RR 0.73 (95% CI Upper Boundary: 0.17%)
• Rebleeding within 30 Days: RR 0.89 (95% CI Upper Boundary: 1.17%)
• Mortality: RR 0.64 (95% CI Upper Boundary: 1.21)
• Surgery/Radiologic Intervention: RR 0.87 (95% CI Upper Boundary: 1.49)
• Urgent Interventions: RR 0.95 (95% CI Upper Boundary: 1.27)
• Length of Hospital Stay: Mean Difference −0.26 days (95% CI)
• Blood Transfusion: Mean Difference −0.22 units (95% CI)

Statistical Significance:

• Primary Outcome: Significant noninferiority.
• Secondary Outcomes: No increased risk with intermittent therapy; some outcomes favored intermittent therapy but not significantly.

Subgroup Analyses:

No significant interaction effects found across predefined subgroups (e.g., route of administration, dose frequency).

Adverse Events/Safety Data:

No summary estimate showed an increased risk with intermittent therapy across all outcomes.

Results Tables

Outcome	Intervention Group	Control Group	Difference (95% CI)	P-value
Recurrent bleeding within 7 days	0.72	-	−2.64% (−0.28%)	-
Recurrent bleeding within 30 days	0.89	-	−0.97% (1.49%)	-
Recurrent bleeding within 3 days	0.73	-	−2.36% (0.17%)	-
Mortality	0.64	-	−0.74% (0.43%)	-
Surgery/Radiologic Intervention	0.87	-	−0.30% (1.12%)	-
Urgent interventions	0.95	-	−0.45% (2.43%)	-
Length of hospital stay, days	-0.26	-	-	-
Blood transfusion, units	−0.22	-	-	-

Abbreviations: PPI, proton pump inhibitor; RI, radiologic intervention.

a Statistical heterogeneity was not noted in any analysis.

b Data represent the mean difference.

Authors' Conclusions

Primary Conclusions:

Intermittent PPI regimens are comparable to continuous PPI infusion regimens in patients with high-risk bleeding ulcers post-endoscopic therapy.

Authors' Interpretation of Results:

Intermittent PPI therapy does not increase the risk of recurrent bleeding and is associated with similar or better outcomes across various secondary measures.

Clinical Implications Stated by Authors:

Guidelines should be revised to recommend intermittent PPI therapy due to its comparable efficacy, greater ease of use, and lower cost.

Future Research Recommendations:

• Studies to determine the most appropriate intermittent PPI regimen, including direct comparisons between oral and intravenous forms.
• Additional research on intermittent PPI therapy's effectiveness in diverse geographic and clinical settings.

Literature Review

A. Previous Studies and Meta-Analyses:

• Neumann I, Letelier LM, Rada G, et al. Comparison of different regimens of proton pump inhibitors for acute peptic ulcer bleeding. Cochrane Database Syst Rev. 2013;6:CD007999.
• Wang CH, Ma MH, Chou HC, et al. High-dose vs non–high-dose proton pump inhibitors after endoscopic treatment in patients with bleeding peptic ulcer: a systematic review and meta-analysis of randomized controlled trials. Arch Intern Med. 2010;170(9):751–758.
• Tsoi KKF, Hirai HW, Sung JJY. Meta-analysis: comparison of oral vs intravenous proton pump inhibitors in patients with peptic ulcer bleeding. Aliment Pharmacol Ther. 2013;38(7):721–728.
• Wu LC, Cao YF, Huang JH, Liao C, Gao F. High-dose vs low-dose proton pump inhibitors for upper gastrointestinal bleeding: a meta-analysis. World J Gastroenterol. 2010;16(20):2558–2565.
• Laine L, Spiegel B, Rostom A, et al. Methodology for randomized trials of patients with nonvariceal upper gastrointestinal bleeding: recommendations from an international consensus conference. Am J Gastroenterol. 2010;105(3):540–550.

B. Contrasting Methodological Quality:

• Variations in dosing schedules, total doses, PPI types, and routes of administration across studies.
• Many studies had unclear risk of bias in allocation concealment and were not blinded.
• Despite variable quality, subgroup analyses showed no significant heterogeneity related to study quality.

C. Comparisons with Guidelines:

• Laine L, Jensen DM. Management of patients with ulcer bleeding. Am J Gastroenterol. 2012;107(3):345–361.
• Barkun AN, Bardou M, Kuipers EJ, et al. International Consensus Recommendations on the Management of Patients with Nonvariceal Upper Gastrointestinal Bleeding. Ann Intern Med. 2010;152(2):101–113.

D. This Trial's Contribution:

• Added evidence supporting the noninferiority of intermittent PPI therapy compared to the standard continuous regimen.
• Confirmed findings of previous meta-analyses but focused specifically on high-risk bleeding ulcers post-endoscopic therapy.
• Suggested revisions to existing guidelines to incorporate intermittent therapy as a viable alternative.

Critical Analysis

A. Strengths:

• Comprehensive Search Strategy: Included multiple databases, meeting abstracts, and bibliographies of prior reviews.
• Predefined Protocol: Clear inclusion/exclusion criteria and outcome measures established a priori.
• Noninferiority Analysis: Addressed a clinically relevant question with a predefined noninferiority margin.
• Sensitivity and Subgroup Analyses: Assessed consistency across various factors and study qualities.

B. Limitations:

• Variability in Intermittent PPI Regimens: Differences in dosing frequency, total dose, and administration routes limited the ability to determine the optimal intermittent regimen.
• Risk of Bias in Included Studies: Many studies had unclear allocation concealment and lacked blinding, potentially impacting internal validity.
• Limited Generalizability: Most studies assessing intragastric pH were conducted in Asia, raising questions about applicability to Western populations.
• Incomplete Data Reporting: Some studies did not provide necessary statistical data, leading to exclusions from certain analyses.

C. Literature Context:

• Consistent Findings: Aligns with previous meta-analyses showing the efficacy of high-dose PPI therapy in reducing rebleeding.
• Guideline Integration: Provides evidence to potentially update international guidelines, emphasizing the practicality of intermittent therapy.
• Addressed Knowledge Gaps: Specifically evaluated the noninferiority of intermittent vs. continuous PPI regimens in a well-defined high-risk population.

Clinical Application

• Intermittent PPI therapy can be adopted as an effective alternative to continuous infusion regimens, reducing costs and resource utilization without compromising patient outcomes.
• Best suited for patients who can tolerate oral medications and settings where continuous infusion resources are limited, such as community or rural practice environments.

How To Use This Info In Practice

Practitioners should consider adopting intermittent PPI regimens for patients with high-risk bleeding ulcers post-endoscopic therapy, aligning with updated guidelines to optimize resource use without increasing rebleeding risk.