|Systematic reviews of the clinical effectiveness and cost-effectiveness of proton pump inhibitors in acute upper gastrointestinal bleeding: H. pylori eradication therapy
|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
This review concluded that rates of bleeding were reduced with H. pylori eradication therapy compared to non-eradication antisecretory therapy with or without subsequent long-term maintenance therapy. Despite concerns about the quality of the data, the conclusions of this well-conducted review are likely to be reliable.
To compare the effectiveness of Helicobacter pylori (H. pylori) eradication therapy with ulcer-healing antisecretory therapy with or without subsequent long-term prophylactic antisecretory therapy in the prevention of recurrent bleeding from peptic ulcer.
The Cochrane Library, MEDLINE, EMBASE and CINAHL databases were searched up to January 2005 using a search filter for randomised controlled trials. Published and unpublished studies written in any language were eligible for inclusion in the review. Search terms were reported. Reference lists of retrieved articles and review articles and abstracts from workshops were searched manually. Authors of articles were contacted where necessary.
Randomised controlled trials (RCTs) that compared the effects of H. pylori eradication therapy with ulcer-healing antisecretory therapy with or without subsequent long-term prophylactic antisecretory therapy on the long-term re-bleeding rates from endoscopically-confirmed peptic ulcer in hospitalised H. pylori-positive patients were eligible for inclusion. Eligible studies were required to report confirmed success of H. pylori eradication at least four weeks after antibiotic treatment in studies with a follow-up of more than six months. Studies that included only patients taking non-steroidal anti-inflammatory drugs (NSAIDs) were excluded.
Most included studies were of patients with duodenal ulcer. Some studies also included patients with gastric ulcer. Some patients used NSAIDs or acetylsalicylic acid previous to inclusion in the studies. Included studies administering eradication therapy mostly used bismuth-based triple therapy and/or omeprazole plus amoxicillin. Eradication treatment duration for the comparison without long-term antisecretory therapy ranged from 10 to 14 days,. Treatment duration for the comparison with long-term antisecretory therapy ranged between seven and 12 days. Antisecretory maintenance therapy mostly involved administration of ranitidine and/or omeprazole. The mean follow-up duration ranged between 12 and 53 months.
Two reviewers independently screened studies for relevance. Disagreements were resolved by consensus.
Assessment of study quality
Two reviewers independently assessed validity using the Jadad scale, including items on randomisation, blinding and withdrawals. Studies were given a score from 0 to 5 (5 indicated greatest quality). Disagreements were resolved by consensus.
Two reviewers independently extracted percentage bleeding rates for each comparison. Odds ratios were calculated, with 95% confidence intervals (CIs). Any discrepancies were resolved by consensus.
Methods of synthesis
Studies were grouped according to comparison. Odds ratios were pooled using random-effects or fixed effect models as appropriate. Absolute risk reduction or risk difference, relative risk reduction and the number of patients needed to treat to prevent one re-bleeding event were calculated. Sensitivity analyses assessed the robustness of the results by removing studies according to quality, type of ulcer disease (duodenal/gastric) and duration of follow-up. Studies in which re-bleeding could potentially have been related to NSAID use were also removed. Assessment of the potential role of H. pylori eradication failure or recurrence of H. pylori infection in patients with re-bleeding was also conducted. Heterogeneity was assessed using the X2 test (a p-value less than 0.1 denoted evidence of heterogeneity).
Results of the review
Nine RCTs and one non-randomised controlled trial (n=1,048) were included in the review. Studies scored between one and three on the Jadad scale.
H. pylori eradication therapy versus non-eradication therapy with antisecretory therapy (without long-term maintenance) (seven RCTs, n=578):
Rates of re-bleeding were significantly greater in patients receiving non-eradication antisecretory therapy without subsequent long-term maintenance antisecretory therapy compared to the H. pylori eradication therapy group (odds ratio was 0.17, 95% CI: 0.10 to 0.32). Relative risk and absolute risk reduction/risk differences were reported in the review. The number needed to treat to prevent one episode of re-bleeding in patients receiving eradication compared to non-eradication therapy was seven (95% CI: 5 to 11). Sensitivity analysis by study quality, NSAID use and H. Pylori eradication failure did not significantly alter the results. There was no evidence of statistical heterogeneity (p=0.41).
H. pylori eradication therapy versus non-eradication therapy with antisecretory therapy (with long-term maintenance) (two RCTs and one non-RCT, n=470):
There were significantly fewer incidences of re-bleeding in patients treated with H. pylori eradication therapy compared to those in the non-eradication antisecretory group (odds ratio was 0.24, 95% CI: 0.09 to 0.67). The number needed to treat to prevent one episode of re-bleeding in the eradication compared to long-term maintenance antisecretory therapy group was 20 (95% CI: 12 to 100). Sensitivity analysis removing patients using NSAIDs reduced the odds ratio to 0.15 (95% CI: 0.04 to 0.53). There was no evidence of statistical heterogeneity (p=0.52).
Sensitivity analysis by quality could not be performed for the second meta-analysis. It was not possible to perform adequate analyses for location of ulcer disease or duration of follow-up for either meta-analysis. Recurrence of H. pylori infection was reported in the review.
H. pylori eradication therapy reduced rates of bleeding compared to non-eradication antisecretory therapy, including proton pump inhibitors (PPI), with or without subsequent long-term maintenance antisecretory therapy. It was not possible to draw conclusions for the comparison of different types of antisecretory therapies with each other or placebo, particularly in H. pylori negative patients, due to a paucity of evidence.
The review question was clear and was supported by clear inclusion criteria. A relevant literature search was conducted using four electronic databases and other appropriate sources. Appropriate measures were taken to minimise the potential for language and publication bias. Appropriate steps were taken during the review process to reduce the risk of reviewer error and bias. Validity was assessed using reliable criteria, but the quality of the majority of studies was low. Appropriate methods were used to investigate statistical heterogeneity and to synthesise the data, although confidence intervals were wide for some studies and sample sizes were small for most studies. Despite certain limitations with the included studies (including small sample sizes and potential bias due to study quality) this was a generally 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 long-term RCTs were required to assess the benefits of H. pylori eradication and the potential factors that could influence recurrence of bleeding despite the eradication of H. pylori, particularly in patients using NSAIDs or who were re-infected with H. pylori.
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: H. pylori eradication therapy Health Technology Assessment 2007; 11(51): 67-74
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 /therapeutic use /economics; Middle Aged; Peptic Ulcer Hemorrhage /drug therapy /economics /prevention & control; Proton Pump Inhibitors /therapeutic use /economics; Quality-Adjusted Life Years; Randomized Controlled Trials as Topic; Treatment Outcome; Upper Gastrointestinal Tract /drug effects
Database entry date
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.