|Systematic reviews of the clinical effectiveness and cost-effectiveness of proton pump inhibitors in acute upper gastrointestinal bleeding: PPI therapy in patients with endoscopically documented acute bleeding from a peptic ulcer
|Leontiadis G I, Sreedharan A, Dorward S, Barton P, Delaney B, Howden C W, Orhewere M, Gisbert J, Sharma V K, Rostom A, Moayyedi P, Forman D
The authors concluded that proton pump inhibitors reduced re-bleeding; no overall effect was observed on mortality. Overall, this was a well-conducted review and, despite some concerns about potential heterogeneity and publication bias, is likely to be reliable.
To assess the clinical effectiveness of proton pump inhibitor (PPI) therapy compared to alternative interventions for the treatment of patients with endoscopically diagnosed acute bleeding from peptic ulcer.
Cochrane Central Register of Controlled Trials, The Cochrane Library, MEDLINE and EMBASE were searched up to November 2004 using a specific randomised controlled trial (RCT) search filter. Search terms were reported. References of articles and reviews, and conference proceedings were searched manually up to November 2004. Experts in the field and pharmaceutical companies were contacted for both published and unpublished studies. No language restrictions were applied.
Randomised controlled trials (RCTs) that compared proton pump inhibitors alone or in combination with an alternative treatment with placebo or H2-receptor antagonists (H2RA) alone or in combination with the same alternative therapy used by the proton pump inhibitor group in hospital patients with endoscopically acute bleeding from peptic ulcer were eligible for inclusion. Studies of patients with other causes of gastrointestinal bleeding were excluded. Eligible studies reported mortality rates (30-day or in-hospital) as the primary outcome. Other outcomes were also reported in the review. Most included studies were conducted in Europe and included patients with recent or active bleeding from peptic ulcer. Interventions were administered intravenously or orally using pantoprazole, omeprazole or lansoprazole. Placebo included intravenous mannitol. H2RA treatment included oral ranitidine or ranitidine, cimetidine or famotidine administered intravenously at various doses and durations. Some studies co-administered endoscopic haemostatic therapy (EHT).
Two reviewers independently screened studies for relevance; any discrepancies were resolved by consensus.
Assessment of study quality
Two reviewers independently assessed validity using previously published criteria, including items for randomisation, allocation concealment (graded as adequate, uncertain, inadequate or not randomised), blinding, comparability of treatment groups and withdrawals. Disagreements were resolved by consensus.
Two reviewers independently extracted the number of events for each outcome measure. Odds ratios with 95% confidence intervals (CIs) were calculated for dichotomous outcomes, including mortality, re-bleeding and surgical intervention rates. Mean differences with 95% CIs were calculated for continuous outcomes. Disagreements were resolved by consensus.
Methods of synthesis
Random-effects and fixed-effect models were used to pool odds ratios. Where statistical heterogeneity was significant (p<0.10), a random-effects model was used. Meta-regression was used where possible to assess the influence of predefined study characteristics (including study validity and type of control treatment used) on the effect of treatment on mortality, re-bleeding and surgical intervention. Sensitivity analyses were undertaken to assess the robustness of the findings by removing one study at a time for each outcome. A post hoc sensitivity analysis was performed by removing studies with potential bias. The number of patients needed to treat (NNT) were calculated for some outcomes.
Statistical heterogeneity was assessed using the X2 and I2 tests, and further investigated using subgroup analyses using predefined criteria. Publication bias was assessed using funnel plot analyses and Egger's test.
Results of the review
Twenty-four RCTs (n=4,416) were included in the review. Sample sizes ranged from 39 to 1,244 patients. Validity assessment showed that 12 studies had adequate concealment, 10 studies were double-blinded and most studies were comparable at baseline. Only six studies reported withdrawal rates.
There were no statistically significant differences between proton pump inhibitor therapy and controls for the primary outcome of mortality (20 studies, n=4,416). Statistically significant differences in favour of proton pump inhibitor therapy were reported for re-bleeding (odds ratio 0.49, 95% CI: 0.37 to 0.65, p<0.00001; 21 studies), persistent bleeding (odds ratio 0.29, 95% CI: 0.09 to 0.89; six studies, although this was clearly stated in only two studies) and surgical interventions (odds ratio 0.61, 95% CI: 0.48 to 0.78; 19 studies). The number needed to treat for re-bleeding was 13 (95% CI: 9 to 25) and number needed to treat for surgical intervention was 33 (95% CI: 20 to 50).
Meta-regression reported a significant association between the treatment effect for mortality and geographical location, with higher treatment effects in favour of proton pump inhibitor treatment in Asian populations (coefficient -1.91, 95% CI: -2.18 to -0.21, p=0.02; 14 studies). Other subgroup analyses failed to find statistically significant differences.
There was evidence of significant statistical heterogeneity for re-bleeding (X2=32.58, p=0.04) and persistent bleeding (p=0.04, I2=56.5%). The authors reported significant clinical heterogeneity. Evidence from funnel plots and/or Egger's tests suggested the presence of publication bias in most of the analyses.
Post hoc analysis and results for secondary and tertiary outcomes were also reported in the review.
Proton pump inhibitor therapy reduced re-bleeding rates in patients with upper gastrointestinal haemorrhage and there was evidence to suggest that the need for surgery was reduced with proton pump inhibitor treatment. There was no overall effect on mortality, but mortality rates were reduced in Asian populations and patients with high-risk endoscopic stigmata at index endoscopy.
This updated review addressed a clear question and was supported by appropriate inclusion criteria. A comprehensive literature search was undertaken using several databases and other appropriate sources. Publications were not restricted by language and attempts were made to try and locate unpublished materials, which minimised the risk of language bias. Publication bias was investigated. Funnel plots and/or Egger's test suggested that a number of analyses were at risk from publication bias, although given the number of included studies, the tests may not be reliable. Validity was assessed using relevant published criteria and attempts were made to minimise the potential for reviewer error or bias at each stage of the review process. Appropriate methods were used to investigate statistical heterogeneity. The authors reported possible clinical heterogeneity for some outcomes, thus it may not have been appropriate to pool these results. Despite the above considerations, this was generally a well-conducted review and the authors’ conclusions are likely to be reliable.
Implications of the review for practice and research
Practice: The authors did not state any implications for practice.
Research: The authors stated that large RCTs were needed to compare the effects of different doses and regimens of proton pump inhibitors in patients with peptic ulcers. Future research may benefit from reporting outcomes by ulcer location and exploring whether mortality was related to episodes of bleeding or unrelated causes.
Funded by the Health Technology Assessment (HTA) Programme, project number 03/12/03.
Leontiadis G I, Sreedharan A, Dorward S, Barton P, Delaney B, Howden C W, Orhewere M, Gisbert J, Sharma V K, Rostom A, Moayyedi P, Forman D. Systematic reviews of the clinical effectiveness and cost-effectiveness of proton pump inhibitors in acute upper gastrointestinal bleeding: PPI therapy in patients with endoscopically documented acute bleeding from a peptic ulcer. Health Technology Assessment 2007; 11(51): 15-39
Other publications of related interest
Leontiadis GI, Sreedharan A, Dorward S, Barton P, Delaney B, Howden CW, Orhewere M, Gisbert J, Sharma VK, Rostom A, Moayyedi P & Forman D. Systematic reviews of the clinical effectiveness and cost-effectiveness of proton pump inhibitors in acute upper gastrointestinal bleeding. Health Technology Assessment 2007;11(51):1-145.
Subject indexing assigned by NLM
Acute Disease; Aged; Anti-Inflammatory Agents, Non-Steroidal /adverse effects /therapeutic use; Congresses as Topic; Cost-Benefit Analysis; Databases, Bibliographic; Duodenal Ulcer /complications; Endoscopy, Gastrointestinal; Gastrointestinal Hemorrhage /drug therapy /economics /prevention & control; Helicobacter Infections /drug therapy; Helicobacter pylori /drug effects; Histamine H2 Antagonists /economics /therapeutic use; Humans; Middle Aged; Peptic Ulcer Hemorrhage /drug therapy /economics /prevention & control; Proton Pump Inhibitors /economics /therapeutic use; Quality-Adjusted Life Years; Randomized Controlled Trials as Topic; Treatment Outcome; Upper Gastrointestinal Tract /drug effects
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This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.