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Systematic reviews of the clinical effectiveness and cost-effectiveness of proton pump inhibitors in acute upper gastrointestinal bleeding: Prophylactic PPI 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 |
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CRD summary This review concluded that H2RAs effectively reduced the risk of gastric and/or duodenal ulcers resulting from NSAID use, but standard-dose H2RAs were inferior to proton pump inhibitors and misoprostol. The authors' conclusions appeared to reflect the evidence presented, but the reliability of the conclusions is unclear due to limitations of the data. Authors' objectives To assess the effectiveness of prophylactic proton pump inhibitor (PPI) therapy in the prevention of bleeding from peptic ulcer in patients taking non-steroidal anti-inflammatory drugs (NSAIDs) compared with no treatment. Searching Current Contents (February to August 2004), EMBASE (to August 2004) and Cochrane Controlled Trials Register (1973 to 2004) were searched, as were MEDLINE, TOXFILE, BIOSIS Previews, Adis LMS Drug Alerts and Pharmaceutical News Index (PNI) through to June 2002. Search terms were reported. In addition, several websites, including the International Agencies for Health Technology Assessment, specialist databases such as DARE, Conference Papers Index, and Health Technology Assessment reports and meeting abstracts were searched to identify grey literature. Trial registries and recent conference proceedings were searched for ongoing trials. Experts in the field and manufacturers were contacted. References of potentially relevant articles were reviewed. Study selection Eligible studies were randomised controlled trials (RCTs) that assessed prostaglandin analogue, standard- or double-dose of H2RA (H2-receptor antagonist) or proton pump inhibitors for the prevention of non-steroidal anti-inflammatory drug (NSAID) induced upper gastrointestinal toxicity in adults taking NSAIDs for more than three weeks and enrolled for the treatment of NSAID-induced ulcers. Studies of healthy volunteers were excluded.
Included studies were divided into primary or secondary prophylaxis. Treatments varied in terms of the drugs and doses used. The primary outcome was the number of patients with endoscopic ulcers or ulcer complications (such as haemorrhage, perforation, pyloric obstruction and death). Endoscopic ulcers were defined as being at least three millimetres in diameter or distinguishable from erosions, as per the authors' description. Secondary outcomes included were reported in the review.
The authors stated neither how the papers were selected nor how many reviewers performed the selection. Assessment of study quality Two reviewers independently assessed study quality using the Jadad scale to give each study a score between 0 and 5 (a score of 5 represented better quality). A separate quality rating was also given for allocation concealment. Discrepancies were resolved by consulting a third reviewer. Data extraction Two reviewers independently extracted dichotomous data on primary and secondary outcomes. Odds ratios were calculated with 95% confidence intervals (CIs), along with relative risks, risk differences and absolute risk reductions. The number needed to treat was also calculated where appropriate. Disagreements were resolved by consensus. Methods of synthesis Odds ratios, relative risks, risk differences, absolute risk reductions and number needed to treat were each pooled using a fixed-effect model or, where heterogeneity was evident, a random-effects model was used. Heterogeneity was assessed using the X2 test. Subgroup analyses were conducted by intervention dose and follow-up duration. Sensitivity analyses were undertaken to assess the robustness of the results according to study quality, primary versus secondary prophylaxis, follow-up duration, treatment dose and certain symptoms. Publication bias was assessed using an inverted funnel plot. Results of the review Forty RCTs were included in the review (study characteristics were reported for 39 studies). Studies reporting sample sizes ranged between 24 and 8,843 patients. Quality of studies ranged between 1 and 5 (two studies scored 5 and nine scored 4). Thirty-five studies were rated with a D for allocation concealment, two were rated as B and two were rated as A.
Proton pump inhibitor versus placebo (five RCTs): Significantly fewer endoscopic ulcers (odds ratio 0.23, 95% CI: 0.18 to 0.31; five RCTs), endoscopic gastric ulcers (odds ratio 0.29, 95% CI: 0.21 to 0.40, p<0.00001; five RCTs) and endoscopic duodenal ulcers (odds ratio 0.18, 95% CI: 0.10 to 0.34, p<0.00001; four RCTs) were reported by patients receiving proton pump inhibitors in comparison with placebo. Significant heterogeneity was, however, evident for gastric and duodenal ulcers.
Proton pump inhibitor (omeprazole) versus H2RA (ranitidine): One RCT reported that proton pump inhibitors were significantly more effective than ranitidine in preventing gastric ulcers (relative risk 0.32, 95% CI: 0.17 to 0.62) and duodenal ulcers (relative risk 0.11, 95% CI: 0.01 to 0.89).
Proton pump inhibitor versus misoprostol: Two secondary prophylaxis studies reported that proton pump inhibitors were significantly more effective in preventing duodenal ulcers compared to placebo (relative risk 0.29, 95% CI: 0.15 to 0.56), but there were no differences between treatment groups for the prevention of gastric ulcers (random-effects model).
Misoprostol versus H2RAs: Two RCTs reported significant benefit from misoprostol compared to ranitidine for the prevention of NSAID-induced gastric ulcers (odds ratio 0.19, 95% CI: 0.08 to 0.48, p=0.0005), but no significant difference in the prevention of duodenal ulcers. There was no evidence of significant heterogeneity.
H2RAs versus placebo: At three months follow-up or more, significant reductions were reported for the risk of duodenal ulcers after treatment with standard dose H2RAs (relative risk 0.36, 95% CI: 0.18 to 0.74) and double-dose H2RAs (relative risk 0.26, 95% CI: 0.11 to 0.65) compared to placebo. However, only double-dose H2RAs were associated with a statistically significant reduction in the risk of gastric ulcers when compared with placebo (relative risk 0.44, 95% CI: 0.26 to 0.74, p=0.002). There was no evidence of statistical heterogeneity.
Comparison of misoprostol versus placebo, and other comparisons were reported in the review.
Adverse events and drop out rates were reported in the review. Results for publication bias were not reported. Cost information At a threshold of £100 per quality adjusted life year (QALY), the most cost-effective intervention was H. pylori eradication. At at threshold of £1,000/QALY, the most cost-effective strategy was H. pylori followed by misoprostol if this was tolerated (otherwise changing to proton pump inhibitors). Authors' conclusions Both standard and double-dose H2RAs effectively reduced the risk of duodenal ulcers resulting from NSAID use; only double-dose H2RAs were effective in reducing the risk of gastric ulcers. Proton pump inhibitors were more effective than standard-dose H2RAs in reducing endoscopic gastric and duodenal ulcers. Misoprostol was more effective in reducing endoscopic gastric ulcers and clinically significant complications from ulcers associated with NSAID use. CRD commentary The review question and supporting inclusion criteria were clear, but the question could not be fully answered due to the lack of evidence directly comparing the treatments of interest. A comprehensive literature search was conducted using several electronic databases and other appropriate sources to identify published and unpublished articles, which reduced the potential for publication bias. The authors did not report whether they applied language restrictions and so the risk of language bias was unclear. Validity was assessed using previously published criteria. The quality of most included studies appeared quite low. Appropriate steps were taken to minimise the potential for reviewer error and bias for validity assessment and data extraction, but it was unclear whether this was the case for the search strategy. Appropriate methods were used to synthesise the data and investigate heterogeneity, using a random-effects model where appropriate. It appeared that there may have been some clinical and methodological differences between studies in terms of patient characteristics and treatment doses. Statistical analyses undertaken were a little confusing, as the authors mentioned calculating relative risk and risk difference, but also presented findings as odds ratios and absolute risk ratios. Sample sizes were generally adequate, but only a small number of studies were included in some of the comparisons and confidence intervals were wide for many of the studies. It was not possible to fully answer the review question due to lack of evidence. The authors' conclusions appeared to reflect the evidence presented, but the reliability of the conclusions is unclear given the limitations of the data. Implications of the review for practice and research Practice: The authors did not state any implications for practice.
Research: The authors stated that further research was required to directly compare proton pump inhibitors and H2RAs with misoprostol. The clinical outcomes of large RCTs that assessed the effectiveness of proton pump inhibitors, misoprostol, H. pylori eradication and combination therapy with proton pump inhibitor and low-dose misoprostol in the prevention of actual upper gastrointestinal bleeds in long-term users of NSAIDs were urgently required. Further short-term studies were also required to add to the long-term benefits of H. pylori eradication and other factors that could be associated with recurrence of bleeding regardless of H. pylori eradication (particularly in patients using NSAIDs and patients with H. pylori re-infection). Funding Funded by the Health Technology Assessment (HTA) Programme, project number 03/12/03. Bibliographic details 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: Prophylactic PPI therapy. Health Technology Assessment 2007; 11(51): 75-97 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. Indexing Status Subject indexing assigned by NLM MeSH 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 & Helicobacter Infections /drug therapy; Helicobacter pylori /drug effects; Histamine H2 Antagonists /economics /therapeutic use; Humans; Middle Aged; Peptic Ulcer Hemorrhage /drug therapy /economics /prevention & Proton Pump Inhibitors /economics /therapeutic use; Quality-Adjusted Life Years; Randomized Controlled Trials as Topic; Treatment Outcome; Upper Gastrointestinal Tract /drug effects; control; control AccessionNumber 12008106883 Date abstract record published 12/08/2009 Record Status 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. |
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