IMPORTANCE: Current guidelines recommend an intravenous bolus dose of a proton pump inhibitor (PPI) followed by continuous PPI infusion after endoscopic therapy in patients with high-risk bleeding ulcers. Substitution of intermittent PPI therapy, if similarly effective as bolus plus continuous-infusion PPI therapy, would decrease the PPI dose, costs, and resource use.
OBJECTIVE: To compare intermittent PPI therapy with the currently recommended bolus plus continuous-infusion PPI regimen for reduction of ulcer rebleeding.
DATA SOURCES: Searches included MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials databases through December 2013; US and European gastroenterology meeting abstracts from 2009 to 2013; and bibliographies of systematic reviews.
STUDY SELECTION: Randomized trials of patients with endoscopically treated high-risk bleeding ulcers (active bleeding, nonbleeding visible vessels, and adherent clots) comparing intermittent doses of PPIs and the currently recommended regimen (80-mg intravenous bolus dose of a PPI followed by an infusion of 8 mg/h for 72 hours).
DATA EXTRACTION AND SYNTHESIS: Duplicate independent data extraction and risk-of-bias assessment were performed. Data were pooled using a fixed-effects model or a random effects model if statistical heterogeneity was present.
MAIN OUTCOMES AND MEASURES: The primary outcome was rebleeding within 7 days; additional predefined outcomes included rebleeding within 3 and 30 days, need for urgent intervention, mortality, red blood cell transfusion, and length of hospital stay. The primary hypothesis, defined before initiation of the literature review, was that intermittent use of PPIs was noninferior to bolus plus continuous infusion of PPIs, with the noninferiority margin predefined as an absolute risk difference of 3%.
RESULTS: The risk ratio of rebleeding within 7 days for intermittent vs bolus plus continuous infusion of PPIs was 0.72 (upper boundary of 1-sided 95% CI, 0.97) and the absolute risk difference was -2.64% (upper boundary of 1-sided 95% CI, -0.28%, which is well below the predefined noninferiority margin of 3%). Risk ratios for rebleeding within 30 days and 3 days, mortality, and urgent interventions were less than 1 and mean differences for blood transfusion and hospital length of stay were less than 0, indicating that no summary estimate showed an increased risk with intermittent therapy. The upper boundaries of 95% CIs for absolute risk differences were less than 1.50% for all predefined rebleeding outcomes.
CONCLUSIONS AND RELEVANCE: Intermittent PPI therapy is comparable to the current guideline-recommended regimen of intravenous bolus plus a continuous infusion of PPIs in patients with endoscopically treated high-risk bleeding ulcers. Guidelines should be revised to recommend intermittent PPI therapy.
BACKGROUND: Peptic ulcer rebleeding (PUR) usually occurs within three days following endoscopic hemostasis. However, recent data have increasingly suggested delayed rebleeding.
OBJECTIVE: To better characterize the timing of PUR (Forrest Ia to IIb) following initially successful endoscopic hemostasis.
METHODS: An exhaustive literature search (1989 to 2013), with cross-referencing, was performed to identify pertinent randomized controlled trial (RCT) arms. Patients receiving high-dose proton pump inhibitor (PPI) infusion following successful modern-day endoscopic hemostasis were included. A sensitivity analysis included any patients receiving PPI doses >40 mg daily. The main outcome measure was 30-day rebleeding, while weighted mean averages at t = three, seven, 14 and 28 to 30 days are also reported.
RESULTS: Of 756 citations, six RCTs were included (561 patients; 58.5% to 89.5% male; 55.3 to 67.5 years of age). Among patients receiving high-dose PPI (five RCTs [393 patients]), 11.5% (95% CI 8.4% to 14.7%) experienced rebleeding, 55.6% (95% CI 41.1% to 70.1%) rebled within three days, 20% (95% CI 8.3% to 31.7%) between four and seven days, 17.8% (95% CI 6.6% to 28.9%) at eight to 14 days, and 6.7% (95% CI 0% to 14%) at 15 to 28 to 30 days. Using the relaxed lower PPI dosing threshold, similar respective rates were 14.4% (95% CI 11.5% to 17.3%) overall, with interval rates of 39.5% (95% CI 28.9% to 50.15%), 34.6% (95% CI 24.2% to 44.9%), 19.7% (95% CI 11% to 28.4%) and 6.2% (95% CI 0.95% to 11.5%). Qualitative review of patient characteristics, limited by small sample size, possible bias and study heterogeneity, suggested increased patient comorbidity and postendoscopic use of lower PPI dosing may predict delayed rebleeding.
CONCLUSION: In patients with high-risk PUR undergoing successful endoscopic hemostasis, most rebled within three days, with many experiencing later rebleeding. Additional research is needed to better predict such an outcome.
BACKGROUND: The efficacy of adjuvant use of intravenous proton pump inhibitors (PPIs) after endoscopic therapy has been proved in peptic ulcer bleeding patients, but the efficacy of oral PPIs is uncertain.
AIM: To compare the clinical outcomes of oral PPIs vs. intravenous PPIs in patients with peptic ulcer bleeding.
METHODS: Prospective randomised controlled trials were systematically searched from OVID databases until June 2012. Trials comparing oral and intravenous PPIs among patients with peptic ulcer bleeding were included. Recurrent bleeding, length of hospitalisation, blood transfusion, requirement of surgery and mortality were measured. The risk of bias, study quality and heterogeneity were also evaluated.
RESULTS: Six randomised trials from 2006 to 2011 were included. A total of 615 patients were randomly assigned to receive oral PPIs (n = 302) or intravenous PPIs (n = 313). The mean age was 60 years and 71.1% was male. No significant difference between oral and intravenous PPIs was observed regarding recurrent bleeding (RR: 0.92, 95% CI: 0.56-1.50), mean volume of blood transfused (-0.02 unit, 95% CI: -0.29-0.24 unit), requirement of surgery (RR: 0.82, 95% CI: 0.19-3.61) and all-cause mortality (RR: 0.88, 95% CI: 0.29-2.71). The duration of hospital stay in days was significantly shortened in those using oral PPIs (-0.74 day, 95% CI: -1.10 day to -0.39 day).
CONCLUSION: Oral PPIs demonstrate a similar effectiveness to intravenous PPIs among patients with peptic ulcer bleeding, but the results were combined from open-labelled trials with limited sample size. A large double-blind non-inferiority trial is required to better assess the role of oral PPIs.
BACKGROUND: Treatment with proton pump inhibitors (PPIs) improves clinical outcomes in patients with peptic ulcer bleeding. However, the optimal dose and route of administration of PPIs remains controversial.
OBJECTIVES: To evaluate the efficacy of different regimens of PPIs in the management of acute peptic ulcer bleeding using evidence from direct comparison randomized controlled trials (RCTs).
We specifically intended to assess the differential effect of the dose and route of administration of PPI on mortality, rebleeding, surgical intervention, further endoscopic haemostatic treatment (EHT), length of hospital stay, transfusion requirements and adverse events.
SEARCH METHODS: We searched CENTRAL (in The Cochrane Library 2010, Issue 3), MEDLINE and EMBASE (from inception to September 2010) and proceedings of major gastroenterology meetings (January 2000 to September 2010), without language restrictions. Original investigators were contacted to request missing data.
SELECTION CRITERIA: RCTs that compared at least two different regimens of the same or a different PPI in patients with acute peptic ulcer bleeding, diagnosed endoscopically.
DATA COLLECTION AND ANALYSIS: Two reviewers independently selected studies, extracted data and assessed risk of bias. We synthesized data using the Mantel-Haenszel random-effects method and performed multivariate meta-regression with random permutations based on Monte Carlo simulation. We measured heterogeneity with the I² statistic and Cochrane Q test and assessed publication bias with funnel plots and Egger’s test. We graded the overall quality of evidence using the GRADE approach.
MAIN RESULTS: Twenty two RCTs were included; risk of bias was high in 17 and unclear in 5. The main analysis included 13 studies (1716 patients) comparing “high” dose regimens (72-hour cumulative dose > 600 mg of intravenous PPI) to other doses; there was no significant heterogeneity for any clinical outcome. We found low quality evidence that did not exclude a potential reduction or increase in mortality, rebleeding, surgical interventions or endoscopic haemostatic treatment (EHT) with “high” dose regimens. For mortality, pooled risk ratio (RR) was 0.85 (95% confidence interval (CI) 0.47 to 1.54); pooled risk difference (RD) was 0 more deaths per 100 patients treated with “high” dose (95% CI from 1 fewer to 2 more deaths per 100 treated). For rebleeding, pooled RR was 1.27 (95% CI 0.96 to 1.67); pooled RD was 2 more rebleeding events per 100 patients treated with “high” dose (95% CI from 0 fewer to 5 more rebleeding events per 100 treated). For surgical interventions, pooled RR was 1.33 (95% CI 0.63 to 2.77); pooled RD was 1 more surgical intervention per 100 patients treated with “high” dose (95% CI from 1 fewer to 2 more surgical interventions per 100 treated). For further EHT, pooled RR was 1.39 (95% CI 0.88 to 2.18), pooled RD was 2 more events per 100 patients treated with “high” dose PPI (95% CI from 1 fewer to 5 more events per 100 treated). We found moderate quality evidence suggesting no important difference between the two regimens with regards to length of hospital stay (mean difference (MD) 0.26 days; 95% CI -0.08 to 0.6 days) or blood transfusion requirements (MD 0.05 units; 95% CI -0.21 to 0.3 units). There was visual and statistical evidence of “inverse” publication bias for mortality (missing small studies with favourable outcomes for “high” dose), but not for any other outcome. The results were similar for all subgroup analyses (according to risk of bias, geographical location, route of administration for non-“high” dose regimens, continuous infusion vs. bolus administration for intravenous non-“high” regimens group), sensitivity analyses (restriction to patients who had EHT for high risk stigmata, use of different dose thresholds for comparative regimens) and post hoc analyses (inclusion of all studies (N = 22) that compared at least two PPI regimens with different cumulative 72 hour doses; restriction of the previous analysis to patients who had EHT for high risk stigmata). Meta-regression analysis did not show any statistically significant associations between treatment effect (for the outcomes of mortality, rebleeding and surgical intervention) and the three study-level factors that were assessed (geographical location (Asia versus not Asia), route of PPI administration (intravenous versus oral), within-study ratio among the 72-hour cumulative doses of the two PPI regimens).
AUTHORS' CONCLUSIONS: There is insufficient evidence for concluding superiority, inferiority or equivalence of high dose PPI treatment over lower doses in peptic ulcer bleeding.
AIM: To evaluate the efficacy of high-dose proton pump inhibitors (PPIs) vs low-dose PPIs for patients with upper gastrointestinal bleeding.
METHODS: PubMed, Embase, the Cochrane Library, and Web of Science were searched to identify relevant randomized controlled trials (RCTs). Eligible trials were RCTs that compared high-dose PPI with low-dose PPI following endoscopic hemostasis. The primary endpoint was rebleeding; secondary endpoints were patient numbers that needed surgery, and mortality. The meta-analysis was performed with a fixed effects model or random effects model.
RESULTS: Nine eligible RCTs including 1342 patients were retrieved. The results showed that high-dose intravenous PPI was not superior to low-dose intravenous PPI in reducing rebleeding [odds ratio (OR) = 1.091, 95% confidential interval (CI): 0.777-1.532], need for surgery (OR = 1.522, 95% CI: 0.643-3.605) and mortality (OR = 1.022, 95% CI: 0.476-2.196). Subgroup analysis according to different region revealed no difference in rebleeding rate between Asian patients (OR = 0.831, 95% CI, 0.467-1.480) and European patients (OR = 1.263, 95% CI: 0.827-1.929).
CONCLUSION: Low-dose intravenous PPI can achieve the same efficacy as high-dose PPI following endoscopic hemostasis.
Current guidelines recommend an intravenous bolus dose of a proton pump inhibitor (PPI) followed by continuous PPI infusion after endoscopic therapy in patients with high-risk bleeding ulcers. Substitution of intermittent PPI therapy, if similarly effective as bolus plus continuous-infusion PPI therapy, would decrease the PPI dose, costs, and resource use.
OBJECTIVE:
To compare intermittent PPI therapy with the currently recommended bolus plus continuous-infusion PPI regimen for reduction of ulcer rebleeding.
DATA SOURCES:
Searches included MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials databases through December 2013; US and European gastroenterology meeting abstracts from 2009 to 2013; and bibliographies of systematic reviews.
STUDY SELECTION:
Randomized trials of patients with endoscopically treated high-risk bleeding ulcers (active bleeding, nonbleeding visible vessels, and adherent clots) comparing intermittent doses of PPIs and the currently recommended regimen (80-mg intravenous bolus dose of a PPI followed by an infusion of 8 mg/h for 72 hours).
DATA EXTRACTION AND SYNTHESIS:
Duplicate independent data extraction and risk-of-bias assessment were performed. Data were pooled using a fixed-effects model or a random effects model if statistical heterogeneity was present.
MAIN OUTCOMES AND MEASURES:
The primary outcome was rebleeding within 7 days; additional predefined outcomes included rebleeding within 3 and 30 days, need for urgent intervention, mortality, red blood cell transfusion, and length of hospital stay. The primary hypothesis, defined before initiation of the literature review, was that intermittent use of PPIs was noninferior to bolus plus continuous infusion of PPIs, with the noninferiority margin predefined as an absolute risk difference of 3%.
RESULTS:
The risk ratio of rebleeding within 7 days for intermittent vs bolus plus continuous infusion of PPIs was 0.72 (upper boundary of 1-sided 95% CI, 0.97) and the absolute risk difference was -2.64% (upper boundary of 1-sided 95% CI, -0.28%, which is well below the predefined noninferiority margin of 3%). Risk ratios for rebleeding within 30 days and 3 days, mortality, and urgent interventions were less than 1 and mean differences for blood transfusion and hospital length of stay were less than 0, indicating that no summary estimate showed an increased risk with intermittent therapy. The upper boundaries of 95% CIs for absolute risk differences were less than 1.50% for all predefined rebleeding outcomes.
CONCLUSIONS AND RELEVANCE:
Intermittent PPI therapy is comparable to the current guideline-recommended regimen of intravenous bolus plus a continuous infusion of PPIs in patients with endoscopically treated high-risk bleeding ulcers. Guidelines should be revised to recommend intermittent PPI therapy.
Systematic Review Question»Systematic review of interventions
