Gastro-Duodenal Ulcers Associated with the Use of Non-Steroidal Anti-Inflammatory Drugs: a Systematic Review of Preventive Pharmacological Interventions
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Gastro-duodenal Ulcers Associated with the Use of Technology Non-steroidal Anti- inflammatory Drugs: A Systematic Review Report of Preventive Issue 38 September 2003 Pharmacological Interventions Publications can be requested from: CCOHTA 600-865 Carling Avenue Ottawa, Ontario, Canada K1S 5S8 Tel. (613) 226-2553 Fax. (613) 226-5392 Email: [email protected] or download from CCOHTA’s web site: http://www.ccohta.ca Cite as: Rostom A, Dubé C, Jolicoeur E, Boucher M, Joyce J. Gastro-duodenal ulcers associated with the use of non-steroidal anti-inflammatory drugs: a systematic review of preventive pharmacological interventions. Ottawa: Canadian Coordinating Office for Health Technology Assessment; 2003. Technology report no 38. Reproduction of this document for non-commercial purposes is permitted provided appropriate credit is given to CCOHTA. CCOHTA is a non-profit organization funded by the federal, provincial and territorial governments. Legal Deposit - 2003 National Library of Canada ISBN: 1-894620-92-5 (print) ISBN: 1-894620-93-3 (electronic version) Publications Mail Agreement Number: 40026386 Canadian Coordinating Office for Health Technology Assessment Gastro-duodenal Ulcers Associated with the Use of Non-steroidal Anti-inflammatory Drugs: A Systematic Review of Preventive Pharmacological Interventions Alaa Rostom MD MSc FRCPC1 1 Catherine Dubé MD MSc FRCPC 1 Emilie Jolicoeur MD 2 Michel Boucher BPharm MSc 2 Janet Joyce MLS September 2003 ________________________ 1 University of Ottawa, Ottawa, Ontario 2 Canadian Coordinating Office for Health Technology Assessment, Ottawa, Ontario Reviewers These individuals kindly provided comments on this report. External Reviewers Isabelle Chabot, PhD Betsy Miller, BScPharm MSc Manager, Health Economics and Executive Director Outcomes Research Patient Access and Outcomes Research Merck Frosst Canada & Co. Pharmacia Canada Inc. Kirkland, Quebec Mississauga, Ontario John M. Fardy, MD MSc FRCPC Andreas Maetzel, MD MSc PhD Associate Professor of Medicine Scientist, Assistant Professor (Gastroenterology) Division of Clinical Decision Making Memorial University of Newfoundland University Health Network St. John's, Newfoundland and University of Toronto Labrador Toronto, Ontario Gail Huxley, Alan B.R. Thomson, MD PhD FRCPC Scientific Development Manager FACP FACG National Medicine Professor of Medicine Boehringer Ingelheim (Canada) Ltd. University of Alberta Burlington, Ontario Edmonton, Alberta John K. Marshall, MD MSc FRCPC Angie Wong, BScPharm MSc Assistant Professor Manager, Outcomes Research Division of Gastroenterology Pharmacia Canada Inc. McMaster University Mississauga, Ontario Hamilton, Ontario This report was also reviewed by Pfizer Canada Inc., Kirkland, Quebec. CCOHTA Scientific Advisory Panel Reviewers Kenneth Marshall, MD George Wells, PhD Professor of Family Medicine (retired) Director, Department of Epidemiology University of Western Ontario and Community Medicine London, Ontario University of Ottawa Ottawa, Ontario This report is a review of existing public literature, studies, materials and other information and documentation (collectively the “source documentation”) which are available to CCOHTA. The accuracy of the contents of the source documentation on which this report is based is not warranted, assured or represented in any way by CCOHTA and CCOHTA does not assume responsibility for the quality, propriety, inaccuracies or reasonableness of any statements, information or conclusions contained in the source documentation. CCOHTA takes sole responsibility for the final form and content of this report. The statements and conclusions in this report are those of CCOHTA and not of its Panel members or reviewers. i Authorship Alaa Rostom, the principal investigator, participated in all aspects of the project and was responsible for the primary writing of the report. Catherine Dubé participated in the design of the project, selection of relevant studies and analysis of the data. She also critically reviewed all drafts of the report. Emilie Jolicoeur participated in the selection of included studies and in data abstraction and assisted in analysis and interpretation of the results. She also critically reviewed all drafts of the report. Michel Boucher participated in the design of the project, selection of relevant studies and writing of the initial draft and all report revisions. He also coordinated the external review process. Janet Joyce was responsible for designing and conducting the literature search, writing the search methods, preparing the search strategies appendix and compiling the bibliography. Conflict of Interest Dr. John K. Marshall declared that he has received speaker’s fees from Merck Frosst Canada & Co. ii REPORT IN BRIEF September 2003 Drugs to Prevent Gastro-duodenal Ulcers Associated with the Use of NSAIDs Technology Name Method • Non-steroidal anti-inflammatory drugs (NSAIDs) For the first objective, a Cochrane Collaboration meta- • Gastroprotective agents: misoprostol, histamine type-2 analysis was updated. For the other objectives, a literature search was used to identify studies that assessed the GI receptor antagonists (H2RAs), proton pump inhibitors (PPIs) safety of the newer COX-2 selective NSAIDs. • Cyclooxygenase (COX)-2 selective NSAIDs: celecoxib, rofecoxib, meloxicam. Conclusions Disease/Condition Gastroprotective agents • Misoprostol, PPIs and double doses of H2RAs are Traditional NSAIDs, which are used to treat painful arthritic effective at reducing the risk of endoscopically and inflammatory disorders, can produce gastro-intestinal (GI) identified NSAID-induced ulcers. adverse effects. The incidence of serious complications is low, • Standard doses of H RAs are ineffective at reducing but it is an important clinical issue because of the widespread 2 the risk of endoscopically identified NSAID-induced use of these medications. ulcers. • Misoprostol is the only agent that has been shown to Technology Description reduce the risk of NSAID-induced clinically Gastroprotective agents can help protect the stomach when important ulcer complications. Its use, however, is an NSAID is used. COX is an enzyme. Type 1 COX (COX- associated with significant adverse effects, 1) is involved in protecting the stomach lining, while the particularly at higher doses. second type (COX-2) may be important in promoting the pain of arthritic diseases. Traditional NSAIDs inhibit the COX-2 selective NSAIDs effects of COX-1 and COX-2. NSAIDs that selectively • COX-2 selective NSAIDs are associated with a lower inhibit COX-2 theoretically should have little effect on the risk of endoscopically identified ulcers and of GI tract. clinically important ulcer complications when compared with traditional non-selective NSAIDs in The Issue general. The efficacy and safety profiles of available gastro- • COX-2 selective NSAIDs were found to be safer than protective agents should be compared when they are used naproxen and ibuprofen (high dose), but no to protect against NSAID-induced GI damage. The GI significant difference was found between the COX-2 safety profiles of COX-2 selective NSAIDs should be selective NSAIDs reviewed and diclofenac. compared with those of traditional non-selective NSAIDs. • Preliminary results indicate that the reduced GI complication rate due to celecoxib may be lost when it is administered with acetylsalicylic acid (ASA). Assessment Objectives This has not been tested for rofecoxib. 1. To assess how well gastroprotective agents protect • Meloxicam does not seem to be safer than traditional against the upper GI damage caused by traditional non- non-selective NSAIDs. selective NSAIDs. • It is unclear whether the co-administration of a COX- 2. To compare the upper GI damage caused by COX-2 2 selective NSAID and a gastroprotective agent selective NSAIDs with that caused by traditional non- significantly improves safety over the use of a COX- selective NSAIDs. 2 selective NSAID alone or the use of a traditional 3. To compare the upper GI damage caused by COX-2 non-selective NSAID with gastroprotection. selective NSAIDs with that caused by placebo. This summary is based on a comprehensive health technology assessment report available from CCOHTA’s web site (www.ccohta.ca): Rostom A, Dubé C, Jolicoeur E, Boucher M, Joyce J. Gastroduodenal ulcers associated with the use of non-steroidal anti-inflammatory drugs: a systematic review of preventive pharmacological interventions. Canadian Coordinating Office For Health Technology Assessment (CCOHTA) 600-865 Carling Avenue, Ottawa, ON, Canada K1S 5S8 Tel: 613-226-2553 Fax: 613-226-5392 www.ccohta.ca CCOHTA is an independent, non-profit health research agency funded by the federal, provincial and territorial governments. EXECUTIVE SUMMARY Background Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used to treat arthritic and inflammatory syndromes and acute and chronic pain. These agents, however, are associated with gastro-intestinal (GI) complications such as perforation or hemorrhage, with an occurrence of about 2% per year in average risk patients and as high as 10% per year in high risk patients. Although the former rate is low, it is important because of the common use of these medications. Several pharmacological strategies have been developed to reduce the risk of NSAID-induced GI complications. One approach is the use of concurrent prophylactic gastroprotective agents such as misoprostol, histamine type-2 receptor antagonists (H2RAs) and proton pump inhibitors (PPIs). Alternatively, newer cyclooxygenase-isoform