The effectiveness of five strategies for the prevention of gastrointestinal toxicity induced by non-steroidal anti-inflammatory drugs: systematic review
BMJ 2004; 329 doi: https://doi.org/10.1136/bmj.38232.680567.EB (Published 21 October 2004) Cite this as: BMJ 2004;329:948
- Lee Hooper (lee.hooper{at}man.ac.uk), lecturer1,
- Tamara J Brown, research associate2,
- Rachel Elliott, clinical senior lecturer3,
- Katherine Payne, research fellow4,
- Chris Roberts, senior lecturer in medical statistics5,
- Deborah Symmons, professor6
- 1 Cochrane Oral Health Group, University of Manchester and Central Manchester and Manchester Children's University Healthcare Trust, Manchester Dental Education Centre, University Dental Hospital, Manchester M15 6FH
- 2 Health Economics Research at Manchester, University of Manchester
- 3 School of Pharmacy and Pharmaceutical Sciences, University of Manchester
- 4 North West Genetics Knowledge Park, Manchester
- 5 Biostatistics Group, School of Epidemiology and Health Sciences, University of Manchester
- 6 ARC Epidemiology Unit, University of Manchester
- Correspondence to: L Hooper
- Accepted 23 August 2004
Abstract
Objectives To assess the effectiveness of five gastroprotective strategies for people taking non-steroidal anti-inflammatory drugs (NSAIDs)—H2 receptor antagonists plus non-selective (or cyclo-oxygenase-1) NSAIDs; proton pump inhibitors plus non-selective NSAIDs; misoprostol plus non-selective NSAIDs; COX-2 selective NSAIDs; or COX-2 specific NSAIDs—in reducing serious gastrointestinal complications, symptomatic ulcers, serious cardiovascular or renal disease, and deaths, and improving quality of life.
Data sources The Cochrane Library, Medline, Embase, Current Controlled Trials, and System for Information on Grey Literature in Europe (SIGLE) were searched to May 2002. Bibliographies and author contacts were used to identify further studies; non-English articles were included.
Review methods Trial selection, data extraction, and quality assessment were performed independently, in duplicate. Articles were rejected only if the study was not a randomised controlled trial; did not assess a gastroprotective strategy versus placebo; included exclusively children or healthy volunteers; lasted less than 21 days; or no review outcomes were measured. Quality assessment included allocation concealment and baseline similarity.
Random effects meta-analysis, meta-regression and subgrouping were used to pool effects and analyse associations with length of follow up, mean age, and baseline gastrointestinal status. Heterogeneity was examined and sensitivity analyses performed.
Results Of 112 included randomised controlled trials (74 666 participants), five were judged to be at low risk of bias, and 138 deaths and 248 serious gastrointestinal events were reported overall. On comparing gastroprotective strategies versus placebo we found no evidence of effectiveness of H2 receptor antagonists for any primary outcomes (few events reported); proton pump inhibitors may reduce the risk of symptomatic ulcers (relative risk 0.09, 95% confidence interval 0.02 to 0.47); misoprostol reduces the risk of serious gastrointestinal complications (0.57, 0.36 to 0.91) and symptomatic ulcers (0.36, 0.20 to 0.67); COX-2 selectives reduce the risk of symptomatic ulcers (0.41, 0.26 to 0.65) and COX-2 specifics reduce the risk of symptomatic ulcers (0.49, 0.38 to 0.62) and possibly serious gastrointestinal complications (0.55, 0.38 to 0.80). All strategies except COX-2 selectives reduce the risk of endoscopic ulcers (at least 3 mm in diameter).
Conclusions Misoprostol, COX-2 specific and selective NSAIDs, and probably proton pump inhibitors significantly reduce the risk of symptomatic ulcers, and misoprostol and probably COX-2 specifics significantly reduce the risk of serious gastrointestinal complications, but data quality is low. More data on H2 receptor antagonists and proton pump inhibitors are needed, as is better reporting of rare but important outcomes.
Footnotes
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Contributors CR was involved in designing, securing funding, and providing statistical support for the review, and in editing the paper. DS was involved in the conception and design of, and securing funding for, the review, coordinating the work, abstracting data from papers, interpreting data, providing a clinical perspective, providing general advice on the review, and editing the paper. KP was involved in the design of the review, editing the paper, and providing an economic perspective. LH was involved in designing, and securing funding for, the review, designing the electronic search strategies, screening search results, screening retrieved papers against inclusion criteria, appraising quality of papers, abstracting data, writing to authors of review papers for additional information, performing meta-regressions and meta-analysis, calculations on reliability and numbers needed to treat, interpretation of the data, providing a methodological perspective, writing the paper, incorporating the edits of others, and final editing. RE was involved in designing, coordinating, and securing funding for the review; designing electronic search strategies; commenting on the review; and providing an economic perspective. TJB was involved in screening search results, checking bibliographies for further studies, organising retrieval of papers, screening retrieved papers against inclusion criteria, appraising quality of papers, abstracting data from papers, writing to authors of papers for additional information, data management for the review, performing meta-analysis and sensitivity analyses of relative risks, organising project team meetings and telephone meetings with external advisers, keeping minutes of meetings, and editing the paper. LH is guarantor.
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Funding NHS Executive, UK (NHS HTA project number 01/40/02).
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Competing interests DS has been reimbursed by Pharmacia for attending a conference.
Ethical approval As this work consisted entirely of secondary research, ethical approval was not required.
- Accepted 23 August 2004