Prevention of NSAID-induced gastroduodenal ulcers (Review)

Rostom A, Dube C, Wells GA, Tugwell P, Welch V, Jolicoeur E, McGowan J, Lanas A

This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library
2002, Issue 4
http://www.thecochranelibrary.com

Prevention of NSAID-induced gastroduodenal ulcers (Review)

Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
 TABLE OF CONTENTS

HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49
Analysis 1.1. Comparison 1 Misoprostol vs placebo - primary efficacy, Outcome 1 Gastric ulcers - 4 - 11 week studies. 57
Analysis 1.2. Comparison 1 Misoprostol vs placebo - primary efficacy, Outcome 2 Duodenal ulcers - 4 - 11 week studies. 58
Analysis 1.3. Comparison 1 Misoprostol vs placebo - primary efficacy, Outcome 3 Total ulcers - 4 - 11 week studies. 59
Analysis 1.4. Comparison 1 Misoprostol vs placebo - primary efficacy, Outcome 4 Gastric ulcers - 12 weeks or longer
studies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60
Analysis 1.5. Comparison 1 Misoprostol vs placebo - primary efficacy, Outcome 5 Duodenal ulcers - 12 weeks or longer
studies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61
Analysis 1.6. Comparison 1 Misoprostol vs placebo - primary efficacy, Outcome 6 Total endoscopic ulcers - 12 weeks or
longer studies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62
Analysis 1.7. Comparison 1 Misoprostol vs placebo - primary efficacy, Outcome 7 Total endoscopic ulcers Chan 2001
removed - 12 weeks or longer studies. . . . . . . . . . . . . . . . . . . . . . . . . . 63
Analysis 1.8. Comparison 1 Misoprostol vs placebo - primary efficacy, Outcome 8 Clinical ulcers - 12 weeks or longer
studies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64
Analysis 2.1. Comparison 2 Misoprostol vs placebo - toxicity causing withdrawal, Outcome 1 Nausea. . . . . . 65
Analysis 2.2. Comparison 2 Misoprostol vs placebo - toxicity causing withdrawal, Outcome 2 Dyspepsia. . . . . 66
Analysis 2.3. Comparison 2 Misoprostol vs placebo - toxicity causing withdrawal, Outcome 3 Constipation. . . . 67
Analysis 2.4. Comparison 2 Misoprostol vs placebo - toxicity causing withdrawal, Outcome 4 Diarrhea. . . . . . 68
Analysis 2.5. Comparison 2 Misoprostol vs placebo - toxicity causing withdrawal, Outcome 5 Abdominal pain. . . 69
Analysis 2.6. Comparison 2 Misoprostol vs placebo - toxicity causing withdrawal, Outcome 6 Flatulence. . . . . 70
Analysis 2.7. Comparison 2 Misoprostol vs placebo - toxicity causing withdrawal, Outcome 7 Vomiting. . . . . . 70
Analysis 2.8. Comparison 2 Misoprostol vs placebo - toxicity causing withdrawal, Outcome 8 Drop-outs due to side-
effects. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71
Analysis 2.9. Comparison 2 Misoprostol vs placebo - toxicity causing withdrawal, Outcome 9 Drop-outs overall. . . 72
Analysis 3.1. Comparison 3 Misoprostol vs placebo - toxicity symptoms only, Outcome 1 Nausea. . . . . . . . 73
Analysis 3.2. Comparison 3 Misoprostol vs placebo - toxicity symptoms only, Outcome 2 Dyspepsia. . . . . . . 74
Analysis 3.3. Comparison 3 Misoprostol vs placebo - toxicity symptoms only, Outcome 3 Constipation. . . . . . 75
Analysis 3.4. Comparison 3 Misoprostol vs placebo - toxicity symptoms only, Outcome 4 Diarrhea. . . . . . . 76
Analysis 3.5. Comparison 3 Misoprostol vs placebo - toxicity symptoms only, Outcome 5 Abdominal pain. . . . . 77
Analysis 3.6. Comparison 3 Misoprostol vs placebo - toxicity symptoms only, Outcome 6 Flatulence. . . . . . . 78
Analysis 4.1. Comparison 4 Misoprostol vs placebo - efficacy by dosage, Outcome 1 Gastric ulcers - 1 month. . . . 79
Analysis 4.2. Comparison 4 Misoprostol vs placebo - efficacy by dosage, Outcome 2 Duodenal ulcers - 1 month. . . 80
Analysis 4.3. Comparison 4 Misoprostol vs placebo - efficacy by dosage, Outcome 3 Total ulcers - 1 month. . . . 81
Analysis 4.4. Comparison 4 Misoprostol vs placebo - efficacy by dosage, Outcome 4 Gastric ulcers - 3-24 months. . 82
Analysis 4.5. Comparison 4 Misoprostol vs placebo - efficacy by dosage, Outcome 5 Gastric ulcers - 3-24 months (sensitivity
analysis excluding Chan 2001). . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83
Analysis 4.6. Comparison 4 Misoprostol vs placebo - efficacy by dosage, Outcome 6 Duodenal ulcers - 3-24 months. 84
Prevention of NSAID-induced gastroduodenal ulcers (Review) i
Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
 Analysis 4.7. Comparison 4 Misoprostol vs placebo - efficacy by dosage, Outcome 7 Total endoscopic ulcers 3-24 months. 85
Analysis 4.8. Comparison 4 Misoprostol vs placebo - efficacy by dosage, Outcome 8 Clinical ulcers - 3-24 months. . 87
Analysis 5.1. Comparison 5 Misoprostol vs placebo - toxicity causing withdrawal - by dose, Outcome 1 Nausea. . . 88
Analysis 5.2. Comparison 5 Misoprostol vs placebo - toxicity causing withdrawal - by dose, Outcome 2 Dyspepsia. . 89
Analysis 5.3. Comparison 5 Misoprostol vs placebo - toxicity causing withdrawal - by dose, Outcome 3 Constipation. 90
Analysis 5.4. Comparison 5 Misoprostol vs placebo - toxicity causing withdrawal - by dose, Outcome 4 Diarrhea. . 91
Analysis 5.5. Comparison 5 Misoprostol vs placebo - toxicity causing withdrawal - by dose, Outcome 5 Abdominal pain. 92
Analysis 5.6. Comparison 5 Misoprostol vs placebo - toxicity causing withdrawal - by dose, Outcome 6 Flatulence. . 93
Analysis 5.7. Comparison 5 Misoprostol vs placebo - toxicity causing withdrawal - by dose, Outcome 7 Vomiting. . 94
Analysis 5.8. Comparison 5 Misoprostol vs placebo - toxicity causing withdrawal - by dose, Outcome 8 Dropouts due to
side effects. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95
Analysis 5.9. Comparison 5 Misoprostol vs placebo - toxicity causing withdrawal - by dose, Outcome 9 Dropouts overall. 96
Analysis 6.1. Comparison 6 Misoprostol vs placebo - symptoms - by dose, Outcome 1 Nausea. . . . . . . . . 97
Analysis 6.2. Comparison 6 Misoprostol vs placebo - symptoms - by dose, Outcome 2 Dyspepsia. . . . . . . . 99
Analysis 6.3. Comparison 6 Misoprostol vs placebo - symptoms - by dose, Outcome 3 Constipation. . . . . . . 100
Analysis 6.4. Comparison 6 Misoprostol vs placebo - symptoms - by dose, Outcome 4 Diarrhea. . . . . . . . 101
Analysis 6.5. Comparison 6 Misoprostol vs placebo - symptoms - by dose, Outcome 5 Abdominal pain. . . . . . 103
Analysis 6.6. Comparison 6 Misoprostol vs placebo - symptoms - by dose, Outcome 6 Flatulence. . . . . . . . 104
Analysis 6.7. Comparison 6 Misoprostol vs placebo - symptoms - by dose, Outcome 7 Vomiting. . . . . . . . 105
Analysis 6.8. Comparison 6 Misoprostol vs placebo - symptoms - by dose, Outcome 8 Dropouts due to side effects. . 106
Analysis 6.9. Comparison 6 Misoprostol vs placebo - symptoms - by dose, Outcome 9 Dropouts overall. . . . . . 107
Analysis 6.10. Comparison 6 Misoprostol vs placebo - symptoms - by dose, Outcome 10 Headache. . . . . . . 108
Analysis 7.1. Comparison 7 H2 Receptor vs placebo - 4 - 11 week studies by dose, Outcome 1 Gastric ulcer. . . . 109
Analysis 7.2. Comparison 7 H2 Receptor vs placebo - 4 - 11 week studies by dose, Outcome 2 Duodenal ulcer. . . 110
Analysis 7.3. Comparison 7 H2 Receptor vs placebo - 4 - 11 week studies by dose, Outcome 3 Total endoscopic ulcers. 111
Analysis 8.1. Comparison 8 H2 Receptor vs placebo 12 weeks or longer - by dose, Outcome 1 Gastric ulcer. . . . 112
Analysis 8.2. Comparison 8 H2 Receptor vs placebo 12 weeks or longer - by dose, Outcome 2 Duodenal ulcer. . . 113
Analysis 8.3. Comparison 8 H2 Receptor vs placebo 12 weeks or longer - by dose, Outcome 3 Total endoscopic ulcers. 114
Analysis 9.1. Comparison 9 H2 Receptor vs placebo - toxicity - by dose, Outcome 1 Total drop-outs. . . . . . . 115
Analysis 9.2. Comparison 9 H2 Receptor vs placebo - toxicity - by dose, Outcome 2 Drop-outs due to side effects. . 116
Analysis 9.3. Comparison 9 H2 Receptor vs placebo - toxicity - by dose, Outcome 3 Dropouts due to GI symptoms. 117
Analysis 9.4. Comparison 9 H2 Receptor vs placebo - toxicity - by dose, Outcome 4 Dropouts due to abdominal pain. 118
Analysis 9.5. Comparison 9 H2 Receptor vs placebo - toxicity - by dose, Outcome 5 Dropouts due to diarrhea. . . 119
Analysis 9.6. Comparison 9 H2 Receptor vs placebo - toxicity - by dose, Outcome 6 Diarrhea. . . . . . . . . 120
Analysis 9.7. Comparison 9 H2 Receptor vs placebo - toxicity - by dose, Outcome 7 Abdominal pain. . . . . . 121
Analysis 9.8. Comparison 9 H2 Receptor vs placebo - toxicity - by dose, Outcome 8 GI symptoms. . . . . . . 122
Analysis 9.9. Comparison 9 H2 Receptor vs placebo - toxicity - by dose, Outcome 9 Flatulence. . . . . . . . 123
Analysis 9.10. Comparison 9 H2 Receptor vs placebo - toxicity - by dose, Outcome 10 Dyspepsia. . . . . . . . 124
Analysis 9.11. Comparison 9 H2 Receptor vs placebo - toxicity - by dose, Outcome 11 Rash. . . . . . . . . 125
Analysis 10.1. Comparison 10 PPI vs placebo - 4 - 11 week studies, Outcome 1 Endoscopic gastric ulcer. . . . . 126
Analysis 10.2. Comparison 10 PPI vs placebo - 4 - 11 week studies, Outcome 2 Endoscopic duodenal ulcer. . . . 126
Analysis 10.3. Comparison 10 PPI vs placebo - 4 - 11 week studies, Outcome 3 Total endoscopic ulcers. . . . . . 127
Analysis 10.4. Comparison 10 PPI vs placebo - 4 - 11 week studies, Outcome 4 Clinical Ulcer (POB). . . . . . 127
Analysis 10.5. Comparison 10 PPI vs placebo - 4 - 11 week studies, Outcome 5 Clinical Ulcer - PUB (POB + symptomatic
ulcer). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128
Analysis 11.1. Comparison 11 PPI vs placebo - 8 weeks or longer studies, Outcome 1 Endoscopic gastric ulcer. . . 129
Analysis 11.2. Comparison 11 PPI vs placebo - 8 weeks or longer studies, Outcome 2 Endoscopic duodenal ulcer. . 130
Analysis 11.3. Comparison 11 PPI vs placebo - 8 weeks or longer studies, Outcome 3 Total endoscopic ulcers. . . . 131
Analysis 12.1. Comparison 12 PPI vs placebo - 12 weeks or longer studies, Outcome 1 Endoscopic gastric ulcer. . . 132
Analysis 12.2. Comparison 12 PPI vs placebo - 12 weeks or longer studies, Outcome 2 Endoscopic duodenal ulcer. . 133
Analysis 12.3. Comparison 12 PPI vs placebo - 12 weeks or longer studies, Outcome 3 Total endoscopic ulcers. . . 134
Analysis 13.1. Comparison 13 PPI vs placebo - toxicity, Outcome 1 Dropouts overall. . . . . . . . . . . . 135
Analysis 13.2. Comparison 13 PPI vs placebo - toxicity, Outcome 2 Dropouts due to side effects. . . . . . . . 135
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Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
 Analysis 13.3. Comparison 13 PPI vs placebo - toxicity, Outcome 3 Diarrhea. . . . . . . . . . . . . . . 136
Analysis 13.4. Comparison 13 PPI vs placebo - toxicity, Outcome 4 Abdominal pain. . . . . . . . . . . . 137
Analysis 13.5. Comparison 13 PPI vs placebo - toxicity, Outcome 5 Flatulence. . . . . . . . . . . . . . 137
Analysis 13.6. Comparison 13 PPI vs placebo - toxicity, Outcome 6 Dyspepsia. . . . . . . . . . . . . . 138
Analysis 14.1. Comparison 14 PPI vs H2-antagonist - 12 weeks or longer studies, Outcome 1 Endoscopic gastric ulcers. 138
Analysis 14.2. Comparison 14 PPI vs H2-antagonist - 12 weeks or longer studies, Outcome 2 Endoscopic duodenal
ulcers. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139
Analysis 14.3. Comparison 14 PPI vs H2-antagonist - 12 weeks or longer studies, Outcome 3 Total endoscopic ulcers. 139
Analysis 14.4. Comparison 14 PPI vs H2-antagonist - 12 weeks or longer studies, Outcome 4 Total clinical ulcers. . 140
Analysis 14.5. Comparison 14 PPI vs H2-antagonist - 12 weeks or longer studies, Outcome 5 Toxicity- dropouts due to
side effects. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 140
Analysis 14.6. Comparison 14 PPI vs H2-antagonist - 12 weeks or longer studies, Outcome 6 Vomiting. . . . . 141
Analysis 14.7. Comparison 14 PPI vs H2-antagonist - 12 weeks or longer studies, Outcome 7 Abdominal pain. . . 141
Analysis 14.8. Comparison 14 PPI vs H2-antagonist - 12 weeks or longer studies, Outcome 8 Diarrhea. . . . . . 142
Analysis 15.1. Comparison 15 Misoprostol Vs PPI (as control) - 12 weeks or longer studies, Outcome 1 Endoscopic gastric
ulcer. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142
Analysis 15.2. Comparison 15 Misoprostol Vs PPI (as control) - 12 weeks or longer studies, Outcome 2 Endoscopic
duodenal ulcer. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 143
Analysis 15.3. Comparison 15 Misoprostol Vs PPI (as control) - 12 weeks or longer studies, Outcome 3 Total endoscopic
ulcers. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 143
Analysis 16.1. Comparison 16 PPI Vs Misoprostol (as control) - 12 weeks or longer studies, Outcome 1 Endoscopic gastric
ulcer. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 144
Analysis 16.2. Comparison 16 PPI Vs Misoprostol (as control) - 12 weeks or longer studies, Outcome 2 Endoscopic
duodenal ulcer. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145
Analysis 16.3. Comparison 16 PPI Vs Misoprostol (as control) - 12 weeks or longer studies, Outcome 3 Total endoscopic
ulcers. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145
Analysis 17.1. Comparison 17 Misoprostol vs PPI - toxicity - 12 weeks or longer studies, Outcome 1 Dropouts overall. 146
Analysis 17.2. Comparison 17 Misoprostol vs PPI - toxicity - 12 weeks or longer studies, Outcome 2 Dropouts due to side
effects. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147
Analysis 18.1. Comparison 18 Misoprostol vs ranitidine 150 mg bid - 1-2 month, Outcome 1 Endoscopic gastric ulcers. 148
Analysis 18.2. Comparison 18 Misoprostol vs ranitidine 150 mg bid - 1-2 month, Outcome 2 Endoscopic duodenal
ulcers. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148
Analysis 18.3. Comparison 18 Misoprostol vs ranitidine 150 mg bid - 1-2 month, Outcome 3 Dropouts due to side
effects. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149
Analysis 18.4. Comparison 18 Misoprostol vs ranitidine 150 mg bid - 1-2 month, Outcome 4 Total endoscopic ulcers. 150
Analysis 18.5. Comparison 18 Misoprostol vs ranitidine 150 mg bid - 1-2 month, Outcome 5 Dropouts overall. . . 150
Analysis 18.6. Comparison 18 Misoprostol vs ranitidine 150 mg bid - 1-2 month, Outcome 6 Dropouts due to abdominal
pain. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 151
Analysis 18.7. Comparison 18 Misoprostol vs ranitidine 150 mg bid - 1-2 month, Outcome 7 Dropouts due to nausea. 151
Analysis 18.8. Comparison 18 Misoprostol vs ranitidine 150 mg bid - 1-2 month, Outcome 8 Dyspepsia. . . . . 152
Analysis 18.9. Comparison 18 Misoprostol vs ranitidine 150 mg bid - 1-2 month, Outcome 9 Abdominal pain
symptoms. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 152
Analysis 18.10. Comparison 18 Misoprostol vs ranitidine 150 mg bid - 1-2 month, Outcome 10 Flatulence symptoms. 153
Analysis 18.11. Comparison 18 Misoprostol vs ranitidine 150 mg bid - 1-2 month, Outcome 11 Nausea symptoms. 153
Analysis 18.12. Comparison 18 Misoprostol vs ranitidine 150 mg bid - 1-2 month, Outcome 12 Diarrhea symptoms. 154
Analysis 19.1. Comparison 19 Nizatidine 150 mg vs 300 mg efficacy, Outcome 1 Total endoscopic ulcers. . . . . 154
Analysis 19.2. Comparison 19 Nizatidine 150 mg vs 300 mg efficacy, Outcome 2 Dropouts overall. . . . . . . 155
Analysis 20.1. Comparison 20 NSAID + PPI vs COX 2, Outcome 1 Clinical Ulcer (POB). . . . . . . . . . 155
APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155
FEEDBACK . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 174
WHAT’S NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 175
HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 176
CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 176
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DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 177
SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 177
DIFFERENCES BETWEEN PROTOCOL AND REVIEW . . . . . . . . . . . . . . . . . . . . . 177
NOTES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 178
INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 178

Prevention of NSAID-induced gastroduodenal ulcers (Review) iv

Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
[Intervention Review]

Prevention of NSAID-induced gastroduodenal ulcers

Alaa Rostom1 , Catherine Dube1 , George A Wells2 , Peter Tugwell3 , Vivian Welch4 , Emilie Jolicoeur5 , Jessie McGowan6 , Angel Lanas7

1
University of Calgary Department of Medicine / Gastroenterology, Foothills Medical Centre, Calgary, Canada. 2 Department of
Epidemiology and Community Medicine, University of Ottawa, Ottawa, Canada. 3 Centre for Global Health, Institute of Population
Health, Faculty of Medicine, University of Ottawa, Ottawa, Canada. 4 Centre for Global Health, Institute of Population Health,
University of Ottawa, Ottawa, Canada. 5 Division of Gastroenterology, A-1 Endoscopy Unit, Ottawa, Canada. 6 Institute of Population
Health/Ottawa Health Research Institute, University of Ottawa, Ottawa, Canada. 7 University of Zaragoza, Zaragoza, Spain

Contact address: Alaa Rostom, University of Calgary Department of Medicine / Gastroenterology, Foothills Medical Centre, 1403 -
29 St. N.W, Calgary, Alberta, T2N 2T9, Canada. arostom@ucalgary.ca.

Editorial group: Cochrane Upper Gastrointestinal and Pancreatic Diseases Group.

Publication status and date: Edited (no change to conclusions), published in Issue 6, 2011.
Review content assessed as up-to-date: 11 May 2009.

Citation: Rostom A, Dube C, Wells GA, Tugwell P, Welch V, Jolicoeur E, McGowan J, Lanas A. Prevention of NSAID-induced gastro-
duodenal ulcers. Cochrane Database of Systematic Reviews 2002, Issue 4. Art. No.: CD002296. DOI: 10.1002/14651858.CD002296.

Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

ABSTRACT

Background

Non-steroidal anti-inflammatory drugs (NSAIDs) are important agents in the management of arthritic and inflammatory conditions,
and are among the most frequently prescribed medications in North America and Europe. However, there is overwhelming evidence
linking these agents to a variety of gastrointestinal (GI) toxicities.

Objectives

To review the effectiveness of common interventions for the prevention of NSAID induced upper GI toxicity.

Search methods

We searched MEDLINE from 1966 to May 2009, Current Contents for six months prior to May 2009, EMBASE to May 2009, and
the Cochrane Controlled Trials Register from 1973 to May 2009. Recent conference proceedings were reviewed and content experts
and companies were contacted.

Selection criteria

Randomized controlled clinical trials (RCTs) of prostaglandin analogues (PA), H2-receptor antagonists (H2RA) or proton pump
inhibitors (PPI) for the prevention of chronic NSAID induced upper GI toxicity were included.

Data collection and analysis

Two independent authors extracted data regarding population characteristics, study design, methodological quality and number of
participants with endoscopic ulcers, ulcer complications, symptoms, overall drop-outs, drop outs due to symptoms. Dichotomous data
were pooled using RevMan 5.0. Heterogeneity was evaluated using a chi square test, and the I square statistic.
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Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Main results

Forty-one RCTs met the inclusion criteria. All doses of misoprostol significantly reduced the risk of endoscopic ulcers. Misoprostol
800 ug/day was superior to 400 ug/day for the prevention of endoscopic gastric ulcers (RR 0.17, and RR 0.39 respectively, P=0.0055).
A dose response relationship was not seen with duodenal ulcers. Misoprostol caused diarrhoea at all doses, although significantly more
at 800 ug/day than 400 ug/day (P=0.0012). Misoprostol also reduced the risk of clinical ulcer complications.

Standard doses of H2RAs were effective at reducing the risk of endoscopic duodenal (RR 0.36; 95% CI 0.18 to 0.74) but not gastric
ulcers (RR 0.73; 95% CI 0.50 to 1.08). Both double dose H2RAs and PPIs were effective at reducing the risk of endoscopic duodenal
and gastric ulcers (RR 0.44; 95% CI 0.26 to 0.74) and RR=0.40;95% CI; 0.32-0.51 respectively for gastric ulcer), and were better
tolerated than misoprostol.

Authors’ conclusions

Misoprostol, PPIs, and double dose H2RAs are effective at preventing chronic NSAID related endoscopic gastric and duodenal ulcers.
Lower doses of misoprostol are less effective and are still associated with diarrhoea. In patients with previous NSAID bleeds, a COX-2
inhibitor alone is equivalent to a tNSAID+PPI, though the re-bleeding rates with both strategies are still relatively high. A strategy of
a COX-2 inhibitor+PPI appears to offer the greatest GI safety in high risk patients.

PLAIN LANGUAGE SUMMARY

Medications to prevent NSAID-induced gastroduodenal ulcers

The results of this meta-analysis demonstrate that misoprostol, proton pump inhibitors, and double doses of H2-receptor antagonists
are effective at reducing the risk of both gastric and duodenal non steroidal anti-inflammatory (NSAID) medications induced ulcers.
In high risk patients, the use of a traditional NSAID + PPI appears equivalent to a COX-2 inhibitor alone. The most effective strategy
in high risk GI patients appears to be the combination of a COX-2 inhibitor + PPI.

BACKGROUND perforation or death are much less common, occurring collectively

Description of the condition
Non-steroidal anti-inflammatory drugs (NSAIDs) are important
agents in the management of arthritic and inflammatory condi-
tions, and are among the most frequently prescribed medications
in North America and Europe (Fries 1990; Wallace 1996). How-
ever, there is overwhelming evidence linking these agents to a va-
riety of gastrointestinal (GI) toxicities (Fries 1990; Stalnikowicz
1993; Smalley 1996; Fries 1991; Griffin 1988; Bollini 1992;
McMahon 1997; Gabriel 1991; Langman 1994; MacDonald
1997; Armstrong 1987; Silverstein 1995). Common side effects
such as nausea and dyspepsia correlate poorly with serious adverse
GI events (Silverstein 1995; Larkai 1987). While endoscopic ul-
cers can be documented in up to 40% of chronic NSAID users
(Stalnikowicz 1993), it is estimated that as many as 85% of these
never become clinically apparent (Silverstein 1995; Maetzel 1998).
Serious NSAID induced GI complications such as haemorrhage,
Prevention of NSAID-induced gastroduodenal ulcers (Review)
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with an incidence of about 1.5% per year (Silverstein 1995). How-
ever, the number of individuals prescribed NSAIDs and the po-
tential for life-threatening adverse events make NSAID toxicity an
important clinical and economic problem.
Description of the intervention
In the late 1990s, evidence from non-clinical and early clinical
trials suggested that the gastrointestinal (GI) safety of the newer
cyclooxygenase-2 (COX-2) selective NSAIDs may be such that a
fundamental change in clinicians’ choice from the use of standard
NSAIDs with a gastro-protective agent to monotherapy with a
COX-2 selective NSAID (COX-2 inhibitors) was on the horizon.
However, much has changed since then in the NSAID field.
The release of the cyclo-oxygenase-2 selective inhibitors (COX-
2s) brought about significant changes in the NSAID market place.
Traditional nonselective NSAIDs (tNSAIDs) prescription num-
bers fell rapidly, to be replaced by COX-2 prescriptions. Addition-
2
ally, overall NSAID prescriptions rose in number suggesting that
clinicians were starting COX-2s on patients who were not con-
sidered candidates for tNSAIDs. The rise of COX-2s continued
until 2004 when greater data regarding their cardiovascular and
other toxicities became available, leading to the withdrawal of most
of these agents from the market over the following years. Non-
naproxen tNSAIDs were also suggested to have important car-
diovascular toxicity, leading to considerable uncertainty amongst
clinicians treating patients with arthritis and other pain disorders
as to the choice of agent to use (Rostom 2009; Rostom 2009b).
How the intervention might work
NSAIDs are believed to cause gastroduodenal mucosal injury
through their inhibition of mucosal prostaglandin production.
Prostaglandins promote mucosal integrity through several mecha-
nisms including: maintenance of mucosal blood flow; promoting
mucosal bicarbonate formation; promoting mucosal mucus for-
mation; and reducing mucosal acid secretion. Three intervention
classes were assessed in this review: misoprostol; H2RAs; and PPIs.
H2RAs and PPIs are believed to exert their gastro-protective ef-
fects from NSAID gastroduodenal injury through the reduction of
gastric acid secretion. Prostaglandin analogues such as misoprostol
are believed to exert their gastro-protection by restoring mucosal
prostaglandin effects (Rostom 2004).
Why it is important to do this review
NSAIDs are amongst the most commonly prescribed medica-
tions worldwide, and are associated with important gastrointesti-
nal harms. The introduction of COX-2’s with their greater GI
safety resulted in important declines in tNSAID prescriptions.
However, with the discovery of cardiovascular (CVS) and other
adverse effects associated with COX-2s, practitioners are returning
to prescribing tNSAIDs with a gastro-protective agent in an effort
to overcome some of the adverse GI effects of tNSAIDs.
OBJECTIVES
The primary objective of this study was to systematically review
the available literature on the effectiveness of the prostaglandin
analogue (PA) misoprostol, H2-receptor antagonists (H2RA), and
proton pump inhibitors (PPI) for the prevention of NSAID in-
duced upper GI toxicity, among patients requiring chronic NSAID
use. The secondary objectives were to review the effect of these
agents on NSAID induced GI symptoms, and to assess the rela-
tionship between the effectiveness of PAs at various doses and their
associated drug induced adverse events.
Prevention of NSAID-induced gastroduodenal ulcers (Review)
Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
METHODS
Criteria for considering studies for this review
Types of studies
Randomized controlled trials were eligible for this meta-analysis.
Types of participants
Participants were eligible if they had taken NSAIDs for greater
than 3 weeks and were enrolled for the prophylaxis of NSAID-
induced ulcers.
Types of interventions
Interventions that were examined include: H2-antagonists, proton
pump inhibitors and misoprostol each used for the prophylaxis of
NSAID induced gastroduodenal ulcers.
Types of outcome measures
Primary outcomes
For each study, the number of participants with: endoscopic ul-
cers; ulcer complications (haemorrhage, perforation, pyloric ob-
struction or death); symptoms (nausea, vomiting, dyspepsia, ab-
dominal pain or diarrhoea); overall drop-outs; and drop outs due
to symptoms were identified. Included studies were also classified
into primary or secondary prophylaxis trials and by the time peri-
ods of outcome measures.
The primary outcomes were:
• endoscopic ulcers (gastric, duodenal and gastroduodenal);
• clinical ulcer complications.
Secondary outcomes
The secondary outcomes were:
• symptoms;
• drop-outs and drop outs due to symptoms
Search methods for identification of studies
Electronic searches
Randomized controlled clinical trials (RCTs) of PA, H2RA or
PPIs for the prevention of NSAID induced upper GI toxicity
were identified in accordance with published recommendations
(Haynes 1994; Hunt 1997). This included identification of articles
3
through electronic databases including originally a MEDLINE
search from 1966 to June 2002, Current Contents for 6 months
prior to June 2002, EMBASE to May 2002, and a search of the
Cochrane Controlled Trials Register from 1973 to 2002. These
searches were updated from 2002 to Dec 2004 and then from
2004 to May 2009.
Searching other resources
In addition to update searches by the Cochrane UGPD Group, the
search strategy for this review was supplemented on two occasions:
1. for the Canadian Coordinating Office for Health
Technology Assessment (CCOHTA) review in 2003;
2. for the Canadian Consensus conference on the use of ASA.
NSAIDs, and COX-2 Inhibitors in 2007-2008.
The CCOHTA search Description: A Dialog® OneSearch® on
MEDLINE®, ToxFile, EMBASE®, BIOSIS Previews®, Phar-
maceutical News Index (PNI)® and Current Contents Search®
for published and scientific meeting literature was performed. The
Cochrane Library was searched separately. The web sites for Inter-
national Agencies for Health Technology Assessment (INAHTA)
web sites, specialized databases (e.g. University of York National
Health Service (NHS) Center for Reviews and Dissemination
(CRD)) and Conference Papers Index, as well as internet searching
(i.e. Google searching), were searched in order to identify health
technology assessment reports, meeting abstracts, and other grey
literature. Trial registries were searched for ongoing trials. Recent
conference proceedings were consulted and content experts and
companies were contacted. The reference lists of all potentially
relevant articles including reviews were reviewed for the identi-
fication of other potential studies. The search strategies used are
shown in Appendix 1; Appendix 2; Appendix 3; Appendix 4.
The search strategy used to supplement the Canadian NSAID
consensus conference is listed in Appendix 5.
Data collection and analysis
Selection of studies
Study selection was performed in duplicate by two independent
authors (AR, CD, VW or EJ). A first level screen to obtain a list
of potentially relevant articles was performed by reviewing the
titles and abstracts of the search results (Rostom 2000). RCTs of
PA, H2RAs or PPIs were considered eligible for inclusion if: these
drugs were used for the prevention of NSAID induced upper GI
toxicity in adults; the duration of NSAID exposure was 4 weeks
or greater (equivalent to > 3 weeks); and endoscopic ulcers were
defined as at least 3mm in diameter and/or could be distinguished
from erosions based on the authors’ description. Studies in healthy
volunteers were excluded. Double doses of H2RAs were defined
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as a dose equivalent to or greater than 300mg of ranitidine twice
daily.
Data extraction and management
Data extraction was performed independently by two authors
(AR,CD, VW, or EJ), with a standardized data extraction sheet.
Differences were resolved by consensus.
Assessment of risk of bias in included studies
Studies included in the review were independently assessed for
quality by two authors (AR, CD, VW) using a validated qual-
ity instrument (Jadad 1996). This instrument rates studies on 3
domains: randomisation; blinding; and completeness of follow-
up accounting. Additionally the studies were assessed for the ad-
equacy of allocation concealment. Differences in ratings were re-
solved by consensus.
Measures of treatment effect
The dichotomous outcomes were analysed with Metaview 5, using
the Mantel-Haenszel relative risk (Greenland 1985) using a fixed
effects model. The risk difference is also presented. A global chi
Square test (1 degree of freedom) was used to assess the difference
between the estimated adjusted relative risk (RR) for high and low
dose misoprostol.
Unit of analysis issues
The primary analysis unit was the proportion of participants with
an outcome over the total number of participants in the group.
Mantel-Haenzel relative risks were calculated for treatment groups
compared to control. No serious analysis issues arose.
Dealing with missing data
Reporting of a primary outcome was an inclusion criteria of this
review. However, some studies did not report on all primary end-
points or all secondary outcomes. In those cases, the studies were
used in the analyses of the endpoints they reported. For each end-
point, the studies contributing to the analysis and the total num-
ber of participants are indicated in the text. In some cases, missing
data could be estimated from survival graphs, or could be calcu-
lated by straight forward estimates (e.g. total ulcers from individ-
ual reporting of gastric and duodenal ulcer data).
Assessment of heterogeneity
Heterogeneity was tested using a Chi-square test with (N-1) de-
grees of freedom, where N equals the number of trials contribut-
ing data. A P value of less than 0.10 was considered evidence of
statistical heterogeneity. Additionally, heterogeneity was deemed
4
to be present if the I square statistic was greater than 50%. Efforts
were made a priori to reduce clinical and statistical heterogeneity
by subdividing analyses by intervention class; dose of intervention
used when available; and study durations. Analyses demonstrating
heterogeneity were presented using a random effects model only
if clinically and statistically appropriate.
Assessment of reporting biases
The presence of publication bias was explored through the use of
an inverted funnel plot (studies’ effect size vs sample size). A review
can be biased if small negative studies are not considered because
these studies are often not published. Heterogeneity was tested
using a chi square test at an alpha of 0.10, and represented graphi-
cally with a L’Abbe plot (L’Abbe 1987). Estimates of heterogeneous
data were obtained using a random effects model (DerSimonian
1986) only if clinically and statistically appropriate.
Data synthesis
Data were analysed using Review Manager (RevMan) version 5.0.
Endoscopic, clinical and symptom-based outcomes were analysed
separately. The primary analyses were expressed as relative risks
using a fixed effects model. A random-effects model was used to
combine ’heterogeneous trials’ only if it was clinically and statis-
tically appropriate. The absolute risk reduction (ARR) and the
number needed to treat (NNT) were calculated for appropriate
clinical endpoints.
Subgroup analysis and investigation of heterogeneity
In addition to dividing the data by the intervention and the specific
outcome under study, subgroup analyses were performed by the
dosages of the intervention used, and the length of follow-up.
Sensitivity analysis
Sensitivity analyses were performed by: the study quality, with the
median quality score used as the cut off to define lower and higher
quality studies; and by primary vs secondary prophylaxis trials.
In the first version of the review, a sensitivity analysis varying the
obtained point estimates from efficacy to intention to treat was
performed and did not have a significant effect on the estimates.
This analysis was not repeated in the updates to the review.
RESULTS
Description of studies
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Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
See: Characteristics of included studies; Characteristics of excluded
studies.
Thirty-nine RCTs met the inclusion criteria: 23 misoprostol trials;
12 H2RA; and 9 PPI trials. Some studies considered more than
one active intervention and seven studies were used for head to
head comparisons. See Characteristics of included studies for a
summary of included studies.
A description of the search result updates over time from the orig-
inal review is detailed below.
Results of the search
Original Cochrane Search Strategy results
Of a total of 970 references identified in the first review, 33 RCTs
met the inclusion criteria: 18 misoprostol trials; nine standard dose
H2RA; three double dose H2RA trials; and four PPI trials. (See
Rostom 2000).
At the July 2001 update, four potentially relevant articles were
found by repeating the electronic searches and reviewing con-
ference proceedings. Of these, two fulfilled the inclusion criteria
(misoprostol Bocanegra 1998; 1 PPI-misoprostol abstract Jensen
2000).
CCOHTA Search Strategy Results (2002)
The updated search identified for tNSAIDs and COX-2s identi-
fied 898 references. Of 241 potentially relevant papers, three new
studies met the inclusion criteria for this review: two PPI papers
(Graham 2002; Bianchi Porro 2000); and two misoprostol papers
(Graham 2002; Chan 2001a). The Graham study considered two
interventions.
Updated Cochrane Searches
An updated search in August 2003 and August 2004 did not reveal
any further new studies.
The Cochrane search was updated from 2004 to May 2009. The
MEDLINE search identified 235 articles with ten potentially rel-
evant studies (Desai 2008; Goldstein 2007; Chan 2007; Lanas
2007; Regula 2006; Scheiman 2006; Goldstein 2005; Lai 2005;
Miyake 2005; Hawkey 2005; Chan 2004b). While some of these
papers provided supporting evidence, none met the inclusion cri-
teria. The EMBASE search identified 549 articles and only iden-
tified eight of the eleven potentially relevant studies identified by
MEDLINE. Similary, out of 41 articles identified in the EBMR
search, only four of the potentially relevant studies were identified.
The non-MEDLINE searches did not identify studies that were
not identified by MEDLINE. While the Chan 2004 paper did not
meet inclusion criteria, the results are presented in the PPI section
as indirect evidence.
5
Canadian Consensus Conference Search Strategy identified two
additional studies not identified in the previous searches (Stupnicki
2003; Lai 2003).
Included studies
See Characteristics of included studies. Thirty-nine studies were
included in the review: 23 misoprostol studies (includes six head
to head); twelve H2RA trials (nine standard dose; three double
dose; one head to head); and nine PPI trials (six direct; five head to
head). Some studies considered more than one intervention. All
the included studies were RCTs in participants with arthritis who
were taking traditional NSAIDs in an outpatient setting.
Excluded studies
See Characteristics of excluded studies. The most common rea-
sons for exclusions were: short term studies <4 weeks; studies not
reporting on desired outcomes; studies that were not RCTs.
Risk of bias in included studies
Methodological quality was assessed by two independent authors
(AR, VW or EJ) using Jadad’s scale (Jadad 1996) with consid-
eration of allocation concealment. Differences were resolved by
consensus. A third reviewer was consulted to resolve any disagree-
ments (CD).
The table of included studies details the Jadad score for the in-
cluded studies. The majority of the studies were of reasonable
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quality with a Jadad score of three or greater (20 studies - Q3; ten
studies - Q4; two studies Q5). Nine studies received a Jadad Score
of two or less.
Allocation
The quality of allocation concealment was unclear in the majority
of the included studies.
Blinding
All the included studies were blinded.
Incomplete outcome data
All the included studies reported on one of the primary endpoints
(endoscopic ulcer; or clinical ulcer complication).
Selective reporting
The inverted funnel plot reveals a lack of small studies of miso-
prostol with small effect sizes, suggesting the potential of publica-
tion bias (Rostom 2000) (please see Figure 1). However, using the
method described by Rosenthal, there would have to be 60 one-
month, and 300 three-month small studies averaging null find-
ings to negate the statistically significant reduction in endoscopic
gastric ulcers observed with misoprostol (Rosenthal 1979). The
symmetrical distribution of studies of H2RAs suggests the absence
of publication bias. Six PPI trials were identified showing similar
distribution as seen with misoprostol (Figure 2).
6
 Figure 1. Funnel plot of comparison: 1 misoprostol vs placebo - Primary Efficacy, outcome: 1.6 Total
endoscopic ulcers - 12 weeks or longer studies.

Prevention of NSAID-induced gastroduodenal ulcers (Review) 7

Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
 Figure 2. Funnel plot of comparison: 11 PPI vs placebo - 8 weeks or longer studies, outcome: 11.3 Total
endoscopic ulcers.
Other potential sources of bias
The observed heterogeneity, based on the estimates for gastric ul-
cers, is represented graphically (L’Abbe 1987) (see Rostom 2000).
Significant heterogeneity was seen only for the three month duo-
denal ulcer pooled estimate with misoprostol. This disappeared
when the studies were grouped by misoprostol dose.
Effects of interventions
Misoprostol
We found twenty-three studies that assessed the long term ef-
fect of misoprostol on the prevention of NSAID ulcers (Graham
2002; Chan 2001a; Hawkey 1998; Bocanegra 1998; Raskin
1996; Agrawal 1995; Raskin 1995; Valentini 1995; Delmas 1994;
Elliot 1994; Graham 1993; Henriksson 1993; Melo Gomes
1993; Roth 1993; Bolten 1992; Verdickt 1992; Agrawal 1991;
Chandresekaran 1991; Saggioro 1991; Graham 1988; Jensen
2000; Silverstein 1995; Stupnicki 2003). Some of these were head
to head studies.
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Endoscopic ulcers
Eleven studies with 3,641participants compared the incidence
of endoscopic ulcers, after at least three months, of misoprostol
to that of placebo (Graham 2002; Chan 2001a; Hawkey 1998;
Agrawal 1995; Raskin 1995; Elliot 1994; Graham 1993; Roth
1993; Verdickt 1992; Agrawal 1991; Graham 1988). The cumu-
lative incidence of endoscopic gastric and duodenal ulcers with
placebo were 15% and 6% respectively. Misoprostol significantly
reduced the relative risk of gastric ulcer and duodenal ulcers by
74% (RR 0.26; 95% CI 0.17 to 0.39, random effects; Analysis
1.4), and 58% (RR 0.42; 95% CI 0.22 to 0.81, random effects;
Analysis 1.5). These relative risks correspond to a 12.0%, and 3%
absolute risk reductions for gastric and duodenal ulcers respec-
tively. The observed heterogeneity in these estimates was due to
inclusion of all misoprostol doses in the analyses. Analysis of the
misoprostol studies stratified by dose eliminated this heterogene-
ity.
Analysis by dose
All the studied doses of misoprostol significantly reduced the risk
of endoscopic ulcers, and a dose response relationship was demon-
8
strated for endoscopic gastric ulcers. Six studies with 2,461 par-
ticipants used misoprostol 400 µg (Chan 2001a; Hawkey 1998;
Agrawal 1995; Raskin 1995; Verdickt 1992; Graham 1988), one
study with 928 participants used 600 µg daily (Raskin 1995), and
seven with 2,423 participants used 800 µg daily (Graham 2002;
Raskin 1995; Elliot 1994; Graham 1993; Roth 1993; Agrawal
1991; Graham 1988). Misoprostol 800 µg daily was associated
with the lowest risk (RR 0.18; 95% CI 0.12 to 0.27; Analysis 4.4)
of endoscopic gastric ulcers when compared to placebo, whereas
misoprostol 400 µg daily was associated with a relative risk of
(RR 0.43; 95% CI 0.28 to 0.67, random effects model for hetero-
geneity; Analysis 4.4). The observed heterogeneity in the 400 µg
dose group was the result of the addition of the Chan study (Chan
2001a). This study compared the relatively more toxic naproxen
with low dose misoprostol to nabumatone alone. In this study the
risk of ulcers was inexplicably greater in the misoprostol group,
but we feel this result is based on the differences between the safety
of the comparator NSAIDS rather than the prophylactic agent. As
a sensitivity analysis, removal of the Chan 2001a study eliminates
the observed heterogeneity without significantly altering the re-
sults, giving low dose misoprostol prophylaxis a RR of 0.39 (95%
CI 0.3 to 0.51; Analysis 4.5). This difference between high and
low dose misoprostol reached statistical significance (P=0.0055).
The intermediate misoprostol dose (600 µg daily) was not sta-
tistically different from either the low or high dose. The pooled
relative risk reduction of 78% (4.7% absolute risk difference, (RR
0.21; 95% CI 0.09 to 0.49; Analysis 4.6) for duodenal ulcers with
misoprostol 800 µg daily was not statistically different from those
of the lower daily misoprostol dosages.
Studies including data with less than 3 months
NSAID exposure
Eight studies, with 2206 participants, assessed the rates of endo-
scopic ulcers with misoprostol compared to placebo at 1 to 1.5
months (Bocanegra 1998; Delmas 1994; Elliot 1994; Henriksson
1993; Melo Gomes 1993; Bolten 1992; Chandresekaran 1991;
Saggioro 1991). The pooling of these studies revealed an 81% rel-
ative risk reduction of gastric ulcers with misoprostol (RR 0.17;
95% CI 0.09 to 0.31; Analysis 1.1) and an 70% relative risk reduc-
tion of duodenal ulcers (RR 0.30; 95% CI 0.14 to 0.62; Analysis
1.2).
One study compared misoprostol to a newer cytoprotective agent,
Dosmafate, for NSAID prophylaxis and found no statistically sig-
nificant difference in ulcer rates between the two agents (Cohen
2000).
Clinical Ulcers
Only one RCT, the MUCOSA trial, evaluated the efficacy of miso-
prostol prophylaxis against clinically important NSAID induced
ulcer complications. In this study, of 8,843 participants studied
Prevention of NSAID-induced gastroduodenal ulcers (Review)
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over six months, the overall GI event incidence was about 1.5%
per year (Silverstein 1995). Misoprostol 800 µg/day was associ-
ated with a statistically significant 40% risk reduction (OR 0.598;
95% CI 0.364 to 0.982) in combined GI events (P=0.049), repre-
senting a risk difference of 0.38% (from 0.95% to 0.57%). Over-
all, approximately 260 participants would have to be treated with
misoprostol to prevent one clinically important GI event. This
NNT would drop as higher risk participants are considered. Miso-
prostol appeared to be ineffective at preventing endoscopically
proven GI haemorrhage alone. However a type II error is likely
since the study was not powered to detect a difference in this end-
point (Silverstein 1995).
Adverse Effects
Misoprostol was associated with a small but statistically significant
1.6 fold excess risk of drop out due to drug induced side effects,
and an excess risk of drop-outs due to nausea (RR 1.26; 95% CI
1.07 to 1.48; Analysis 2.1), diarrhoea (RR 2.36; 95% CI 2.01 to
2.77; Analysis 2.4), and abdominal pain (RR 1.36; 95% CI 1.20
to 1.55; Analysis 2.5). In the MUCOSA trial, 732 out of 4404
participants on misoprostol experienced diarrhoea or abdominal
pain, compared to 399 out of 4,439 on placebo for a relative risk
of 1.82 associated with misoprostol (p<0.001). Overall, 27% of
participants on misoprostol experienced one or more side-effects
(Silverstein 1995).
When analysed by dose, only misoprostol 800 µg daily showed
a statistically significant excess risk of drop-outs due to diarrhoea
(RR 2.45; 95% CI 2.09 to 2.88; Analysis 5.4), and abdominal
pain (RR 1.38; 95% CI 1.17 to 1.63; Analysis 5.5). Both miso-
prostol doses were associated with a statistically significant risk of
diarrhoea. However, the risk of diarrhoea with 800µg/day (RR
3.16; 95% CI 2.33 to 4.29) was significantly higher than that seen
with 400 µg/day (RR 1.76 95% CI 1.37 to 2.26) (Analysis 6.4).
Analyses by Quality
Both high and low quality misoprostol trials demonstrated a sta-
tistically significant reduction of endoscopic ulcers.
H2-Receptor Antagonists
Six trials with 942 participants assessed the effect of standard
dose H2RAs on the prevention of endoscopic NSAID ulcers at
one month (Berkowitz 1987; Ehsanullah 1988; Robinson 1991;
Robinson 1989; Taha 1996; van Groenendaci 1996), and five tri-
als with 1,005 participants assessed these outcomes at 3 months
or longer (Ehsanullah 1988; Taha 1996; Levine 1993; Swift 1989;
Simon 1994). Standard dose H2RAs are effective at reducing the
risk of duodenal ulcers (RR 0.24; 95% CI 0.10 to 0.57; Analysis
7.2, and RR 0.36; 95% CI 0.18 to 0.74; Analysis 8.2 at one and
three or more months respectively), but not of gastric ulcers (NS).
9
One study did not have a placebo comparator and was not in-
cluded in the pooled estimate (Simon 1994).
Three RCTs with 298 participants assessed the efficacy of double
dose H2RAs for the prevention of NSAID induced upper GI tox-
icity (Taha 1996; Hudson 1997; Ten Wolde 1996). Double dose
H2RAs when compared to placebo were associated with a statisti-
cally significant reduction in the risk of both duodenal (RR 0.26;
95% CI 0.11 to 0.65; Analysis 8.2) and gastric ulcers (RR 0.44;
95% CI 0.26 to 0.74; Analysis 8.1). This 56% relative risk reduc-
tion in gastric ulcer corresponds to a 12% absolute risk difference
(from 23.1% to 11.3%). Analysis of the secondary prophylaxis
studies alone yielded similar results.
Symptoms
H2RAs, in standard or double doses, were not associated with an
excess risk of total drop-outs, dropouts due to side-effects, or symp-
toms when compared to placebo. However, high dose H2RAs sig-
nificantly reduced symptoms of abdominal pain when compared
to placebo (RR 0.57; 95% CI 0.33 to 0.98) Analysis 9.7).
Analyses by Quality
In contrast to high quality trials, low quality trials failed to demon-
strate a benefit of standard dose H2RAs for the prevention of en-
doscopic duodenal ulcers. No significant differences were observed
by quality for dropouts and symptoms.
Proton Pump Inhibitors
Six RCTs with 1259 participants assessed the effect of PPIs on the
prevention of NSAID induced upper GI toxicity (Graham 2002;
Bianchi Porro 2000; Hawkey 1998; Ekstrom 1996; Cullen 1998;
Lai 2003).
PPIs compared to placebo
PPIs significantly reduced the risk of both endoscopic duodenal
(RR 0.20; 95% CI 0.10 to 0.39; Analysis 11.2) and gastric ul-
cers (RR 0.39; 95% CI 0.31 to 0.50; Analysis 11.1) compared
to placebo (Bianchi Porro 2000; Cullen 1998; Ekstrom 1996;
Graham 2002; Hawkey 1998; Lai 2003). The results were similar
for both primary and secondary prophylaxis trials.
Clinical Ulcers
Small studies in relatively high risk participants have emerged that
suggest that PPIs can reduce the risk of clinically important ulcer
complications. A small 8 week study found that PPIs reduce the
risk of endoscopic ulcers but there were also fewer bleeds or symp-
tomatic ulcers in the PPI group compared to placebo (Lai 2003).
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Another study which did not meet the inclusion criteria has shown
that a strategy of a COX-2 alone is associated with similar rebleed-
ing rates as a strategy of a tNSAID with a PPI (Chan 2004b). Sev-
eral studies have shown that COX-2 inhibitors reduce the risk of
clinically important ulcer complications (Rostom 2007), therefore
suggesting that a strategy of a tNSAID with a PPI also reduces the
risk of clinical ulcer complications. However, the rate of rebleed-
ing in this study was relatively high suggesting that in high risk
participants, neither strategy was sufficient.
Symptoms
Four omeprazole trials used the same composite endpoints to
define treatment success (Cullen 1998; Ekstrom 1996; Hawkey
1998; Yeomans 1998). In these trials omeprazole significantly re-
duced “dyspeptic symptoms” as defined by the authors. In the
combined analysis, drop-outs overall and drop-outs due to side
effects were not different from placebo. These results are also sup-
ported by a recent study by Hawkey et al that reported statisti-
cally significant improvement in dyspeptic symptoms in NSAID
participants taking esomeprazole compared to placebo (Hawkey
2005).
Analyses by Quality
No significant differences were observed with analysis by quality.
Head to Head Comparisons
Misoprostol vs ranitidine
Two trials with 600 participants compared misoprostol to raniti-
dine 150 mg twice daily (Raskin 1995; Valentini 1995). Misopros-
tol appears superior to standard dose ranitidine for the prevention
of NSAID induced gastric ulcers (RR 0.12; 95% CI 0.03 to 0.51;
Analysis 18.1) but not for duodenal ulcers (RR 1.00; 95% CI 0.14
to 7.05; Analysis 18.2).
Omeprazole vs ranitidine
Yeomans et. al. in a study of 425 participants, compared omepra-
zole 20mg daily to ranitidine 150 mg twice daily for NSAID pro-
phylaxis (Yeomans 1998). In this study, omeprazole was superior
to standard dose ranitidine for the prevention of both gastric (RR
0.32; 95% CI 0.17 to 0.62; Analysis 14.1) and duodenal ulcers
(RR 0.11; 95% CI 0.01 to 0.89; Analysis 14.2).
PPI vs misoprostol
Four trials with a total of 1478 participants (Graham 2002;
Hawkey 1998; Jensen 2000; Stupnicki 2003) compared a PPI to
misoprostol. Two studies compared low dose misoprostol (400
10
µg) daily to a standard dose PPI (Hawkey 1998; Stupnicki 2003),
while the Graham 2002 study compared high dose misoprostol
(800 µg) to lansoprazole 15 or 30 mg daily. PPIs are statistically
superior to misoprostol for the prevention of duodenal ulcer (RR
0.25; 95% CI 0.11 to 0.56; Analysis 16.2 (Hawkey 1998)), but
not gastric ulcer (RR 1.61; 95% CI 0.85 to 3.06; random effects
Analysis 16.1) (Hawkey 1998; Graham 2002)) or total gastro-
duodenal ulcers (RR 0.90; 95% CI 0.47 to 1.72, random effects;
Analysis 16.3 ). Individually the Hawkey trial showed a non-signif-
icant trend towards greater benefit with misoprostol over omepra-
zole for the prevention of gastric ulcers, while the Graham 2002
study actually showed that misoprostol was superior to lansopra-
zole for the prevention of gastric ulcers. The pooled results mir-
ror these findings but failed to reach statistical significance (RR
0.62; 95% CI 0.33 to 1.18; Analysis 15.1, random effects). These
analyses utilized a small number of studies (duodenal -one study;
gastric - two studies; total ulcers - four studies) and demonstrated
important clinical and statistical heterogeneity likely stemming in
part from differences in intervention doses.
Symptoms
In the two head to head comparisons of omeprazole and miso-
prostol (Graham 2002; Hawkey 1998), PPIs were associated with
significantly less drop-outs overall (RR 0.71; 95% CI 0.52 to 0.97;
Analysis 17.1), as well as significantly less drop-outs due to side-
effects (RR 0.48; 95% CI 0.29 to 0.78; Analysis 17.2). When
compared to H2RA used for less than two months, misoprostol
caused significantly more drop-outs due to abdominal pain (RR
3.00, 95% CI 1.11, 8.14; Analysis 18.6) and more symptoms of
diarrhoea (RR 2.03, 95% CI 1.38, 2.99; Analysis 18.12). There
were no significant differences in drop-outs due to side-effects (RR
1.90; 95% CI 0.77 to 4.67; Analysis 14.5) or symptoms of ab-
dominal pain or diarrhoea between low dose H2RAs and PPIs.
Misoprostol also appears to be associated with a lower quality of
life amongst chronic NSAID users compared to PPIs (Yeomans
2001).
DISCUSSION
The results of this meta-analysis demonstrate that misoprostol,
PPIs, and double doses of H2RAs are effective at reducing the
risk of both endoscopic gastric and duodenal NSAID induced
ulcers. Standard doses of H2RAs are not effective at reducing the
risk of NSAID induced gastric ulcers. Misoprostol is the only
prophylactic agent to date that has been evaluated in a true clinical
outcome trial, and has been shown to reduce the risk of NSAID
related ulcer complications. However, its use is associated with
significant adverse effects particularly at higher doses.
It is difficult to comment on the relative efficacy of the different
prophylactic agents since the studies involving head to head com-
Prevention of NSAID-induced gastroduodenal ulcers (Review)
Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
parisons often used doses of the comparator drug that are known
to be less effective. For example, misoprostol and omeprazole were
compared to standard dose ranitidine, and omeprazole was com-
pared to misoprostol 400 µg/day in one study. However, with
these limitations in mind, misoprostol was found to be superior
to standard dose H2RAs at reducing endoscopic gastric ulcers.
Omeprazole was superior to standard dose ranitidine at reducing
the risk of both endoscopic gastric and duodenal ulcers. How-
ever, omeprazole was superior to misoprostol at reducing the risk
of endoscopic duodenal but not gastric ulcers. In fact based on a
single study misoprostol appeared superior to lansoprazole for the
secondary prevention of NSAID induced gastric ulcers (Graham
2002). The true clinical implications of this last point is not clear
and may be small, but requires further research.
Overall we found that H2RAs and PPIs were better tolerated than
misoprostol, and reduced NSAID related dyspeptic symptoms.
Unfortunately, the reporting of symptoms and drug induced side
effects were variable in these studies, a problem seen in a variety
of other clinical trials. For the current review we concentrated on
the reporting of side-effects causing drop-out from the studies. We
felt that this end-point would be more reliably reported than side-
effects alone. The definitions of dyspepsia, and abdominal pain
were also variable or not given in these trials, so we combined these
as a composite endpoint. The reporting of diarrhoea was more
uniform, likely because it is a common side effect of misoprostol,
and this end-point was used as a symptom not causing drop-out.
Great care was taken in the abstraction and interpretation of the
side-effect data, but the variable reporting of these endpoints may
be a potential source of bias.
Because misoprostol is associated with more frequent adverse
symptoms than the other agents, we also looked at the effect of
dose on the efficacy and tolerability of this agent. Misoprostol 800
µg/day is more effective at reducing gastric ulcers than 400 µg/
day. However, both 400 µg and 800 µg daily are associated with
significantly more diarrhoea than placebo, and the effectiveness of
low doses of misoprostol in the reduction of clinical ulcer compli-
cations is not well studied. Therefore, the practice of using lower
doses of misoprostol to avoid its associated adverse effects should
be questioned.
High risk GI patients represent another area of clinical importance.
Several strategies have been evaluated in high risk patients with
previous GI bleeding (see GI safety of COX-2 review). The studies
focused on comparisons of COX-2 inhibitors (COX-2s) alone and
in combination with a PPI, and showed that a strategy of a COX-
2 alone was similar to a strategy of using a traditional NSAID with
a PPI. However, the rate of re-bleeding with both strategies was
still relatively high suggesting that neither strategy was completely
effective. However, strategy of a COX-2 + PPI was associated with
the greatest protection from recurrent re-bleeding (Chan 2004b;
Lai 2005; Chan 2007).
11
A lot has changed in the NSAID field since the last update of this
review. In the early 2000s, it appeared that COX-2s were going to
completely replace traditional non selective NSAIDs. In fact, pre-
scriptions, and sales of traditional NSAIDs dropped while COX-
2 prescriptions rose to level that suggested that physicians were
prescribing COX-2s to patients that were not previously treated
with NSAIDs. However, by 2004, greater information regarding
the cardiovascular (CVS) safety of COX-2s started to emerge. A
large systematic review demonstrated that COX-2 were associated
with increased risk of CVS events (Kearney 2006). In addition,
one COX-2 was found to be associated with a serious dermatologic
disorder while another was associated with higher than expected
rates of hepatotoxicity. These factors ultimately led to the with-
drawal of most of these agents from the market place. In North
America, only celecoxib remains. These events, resulted in a pre-
cipitous fall in COX-2 prescriptions, with a resurgence in tradi-
tional NSAID use along with a gastro-protective agent such as a
PPI. However, traditional NSAIDs were not left unscathed. Sev-
eral lines of data also suggested that non-naproxen NSAIDs were
associated with similar CVS toxicity as the COX-2s, further cast-
ing confusion amongst clinicians (Kearney 2006; Rostom 2009).
Recently several consensus guidelines have been published to help
guide clinicians in their management of patients with arthritic
conditions (Rostom 2009; Bhatt 2008; Chan 2008).
The ideal means of reducing the risk of upper GI toxicity among
chronic NSAIDs users is complex. Several factors influence the
risk of NSAID related upper GI toxicity: increasing age (>65),
previous peptic ulcer disease, co-morbid medical illnesses, the type
of NSAID, the use of multiple NSAIDS and the combined use
of NSAIDs and corticosteroids (Fries 1991; Bollini 1992; Gabriel
1991; Silverstein 1995; Hallas 1995; Hansen 1996; Laporte 1991;
Rodriguez 1997; Hochain 1995). Therefore, younger patients
without co-morbidities or previous GI NSAID complications can
be treated with a traditional NSAID alone (Rostom 2009; Maetzel
1998).
For patients with low gastrointestinal risk and high cardiovascular
risk, naproxen may be preferred because of the potentially lower
cardiovascular risk than with other tNSAIDs or COX-2 inhibitors.
However, since these patients are assumed to be on low-dose ASA
therapy, the combination of naproxen plus ASA would increase the
gastrointestinal risk, and therefore, the addition of a gastro-pro-
tective agent such as a PPI should be considered (Rostom 2009).
For patients at very high risk of upper gastrointestinal events, a
combination of a COX-2 inhibitor plus a PPI may offer the best
gastrointestinal safety profile. When both gastrointestinal and car-
diovascular risks are high, the optimal strategy is to avoid NSAID
therapy if at all possible. If the NSAID therapy is deemed neces-
sary, then the clinician must prioritise the cardiovascular and gas-
trointestinal risks, recognizing that these patients are likely taking
ASA for their cardiovascular risk and choose a strategy that ad-
dresses the clinical profile recognizing, that there would likely be
Prevention of NSAID-induced gastroduodenal ulcers (Review)
Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
incomplete protection either on the CVS or GI side with a choice
of COX-2 + PPI or naproxen + PPI respectively.
Summary of main results
Misoprostol at 800 µg daily reduces the occurrence of NSAID re-
lated clinical ulcer complications. Lower doses of misoprostol are
associated with fewer side effects of diarrhoea but are less effective
at preventing endoscopic gastric ulcers. The effects of low doses
of misoprostol on ulcer complications are unknown, so the use
of lower doses may be associated with a significant clinical trade-
off. Standard doses of H2RAs should not be used for prophylaxis
against NSAID toxicity. Double doses of H2RAs and standard
doses of PPIs are effective at preventing endoscopic duodenal and
gastric ulcers, reduce NSAID related dyspepsia and are better tol-
erated than misoprostol. In high risk GI patients, a COX-2 alone
or a traditional NSAID + a PPI offer similar but potentially in-
sufficient protection from recurrent bleeding and a COX-2 + PPI
can be considered.
Overall completeness and applicability of
evidence
This systematic review includes all the published data that we could
identify for the long term prevention (four weeks or greater) of
tNSAID related gastroduodenal injury. This field rapidly evolved
with the introduction of COX-2 inhibitors, but with the recogni-
tion of the toxicity of those agents, clinicians are moving back to-
ward using tNSIADs with gastro-protection. While there is a sin-
gle large outcome study for the prevention of clinical ulcer events
such as bleeding with misoprostol, and multiple such studies for
the COX-2 inhibitors, there is less direct evidence for the PPIs.
However, there is data that suggests in high risk GI patients who
require NSAIDs, a COX-2 alone and a tNSAID with a PPI offer
similar protection from recurrent bleeding. No such data exists for
H2RAs, and it is unlikely that a large outcome study with PPIs or
H2RAs would now be conducted in average risk arthritic patients
requiring long term tNSAID use.
Quality of the evidence
Overall there is good quality evidence for the interventions assessed
in this review. There is good quality endoscopic and clinical ulcer
outcome data for misoprostol for the prevention of gastroduodenal
ulcers and ulcer complications. There is good quality endoscopic
data for the prevention of gastroduodenal endoscopically detected
ulcers for H2RAs and PPIs. There is new evidence suggesting that
PPIs added to tNSAIDs are as effective as the use of COX-2s for
the prevention of recurrent bleeding.
12
Potential biases in the review process
The review was conducted according to standard systematic review
methodology.
Agreements and disagreements with other
studies or reviews
The results of this systematic review are in agreement with other
reviews and with recent consensus guidelines (Rostom 2009; Bhatt
2008; Chan 2008; Brown 2006).
AUTHORS’ CONCLUSIONS
Implications for practice
• Standard doses of H2RAs should not be used for the
prevention of NSAID related Upper GI toxicity, since they are
ineffective at preventing NSAID related gastric ulcers.
• Double doses of H2RAs and standard doses of PPIs are
effective prophylactic agents based on the results of endoscopic
studies.
• Misoprostol is an effective NSAID prophylactic agent based
on both a clinical outcome study and multiple endoscopic
studies, and may be slightly more effective at reducing NSAID
induced gastric ulcers than PPIs - though the true clinical
implications of this last point my be small. Misoprostol use is
associated with greater adverse effects then the other agents.
• In high risk GI patients, a strategy of a COX-2 inhibitor or
a traditional NSAID + a PPI appear to offer similar though
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• Gastrointestinal and cardiovascular risk stratification should
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ACKNOWLEDGEMENTS
We would also like to thank the Cochrane UGPD group for their
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15
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Pharmacology & Therapeutics 2007;26(8):1101–11.
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Asociacion Espanola de Gastroenterologia (AEG). Effect of
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Gastroenterology 2007;102(3):507–15.
Melo Gomes 1992 {published data only}
Melo Gomes JA. The safety of Arthrotec in patients with
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Miyake 2005 {published data only}
Miyake K, Ueki N, Suzuki K, Shinji Y, Kusunoki M,
Hiratsuka T, et al.Preventive therapy for non-steroidal anti-
inflammatory drug-induced ulcers in Japanese patients with
rheumatoid arthritis: the current situation and a prospective
controlled-study of the preventive effects of lansoprazole
or famotidine. Alimentary Pharmacology and Therapeutics
2005;21(Suppl 2):67-72.
Regula 2006 {published data only}
Regula J, Butruk E, Dekkers CP, de Boer SY, Raps D, Simon
L, et al.Prevention of NSAID-associated gastrointestinal
lesions: a comparison study pantoprazole versus omeprazole.
American Journal of Gastroenterology 2006;101(8):1747–55.
16
Rose 1999 {published and unpublished data}
Rose P, Huang B, Lukasik N, Collis C. Evidence that
lansoprazole is effective in preventing NSAID induced
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∗
Indicates the major publication for the study
19
CHARACTERISTICS OF STUDIES

Characteristics of included studies [ordered by study ID]

Agrawal 1991

Methods Randomized controlled trial

Double-blind
Sample size at entry: misoprostol: 179; sucralfate: 177
Study duration: 12 weeks

Participants Patient: osteoarthritis

Median age (yrs): misoprostol: 60; sucralfate: 60
Sex % F: misoprostol: 56; sucralfate: 59
Type of NSAID: ibuprofen, naproxen, piroxicam
Previous peptic ulcers (%): misoprostol: 22; sucralfate: 27
Primary vs secondary prophylaxis: primary
H pylori positive(%): not mentioned

Interventions 1) misoprostol 200µg x 4 = 800µg

2) sucralfate 1g x 4 = 4g

Outcomes Endoscopic gastric ulcers (>3 mm)

Endoscopic duodenal ulcers (>3 mm)
Gastric ulcers (>5 mm)
Withdrawals overall
Withdrawals due to side effects
Drop out due to diarrhea
Drop out due to dyspepsia

Notes Quality = 2

Risk of bias

Bias Authors’ judgement Support for judgement

Allocation concealment (selection bias) Unclear risk D - Not used

Agrawal 1995

Methods Randomized controlled trial

Single-blind
Sample size at entry: misoprostol: 193; placebo: 191
Study duration: up to 52 weeks

Participants Patient: rheumatoid arthritis and osteoarthritis

Mean age (yrs): misoprostol: 57.3; placebo: 57.5
Sex % F: Misoprostrol: 66; placebo: 70
Type of NSAID: diclofenac

Prevention of NSAID-induced gastroduodenal ulcers (Review) 20

Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Agrawal 1995 (Continued)

Previous peptic ulcers (%): all

Primary vs secondary prophylaxis: secondary
H pylori positive (%): not mentioned

Interventions 1) misoprostol 200 µg 2-3/day (400-600 µg) + diclofenac

2) placebo + diclofenac 50 mg BID/ TID

Outcomes Gastric endoscopic ulcers

Duodenal endoscopic ulcers
Total gastroduodenal ulcers
Drop-outs due to side-effects
Abdominal pain
Diarrhea
Dyspepsia
Nausea

Notes Quality = 1

Risk of bias

Bias Authors’ judgement Support for judgement

Allocation concealment (selection bias) Unclear risk D - Not used

Berkowitz 1987

Methods Randomized controlled trial

Double-blind
Sample size at entry: ranitidine: 25; placebo: 25
Study duration: 4 weeks

Participants Patient: rheumatic

Mean age (yrs): ranitidine: 28.5; placebo: 26.2
Sex % F: ranitidine: 0; placebo: 0
Type of NSAID: aspirin
Previous peptic ulcers (%): 0
Primary vs secondary prophylaxis: primary
H pylori positive (%): not mentioned

Interventions 1) ranitidine 150 mg bid and 650 mg aspirin qid

2) placebo bid and 650 mg aspiring qid

Outcomes Endoscopic gastric ulcer (>3 mm)

Endoscopic duodenal ulcer (>3 mm)
Withdrawals overall
Withdrawals due to side effects

Notes Quality = 3

Prevention of NSAID-induced gastroduodenal ulcers (Review) 21

Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Berkowitz 1987 (Continued)

Risk of bias

Bias Authors’ judgement Support for judgement

Allocation concealment (selection bias) Unclear risk D - Not used

Bianchi Porro 2000

Methods Randomized controlled trial

Double-blind
Sample size at entry: Pantoprazole: 70; placebo: 34
Study duration: 12 weeks

Participants Patient: rheumatoid arthritis and osteoarthritis

Mean age (yrs): Pantoprazole: 58; placebo: 59
Sex % F: pantoprazole: 82.9; placebo: 82.4
Type of NSAID: diclofenac, ketoprofen, Indocid
Previous peptic ulcers (%): pantoprazole: 25; placebo: 5
Primary vs secondary prophylaxis: primary
H pylori positive (%): pantoprazole: 37; placebo: 50

Interventions 1) placebo
2) pantoprazole 40mg /day

Outcomes Lanza Score

Endoscopic ulcer = 4
Adverse effects

Notes Quality = 3

Risk of bias

Bias Authors’ judgement Support for judgement

Allocation concealment (selection bias) Unclear risk B - Unclear

Bocanegra 1998

Methods Randomized controlled trial

Double-blind
Sample size at entry: diclofenac 50mg+misoprostol 200µg tid: 154, diclofenac
75mg+misoprostol 200µg bid: 152, diclofenac 75mg Bid: 175, placebo: 91
Study duration: 6 weeks

Participants Patient: osteoarthritis

Mean age (yrs): diclofenac 50mg+misoprostol 200µg tid: 62.9, diclofenac
75mg+misoprostol 200µg bid: 62.3, diclofenac 75mg Bid: 62.8, placebo: 61.5

Prevention of NSAID-induced gastroduodenal ulcers (Review) 22

Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Bocanegra 1998 (Continued)

Sex % F: diclofenac 50mg+misoprostol 200µg tid: 71, diclofenac 75mg+misoprostol

200µg bid: 68, diclofenac 75mg Bid: 67, placebo: 68
Type of NSAID: diclofenac, misoprostol
Previous peptic ulcers (%): not mentioned
Primary vs secondary prophylaxis: primary
H pylori positive (%): not mentioned

Interventions 1) diclofenac 75mg bid

2) diclofenac 75mg+misoprostol 200µg bid
3) diclofenac 50mg+misoprostol 200µg tid
4) placebo

Outcomes Endoscopic gastric ulcers (>3mm)

Endoscopic duodenal ulcers (>3mm)
Side-effects
Side-effects causing withdrawal
Withdrawal overall

Notes Quality=3

Risk of bias

Bias Authors’ judgement Support for judgement

Allocation concealment (selection bias) Unclear risk D - Not used

Bolten 1992

Methods Randomized controlled trial

Double-blind
Sample size at entry: misoprostol: 178; placebo: 183
Study duration: 4 weeks

Participants Patient: osteoarthritis

Mean age (yrs): misoprostol: 59.2; placebo: 61.3
Sex % F: misoprostol: 75.8; placebo: 70.5
Type of NSAID: diclofenac
Previous peptic ulcers (%): misoprostol: 0; placebo: 4
Primary vs secondary prophylaxis: primary
H pylori positive (%): not mentioned

Interventions 1) misoprostol 400-600µg/day (Arthrotec) 2) placebo

Outcomes Endoscopic ulcers (gastric, duodenal, total) at 1 month

Dropouts overall

Notes Quality = 4

Prevention of NSAID-induced gastroduodenal ulcers (Review) 23

Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Bolten 1992 (Continued)

Risk of bias

Bias Authors’ judgement Support for judgement

Allocation concealment (selection bias) Unclear risk D - Not used

Chan 2001a

Methods Randomized controlled trial

Double-blind
Sample size at entry: misoprostol: 45; nabumetone: 45
Study duration: 24 weeks

Participants Patient: high risk NSAID ulcers user

Mean age (yrs): misoprostol: 75; nabumetone: 74
Sex % F: misoprostol: 62; nabumetone: 67
Type of NSAID: naproxen
Previous peptic ulcers (%): all
Primary vs secondary prophylaxis: secondary
H pylori positive (%): 0

Interventions 1) naproxen+misoprostol 200 bid 2) 1000-1500mg

Outcomes Ucers or bleeding

Adverse events

Notes Quality=4

Risk of bias

Bias Authors’ judgement Support for judgement

Allocation concealment (selection bias) Low risk A - Adequate

Chan 2001b

Methods Randomized controlled trial

Double-blind
Sample size at entry: omeprazole: 66; celecoxib: 64
Study duration: 24 weeks

Participants Patient: arthritis

Mean age (yrs): omeprazole: 68; celecoxib: 66
Sex % F: omeprazole: 58; celecoxib: 55
Type of NSAID: diclofenac
Previous peptic ulcers (%): all
Primary vs secondary prophylaxis: secondary

Prevention of NSAID-induced gastroduodenal ulcers (Review) 24

Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Chan 2001b (Continued)

H pylori positive (%): 0

Interventions 1) diclofenac 75mg bid + omeprazole 20mg daily 2) celecoxib 200 mg bid

Outcomes Recurrent ulcer bleeding

Notes quality=3

Risk of bias

Bias Authors’ judgement Support for judgement

Allocation concealment (selection bias) Unclear risk D - Not used

Chan 2004

Methods Randomized controlled trial

Double blind
Sample size at entry: omeprazole: 106; celecoxib: 116
Study duration: 6 months

Participants Patient: arthritis

Mean age (yrs): omeprazole: 68; celecoxib: 68
Sex % F: omeprazole: 50.9; celecoxib: 53.4
Type of NSAID: diclofenac
Previous peptic ulcers (%): all
Primary vs secondary prophylaxis: secondary
H pylori positive (%): 0

Interventions 1) diclofenac 75mg bid + omeprazole 20mg daily 2) celecoxib 200 mg bid

Outcomes Recurrent ulcer bleeding

Notes Quality=3

Chandresekaran 1991

Methods Randomized controlled trial

Double-blind
Sample size at entry: misoprostol: 45; placebo: 45
Study duration: 4 weeks

Participants Patient: rheumatoid arthritis, osteoarthritis and spondyloarthropathy

Mean age (yrs): 39.9
Sex % F: 47%
Type of NSAID:ASA, ibuprofen, diclofenac, indomethacin
Previous peptic ulcers (%): n/a - but no history of gastroduodenal surgery

Prevention of NSAID-induced gastroduodenal ulcers (Review) 25

Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Chandresekaran 1991 (Continued)

Primary vs secondary prophylaxis:primary

H pylori positive (%): n/a

Interventions 1) misoprostol 200 µg tid

2) placebo

Outcomes Endoscopic ulcers

Notes Quality = 4

Risk of bias

Bias Authors’ judgement Support for judgement

Allocation concealment (selection bias) Unclear risk D - Not used

Cullen 1998

Methods Randomized controlled trial

Double blind
Sample size at entry: omeprazole: 83; placebo: 85
Study duration: up to 6 months

Participants Patient: rheumatoid arthritis, osteoarthritis

Mean age (yrs): omeprazole: 55; placebo: 56
Sex % F: omeprazole: 64.7; placebo: 68.7
Type of NSAID: naproxen
Previous peptic ulcers (%): omeprazole: 27; placebo: 21
Primary vs secondary prophylaxis: primary
H pylori positive (%): omeprazole: 35.5; placebo: 27.3

Interventions 1) omeprazole 20 mg daily

2) placebo

Outcomes Endoscopic ulcers

Notes Quality = 2

Risk of bias

Bias Authors’ judgement Support for judgement

Allocation concealment (selection bias) Unclear risk D - Not used

Prevention of NSAID-induced gastroduodenal ulcers (Review) 26

Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Delmas 1994

Methods Randomized controlled trial

Double blind
Sample size at entry:256
Study duration:4 weeks

Participants Patient: osteoarthritis, rheumatoid arthritis, or other rheumatic diseases and prior NSAID
use in last 10 days
Median age (yrs): n/a
Sex % F:n/a
Type of NSAID:diclofenac, naproxen, piroxicam, ibuprofen, indomethacin, ketoprofen,
or tiaprofenic acid
Previous peptic ulcers (%): n/a but none on entry had ulcers
Primary vs secondary prophylaxis:primary
H pylori positive (%):n/a

Interventions 1) misoprostol 400

2) misoprostol 800
3) placebo (any NSAID)

Outcomes Gastric ulcers

Duodenal ulcers

Notes Quality = 3

Risk of bias

Bias Authors’ judgement Support for judgement

Allocation concealment (selection bias) Unclear risk D - Not used

Ehsanullah 1988

Methods Randomized controlled trial

Double blind
Sample size at entry: ranitidine: 137; placebo: 126
Study duration: up to 8 weeks

Participants Patient: rheumatoid arthritis and osteoarthritis

Mean age (yrs): ranitidine: 57.7; placebo: 60
Sex % F: ranitidine: 57.7; placebo: 62.7
Type of NSAID: not mentioned
Previous peptic ulcers (%): ranitidine: 11; placebo: 11
Primary vs secondary prophylaxis: primary
H pylori positive (%): not mentioned

Interventions 1) ranitidine 150 mg bid

2) placebo

Prevention of NSAID-induced gastroduodenal ulcers (Review) 27

Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Ehsanullah 1988 (Continued)

Outcomes Endoscopic ulcers

adverse events

Notes Quality = 5

Risk of bias

Bias Authors’ judgement Support for judgement

Allocation concealment (selection bias) Unclear risk D - Not used

Ekstrom 1996

Methods Randomized controlled trial

Double blind
Sample size at entry: omeprazole: 86; placebo: 91
Study duration: 3 months

Participants Patient: osteoarthritis, rheumatoid arthritis, spondylarthritis, ankylosing spondylitis

Mean age (yrs): omeprazole: 58; placebo: 59
Sex % F: omeprazole: 63.5; placebo: 74.4
Type of NSAID: naproxen
Previous peptic ulcers (%): omeprazole: 27; placebo: 21
Primary vs secondary prophylaxis: primary
H pylori positive (%): omeprazole: 53; placebo: 51

Interventions 1) omeprazole 20 mg daily

2) placebo

Outcomes Endoscopic ulcers

Notes Quality = 3

Risk of bias

Bias Authors’ judgement Support for judgement

Allocation concealment (selection bias) Unclear risk D - Not used

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Elliot 1994

Methods Randomized controlled trial

Double-blind
Sample size at entry: misoprostol: 40: placebo: 43
Study duration: 12 months

Participants Patient: rheumatic arthritis, osteoarthritis

Mean age (yrs): misoprostol: 65; placebo: 65
Sex % F: misoprostol: 37.5, placebo: 51.2
Type of NSAID: pisoxica, ibuprofen, naproxen
Previous peptic ulcers (%): misoprostol: 28; placebo: 28
Primary vs secondary prophylaxis: primary
H pylori positive (%): not mentioned

Interventions 1) misoprostol 200 µg qid or bd or td depending on frequency of NSAID use

2) placebo (same protocol as misoprostol, with NSAID)

Outcomes Endoscopic gastric ulcers (>3 mm), mean size 6 mm

Endosopic duodenal ulcers (>3 mm)
Clinical ulcers
Withdrawals overall
Withdrawals due to side effects
Drop out due to diarrhea

Notes Quality=4

Risk of bias

Bias Authors’ judgement Support for judgement

Allocation concealment (selection bias) Unclear risk D - Not used

Graham 1988

Methods Randomized controlled trial

Double-blind
Sample size at entry: isosprotol 100: 143; misoprostol 200: 139; placebo: 138
Study duration: 12 weeks

Participants Patient: osteoarthritis

Mean age (yrs): 58.9
Sex % F: 65
Type of NSAID: ibuprofen; piroxen; naproxen
Previous peptic ulcers (%): 13
Primary vs secondary prophylaxis: primary
H pylori positive (%): not mentioned

Interventions 1) placebo x 4
2) misoprostol 100 µg x 4

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Graham 1988 (Continued)

3) misoprostol 200 µg x 4

Outcomes Endoscopic gastric ulcers (>3 mm)

Endoscopic gastric ulcers (>5 mm)
Clinical ulcers:
Withdrawals overall
Withdrawals due to side effects

Notes Qualtiy=3

Risk of bias

Bias Authors’ judgement Support for judgement

Allocation concealment (selection bias) Unclear risk D - Not used

Graham 1993

Methods Randomized controlled trial

Double-blind
Sample size at entry: misoprostol: 320; placebo: 323
Study duration: 12 weeks

Participants Patient: rheumatoid arthritis, osteoarthritis, Reiter syndrome, psoriatic arthritis, ankylosing
spondylitis
Median age (yrs): misoprostol: 59; placebo: 61
Sex % F: misoprostol: 47; placebo: 50
Type of NSAID: ibuprofen, piroxicam, naproxen, sulindac, tolmetin, indomethacin, di-
clofenac
Previous peptic ulcers (%): misoprostol: 25; placebo: 26
Primary vs secondary prophylaxis: primary
H pylori positive (%): not mentioned

Interventions 1) misoprostol 800 µg (200 µg x 4)

2) placebo

Outcomes Endoscopic gastric ulcers (>5 mm)

Endoscopic duodenal ulcers (>5 mm)
Clinical ulcers:
Withdrawals overall
Withdrawals due to side effects
Diarhea drop out
Nausea drop out
Abdominal pain drop out

Notes Qualtiy=3

Risk of bias

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Graham 1993 (Continued)

Bias Authors’ judgement Support for judgement

Allocation concealment (selection bias) Unclear risk D - Not used

Graham 2002

Methods Randomized controlled trial

Double-blind
Sample size at entry: misoprostol:134; lansoprazole 15mg : 136; lansoprazole 30mg: 133;
placebo: 134
Study duration: 12 weeks

Participants Patient: History of endoscopically documented gastric ulcer with or without GI bleeding
Mean age (yrs): misoprostol:59.4; lansoprazole 15mg : 61.6; lansoprazole 30mg: 60.2;
placebo: 60.5
Sex % F: misoprostol:68; lansoprazole 15mg : 63; lansoprazole 30mg: 64; placebo: 65
Type of NSAID: ibuprofen, naproxen, diclofenac, aspirin, piroxicam
Previous peptic ulcers (%): all
Primary vs secondary prophylaxis: secondary
H pylori positive (%): 15

Interventions 1) placebo
2) misoprostol 800µg
3) lansoprazole 15 mg
4) lansoprazole 30 mg

Outcomes Endoscopic gastric ulcers

Notes Quality=4

Risk of bias

Bias Authors’ judgement Support for judgement

Allocation concealment (selection bias) Unclear risk B - Unclear

Hawkey 1998

Methods Randomized controlled trial

Double-blind
Sample size at entry: omeprazole: 274; misoprostol: 296; placebo: 155
Study duration: 6 months

Participants Patient: rheumatoid arthritis, osteoarthritis

Mean age (yrs): omeprazole: 58; misoprostol: 58; placebo: 57
Sex % F: omeprazole: 63; misoprostol: 60; placebo: 69
Type of NSAID: diclofenac, ketoprofen, naproxen

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Hawkey 1998 (Continued)

Previous peptic ulcers (%): omeprazole: 29; misoprostol: 27; placebo: 31

Primary vs secondary prophylaxis: primary
H pylori positive (%):omeprazole: 42; misoprostol: 41; placebo: 38

Interventions 1) omeprazole 20 mg
2) misoprostol 200 µg bid = 400 µg
3) placebo

Outcomes Endoscopic gastric ulcers (>3 mm)

Endoscopic gastric ulcers (>5 mm)
Endoscopic duodenal ulcers (>3 mm)
Endoscopic duodenal ulcers (>5 mm)
Clinical ulcers: ?
Withdrawals overall
Withdrawals due to side effects

Notes Quality = 3

Risk of bias

Bias Authors’ judgement Support for judgement

Allocation concealment (selection bias) Unclear risk D - Not used

Henriksson 1993

Methods Randomized controlled trial

Double-blind
Sample size at entry: misoprostol: 19; placebo: 20
Study duration: 30 months

Participants Patient: rheumatoid arthritis

Mean age (yrs): misoprostol: 60; placebo: 54
Sex % F: misoprostol: 84; placebo: 66
Type of NSAID: diclofenac, naproxen, ibuprofen, ketoprofen, piroxicam
Previous peptic ulcers (%): misoprostol: 0; placebo: 5
Primary vs secondary prophylaxis: primary
H pylori positive (%): 33

Interventions 1) misoprostol 200 µg tid

2) placebo tid

Outcomes Endoscopic gastric ulcers

Endoscopic duodenal ulcers
Drop-outs overall
Abdominal pain
Diarrhea
GI symptoms

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Henriksson 1993 (Continued)

Notes Quality = 4

Risk of bias

Bias Authors’ judgement Support for judgement

Allocation concealment (selection bias) Unclear risk D - Not used

Hudson 1997

Methods Randomized controlled trial

Double-blind
Sample size at entry: famotidine: 39; placebo: 39
Study duration: up to 24 weeks

Participants Patient: rheumatoid arthritis and osteoarthritis

Median age (yrs): famotidine: 58; placebo: 55
Sex % F: famotidine: 64.1; placebo: 49.1
Type of NSAID: diclofenac
Previous peptic ulcers (%): famotidine: 31; placebo: 28
Primary vs secondary prophylaxis: primary
H pylori positive (%): 46

Interventions 1) famotidine 40 mg bid (high dose)

2) placebo bid

Outcomes Endoscopic ulcers

Notes Quality = 3

Risk of bias

Bias Authors’ judgement Support for judgement

Allocation concealment (selection bias) Unclear risk D - Not used

Jensen 2000

Methods Randomized controlled trial

Double-blind
Sample size at entry: omeprazole: 23; misoprostol: 23
Study duration:32 weeks

Participants Patient: high risk with previous NSAID or ASA ulcer who need continuation of NSAID
Mean age (yrs):n/a
Sex % F:n/a

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Jensen 2000 (Continued)

Type of NSAID:ASA >=325mg, or ’moderate dose’ NSAIDs

Previous peptic ulcers (%):all
Primary vs secondary prophylaxis:secondary
H pylori positive (%):n/a

Interventions 1) omeprazole 20mg bid 2) misoprostol 200µg qid

Outcomes UGI bleeding

Symptomatic ulcer recurrence
Unrelieved UGI symptoms

Notes Abstract - Can’t determine some results

Risk of bias

Bias Authors’ judgement Support for judgement

Allocation concealment (selection bias) Unclear risk D - Not used

Lai 2003

Methods Randomized controlled trial

Double-blind
Sample size at entry: lansoprazole: 22; no treatment: 21
Study duration: 5 weeks

Participants Patient: rheumatoid arthritis and osteoarthritis

Mean age (yrs): lansoprazole: 67.1; No treatment: 70.2
Sex % F: lansoprazole: 36.4; No treatment: 52.4
Type of NSAID: naproxen
Previous peptic ulcers (%): all
Primary vs secondary prophylaxis: secondary
H pylori positive (%): 54

Interventions 1) naproxen 750 mg tid + either 30 mg of lansoprazole 2) no treatment for 8 weeks

Outcomes Primary: symptomatic and complicated ulcers

secondary: cumulative
Relapse of all ulcers

Notes Quality = 3

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Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Levine 1993

Methods Randomized controlled trial

Double-blind
Sample size at entry: niztidine: 248; placebo: 248
Study duration: 3 months

Participants Patient:osteoarthritis
Mean age (yrs): niztidine: 56.9; placebo: 51.5
Sex % F: niztidine: 64.9; placebo: 66.1
Type of NSAID: piroxicam, ibuprofen, naproxen, diclofenac
Previous peptic ulcers (%): nizatidine: 17.3; placebo: 18.1
Primary vs secondary prophylaxis: primary
H pylori positive: nizatidine: 38.3; placebo: 56.2

Interventions 1) nizatidine 150 mg bid

2) placebo

Outcomes Endoscopic ulcers

Symptoms

Notes Quality =3

Risk of bias

Bias Authors’ judgement Support for judgement

Allocation concealment (selection bias) Unclear risk D - Not used

Melo Gomes 1993

Methods Randomized controlled trial

Double-blind
Sample size at entry: diclofenac/misoprostol: 216; piroxicam: 217; naproxen: 210
Study duration: 4 weeks

Participants Patient: osteoarthritis

Mean age (yrs): diclofenac/misoprostol: 60.7; piroxicam: 58.7; naproxen: 59.5
Sex % F: diclofenac/misoprostol: 76; piroxicam: 75; naproxen: 77
Type of NSAID: diclofenac, misoprostol, piroxicam, naproxen
Previous peptic ulcers (%): 0
Primary vs secondary prophylaxis:primary
H pylori positive (%): not mentioned

Interventions 1) diclofenac/misoprostol
2) piroxicam
3) naproxen

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Melo Gomes 1993 (Continued)

Outcomes Endoscopic ulcers

Endoscopic gastric ulcers
Endoscopic duodenal ulcers
Abdominal pain
Diarrhea
Dyspepsia
Nausea

Notes Quality = 3

Risk of bias

Bias Authors’ judgement Support for judgement

Allocation concealment (selection bias) Unclear risk D - Not used

Raskin 1995

Methods Randomized controlled trial

Double-blind
Sample size at entry: misoprostol 400: 462; misoprostol 600: 474; misoprostol 800: 228;
placebo: 454
Study duration: 3 months

Participants Patient: rheumatoid arthritis, osteoarthritis, psoriatic arthritis, ankylosing spondylitis, Re-
iter syndrome
Median age (yrs): misoprostol 400: 58; misoprostol 600: 58; misoprostol 800: 58; placebo:
58
Sex % F: misoprostol 400: 56; misoprostol 600: 60; misoprostol 800: 60; placebo: 59
Type of NSAID: diclofenac, ketoprofen; naproxen
Previous peptic ulcers (%): 0
Primary vs secondary prophylaxis: primary
H pylori positive (%): not mentioned

Interventions 1) placebo: 4 x day

2) misoprostol 200 µg x 2 = 400 µg
3) misoprostol 200 µg x 3 = 600 µg
4) misoprostol 200 µg x 4 = 800 µg

Outcomes Endoscopic gastric ulcers (>3 mm)

Endoscopic duodenal ulcers (>3 mm)
Clinical ulcers: not mentioned
Withdrawals overall
Withdrawals due to side effects
All adverse events

Notes Quality = 5

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Raskin 1995 (Continued)

Risk of bias

Bias Authors’ judgement Support for judgement

Allocation concealment (selection bias) Unclear risk D - Not used

Raskin 1996

Methods Randomized controlled trial

Double-blind
Sample size at entry: misoprostol: 269; ranitidine: 269
Study duration: 8 weeks

Participants Patient: rheumatoid arthritis, osteoarthritis, psoriatic arthritis, ankylosing spondylitis, Re-
iter syndrome
Mean age (yrs): misoprostol: 61; ranitidine: 60
Sex % F: misoprostol: 53; ranitidine: 57
Type of NSAID: ibuprofen, naproxen, piroxen, sulindac
Previous peptic ulcers (%): misoprostol: 23; ranitidine: 21
Primary vs secondary prophylaxis: primary
H pylori positive (%): not mentioned

Interventions 1) misoprostol 200 µg qid

2) ranitidine 150 mg bid

Outcomes Endoscopic gastric ulcer (>3 mm)

Endoscopic duodenal ulcers (>3 mm)
Clinical ulcers
Withdrawals overall
Withdrawals due to side effects
Nausea

Notes Quality = 3

Risk of bias

Bias Authors’ judgement Support for judgement

Allocation concealment (selection bias) Low risk A - Adequate

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Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Robinson 1989

Methods Randomized controlled trial

Double-blind
Sample size at entry: ranitidine 150 mg bid: 72; placebo: 72
Study duration: 8 weeks

Participants Patient: arthritis

Mean age (yrs): ranitidine 150 mg bid: 48.9; placebo: 44.5
Sex % F: ranitidine 150 mg bid: 60; placebo: 69
Type of NSAID: naproxen, sulindac, ibuprofen, piroxicam, indomethacin
Previous peptic ulcers (%): 0
Primary vs secondary prophylaxis: primary
H pylori positive (%): not mentioned

Interventions 1) ranitidine 150 mg bid

2) placebo bid

Outcomes Endoscopic duodenal ulcers

Endoscopic gastric ulcers
Adverse events

Notes Quality = 3

Risk of bias

Bias Authors’ judgement Support for judgement

Allocation concealment (selection bias) Unclear risk D - Not used

Robinson 1991

Methods Randomized controlled trial

Double-blind
Sample size at entry : placebo: 330; ranitidine: 343
Study duration: 4 & 8 weeks

Participants Patient: with no ulcers, confirmed by endoscopy

Mean age (yrs): placebo: 50.7; ranitidine: 51.2
Sex % F: placebo: 64; ranitidine: 58
Type of NSAID: aspirin, diclofenac, ibuprofen, indomethacin, naproxen, piroxicam, sulin-
dac
Previous peptic ulcers (%): none
Primary vs secondary prophylaxis: primary
H pylori positive (%): not mentioned

Interventions ranitidine 150 mg bid

placebo

Outcomes Duodenal ulcers (unspecified criteria)

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Robinson 1991 (Continued)

Notes Qualtiy=2

Risk of bias

Bias Authors’ judgement Support for judgement

Allocation concealment (selection bias) Unclear risk D - Not used

Roth 1987

Methods Randomized controlled trial

Double-blind
Sample size at entry: placebo: 46; cimetidine: 48
Study duration: 2 months

Participants Patient: rheumatoid arthritis, osteoarthritis

Mean age (yrs): not mentioned
Sex % F: not mentioned
Type of NSAID: various
Previous peptic ulcers (%): all
Primary vs secondary prophylaxis: secondary
H pylori positive (%): not mentioned

Interventions Cimetidine 400 mg per day

placebo

Outcomes Total endoscopic ulcers

Notes Quality =1

Risk of bias

Bias Authors’ judgement Support for judgement

Allocation concealment (selection bias) Unclear risk D - Not used

Roth 1993

Methods Randomized controlled trial

Double-blind
Sample size at entry: nabumetone: 58; ibuprofen: 53; ibuprofen and misoprostol: 60
Study duration: 12 weeks

Participants Patient: rheumatoid arthritis, osteoarthritis

Mean age (yrs): nabumetone: 70; ibuprofen: 70; ibuprofen and misoprostol: 70
Sex % F: nabumetone: 67; ibuprofen: 77; ibuprofen and misoprostol: 82
Type of NSAID: nabumetone, ibuprofen
Prevention of NSAID-induced gastroduodenal ulcers (Review) 39
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Roth 1993 (Continued)

Previous peptic ulcers (%): nabumetone: 17; ibuprofen: 26; ibuprofen and misoprostol:
23
Primary vs secondary prophylaxis: primary
H pylori positive (%): not mentioned

Interventions 1) nabumetone 1000 mg x ?

2) ibuprofen 600 mg x 4/day
3) ibuprofen and misoprostol 600 mg/200 mg x 4/day

Outcomes Endosopic gastric ulcers (>3 mm)

Endoscopic duodenal ulcers (>3 mm)
Clinical ulcers
Withdrawals overall
Withdrawals due to side effects
GI Side Effects

Notes Quality = 2

Risk of bias

Bias Authors’ judgement Support for judgement

Allocation concealment (selection bias) Unclear risk D - Not used

Saggioro 1991

Methods Randomized controlled trial

Double-blind
Sample size at entry: misoprostol: 82; placebo: 84
Study duration:4 weeks

Participants Patient: rheumatoid arthritis, osteoarthritis

Mean age (yrs): 56
Sex % F: 59.5
Type of NSAID:piroxicam, diclofenac, naproxen, ibuprofen
Previous peptic ulcers (%):none
Primary vs secondary prophylaxis:
H pylori positive (%):n/a

Interventions 1) misoprostol 200 µg qid

2) placebo

Outcomes Endoscopic ulcers

Symptoms

Notes Quality = 3

Risk of bias

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Saggioro 1991 (Continued)

Bias Authors’ judgement Support for judgement

Allocation concealment (selection bias) Unclear risk D - Not used

Silverstein 1995

Methods Randomized controlled trial

Double-blind
Sample size at entry: misoprostol: 440; placebo: 443
Study duration: 6 months

Participants Patient: rheumatoid arthritis

Median age (yrs): misoprostol: 67.6; placebo: 67.6
Sex % F: misoprostol: 71.1; placebo: 70.6
Type of NSAID: diclofenac, indomethacin; ketoprofen ; naproxen, piroxicam, sulindac
Previous peptic ulcers (%): misoprostol: 14.6; placebo: 14.4
Primary vs secondary prophylaxis: primary
H pylori positive (%): not mentioned

Interventions 1) misoprostol 200 µg x 4/day or 100 µg x 4 if poorly treated

2) placebo

Outcomes Endoscopic gastric ulcers (>3 mm)

Endoscopic duodenal ulcers (>3 mm)
Clinical ulcers: category 1-6
Withdrawals overall
Withdrawals due to side effects

Notes Quality = 4

Risk of bias

Bias Authors’ judgement Support for judgement

Allocation concealment (selection bias) Unclear risk D - Not used

Simon 1994

Methods Randomized controlled trial

Double-blind
Sample size at entry: nizatidine 300mg daily: 93; nizatidine 150mg bid: 151; nizatidine
300mg bid: 90
Study duration: 3 weeks

Participants Patient: rheumatoid arthritis with an ulcer

Median age (yrs): nizatidine 300mg daily: 58; nizatidine 150mg bid: 55; nizatidine 300mg
bid: 57

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Simon 1994 (Continued)

Sex % F: nizatidine 300mg daily: 45.3; nizatidine 150mg bid: 37.6; nizatidine 300mg bid:
38.9
Type of NSAID:
Previous peptic ulcers (%): all
Primary vs secondary prophylaxis: secondary
H pylori positive (%): not mentioned

Interventions 1) Nizatidine 150 mg daily

2) Nizatidine 150 mg bid

Outcomes Endoscopic ulcers

Notes Quality =2

Risk of bias

Bias Authors’ judgement Support for judgement

Allocation concealment (selection bias) Unclear risk D - Not used

Stupnicki 2003

Methods Randomized controlled trial

Double-blind
Sample size at entry: pantoprazole: 257; misoprostol: 258
Study duration: 4 weeks

Participants Patient: rheumatoid arthritis

Mean age (yrs): pantoprazole: 55; misoprostol: 55
Sex % F: pantoprazole: 64; misoprostol: 64
Type of NSAID: diclofenac
Previous peptic ulcers (%): pantoprazole: 23; misoprostol: 22.5
Primary vs secondary prophylaxis: primary
H pylori positive (%): pantoprazole: 33; misoprostol: 31

Interventions 1) misoprostol 400µg/day 2) pantoprazole 40mg/day

Outcomes Endoscopic ulcers

Serious adverse events

Notes Quality: randomisation 2; blinding 1; follow up 1:

Prevention of NSAID-induced gastroduodenal ulcers (Review) 42

Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Swift 1989

Methods Randomized controlled trial

Double-blind
Sample size at entry: famotidine: 51; cimetidine: 54
Study duration: 7 weeks

Participants Patient: rheumatoid arthritis + 4 osteoarthritis

Mean age (yrs): famotidine: 45; cimetidine: 39
Sex % F: famotidine: 25.5; cimetidine: 25.9
Type of NSAID:indomethacin sulindac, naproxen, ibuprofen, piroxicam, ketoprofen, +
others
Previous peptic ulcers (%):n/a
Primary vs secondary prophylaxis:primary
H pylori positive (%):n/a

Interventions 1) ranitidine 150 mg bid for 7 weeks then ranitidine 300 mg bid for 7 weeks
2) placebo for 14 weeks

Outcomes Gastritis
Lanza score
Gastric ulcers
Faecal blood loss

Notes Quality = 4

Risk of bias

Bias Authors’ judgement Support for judgement

Allocation concealment (selection bias) Unclear risk D - Not used

Taha 1996

Methods Randomized controlled trial

Double-blind
Sample size at entry: famotidine 20 mg bid: 95, famotidine 40 mg bid: 97, placebo: 93
Study duration: 24 weeks

Participants Patient: rheumatoid, osteoarthritis

Mean age (yrs): famotidine 20 mg bid: 57.2, famotidine 40 mg bid: 55, placebo: 53.4
Sex % F: famotidine 20 mg bid: 73, famotidine 40 mg bid: 70, placebo: 76
Type of NSAID: diclofenac, naproxen, indomethacin, ketoprofen, ibuprofen, febufen
Previous peptic ulcers (%): famotidine 20 mg bid: 16, famotidine 40 mg bid: 13, placebo:
10
Primary vs secondary prophylaxis: primary
H pylori positive (%): 20 mg bid: 51, famotidine 40 mg bid: 49, placebo: 49

Interventions 1) famotidine 20 mg bid

2) famotidine 40 mg bid

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Taha 1996 (Continued)

3) placebo

Outcomes Endoscopic ulcers

Symptoms

Notes Quality =4

Risk of bias

Bias Authors’ judgement Support for judgement

Allocation concealment (selection bias) Unclear risk D - Not used

Ten Wolde 1996

Methods Randomized controlled trial

Double-blind
Sample size at entry: ranitidine: 15; placebo: 15
Study duration: 12 months

Participants Patient: rheumatic arthritis

Mean age (yrs): ranitidine: 67; placebo: 58
Sex % F: ranitidine: 40; placebo: 60
Type of NSAID: diclofenac
Previous peptic ulcers (%): all
Primary vs secondary prophylaxis: secondary
H pylori positive (%): 45

Interventions 1) ranitidine 300 mg bid + NSAIDs

2) placebo bid + NSAIDs

Outcomes Gastric duodenal ulcers

Duodenal endoscopic ulcers
Total endoscopic ulcers

Notes Quality = 3

Risk of bias

Bias Authors’ judgement Support for judgement

Allocation concealment (selection bias) Unclear risk D - Not used

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Valentini 1995

Methods Randomized controlled trial

Single-blind
Sample size at entry: misoprostol: 23; ranitidine: 26
Study duration: not mentioned

Participants Patient: cancer

Mean age (yrs): misoprostol: 59.2; ranitidine: 59.8
Sex % F: misoprostol: 56; ranitidine: 54
Type of NSAID: diclofenac
Previous peptic ulcers (%): 0
Primary vs secondary prophylaxis: primary
H pylori positive (%): not mentioned

Interventions 1) misoprostol 200 µg bid and diclofenac 200 mg/day

2) ranitidine 150 mg bid and diclofenac 200 mg/day

Outcomes Gastric ulcers ->6 mm

Duodenal ulcers, > 6 mm
Gastric erosions
Duodenal erosions
Nausea, abdominal pain, vomiting, diarrhea

Notes Quality = 2

Risk of bias

Bias Authors’ judgement Support for judgement

Allocation concealment (selection bias) Unclear risk D - Not used

van Groenendaci 1996

Methods Randomized controlled trial

Double-blind
Sample size at entry: ranitidine 150mg: 47, placebo: 47; ranitidine 300mg: 30
Study duration: 4 weeks

Participants Patient: rheumatoid arthritis, osteoarthritis

Mean age (yrs): ranitidine 150mg: 57.5, placebo: 56; ranitidine 300mg: 55
Sex % F: ranitidine 150mg: 76.6, placebo: 74.5; ranitidine 300mg: 73.3
Type of NSAID: ketoprofen, indomethacin, naproxen, piroxicam, salicylates
Previous peptic ulcers (%): not mentioned
Primary vs secondary prophylaxis: primary
H pylori positive (%): not mentioned

Interventions 1) ranitidine 150 mg bid

2) placebo bid

Prevention of NSAID-induced gastroduodenal ulcers (Review) 45

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van Groenendaci 1996 (Continued)

Outcomes Endoscopic ulcers and erosions

GI symptoms

Notes Quality = 1

Risk of bias

Bias Authors’ judgement Support for judgement

Allocation concealment (selection bias) Unclear risk D - Not used

Verdickt 1992

Methods Randomized controlled trial

Double-blind
Sample size at entry: diclofenac and misoprostol: 164; diclofenac and placebo: 175
Study duration: 12 weeks

Participants Patient: rheumatoid arthritis

Mean age (yrs): diclofenac and misoprostol: 53.2; diclofenac and placebo: 53.4
Sex % F: diclofenac and misoprostol: 75; diclofenac and placebo: 78
Type of NSAID: diclofenac
Previous peptic ulcers (%): not mentioned
Primary vs secondary prophylaxis: primary
H pylori positive (%): not mentioned

Interventions 50 mg diclofenac and misoprostol (200 mcg)

50 mg diclofenac and placebo

Outcomes Endoscopic gastric ulcers (>3 mm), ulcer of any size

Endoscopic duodenal ulcers (>3 mm), ulcer of any size
Clinical ulcers:
Withdrawals overall
Withdrawals due to side effects
Worse arthritis withdrawal

Notes Quality = 3

Risk of bias

Bias Authors’ judgement Support for judgement

Allocation concealment (selection bias) Unclear risk D - Not used

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Yeomans 1998

Methods Randomized controlled trial

Double-blind
Sample size at entry: omeprazole: 210; ranitidine: 215
Study duration: 4 & 8 weeks

Participants Patient: rheumatoid arthritis, osteoarthritis

Mean age (yrs): omeprazole: 56; ranitidine: 56
Sex % F: omeprazole: 69.5; ranitidine: 69.3
Type of NSAID: diclofenac, indomethacin, naproxen
Previous peptic ulcers (%): omeprazole: 25.3; ranitidine: 31.6
Primary vs secondary prophylaxis: primary
H pylori positive (%): omeprazole: 49.5; ranitidine: 46.5

Interventions 1) omeprazole 20 mg
2) ranitidine 150 mg bid

Outcomes Endoscopic ulcers

Notes Quality = 3

Risk of bias

Bias Authors’ judgement Support for judgement

Allocation concealment (selection bias) Unclear risk D - Not used

Characteristics of excluded studies [ordered by study ID]

Study Reason for exclusion

Agrawal 1999 Compared diclofenac + misoprostol to nabumetone - study differences partially due to NSAID differences

Agrawal 2000 NSAID ulcer treatment not prophylaxis

Bianchi Porro 1997 Acute - only 14 days of treatment

Bianchi Porro 1998 Acute - only 3 week study

Caldwell 1989 Healing study

Cohen de Lara 2000 Misoprostol vs dosmalfate not placebo

Daneshmend 1990 Acute < 2 weeks of NSAID exposure

Desai 2008 Acute and in healthy volunteers

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(Continued)

Donnelly 2000 Only assessed erosions and not ulcers

Geis 1991 Required data could not be extracted

Geis 1992 Duplicate data

Goldstein 2004 Post hoc analysis of previous study

Goldstein 2005 Healing phase study not prevention

Goldstein 2007 Healing phase not prevention

Lanas 2007 Not RCT

Melo Gomes 1992 Duplicate publication of Bolten 1992 in OA patients and Verdickt 1992 in rheumatoid arthritis patients

Miyake 2005 Study does not appear to be randomised

Regula 2006 PPI vs PPI study - no placebo or separate control group

Rose 1999 Abstract incomplete, group sizes not stated

May be included in future revision when published in full

Rugstad 1994 No ulcer outcomes, only GI symptoms

Ryan 1987 < 3 weeks of prophylaxis

Scheiman 2006 participants were on both tNSAIDs and COX-2 inhibitors

Walan 1984 Prophylaxis phase cannot be extracted

Yilmaz 2007 Healing phase study on acute bleed

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DATA AND ANALYSES

Comparison 1. Misoprostol vs placebo - primary efficacy

No. of No. of
Outcome or subgroup title studies participants Statistical method Effect size

1 Gastric ulcers - 4 - 11 week 8 2033 Risk Ratio (M-H, Fixed, 95% CI) 0.17 [0.09, 0.31]
studies
2 Duodenal ulcers - 4 - 11 week 6 1546 Risk Ratio (M-H, Fixed, 95% CI) 0.30 [0.14, 0.62]
studies
3 Total ulcers - 4 - 11 week studies 4 1323 Risk Ratio (M-H, Fixed, 95% CI) 0.24 [0.14, 0.42]
4 Gastric ulcers - 12 weeks or 11 3641 Risk Ratio (M-H, Random, 95% CI) 0.26 [0.17, 0.39]
longer studies
5 Duodenal ulcers - 12 weeks or 8 2785 Risk Ratio (M-H, Random, 95% CI) 0.42 [0.22, 0.81]
longer studies
6 Total endoscopic ulcers - 12 6 1791 Risk Ratio (M-H, Random, 95% CI) 0.34 [0.20, 0.59]
weeks or longer studies
7 Total endoscopic ulcers Chan 5 1701 Risk Ratio (M-H, Fixed, 95% CI) 0.28 [0.20, 0.38]
2001 removed - 12 weeks or
longer studies
8 Clinical ulcers - 12 weeks or 2 9276 Risk Ratio (M-H, Fixed, 95% CI) 0.48 [0.27, 0.87]
longer studies

Comparison 2. Misoprostol vs placebo - toxicity causing withdrawal

No. of No. of
Outcome or subgroup title studies participants Statistical method Effect size

1 Nausea 6 11021 Risk Ratio (M-H, Fixed, 95% CI) 1.26 [1.07, 1.48]
2 Dyspepsia 7 10634 Risk Ratio (M-H, Fixed, 95% CI) 1.14 [0.95, 1.36]
3 Constipation 2 9199 Risk Ratio (M-H, Fixed, 95% CI) 0.64 [0.38, 1.06]
4 Diarrhea 10 11793 Risk Ratio (M-H, Fixed, 95% CI) 2.36 [2.01, 2.77]
5 Abdominal pain 6 11098 Risk Ratio (M-H, Fixed, 95% CI) 1.36 [1.20, 1.55]
6 Flatulence 3 9638 Risk Ratio (M-H, Random, 95% CI) 2.46 [0.91, 6.65]
7 Vomiting 2 9525 Risk Ratio (M-H, Random, 95% CI) 1.62 [0.36, 7.31]
8 Drop-outs due to side-effects 12 12146 Risk Ratio (M-H, Fixed, 95% CI) 1.41 [1.31, 1.51]
9 Drop-outs overall 15 13239 Risk Ratio (M-H, Random, 95% CI) 1.44 [1.11, 1.86]

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Comparison 3. Misoprostol vs placebo - toxicity symptoms only

No. of No. of
Outcome or subgroup title studies participants Statistical method Effect size

1 Nausea 10 2835 Risk Ratio (M-H, Random, 95% CI) 1.41 [0.81, 2.45]
2 Dyspepsia 10 2696 Risk Ratio (M-H, Random, 95% CI) 1.17 [0.85, 1.63]
3 Constipation 2 469 Risk Ratio (M-H, Fixed, 95% CI) 0.58 [0.22, 1.57]
4 Diarrhea 13 3409 Risk Ratio (M-H, Random, 95% CI) 2.59 [1.89, 3.55]
5 Abdominal pain 9 2621 Risk Ratio (M-H, Random, 95% CI) 1.20 [0.87, 1.65]
6 Flatulence 5 1542 Risk Ratio (M-H, Fixed, 95% CI) 1.36 [0.97, 1.91]

Comparison 4. Misoprostol vs placebo - efficacy by dosage

No. of No. of
Outcome or subgroup title studies participants Statistical method Effect size

1 Gastric ulcers - 1 month 8 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
1.1 Low dose (400-600 ug) 5 1555 Risk Ratio (M-H, Fixed, 95% CI) 0.22 [0.11, 0.41]
1.2 Mid-range dose (600 ug) 2 370 Risk Ratio (M-H, Fixed, 95% CI) 0.22 [0.07, 0.69]
1.3 High dose (800 ug) 4 710 Risk Ratio (M-H, Fixed, 95% CI) 0.10 [0.03, 0.32]
2 Duodenal ulcers - 1 month 6 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
2.1 Low dose (400-600 ug) 4 1274 Risk Ratio (M-H, Fixed, 95% CI) 0.21 [0.08, 0.56]
2.2 Mid-range dose (600 ug) 3 410 Risk Ratio (M-H, Fixed, 95% CI) 0.62 [0.25, 1.58]
2.3 High dose (800 ug) 1 183 Risk Ratio (M-H, Fixed, 95% CI) 0.64 [0.06, 6.97]
3 Total ulcers - 1 month 4 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
3.1 Low dose (400-600 ug) 3 1091 Risk Ratio (M-H, Fixed, 95% CI) 0.22 [0.11, 0.43]
3.2 Mid-range dose (600 ug) 2 370 Risk Ratio (M-H, Fixed, 95% CI) 0.37 [0.17, 0.79]
3.3 High dose (800 ug) 0 0 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]
4 Gastric ulcers - 3-24 months 11 Risk Ratio (M-H, Random, 95% CI) Subtotals only
4.1 Low dose (400-600 ug) 6 2461 Risk Ratio (M-H, Random, 95% CI) 0.43 [0.28, 0.67]
4.2 Mid-range dose (600 ug) 1 928 Risk Ratio (M-H, Random, 95% CI) 0.24 [0.13, 0.44]
4.3 High dose (800 ug) 7 2377 Risk Ratio (M-H, Random, 95% CI) 0.18 [0.12, 0.27]
5 Gastric ulcers - 3-24 months 10 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
(sensitivity analysis excluding
Chan 2001)
5.1 Low dose (400-600 ug) 5 2371 Risk Ratio (M-H, Fixed, 95% CI) 0.39 [0.30, 0.51]
5.2 Mid-range dose (600 ug) 1 928 Risk Ratio (M-H, Fixed, 95% CI) 0.24 [0.13, 0.44]
5.3 High dose (800 ug) 7 2377 Risk Ratio (M-H, Fixed, 95% CI) 0.17 [0.11, 0.24]
6 Duodenal ulcers - 3-24 months 8 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
6.1 Low dose (400-600 ug) 5 2180 Risk Ratio (M-H, Fixed, 95% CI) 0.56 [0.39, 0.81]
6.2 Mid-range dose (600 ug) 1 928 Risk Ratio (M-H, Fixed, 95% CI) 0.46 [0.23, 0.93]
6.3 High dose (800 ug) 4 1521 Risk Ratio (M-H, Fixed, 95% CI) 0.21 [0.09, 0.49]
7 Total endoscopic ulcers 3-24 6 Risk Ratio (M-H, Random, 95% CI) Subtotals only
months
7.1 Low dose (400-600 ug) 3 813 Risk Ratio (M-H, Random, 95% CI) 0.60 [0.27, 1.31]
7.2 Mid-range dose (600 ug) 0 0 Risk Ratio (M-H, Random, 95% CI) 0.0 [0.0, 0.0]
7.3 High dose (800 ug) 3 978 Risk Ratio (M-H, Random, 95% CI) 0.22 [0.14, 0.34]
8 Clinical ulcers - 3-24 months 2 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
Prevention of NSAID-induced gastroduodenal ulcers (Review) 50
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 8.1 Low dose (400-600 ug) 1 433 Risk Ratio (M-H, Fixed, 95% CI) 0.33 [0.01, 8.17]
8.2 Mid-range dose (600 ug) 0 0 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]
8.3 High dose (800 ug) 1 8843 Risk Ratio (M-H, Fixed, 95% CI) 0.49 [0.27, 0.89]

Comparison 5. Misoprostol vs placebo - toxicity causing withdrawal - by dose

No. of No. of
Outcome or subgroup title studies participants Statistical method Effect size

1 Nausea 6 Risk Ratio (M-H, Random, 95% CI) Subtotals only

1.1 Misoprostol 400 ug/day 3 1629 Risk Ratio (M-H, Random, 95% CI) 0.87 [0.44, 1.74]
1.2 Misoprostol 600 ug/day 2 1234 Risk Ratio (M-H, Random, 95% CI) 0.41 [0.06, 2.93]
1.3 Misoprostol 800 ug/day 4 10281 Risk Ratio (M-H, Random, 95% CI) 1.22 [1.00, 1.48]
2 Dyspepsia 7 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
2.1 Misoprostol 400 ug/day 3 1629 Risk Ratio (M-H, Fixed, 95% CI) 0.48 [0.20, 1.11]
2.2 Misoprostol 600 ug/day 2 1214 Risk Ratio (M-H, Fixed, 95% CI) 0.69 [0.32, 1.47]
2.3 Misoprostol 800 ug/day 5 10157 Risk Ratio (M-H, Fixed, 95% CI) 1.16 [0.96, 1.39]
3 Constipation 2 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
3.1 Misoprostol 400 ug/day 0 0 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]
3.2 Misoprostol 600 ug/day 0 0 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]
3.3 Misoprostol 800 ug/day 2 9199 Risk Ratio (M-H, Fixed, 95% CI) 0.64 [0.38, 1.06]
4 Diarrhea 10 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
4.1 Misoprostol 400 ug/day 4 2062 Risk Ratio (M-H, Fixed, 95% CI) 1.50 [0.78, 2.90]
4.2 Misoprostol 600 ug/day 2 1234 Risk Ratio (M-H, Fixed, 95% CI) 2.67 [1.20, 5.95]
4.3 Misoprostol 800 ug/day 7 10886 Risk Ratio (M-H, Fixed, 95% CI) 2.45 [2.09, 2.88]
5 Abdominal pain 6 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
5.1 Misoprostol 400 ug/day 3 1733 Risk Ratio (M-H, Fixed, 95% CI) 1.53 [0.90, 2.59]
5.2 Misoprostol 600 ug/day 1 928 Risk Ratio (M-H, Fixed, 95% CI) 1.92 [1.04, 3.51]
5.3 Misoprostol 800 ug/day 4 10291 Risk Ratio (M-H, Fixed, 95% CI) 1.38 [1.17, 1.63]
6 Flatulence 3 Risk Ratio (M-H, Random, 95% CI) Subtotals only
6.1 Misoprostol 400 ug/day 1 916 Risk Ratio (M-H, Random, 95% CI) 1.97 [0.60, 6.48]
6.2 Misoprostol 600 ug/day 1 928 Risk Ratio (M-H, Random, 95% CI) 4.31 [1.47, 12.64]
6.3 Misoprostol 800 ug/day 3 9638 Risk Ratio (M-H, Random, 95% CI) 2.46 [0.91, 6.65]
7 Vomiting 2 Risk Ratio (M-H, Random, 95% CI) Subtotals only
7.1 Misoprostol 400 ug/day 1 916 Risk Ratio (M-H, Random, 95% CI) 0.49 [0.04, 5.40]
7.2 Misoprostol 600 ug/day 1 928 Risk Ratio (M-H, Random, 95% CI) 1.44 [0.24, 8.56]
7.3 Misoprostol 800 ug/day 2 9525 Risk Ratio (M-H, Random, 95% CI) 1.46 [0.34, 6.25]
8 Dropouts due to side effects 12 Risk Ratio (M-H, Random, 95% CI) Subtotals only
8.1 Misoprostol 400 ug/day 5 2176 Risk Ratio (M-H, Random, 95% CI) 1.15 [0.88, 1.51]
8.2 Misoprostol 600 ug/day 1 928 Risk Ratio (M-H, Random, 95% CI) 1.09 [0.76, 1.57]
8.3 Misoprostol 800 ug/day 9 11521 Risk Ratio (M-H, Random, 95% CI) 1.68 [1.31, 2.17]
9 Dropouts overall 11 Risk Ratio (M-H, Random, 95% CI) Subtotals only
9.1 Misoprostol 400 ug/day 5 2073 Risk Ratio (M-H, Random, 95% CI) 0.96 [0.82, 1.14]
9.2 Misoprostol 600 ug/day 2 968 Risk Ratio (M-H, Random, 95% CI) 1.10 [0.88, 1.36]
9.3 Misoprostol 800 ug/day 8 10703 Risk Ratio (M-H, Random, 95% CI) 1.35 [1.10, 1.65]

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Comparison 6. Misoprostol vs placebo - symptoms - by dose

No. of No. of
Outcome or subgroup title studies participants Statistical method Effect size

1 Nausea 10 Risk Ratio (M-H, Random, 95% CI) Subtotals only

1.1 Misoprostol 400 ug/day 7 3043 Risk Ratio (M-H, Random, 95% CI) 1.46 [1.13, 1.89]
1.2 Misoprostol 600 ug/day 2 1234 Risk Ratio (M-H, Random, 95% CI) 1.27 [1.01, 1.60]
1.3 Misoprostol 800 ug/day 5 1576 Risk Ratio (M-H, Random, 95% CI) 0.97 [0.54, 1.75]
2 Dyspepsia 13 Risk Ratio (M-H, Random, 95% CI) Subtotals only
2.1 Misoprostol 400 ug/day 8 3219 Risk Ratio (M-H, Random, 95% CI) 0.99 [0.80, 1.23]
2.2 Misoprostol 600 ug/day 5 1539 Risk Ratio (M-H, Random, 95% CI) 0.82 [0.70, 0.97]
2.3 Misoprostol 800 ug/day 6 1849 Risk Ratio (M-H, Random, 95% CI) 1.23 [0.83, 1.82]
3 Constipation 2 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
3.1 Misoprostol 400 ug/day 0 0 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]
3.2 Misoprostol 600 ug/day 2 469 Risk Ratio (M-H, Fixed, 95% CI) 0.58 [0.22, 1.57]
3.3 Misoprostol 800 ug/day 0 0 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]
4 Diarrhea 16 Risk Ratio (M-H, Random, 95% CI) Subtotals only
4.1 Misoprostol 400 ug/day 8 3219 Risk Ratio (M-H, Random, 95% CI) 1.76 [1.37, 2.26]
4.2 Misoprostol 600 ug/day 4 1363 Risk Ratio (M-H, Random, 95% CI) 2.13 [1.28, 3.55]
4.3 Misoprostol 800 ug/day 9 2580 Risk Ratio (M-H, Random, 95% CI) 3.16 [2.33, 4.29]
5 Abdominal pain 11 Risk Ratio (M-H, Random, 95% CI) Subtotals only
5.1 Misoprostol 400 ug/day 7 2943 Risk Ratio (M-H, Random, 95% CI) 1.30 [1.07, 1.60]
5.2 Misoprostol 600 ug/day 3 1273 Risk Ratio (M-H, Random, 95% CI) 1.17 [0.85, 1.60]
5.3 Misoprostol 800 ug/day 5 1845 Risk Ratio (M-H, Random, 95% CI) 0.97 [0.57, 1.64]
6 Flatulence 5 Risk Ratio (M-H, Random, 95% CI) Subtotals only
6.1 Misoprostol 400 ug/day 4 1897 Risk Ratio (M-H, Random, 95% CI) 1.63 [1.06, 2.52]
6.2 Misoprostol 600 ug/day 1 928 Risk Ratio (M-H, Random, 95% CI) 1.35 [1.06, 1.71]
6.3 Misoprostol 800 ug/day 3 1411 Risk Ratio (M-H, Random, 95% CI) 1.56 [1.24, 1.96]
7 Vomiting 2 Risk Ratio (M-H, Random, 95% CI) Subtotals only
7.1 Misoprostol 400 ug/day 1 916 Risk Ratio (M-H, Random, 95% CI) 0.49 [0.04, 5.40]
7.2 Misoprostol 600 ug/day 1 928 Risk Ratio (M-H, Random, 95% CI) 1.44 [0.24, 8.56]
7.3 Misoprostol 800 ug/day 2 9525 Risk Ratio (M-H, Random, 95% CI) 1.46 [0.34, 6.25]
8 Dropouts due to side effects 12 Risk Ratio (M-H, Random, 95% CI) Subtotals only
8.1 Misoprostol 400 ug/day 5 2176 Risk Ratio (M-H, Random, 95% CI) 1.15 [0.88, 1.51]
8.2 Misoprostol 600 ug/day 1 928 Risk Ratio (M-H, Random, 95% CI) 1.09 [0.76, 1.57]
8.3 Misoprostol 800 ug/day 9 11521 Risk Ratio (M-H, Random, 95% CI) 1.68 [1.31, 2.17]
9 Dropouts overall 11 Risk Ratio (M-H, Random, 95% CI) Subtotals only
9.1 Misoprostol 400 ug/day 5 2073 Risk Ratio (M-H, Random, 95% CI) 0.96 [0.82, 1.14]
9.2 Misoprostol 600 ug/day 2 968 Risk Ratio (M-H, Random, 95% CI) 1.10 [0.88, 1.36]
9.3 Misoprostol 800 ug/day 8 10703 Risk Ratio (M-H, Random, 95% CI) 1.35 [1.10, 1.65]
10 Headache 2 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
10.1 Misoprostol 400 ug/day 2 700 Risk Ratio (M-H, Fixed, 95% CI) 0.64 [0.38, 1.06]
10.2 Misoprostol 600 ug/day 0 0 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]
10.3 Misoprostol 800 ug/day 0 0 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]

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Comparison 7. H2 Receptor vs placebo - 4 - 11 week studies by dose

No. of No. of
Outcome or subgroup title studies participants Statistical method Effect size

1 Gastric ulcer 5 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
1.1 High dose 1 190 Risk Ratio (M-H, Fixed, 95% CI) 0.19 [0.04, 0.85]
1.2 Low dose 5 715 Risk Ratio (M-H, Fixed, 95% CI) 0.59 [0.31, 1.13]
2 Duodenal ulcer 6 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
2.1 High dose 1 190 Risk Ratio (M-H, Fixed, 95% CI) 0.16 [0.02, 1.30]
2.2 Low dose 6 942 Risk Ratio (M-H, Fixed, 95% CI) 0.24 [0.10, 0.57]
3 Total endoscopic ulcers 6 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
3.1 High dose 2 268 Risk Ratio (M-H, Fixed, 95% CI) 0.25 [0.11, 0.53]
3.2 Low dose 5 597 Risk Ratio (M-H, Fixed, 95% CI) 0.40 [0.23, 0.71]

Comparison 8. H2 Receptor vs placebo 12 weeks or longer - by dose

No. of No. of
Outcome or subgroup title studies participants Statistical method Effect size

1 Gastric ulcer 6 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
1.1 High dose 3 298 Risk Ratio (M-H, Fixed, 95% CI) 0.44 [0.26, 0.74]
1.2 Low dose 4 1005 Risk Ratio (M-H, Fixed, 95% CI) 0.73 [0.50, 1.08]
2 Duodenal ulcer 5 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
2.1 High dose 3 298 Risk Ratio (M-H, Fixed, 95% CI) 0.26 [0.11, 0.65]
2.2 Low dose 3 981 Risk Ratio (M-H, Fixed, 95% CI) 0.36 [0.18, 0.74]
3 Total endoscopic ulcers 5 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
3.1 High dose 3 298 Risk Ratio (M-H, Fixed, 95% CI) 0.41 [0.26, 0.63]
3.2 Low dose 3 981 Risk Ratio (M-H, Fixed, 95% CI) 0.63 [0.45, 0.88]

Comparison 9. H2 Receptor vs placebo - toxicity - by dose

No. of No. of
Outcome or subgroup title studies participants Statistical method Effect size

1 Total drop-outs 7 Risk Ratio (M-H, Random, 95% CI) Subtotals only
1.1 High dose 3 292 Risk Ratio (M-H, Random, 95% CI) 0.84 [0.41, 1.70]
1.2 Low dose 6 1199 Risk Ratio (M-H, Random, 95% CI) 0.82 [0.66, 1.01]
2 Drop-outs due to side effects 6 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
2.1 High dose 2 102 Risk Ratio (M-H, Fixed, 95% CI) 1.0 [0.21, 4.65]
2.2 Low dose 5 1011 Risk Ratio (M-H, Fixed, 95% CI) 0.86 [0.58, 1.28]
3 Dropouts due to GI symptoms 2 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
3.1 High dose 0 0 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]
3.2 Low dose 2 793 Risk Ratio (M-H, Fixed, 95% CI) 0.71 [0.41, 1.23]
4 Dropouts due to abdominal pain 1 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
4.1 High dose 1 190 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]
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 4.2 Low dose 1 188 Risk Ratio (M-H, Fixed, 95% CI) 2.94 [0.12, 71.20]
5 Dropouts due to diarrhea 1 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
5.1 High dose 1 190 Risk Ratio (M-H, Fixed, 95% CI) 2.88 [0.12, 69.76]
5.2 Low dose 1 188 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]
6 Diarrhea 1 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
6.1 High dose 1 190 Risk Ratio (M-H, Fixed, 95% CI) 2.88 [0.12, 69.76]
6.2 Low dose 1 188 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]
7 Abdominal pain 1 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
7.1 High dose 1 190 Risk Ratio (M-H, Fixed, 95% CI) 0.57 [0.33, 0.98]
7.2 Low dose 1 188 Risk Ratio (M-H, Fixed, 95% CI) 0.65 [0.39, 1.10]
8 GI symptoms 2 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
8.1 High dose 0 0 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]
8.2 Low dose 2 520 Risk Ratio (M-H, Fixed, 95% CI) 0.59 [0.29, 1.19]
9 Flatulence 1 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
9.1 High dose 0 0 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]
9.2 Low dose 1 496 Risk Ratio (M-H, Fixed, 95% CI) 2.43 [1.03, 5.75]
10 Dyspepsia 2 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
10.1 High dose 0 0 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]
10.2 Low dose 2 520 Risk Ratio (M-H, Fixed, 95% CI) 0.59 [0.29, 1.19]
11 Rash 2 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
11.1 High dose 1 190 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]
11.2 Low dose 2 684 Risk Ratio (M-H, Fixed, 95% CI) 3.85 [1.20, 12.33]

Comparison 10. PPI vs placebo - 4 - 11 week studies

No. of No. of
Outcome or subgroup title studies participants Statistical method Effect size

1 Endoscopic gastric ulcer 1 43 Risk Ratio (M-H, Fixed, 95% CI) 0.14 [0.02, 1.02]
2 Endoscopic duodenal ulcer 1 43 Risk Ratio (M-H, Fixed, 95% CI) 0.48 [0.05, 4.88]
3 Total endoscopic ulcers 1 43 Risk Ratio (M-H, Fixed, 95% CI) 0.21 [0.05, 0.87]
4 Clinical Ulcer (POB) 1 43 Risk Ratio (M-H, Fixed, 95% CI) 0.11 [0.01, 1.86]
5 Clinical Ulcer - PUB (POB + 1 43 Odds Ratio (M-H, Fixed, 95% CI) 0.06 [0.01, 0.56]
symptomatic ulcer)

Comparison 11. PPI vs placebo - 8 weeks or longer studies

No. of No. of
Outcome or subgroup title studies participants Statistical method Effect size

1 Endoscopic gastric ulcer 6 1230 Risk Ratio (M-H, Fixed, 95% CI) 0.39 [0.31, 0.50]
2 Endoscopic duodenal ulcer 5 883 Risk Ratio (M-H, Fixed, 95% CI) 0.20 [0.10, 0.39]
3 Total endoscopic ulcers 6 1259 Risk Ratio (M-H, Fixed, 95% CI) 0.34 [0.28, 0.42]

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Comparison 12. PPI vs placebo - 12 weeks or longer studies

No. of No. of
Outcome or subgroup title studies participants Statistical method Effect size

1 Endoscopic gastric ulcer 5 1187 Risk Ratio (M-H, Fixed, 95% CI) 0.40 [0.32, 0.51]
2 Endoscopic duodenal ulcer 4 840 Risk Ratio (M-H, Fixed, 95% CI) 0.19 [0.09, 0.37]
3 Total endoscopic ulcers 5 1216 Risk Ratio (M-H, Fixed, 95% CI) 0.35 [0.28, 0.43]

Comparison 13. PPI vs placebo - toxicity

No. of No. of
Outcome or subgroup title studies participants Statistical method Effect size

1 Dropouts overall 2 833 Risk Ratio (M-H, Fixed, 95% CI) 0.89 [0.62, 1.29]
2 Dropouts due to side effects 4 1113 Risk Ratio (M-H, Fixed, 95% CI) 1.20 [0.66, 2.15]
3 Diarrhea 2 832 Risk Ratio (M-H, Fixed, 95% CI) 1.66 [0.85, 3.22]
4 Abdominal pain 2 832 Risk Ratio (M-H, Fixed, 95% CI) 0.88 [0.39, 1.98]
5 Flatulence 1 430 Risk Ratio (M-H, Fixed, 95% CI) 0.79 [0.25, 2.44]
6 Dyspepsia 2 345 Risk Ratio (M-H, Fixed, 95% CI) 0.50 [0.30, 0.82]

Comparison 14. PPI vs H2-antagonist - 12 weeks or longer studies

No. of No. of
Outcome or subgroup title studies participants Statistical method Effect size

1 Endoscopic gastric ulcers 1 425 Risk Ratio (M-H, Fixed, 95% CI) 0.32 [0.17, 0.62]
2 Endoscopic duodenal ulcers 1 425 Risk Ratio (M-H, Fixed, 95% CI) 0.11 [0.01, 0.89]
3 Total endoscopic ulcers 1 425 Risk Ratio (M-H, Fixed, 95% CI) 0.28 [0.15, 0.51]
4 Total clinical ulcers 1 425 Risk Ratio (M-H, Fixed, 95% CI) 3.07 [0.13, 74.96]
5 Toxicity- dropouts due to side 1 425 Risk Ratio (M-H, Fixed, 95% CI) 1.90 [0.77, 4.67]
effects
6 Vomiting 1 2 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]
7 Abdominal pain 1 2 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]
8 Diarrhea 1 2 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]

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Comparison 15. Misoprostol Vs PPI (as control) - 12 weeks or longer studies

No. of No. of
Outcome or subgroup title studies participants Statistical method Effect size

1 Endoscopic gastric ulcer 2 917 Risk Ratio (M-H, Random, 95% CI) 0.62 [0.33, 1.18]
2 Endoscopic duodenal ulcer 1 570 Risk Ratio (M-H, Fixed, 95% CI) 3.97 [1.77, 8.88]
3 Total endoscopic ulcers 4 1478 Risk Ratio (M-H, Random, 95% CI) 1.11 [0.58, 2.13]

Comparison 16. PPI Vs Misoprostol (as control) - 12 weeks or longer studies

No. of No. of
Outcome or subgroup title studies participants Statistical method Effect size

1 Endoscopic gastric ulcer 2 917 Risk Ratio (M-H, Random, 95% CI) 1.61 [0.85, 3.06]
2 Endoscopic duodenal ulcer 1 570 Risk Ratio (M-H, Fixed, 95% CI) 0.25 [0.11, 0.56]
3 Total endoscopic ulcers 4 1478 Risk Ratio (M-H, Random, 95% CI) 0.90 [0.47, 1.72]

Comparison 17. Misoprostol vs PPI - toxicity - 12 weeks or longer studies

No. of No. of
Outcome or subgroup title studies participants Statistical method Effect size

1 Dropouts overall 2 974 Risk Ratio (M-H, Fixed, 95% CI) 0.71 [0.52, 0.97]
2 Dropouts due to side effects 3 1019 Risk Ratio (M-H, Fixed, 95% CI) 0.48 [0.29, 0.78]

Comparison 18. Misoprostol vs ranitidine 150 mg bid - 1-2 month

No. of No. of
Outcome or subgroup title studies participants Statistical method Effect size

1 Endoscopic gastric ulcers 2 599 Risk Ratio (M-H, Fixed, 95% CI) 0.12 [0.03, 0.51]
2 Endoscopic duodenal ulcers 2 599 Risk Ratio (M-H, Fixed, 95% CI) 1.0 [0.14, 7.05]
3 Dropouts due to side effects 2 599 Risk Ratio (M-H, Fixed, 95% CI) 1.98 [1.16, 3.37]
4 Total endoscopic ulcers 1 538 Risk Ratio (M-H, Fixed, 95% CI) 0.23 [0.07, 0.80]
5 Dropouts overall 2 599 Risk Ratio (M-H, Fixed, 95% CI) 1.20 [0.94, 1.54]
6 Dropouts due to abdominal pain 1 538 Risk Ratio (M-H, Fixed, 95% CI) 3.0 [1.11, 8.14]
7 Dropouts due to nausea 1 538 Risk Ratio (M-H, Fixed, 95% CI) 3.67 [1.03, 13.00]
8 Dyspepsia 2 599 Risk Ratio (M-H, Random, 95% CI) 2.49 [0.39, 15.92]
9 Abdominal pain symptoms 1 538 Risk Ratio (M-H, Fixed, 95% CI) 1.24 [1.01, 1.52]
10 Flatulence symptoms 1 538 Risk Ratio (M-H, Fixed, 95% CI) 1.48 [1.10, 1.99]
11 Nausea symptoms 1 538 Risk Ratio (M-H, Fixed, 95% CI) 1.10 [0.81, 1.50]
12 Diarrhea symptoms 1 538 Risk Ratio (M-H, Fixed, 95% CI) 2.03 [1.38, 2.99]

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Comparison 19. Nizatidine 150 mg vs 300 mg efficacy

No. of No. of
Outcome or subgroup title studies participants Statistical method Effect size

1 Total endoscopic ulcers 1 237 Risk Ratio (M-H, Fixed, 95% CI) 2.88 [0.59, 13.96]
2 Dropouts overall 1 237 Risk Ratio (M-H, Fixed, 95% CI) 0.72 [0.26, 2.01]

Comparison 20. NSAID + PPI vs COX 2

No. of No. of
Outcome or subgroup title studies participants Statistical method Effect size

1 Clinical Ulcer (POB) 1 130 Odds Ratio (M-H, Fixed, 95% CI) 2.03 [0.49, 8.51]

Analysis 1.1. Comparison 1 Misoprostol vs placebo - primary efficacy, Outcome 1 Gastric ulcers - 4 - 11
week studies.
Review: Prevention of NSAID-induced gastroduodenal ulcers

Comparison: 1 Misoprostol vs placebo - primary efficacy

Outcome: 1 Gastric ulcers - 4 - 11 week studies

Study or subgroup Misoprostol Control Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
Saggioro 1991 0/82 4/84 6.5 % 0.11 [ 0.01, 2.08 ]

Chandresekaran 1991 0/45 4/45 6.6 % 0.11 [ 0.01, 2.01 ]

Bocanegra 1998 7/301 11/138 22.1 % 0.29 [ 0.12, 0.74 ]

Bolten 1992 0/178 3/183 5.0 % 0.15 [ 0.01, 2.82 ]

Delmas 1994 0/80 3/103 4.5 % 0.18 [ 0.01, 3.50 ]

Elliot 1994 1/40 7/43 9.9 % 0.15 [ 0.02, 1.19 ]

Graham 1988 1/140 17/138 25.0 % 0.06 [ 0.01, 0.43 ]

Melo Gomes 1993 3/216 14/217 20.4 % 0.22 [ 0.06, 0.74 ]

Total (95% CI) 1082 951 100.0 % 0.17 [ 0.09, 0.31 ]

Total events: 12 (Misoprostol), 63 (Control)
Heterogeneity: Chi2 = 2.76, df = 7 (P = 0.91); I2 =0.0%
Test for overall effect: Z = 5.79 (P < 0.00001)
Test for subgroup differences: Not applicable

0.001 0.01 0.1 1 10 100 1000

Favours Misoprostol Favours Control

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 Analysis 1.2. Comparison 1 Misoprostol vs placebo - primary efficacy, Outcome 2 Duodenal ulcers - 4 - 11
week studies.
Review: Prevention of NSAID-induced gastroduodenal ulcers

Comparison: 1 Misoprostol vs placebo - primary efficacy

Outcome: 2 Duodenal ulcers - 4 - 11 week studies

Study or subgroup Misoprostol Control Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
Chandresekaran 1991 0/45 2/45 8.5 % 0.20 [ 0.01, 4.05 ]

Bocanegra 1998 9/301 7/138 32.8 % 0.59 [ 0.22, 1.55 ]

Bolten 1992 0/178 3/183 11.8 % 0.15 [ 0.01, 2.82 ]

Delmas 1994 1/80 2/103 6.0 % 0.64 [ 0.06, 6.97 ]

Henriksson 1993 0/20 1/20 5.1 % 0.33 [ 0.01, 7.72 ]

Melo Gomes 1993 0/216 10/217 35.8 % 0.05 [ 0.00, 0.81 ]

Total (95% CI) 840 706 100.0 % 0.30 [ 0.14, 0.62 ]

Total events: 10 (Misoprostol), 25 (Control)
Heterogeneity: Chi2 = 4.18, df = 5 (P = 0.52); I2 =0.0%
Test for overall effect: Z = 3.22 (P = 0.0013)
Test for subgroup differences: Not applicable

0.002 0.1 1 10 500

Favours Misoprostol Favours Control

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 Analysis 1.3. Comparison 1 Misoprostol vs placebo - primary efficacy, Outcome 3 Total ulcers - 4 - 11 week
studies.
Review: Prevention of NSAID-induced gastroduodenal ulcers

Comparison: 1 Misoprostol vs placebo - primary efficacy

Outcome: 3 Total ulcers - 4 - 11 week studies

Study or subgroup Misoprostol Control Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
Chandresekaran 1991 0/45 5/45 9.8 % 0.09 [ 0.01, 1.60 ]

Bocanegra 1998 15/301 17/138 41.5 % 0.40 [ 0.21, 0.79 ]

Bolten 1992 0/178 6/183 11.4 % 0.08 [ 0.00, 1.39 ]

Melo Gomes 1993 3/216 21/217 37.3 % 0.14 [ 0.04, 0.47 ]

Total (95% CI) 740 583 100.0 % 0.24 [ 0.14, 0.42 ]

Total events: 18 (Misoprostol), 49 (Control)
Heterogeneity: Chi2 = 4.11, df = 3 (P = 0.25); I2 =27%
Test for overall effect: Z = 5.01 (P < 0.00001)
Test for subgroup differences: Not applicable

0.005 0.1 1 10 200

Favours Misoprostol Favours Control

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 Analysis 1.4. Comparison 1 Misoprostol vs placebo - primary efficacy, Outcome 4 Gastric ulcers - 12 weeks
or longer studies.

Review: Prevention of NSAID-induced gastroduodenal ulcers

Comparison: 1 Misoprostol vs placebo - primary efficacy

Outcome: 4 Gastric ulcers - 12 weeks or longer studies

Study or subgroup Misoprostol Control Risk Ratio Weight Risk Ratio

M- M-
H,Random,95% H,Random,95%
n/N n/N CI CI
Agrawal 1991 2/179 21/177 5.9 % 0.09 [ 0.02, 0.40 ]

Graham 1993 6/320 25/323 10.9 % 0.24 [ 0.10, 0.58 ]

Verdickt 1992 4/164 6/175 7.2 % 0.71 [ 0.20, 2.48 ]

Elliot 1994 4/40 11/43 8.9 % 0.39 [ 0.14, 1.13 ]

Raskin 1995 6/228 51/454 11.5 % 0.23 [ 0.10, 0.54 ]

Agrawal 1995 6/193 20/191 10.7 % 0.30 [ 0.12, 0.72 ]

Chan 2001a 4/45 2/45 4.8 % 2.00 [ 0.39, 10.38 ]

Graham 1988 2/140 30/138 6.1 % 0.07 [ 0.02, 0.27 ]

Graham 2002 9/111 54/111 14.0 % 0.17 [ 0.09, 0.32 ]

Hawkey 1998 31/296 50/155 18.1 % 0.32 [ 0.22, 0.49 ]

Roth 1993 0/60 7/53 1.9 % 0.06 [ 0.00, 1.01 ]

Total (95% CI) 1776 1865 100.0 % 0.26 [ 0.17, 0.39 ]

Total events: 74 (Misoprostol), 277 (Control)
Heterogeneity: Tau2 = 0.20; Chi2 = 19.33, df = 10 (P = 0.04); I2 =48%
Test for overall effect: Z = 6.42 (P < 0.00001)
Test for subgroup differences: Not applicable

0.005 0.1 1 10 200

Favours Misoprostol Favours Control

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 Analysis 1.5. Comparison 1 Misoprostol vs placebo - primary efficacy, Outcome 5 Duodenal ulcers - 12
weeks or longer studies.

Review: Prevention of NSAID-induced gastroduodenal ulcers

Comparison: 1 Misoprostol vs placebo - primary efficacy

Outcome: 5 Duodenal ulcers - 12 weeks or longer studies

Study or subgroup Misoprostol Control Risk Ratio Weight Risk Ratio

M- M-
H,Random,95% H,Random,95%
n/N n/N CI CI
Verdickt 1992 2/164 12/175 12.4 % 0.18 [ 0.04, 0.78 ]

Graham 1993 2/320 15/323 12.5 % 0.13 [ 0.03, 0.58 ]

Elliot 1994 1/40 0/43 3.8 % 3.22 [ 0.13, 76.82 ]

Raskin 1995 2/228 23/454 12.9 % 0.17 [ 0.04, 0.73 ]

Agrawal 1995 9/193 15/191 22.4 % 0.59 [ 0.27, 1.32 ]

Chan 2001a 1/45 1/45 4.9 % 1.00 [ 0.06, 15.50 ]

Hawkey 1998 30/296 19/155 27.4 % 0.83 [ 0.48, 1.42 ]

Roth 1993 0/60 1/53 3.8 % 0.30 [ 0.01, 7.09 ]

Total (95% CI) 1346 1439 100.0 % 0.42 [ 0.22, 0.81 ]

Total events: 47 (Misoprostol), 86 (Control)
Heterogeneity: Tau2 = 0.33; Chi2 = 12.74, df = 7 (P = 0.08); I2 =45%
Test for overall effect: Z = 2.58 (P = 0.010)
Test for subgroup differences: Not applicable

0.01 0.1 1 10 100

Favours Misoprostol Favours Control

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 Analysis 1.6. Comparison 1 Misoprostol vs placebo - primary efficacy, Outcome 6 Total endoscopic ulcers -
12 weeks or longer studies.

Review: Prevention of NSAID-induced gastroduodenal ulcers

Comparison: 1 Misoprostol vs placebo - primary efficacy

Outcome: 6 Total endoscopic ulcers - 12 weeks or longer studies

Study or subgroup Misoprostol Control Risk Ratio Weight Risk Ratio

M- M-
H,Random,95% H,Random,95%
n/N n/N CI CI
Verdickt 1992 6/164 17/175 17.1 % 0.38 [ 0.15, 0.93 ]

Graham 1993 8/320 37/323 20.2 % 0.22 [ 0.10, 0.46 ]

Agrawal 1995 15/193 32/191 24.0 % 0.46 [ 0.26, 0.83 ]

Chan 2001a 5/45 3/45 10.6 % 1.67 [ 0.42, 6.56 ]

Graham 2002 13/111 58/111 24.8 % 0.22 [ 0.13, 0.38 ]

Roth 1993 0/60 8/53 3.3 % 0.05 [ 0.00, 0.88 ]

Total (95% CI) 893 898 100.0 % 0.34 [ 0.20, 0.59 ]

Total events: 47 (Misoprostol), 155 (Control)
Heterogeneity: Tau2 = 0.23; Chi2 = 11.61, df = 5 (P = 0.04); I2 =57%
Test for overall effect: Z = 3.90 (P = 0.000097)
Test for subgroup differences: Not applicable

0.002 0.1 1 10 500

Favours Misoprostol Favours Control

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 Analysis 1.7. Comparison 1 Misoprostol vs placebo - primary efficacy, Outcome 7 Total endoscopic ulcers
Chan 2001 removed - 12 weeks or longer studies.

Review: Prevention of NSAID-induced gastroduodenal ulcers

Comparison: 1 Misoprostol vs placebo - primary efficacy

Outcome: 7 Total endoscopic ulcers Chan 2001 removed - 12 weeks or longer studies

Study or subgroup Misoprostol Control Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

Agrawal 1995 15/193 32/191 21.1 % 0.46 [ 0.26, 0.83 ]

Graham 2002 13/111 58/111 38.0 % 0.22 [ 0.13, 0.38 ]

Verdickt 1992 6/164 17/175 10.8 % 0.38 [ 0.15, 0.93 ]

Roth 1993 0/60 8/53 5.9 % 0.05 [ 0.00, 0.88 ]

Graham 1993 8/320 37/323 24.2 % 0.22 [ 0.10, 0.46 ]

Total (95% CI) 848 853 100.0 % 0.28 [ 0.20, 0.38 ]

Total events: 42 (Misoprostol), 152 (Control)
Heterogeneity: Chi2 = 5.76, df = 4 (P = 0.22); I2 =31%
Test for overall effect: Z = 7.81 (P < 0.00001)
Test for subgroup differences: Not applicable

0.005 0.1 1 10 200

Favours Misoprostol Favours Control

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 Analysis 1.8. Comparison 1 Misoprostol vs placebo - primary efficacy, Outcome 8 Clinical ulcers - 12 weeks
or longer studies.

Review: Prevention of NSAID-induced gastroduodenal ulcers

Comparison: 1 Misoprostol vs placebo - primary efficacy

Outcome: 8 Clinical ulcers - 12 weeks or longer studies

Study or subgroup Misoprostol Control Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
Melo Gomes 1993 0/216 1/217 4.4 % 0.33 [ 0.01, 8.17 ]

Silverstein 1995 16/4404 33/4439 95.6 % 0.49 [ 0.27, 0.89 ]

Total (95% CI) 4620 4656 100.0 % 0.48 [ 0.27, 0.87 ]

Total events: 16 (Misoprostol), 34 (Control)
Heterogeneity: Chi2 = 0.05, df = 1 (P = 0.82); I2 =0.0%
Test for overall effect: Z = 2.44 (P = 0.015)
Test for subgroup differences: Not applicable

0.01 0.1 1 10 100

Favours Misoprostol Favours Control

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 Analysis 2.1. Comparison 2 Misoprostol vs placebo - toxicity causing withdrawal, Outcome 1 Nausea.

Review: Prevention of NSAID-induced gastroduodenal ulcers

Comparison: 2 Misoprostol vs placebo - toxicity causing withdrawal

Outcome: 1 Nausea

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

Agrawal 1991 3/179 1/177 0.4 % 2.97 [ 0.31, 28.25 ]

Graham 1993 7/320 6/323 2.6 % 1.18 [ 0.40, 3.47 ]

Raskin 1995 67/228 86/454 24.6 % 1.55 [ 1.18, 2.05 ]

Agrawal 1995 0/193 2/191 1.1 % 0.20 [ 0.01, 4.10 ]

Roth 1993 2/60 1/53 0.5 % 1.77 [ 0.16, 18.93 ]

Silverstein 1995 192/4404 166/4439 70.8 % 1.17 [ 0.95, 1.43 ]

Total (95% CI) 5384 5637 100.0 % 1.26 [ 1.07, 1.48 ]

Total events: 271 (Treatment), 262 (Control)
Heterogeneity: Chi2 = 4.80, df = 5 (P = 0.44); I2 =0.0%
Test for overall effect: Z = 2.81 (P = 0.0050)
Test for subgroup differences: Not applicable

0.01 0.1 1 10 100

Favours Treatment Favours Control

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 Analysis 2.2. Comparison 2 Misoprostol vs placebo - toxicity causing withdrawal, Outcome 2 Dyspepsia.

Review: Prevention of NSAID-induced gastroduodenal ulcers

Comparison: 2 Misoprostol vs placebo - toxicity causing withdrawal

Outcome: 2 Dyspepsia

Study or subgroup Treatment Control Risk Ratio Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

Agrawal 1991 15/179 10/177 1.48 [ 0.68, 3.21 ]

Saggioro 1991 3/82 1/84 3.07 [ 0.33, 28.94 ]

Chandresekaran 1991 11/45 13/45 0.85 [ 0.43, 1.68 ]

Raskin 1995 8/228 13/454 1.23 [ 0.52, 2.91 ]

Agrawal 1995 0/193 0/191 0.0 [ 0.0, 0.0 ]

Roth 1993 1/60 0/53 2.66 [ 0.11, 63.84 ]

Silverstein 1995 202/4404 182/4439 1.12 [ 0.92, 1.36 ]

Total (95% CI) 5191 5443 1.14 [ 0.95, 1.36 ]

Total events: 240 (Treatment), 219 (Control)
Heterogeneity: Chi2 = 2.24, df = 5 (P = 0.81); I2 =0.0%
Test for overall effect: Z = 1.41 (P = 0.16)
Test for subgroup differences: Not applicable

0.2 0.5 1 2 5
Favours Treatment Favours Control

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 Analysis 2.3. Comparison 2 Misoprostol vs placebo - toxicity causing withdrawal, Outcome 3 Constipation.

Review: Prevention of NSAID-induced gastroduodenal ulcers

Comparison: 2 Misoprostol vs placebo - toxicity causing withdrawal

Outcome: 3 Constipation

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
Agrawal 1991 1/179 1/177 2.7 % 0.99 [ 0.06, 15.69 ]

Silverstein 1995 23/4404 37/4439 97.3 % 0.63 [ 0.37, 1.05 ]

Total (95% CI) 4583 4616 100.0 % 0.64 [ 0.38, 1.06 ]

Total events: 24 (Treatment), 38 (Control)
Heterogeneity: Chi2 = 0.10, df = 1 (P = 0.75); I2 =0.0%
Test for overall effect: Z = 1.74 (P = 0.082)
Test for subgroup differences: Not applicable

0.1 0.2 0.5 1 2 5 10

Favours Treatment Favours Control

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 Analysis 2.4. Comparison 2 Misoprostol vs placebo - toxicity causing withdrawal, Outcome 4 Diarrhea.

Review: Prevention of NSAID-induced gastroduodenal ulcers

Comparison: 2 Misoprostol vs placebo - toxicity causing withdrawal

Outcome: 4 Diarrhea

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

Agrawal 1991 5/179 1/177 0.5 % 4.94 [ 0.58, 41.89 ]

Graham 1993 2/320 3/323 1.5 % 0.67 [ 0.11, 4.00 ]

Saggioro 1991 2/82 0/84 0.2 % 5.12 [ 0.25, 105.06 ]

Elliot 1994 5/40 1/43 0.5 % 5.38 [ 0.66, 44.04 ]

Chandresekaran 1991 0/45 1/45 0.7 % 0.33 [ 0.01, 7.97 ]

Raskin 1995 8/228 6/454 2.0 % 2.65 [ 0.93, 7.56 ]

Agrawal 1995 0/193 3/191 1.8 % 0.14 [ 0.01, 2.72 ]

Melo Gomes 1993 3/216 0/217 0.2 % 7.03 [ 0.37, 135.33 ]

Roth 1993 3/60 1/53 0.5 % 2.65 [ 0.28, 24.71 ]

Silverstein 1995 438/4404 185/4439 92.0 % 2.39 [ 2.02, 2.82 ]

Total (95% CI) 5767 6026 100.0 % 2.36 [ 2.01, 2.77 ]

Total events: 466 (Treatment), 201 (Control)
Heterogeneity: Chi2 = 8.75, df = 9 (P = 0.46); I2 =0.0%
Test for overall effect: Z = 10.50 (P < 0.00001)
Test for subgroup differences: Not applicable

0.01 0.1 1 10 100

Favours Treatment Favours Control

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 Analysis 2.5. Comparison 2 Misoprostol vs placebo - toxicity causing withdrawal, Outcome 5 Abdominal
pain.

Review: Prevention of NSAID-induced gastroduodenal ulcers

Comparison: 2 Misoprostol vs placebo - toxicity causing withdrawal

Outcome: 5 Abdominal pain

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
Graham 1993 6/320 5/323 1.5 % 1.21 [ 0.37, 3.93 ]

Raskin 1995 112/228 168/454 33.1 % 1.33 [ 1.11, 1.59 ]

Agrawal 1995 11/193 4/191 1.2 % 2.72 [ 0.88, 8.40 ]

Melo Gomes 1993 8/216 3/217 0.9 % 2.68 [ 0.72, 9.96 ]

Roth 1993 4/60 2/53 0.6 % 1.77 [ 0.34, 9.26 ]

Silverstein 1995 284/4404 214/4439 62.8 % 1.34 [ 1.13, 1.59 ]

Total (95% CI) 5421 5677 100.0 % 1.36 [ 1.20, 1.55 ]

Total events: 425 (Treatment), 396 (Control)
Heterogeneity: Chi2 = 2.73, df = 5 (P = 0.74); I2 =0.0%
Test for overall effect: Z = 4.82 (P < 0.00001)
Test for subgroup differences: Not applicable

0.1 0.2 0.5 1 2 5 10

Favours Treatment Favours Control

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 Analysis 2.6. Comparison 2 Misoprostol vs placebo - toxicity causing withdrawal, Outcome 6 Flatulence.

Review: Prevention of NSAID-induced gastroduodenal ulcers

Comparison: 2 Misoprostol vs placebo - toxicity causing withdrawal

Outcome: 6 Flatulence

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio

M- M-
H,Random,95% H,Random,95%
n/N n/N CI CI
Raskin 1995 11/228 4/454 33.7 % 5.48 [ 1.76, 17.01 ]

Roth 1993 1/60 0/53 8.4 % 2.66 [ 0.11, 63.84 ]

Silverstein 1995 183/4404 121/4439 57.9 % 1.52 [ 1.22, 1.91 ]

Total (95% CI) 4692 4946 100.0 % 2.46 [ 0.91, 6.65 ]

Total events: 195 (Treatment), 125 (Control)
Heterogeneity: Tau2 = 0.43; Chi2 = 4.80, df = 2 (P = 0.09); I2 =58%
Test for overall effect: Z = 1.77 (P = 0.077)
Test for subgroup differences: Not applicable

0.02 0.1 1 10 50
Favours Treatment Favours Control

Analysis 2.7. Comparison 2 Misoprostol vs placebo - toxicity causing withdrawal, Outcome 7 Vomiting.

Review: Prevention of NSAID-induced gastroduodenal ulcers

Comparison: 2 Misoprostol vs placebo - toxicity causing withdrawal

Outcome: 7 Vomiting

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio

M- M-
H,Random,95% H,Random,95%
n/N n/N CI CI
Raskin 1995 4/228 2/454 42.2 % 3.98 [ 0.73, 21.58 ]

Silverstein 1995 5/4404 6/4439 57.8 % 0.84 [ 0.26, 2.75 ]

Total (95% CI) 4632 4893 100.0 % 1.62 [ 0.36, 7.31 ]

Total events: 9 (Treatment), 8 (Control)
Heterogeneity: Tau2 = 0.66; Chi2 = 2.18, df = 1 (P = 0.14); I2 =54%
Test for overall effect: Z = 0.63 (P = 0.53)
Test for subgroup differences: Not applicable

0.05 0.2 1 5 20
Favours Treatment Favours Control

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 Analysis 2.8. Comparison 2 Misoprostol vs placebo - toxicity causing withdrawal, Outcome 8 Drop-outs due
to side-effects.
Review: Prevention of NSAID-induced gastroduodenal ulcers

Comparison: 2 Misoprostol vs placebo - toxicity causing withdrawal

Outcome: 8 Drop-outs due to side-effects

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
Agrawal 1991 31/179 16/177 1.6 % 1.92 [ 1.09, 3.38 ]

Saggioro 1991 6/82 1/84 0.1 % 6.15 [ 0.76, 49.94 ]

Verdickt 1992 18/164 15/175 1.4 % 1.28 [ 0.67, 2.46 ]

Elliot 1994 5/40 1/43 0.1 % 5.38 [ 0.66, 44.04 ]

Raskin 1995 46/228 49/454 3.2 % 1.87 [ 1.29, 2.71 ]

Agrawal 1995 11/193 9/191 0.9 % 1.21 [ 0.51, 2.85 ]

Delmas 1994 10/80 6/103 0.5 % 2.15 [ 0.81, 5.66 ]

Graham 1988 27/140 26/138 2.6 % 1.02 [ 0.63, 1.66 ]

Graham 2002 14/134 9/134 0.9 % 1.56 [ 0.70, 3.47 ]

Hawkey 1998 23/296 3/155 0.4 % 4.01 [ 1.22, 13.16 ]

Roth 1993 18/60 7/53 0.7 % 2.27 [ 1.03, 5.01 ]

Silverstein 1995 1210/4404 896/4439 87.6 % 1.36 [ 1.26, 1.47 ]

Total (95% CI) 6000 6146 100.0 % 1.41 [ 1.31, 1.51 ]

Total events: 1419 (Treatment), 1038 (Control)
Heterogeneity: Chi2 = 14.65, df = 11 (P = 0.20); I2 =25%
Test for overall effect: Z = 9.42 (P < 0.00001)
Test for subgroup differences: Not applicable

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 Analysis 2.9. Comparison 2 Misoprostol vs placebo - toxicity causing withdrawal, Outcome 9 Drop-outs
overall.
Review: Prevention of NSAID-induced gastroduodenal ulcers

Comparison: 2 Misoprostol vs placebo - toxicity causing withdrawal

Outcome: 9 Drop-outs overall

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio

M- M-
H,Random,95% H,Random,95%
n/N n/N CI CI
Agrawal 1991 57/179 46/177 8.6 % 1.23 [ 0.88, 1.70 ]

Verdickt 1992 32/164 31/175 7.7 % 1.10 [ 0.71, 1.72 ]

Graham 1993 105/320 83/323 9.2 % 1.28 [ 1.00, 1.63 ]

Saggioro 1991 9/82 4/84 3.4 % 2.30 [ 0.74, 7.19 ]

Elliot 1994 13/40 5/43 4.3 % 2.80 [ 1.09, 7.14 ]

Raskin 1995 74/228 15/454 7.0 % 9.82 [ 5.77, 16.72 ]

Bolten 1992 16/178 16/183 6.0 % 1.03 [ 0.53, 1.99 ]

Delmas 1994 31/80 16/103 7.0 % 2.49 [ 1.47, 4.23 ]

Graham 1988 41/140 42/138 8.4 % 0.96 [ 0.67, 1.38 ]

Graham 2002 23/134 23/134 7.1 % 1.00 [ 0.59, 1.69 ]

Hawkey 1998 50/296 16/155 7.0 % 1.64 [ 0.96, 2.78 ]

Henriksson 1993 1/20 0/20 0.6 % 3.00 [ 0.13, 69.52 ]

Melo Gomes 1993 23/216 17/217 6.5 % 1.36 [ 0.75, 2.47 ]

Roth 1993 15/60 28/53 7.2 % 0.47 [ 0.29, 0.79 ]

Silverstein 1995 1851/4404 1617/4439 10.0 % 1.15 [ 1.10, 1.22 ]

Total (95% CI) 6541 6698 100.0 % 1.44 [ 1.11, 1.86 ]

Total events: 2341 (Treatment), 1959 (Control)
Heterogeneity: Tau2 = 0.17; Chi2 = 91.90, df = 14 (P<0.00001); I2 =85%
Test for overall effect: Z = 2.78 (P = 0.0055)
Test for subgroup differences: Not applicable

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 Analysis 3.1. Comparison 3 Misoprostol vs placebo - toxicity symptoms only, Outcome 1 Nausea.

Review: Prevention of NSAID-induced gastroduodenal ulcers

Comparison: 3 Misoprostol vs placebo - toxicity symptoms only

Outcome: 1 Nausea

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio

M- M-
H,Random,95% H,Random,95%
n/N n/N CI CI
Agrawal 1991 9/179 18/177 11.5 % 0.49 [ 0.23, 1.07 ]

Saggioro 1991 9/82 15/84 11.5 % 0.61 [ 0.29, 1.33 ]

Verdickt 1992 18/164 5/175 10.2 % 3.84 [ 1.46, 10.11 ]

Agrawal 1995 11/193 6/191 10.1 % 1.81 [ 0.68, 4.81 ]

Bolten 1992 19/178 2/183 7.4 % 9.77 [ 2.31, 41.32 ]

Delmas 1994 12/80 31/103 12.6 % 0.50 [ 0.27, 0.91 ]

Graham 1988 22/140 21/138 12.9 % 1.03 [ 0.60, 1.79 ]

Graham 2002 6/111 0/111 3.0 % 13.00 [ 0.74, 228.02 ]

Melo Gomes 1993 18/216 11/217 11.8 % 1.64 [ 0.80, 3.40 ]

Roth 1993 9/60 4/53 9.2 % 1.99 [ 0.65, 6.08 ]

Total (95% CI) 1403 1432 100.0 % 1.41 [ 0.81, 2.45 ]

Total events: 133 (Treatment), 113 (Control)
Heterogeneity: Tau2 = 0.54; Chi2 = 35.41, df = 9 (P = 0.00005); I2 =75%
Test for overall effect: Z = 1.22 (P = 0.22)
Test for subgroup differences: Not applicable

0.05 0.2 1 5 20
Favours Treatment Favours Control

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 Analysis 3.2. Comparison 3 Misoprostol vs placebo - toxicity symptoms only, Outcome 2 Dyspepsia.

Review: Prevention of NSAID-induced gastroduodenal ulcers

Comparison: 3 Misoprostol vs placebo - toxicity symptoms only

Outcome: 2 Dyspepsia

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio

M- M-
H,Random,95% H,Random,95%
n/N n/N CI CI
Agrawal 1991 55/179 42/177 13.4 % 1.29 [ 0.92, 1.83 ]

Verdickt 1992 18/164 12/175 9.2 % 1.60 [ 0.80, 3.22 ]

Saggioro 1991 24/82 46/84 12.9 % 0.53 [ 0.36, 0.79 ]

Elliot 1994 21/40 10/43 10.1 % 2.26 [ 1.22, 4.19 ]

Agrawal 1995 18/193 9/191 8.4 % 1.98 [ 0.91, 4.30 ]

Bolten 1992 16/178 8/183 7.9 % 2.06 [ 0.90, 4.68 ]

Delmas 1994 12/80 18/103 9.5 % 0.86 [ 0.44, 1.68 ]

Graham 1988 23/140 18/138 10.7 % 1.26 [ 0.71, 2.23 ]

Melo Gomes 1993 18/216 25/217 10.6 % 0.72 [ 0.41, 1.29 ]

Roth 1993 8/60 8/53 7.2 % 0.88 [ 0.36, 2.19 ]

Total (95% CI) 1332 1364 100.0 % 1.17 [ 0.85, 1.63 ]

Total events: 213 (Treatment), 196 (Control)
Heterogeneity: Tau2 = 0.18; Chi2 = 27.93, df = 9 (P = 0.00098); I2 =68%
Test for overall effect: Z = 0.96 (P = 0.34)
Test for subgroup differences: Not applicable

0.2 0.5 1 2 5
Favours Treatment Favours Control

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 Analysis 3.3. Comparison 3 Misoprostol vs placebo - toxicity symptoms only, Outcome 3 Constipation.

Review: Prevention of NSAID-induced gastroduodenal ulcers

Comparison: 3 Misoprostol vs placebo - toxicity symptoms only

Outcome: 3 Constipation

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
Agrawal 1991 5/179 8/177 79.1 % 0.62 [ 0.21, 1.85 ]

Roth 1993 1/60 2/53 20.9 % 0.44 [ 0.04, 4.73 ]

Total (95% CI) 239 230 100.0 % 0.58 [ 0.22, 1.57 ]

Total events: 6 (Treatment), 10 (Control)
Heterogeneity: Chi2 = 0.06, df = 1 (P = 0.80); I2 =0.0%
Test for overall effect: Z = 1.07 (P = 0.28)
Test for subgroup differences: Not applicable

0.05 0.2 1 5 20
Favours Treatment Favours Control

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 Analysis 3.4. Comparison 3 Misoprostol vs placebo - toxicity symptoms only, Outcome 4 Diarrhea.

Review: Prevention of NSAID-induced gastroduodenal ulcers

Comparison: 3 Misoprostol vs placebo - toxicity symptoms only

Outcome: 4 Diarrhea

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio

M- M-
H,Random,95% H,Random,95%
n/N n/N CI CI
Agrawal 1991 45/179 9/177 9.5 % 4.94 [ 2.49, 9.81 ]

Saggioro 1991 7/82 0/84 1.1 % 15.36 [ 0.89, 264.69 ]

Verdickt 1992 30/164 18/175 11.4 % 1.78 [ 1.03, 3.06 ]

Elliot 1994 8/40 5/43 6.0 % 1.72 [ 0.61, 4.82 ]

Agrawal 1995 19/193 14/191 9.8 % 1.34 [ 0.69, 2.60 ]

Bolten 1992 32/178 22/183 12.0 % 1.50 [ 0.91, 2.47 ]

Delmas 1994 8/80 5/103 5.7 % 2.06 [ 0.70, 6.06 ]

Graham 1988 54/140 18/138 12.4 % 2.96 [ 1.83, 4.77 ]

Graham 2002 29/111 4/111 6.2 % 7.25 [ 2.64, 19.94 ]

Hawkey 1998 25/296 7/155 8.0 % 1.87 [ 0.83, 4.23 ]

Henriksson 1993 1/20 0/20 0.9 % 3.00 [ 0.13, 69.52 ]

Melo Gomes 1993 39/216 12/217 10.4 % 3.27 [ 1.76, 6.06 ]

Roth 1993 26/60 4/53 6.4 % 5.74 [ 2.14, 15.39 ]

Total (95% CI) 1759 1650 100.0 % 2.59 [ 1.89, 3.55 ]

Total events: 323 (Treatment), 118 (Control)
Heterogeneity: Tau2 = 0.15; Chi2 = 24.11, df = 12 (P = 0.02); I2 =50%
Test for overall effect: Z = 5.95 (P < 0.00001)
Test for subgroup differences: Not applicable

0.005 0.1 1 10 200

Favours Treatment Favours Control

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 Analysis 3.5. Comparison 3 Misoprostol vs placebo - toxicity symptoms only, Outcome 5 Abdominal pain.

Review: Prevention of NSAID-induced gastroduodenal ulcers

Comparison: 3 Misoprostol vs placebo - toxicity symptoms only

Outcome: 5 Abdominal pain

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio

M- M-
H,Random,95% H,Random,95%
n/N n/N CI CI
Verdickt 1992 31/164 44/175 16.4 % 0.75 [ 0.50, 1.13 ]

Agrawal 1995 23/193 15/191 12.1 % 1.52 [ 0.82, 2.82 ]

Bolten 1992 57/178 34/183 17.2 % 1.72 [ 1.19, 2.50 ]

Graham 1988 25/140 25/138 14.4 % 0.99 [ 0.60, 1.63 ]

Graham 2002 8/111 0/111 1.2 % 17.00 [ 0.99, 291.00 ]

Hawkey 1998 14/296 9/155 9.1 % 0.81 [ 0.36, 1.84 ]

Henriksson 1993 8/20 1/20 2.3 % 8.00 [ 1.10, 58.19 ]

Melo Gomes 1993 45/216 34/217 16.5 % 1.33 [ 0.89, 1.99 ]

Roth 1993 12/60 13/53 10.9 % 0.82 [ 0.41, 1.63 ]

Total (95% CI) 1378 1243 100.0 % 1.20 [ 0.87, 1.65 ]

Total events: 223 (Treatment), 175 (Control)
Heterogeneity: Tau2 = 0.12; Chi2 = 19.24, df = 8 (P = 0.01); I2 =58%
Test for overall effect: Z = 1.13 (P = 0.26)
Test for subgroup differences: Not applicable

0.005 0.1 1 10 200

Favours Treatment Favours Control

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 Analysis 3.6. Comparison 3 Misoprostol vs placebo - toxicity symptoms only, Outcome 6 Flatulence.

Review: Prevention of NSAID-induced gastroduodenal ulcers

Comparison: 3 Misoprostol vs placebo - toxicity symptoms only

Outcome: 6 Flatulence

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
Verdickt 1992 10/164 16/175 29.5 % 0.67 [ 0.31, 1.43 ]

Bolten 1992 16/178 6/183 11.3 % 2.74 [ 1.10, 6.85 ]

Graham 1988 25/140 19/138 36.5 % 1.30 [ 0.75, 2.24 ]

Hawkey 1998 10/296 5/155 12.5 % 1.05 [ 0.36, 3.01 ]

Roth 1993 14/60 5/53 10.1 % 2.47 [ 0.95, 6.41 ]

Total (95% CI) 838 704 100.0 % 1.36 [ 0.97, 1.91 ]

Total events: 75 (Treatment), 51 (Control)
Heterogeneity: Chi2 = 7.40, df = 4 (P = 0.12); I2 =46%
Test for overall effect: Z = 1.79 (P = 0.074)
Test for subgroup differences: Not applicable

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 Analysis 4.1. Comparison 4 Misoprostol vs placebo - efficacy by dosage, Outcome 1 Gastric ulcers - 1 month.

Review: Prevention of NSAID-induced gastroduodenal ulcers

Comparison: 4 Misoprostol vs placebo - efficacy by dosage

Outcome: 1 Gastric ulcers - 1 month

Study or subgroup Misoprostol Control Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 Low dose (400-600 ug)

Bocanegra 1998 4/159 11/138 23.8 % 0.32 [ 0.10, 0.97 ]

Bolten 1992 0/178 3/183 7.0 % 0.15 [ 0.01, 2.82 ]

Delmas 1994 0/80 3/103 6.2 % 0.18 [ 0.01, 3.50 ]

Graham 1988 3/143 17/138 34.9 % 0.17 [ 0.05, 0.57 ]

Melo Gomes 1993 3/216 14/217 28.2 % 0.22 [ 0.06, 0.74 ]

Subtotal (95% CI) 776 779 100.0 % 0.22 [ 0.11, 0.41 ]

Total events: 10 (Misoprostol), 48 (Control)
Heterogeneity: Chi2 = 0.66, df = 4 (P = 0.96); I2 =0.0%
Test for overall effect: Z = 4.63 (P < 0.00001)
2 Mid-range dose (600 ug)
Bocanegra 1998 3/142 11/138 71.3 % 0.27 [ 0.08, 0.93 ]

Chandresekaran 1991 0/45 4/45 28.7 % 0.11 [ 0.01, 2.01 ]

Subtotal (95% CI) 187 183 100.0 % 0.22 [ 0.07, 0.69 ]

Total events: 3 (Misoprostol), 15 (Control)
Heterogeneity: Chi2 = 0.30, df = 1 (P = 0.59); I2 =0.0%
Test for overall effect: Z = 2.59 (P = 0.0096)
3 High dose (800 ug)
Delmas 1994 0/80 3/103 9.8 % 0.18 [ 0.01, 3.50 ]

Elliot 1994 1/40 7/43 21.5 % 0.15 [ 0.02, 1.19 ]

Graham 1988 1/140 17/138 54.6 % 0.06 [ 0.01, 0.43 ]

Saggioro 1991 0/82 4/84 14.2 % 0.11 [ 0.01, 2.08 ]

Subtotal (95% CI) 342 368 100.0 % 0.10 [ 0.03, 0.32 ]

Total events: 2 (Misoprostol), 31 (Control)
Heterogeneity: Chi2 = 0.63, df = 3 (P = 0.89); I2 =0.0%
Test for overall effect: Z = 3.90 (P = 0.000096)

0.005 0.1 1 10 200

Favours Misoprostol Favours Control

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 Analysis 4.2. Comparison 4 Misoprostol vs placebo - efficacy by dosage, Outcome 2 Duodenal ulcers - 1
month.
Review: Prevention of NSAID-induced gastroduodenal ulcers

Comparison: 4 Misoprostol vs placebo - efficacy by dosage

Outcome: 2 Duodenal ulcers - 1 month

Study or subgroup Misoprostol Control Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 Low dose (400-600 ug)

Bocanegra 1998 3/159 7/138 32.3 % 0.37 [ 0.10, 1.41 ]

Bolten 1992 0/178 3/183 14.9 % 0.15 [ 0.01, 2.82 ]

Delmas 1994 1/80 2/103 7.5 % 0.64 [ 0.06, 6.97 ]

Melo Gomes 1993 0/216 10/217 45.2 % 0.05 [ 0.00, 0.81 ]

Subtotal (95% CI) 633 641 100.0 % 0.21 [ 0.08, 0.56 ]

Total events: 4 (Misoprostol), 22 (Control)
Heterogeneity: Chi2 = 2.64, df = 3 (P = 0.45); I2 =0.0%
Test for overall effect: Z = 3.15 (P = 0.0016)
2 Mid-range dose (600 ug)
Bocanegra 1998 6/142 7/138 64.0 % 0.83 [ 0.29, 2.42 ]

Chandresekaran 1991 0/45 2/45 22.5 % 0.20 [ 0.01, 4.05 ]

Henriksson 1993 0/20 1/20 13.5 % 0.33 [ 0.01, 7.72 ]

Subtotal (95% CI) 207 203 100.0 % 0.62 [ 0.25, 1.58 ]

Total events: 6 (Misoprostol), 10 (Control)
Heterogeneity: Chi2 = 0.99, df = 2 (P = 0.61); I2 =0.0%
Test for overall effect: Z = 1.00 (P = 0.32)
3 High dose (800 ug)
Delmas 1994 1/80 2/103 100.0 % 0.64 [ 0.06, 6.97 ]

Subtotal (95% CI) 80 103 100.0 % 0.64 [ 0.06, 6.97 ]

Total events: 1 (Misoprostol), 2 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 0.36 (P = 0.72)

0.005 0.1 1 10 200

Favours Misoprostol Favours Control

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 Analysis 4.3. Comparison 4 Misoprostol vs placebo - efficacy by dosage, Outcome 3 Total ulcers - 1 month.

Review: Prevention of NSAID-induced gastroduodenal ulcers

Comparison: 4 Misoprostol vs placebo - efficacy by dosage

Outcome: 3 Total ulcers - 1 month

Study or subgroup Misoprostol Control Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 Low dose (400-600 ug)

Bocanegra 1998 7/159 17/138 39.9 % 0.36 [ 0.15, 0.84 ]

Bolten 1992 0/178 6/183 14.1 % 0.08 [ 0.00, 1.39 ]

Melo Gomes 1993 3/216 21/217 46.0 % 0.14 [ 0.04, 0.47 ]

Subtotal (95% CI) 553 538 100.0 % 0.22 [ 0.11, 0.43 ]

Total events: 10 (Misoprostol), 44 (Control)
Heterogeneity: Chi2 = 2.23, df = 2 (P = 0.33); I2 =10%
Test for overall effect: Z = 4.46 (P < 0.00001)
2 Mid-range dose (600 ug)
Bocanegra 1998 8/142 17/138 75.8 % 0.46 [ 0.20, 1.02 ]

Chandresekaran 1991 0/45 5/45 24.2 % 0.09 [ 0.01, 1.60 ]

Subtotal (95% CI) 187 183 100.0 % 0.37 [ 0.17, 0.79 ]

Total events: 8 (Misoprostol), 22 (Control)
Heterogeneity: Chi2 = 1.19, df = 1 (P = 0.28); I2 =16%
Test for overall effect: Z = 2.56 (P = 0.010)
3 High dose (800 ug)
Subtotal (95% CI) 0 0 0.0 % 0.0 [ 0.0, 0.0 ]
Total events: 0 (Misoprostol), 0 (Control)
Heterogeneity: not applicable
Test for overall effect: not applicable

0.005 0.1 1 10 200

Favours Misoprostol Favours Control

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 Analysis 4.4. Comparison 4 Misoprostol vs placebo - efficacy by dosage, Outcome 4 Gastric ulcers - 3-24
months.
Review: Prevention of NSAID-induced gastroduodenal ulcers

Comparison: 4 Misoprostol vs placebo - efficacy by dosage

Outcome: 4 Gastric ulcers - 3-24 months

Study or subgroup Misoprostol Control Risk Ratio Weight Risk Ratio

M- M-
H,Random,95% H,Random,95%
n/N n/N CI CI

1 Low dose (400-600 ug)

Agrawal 1995 6/193 20/191 14.3 % 0.30 [ 0.12, 0.72 ]

Chan 2001a 5/45 2/45 6.2 % 2.50 [ 0.51, 12.22 ]

Graham 1988 8/143 30/138 17.4 % 0.26 [ 0.12, 0.54 ]

Hawkey 1998 31/296 50/155 27.0 % 0.32 [ 0.22, 0.49 ]

Raskin 1995 29/462 51/454 26.0 % 0.56 [ 0.36, 0.87 ]

Verdickt 1992 4/164 6/175 9.1 % 0.71 [ 0.20, 2.48 ]

Subtotal (95% CI) 1303 1158 100.0 % 0.43 [ 0.28, 0.67 ]

Total events: 83 (Misoprostol), 159 (Control)
Heterogeneity: Tau2 = 0.14; Chi2 = 10.97, df = 5 (P = 0.05); I2 =54%
Test for overall effect: Z = 3.76 (P = 0.00017)
2 Mid-range dose (600 ug)
Raskin 1995 13/474 51/454 100.0 % 0.24 [ 0.13, 0.44 ]

Subtotal (95% CI) 474 454 100.0 % 0.24 [ 0.13, 0.44 ]

Total events: 13 (Misoprostol), 51 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 4.64 (P < 0.00001)
3 High dose (800 ug)
Agrawal 1991 2/179 21/177 7.9 % 0.09 [ 0.02, 0.40 ]

Elliot 1994 4/40 11/43 13.7 % 0.39 [ 0.14, 1.13 ]

Graham 1988 2/140 30/138 8.1 % 0.07 [ 0.02, 0.27 ]

Graham 1993 6/320 25/323 19.1 % 0.24 [ 0.10, 0.58 ]

Graham 2002 8/111 54/111 28.1 % 0.15 [ 0.07, 0.30 ]

Raskin 1995 6/228 51/454 21.0 % 0.23 [ 0.10, 0.54 ]

Roth 1993 0/60 7/53 2.1 % 0.06 [ 0.00, 1.01 ]

Subtotal (95% CI) 1078 1299 100.0 % 0.18 [ 0.12, 0.27 ]

Total events: 28 (Misoprostol), 199 (Control)
Heterogeneity: Tau2 = 0.03; Chi2 = 6.71, df = 6 (P = 0.35); I2 =11%
Test for overall effect: Z = 8.07 (P < 0.00001)

0.005 0.1 1 10 200

Favours Misoprostol Favours Control

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 Analysis 4.5. Comparison 4 Misoprostol vs placebo - efficacy by dosage, Outcome 5 Gastric ulcers - 3-24
months (sensitivity analysis excluding Chan 2001).

Review: Prevention of NSAID-induced gastroduodenal ulcers

Comparison: 4 Misoprostol vs placebo - efficacy by dosage

Outcome: 5 Gastric ulcers - 3-24 months (sensitivity analysis excluding Chan 2001)

Study or subgroup Misoprostol Control Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 Low dose (400-600 ug)

Agrawal 1995 6/193 20/191 11.6 % 0.30 [ 0.12, 0.72 ]

Graham 1988 8/143 30/138 17.6 % 0.26 [ 0.12, 0.54 ]

Hawkey 1998 31/296 50/155 37.8 % 0.32 [ 0.22, 0.49 ]

Raskin 1995 29/462 51/454 29.6 % 0.56 [ 0.36, 0.87 ]

Verdickt 1992 4/164 6/175 3.3 % 0.71 [ 0.20, 2.48 ]

Subtotal (95% CI) 1258 1113 100.0 % 0.39 [ 0.30, 0.51 ]

Total events: 78 (Misoprostol), 157 (Control)
Heterogeneity: Chi2 = 5.85, df = 4 (P = 0.21); I2 =32%
Test for overall effect: Z = 7.16 (P < 0.00001)
2 Mid-range dose (600 ug)
Raskin 1995 13/474 51/454 100.0 % 0.24 [ 0.13, 0.44 ]

Subtotal (95% CI) 474 454 100.0 % 0.24 [ 0.13, 0.44 ]

Total events: 13 (Misoprostol), 51 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 4.64 (P < 0.00001)
3 High dose (800 ug)
Agrawal 1991 2/179 21/177 11.5 % 0.09 [ 0.02, 0.40 ]

Elliot 1994 4/40 11/43 5.8 % 0.39 [ 0.14, 1.13 ]

Graham 1988 2/140 30/138 16.5 % 0.07 [ 0.02, 0.27 ]

Graham 1993 6/320 25/323 13.6 % 0.24 [ 0.10, 0.58 ]

Graham 2002 8/111 54/111 29.5 % 0.15 [ 0.07, 0.30 ]

Raskin 1995 6/228 51/454 18.6 % 0.23 [ 0.10, 0.54 ]

Roth 1993 0/60 7/53 4.4 % 0.06 [ 0.00, 1.01 ]

Subtotal (95% CI) 1078 1299 100.0 % 0.17 [ 0.11, 0.24 ]

0.005 0.1 1 10 200

Favours Misoprostol Favours Control
(Continued . . . )

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 (. . . Continued)
Study or subgroup Misoprostol Control Risk Ratio Weight Risk Ratio
n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
Total events: 28 (Misoprostol), 199 (Control)
Heterogeneity: Chi2 = 6.71, df = 6 (P = 0.35); I2 =11%
Test for overall effect: Z = 9.28 (P < 0.00001)

0.005 0.1 1 10 200

Favours Misoprostol Favours Control

Analysis 4.6. Comparison 4 Misoprostol vs placebo - efficacy by dosage, Outcome 6 Duodenal ulcers - 3-24
months.
Review: Prevention of NSAID-induced gastroduodenal ulcers

Comparison: 4 Misoprostol vs placebo - efficacy by dosage

Outcome: 6 Duodenal ulcers - 3-24 months

Study or subgroup Misoprostol Control Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 Low dose (400-600 ug)

Agrawal 1995 9/193 15/191 19.9 % 0.59 [ 0.27, 1.32 ]

Chan 2001a 2/45 1/45 1.3 % 2.00 [ 0.19, 21.28 ]

Hawkey 1998 30/296 19/155 32.9 % 0.83 [ 0.48, 1.42 ]

Raskin 1995 9/462 23/454 30.6 % 0.38 [ 0.18, 0.82 ]

Verdickt 1992 2/164 12/175 15.3 % 0.18 [ 0.04, 0.78 ]

Subtotal (95% CI) 1160 1020 100.0 % 0.56 [ 0.39, 0.81 ]

Total events: 52 (Misoprostol), 70 (Control)
Heterogeneity: Chi2 = 6.36, df = 4 (P = 0.17); I2 =37%
Test for overall effect: Z = 3.14 (P = 0.0017)
2 Mid-range dose (600 ug)
Raskin 1995 11/474 23/454 100.0 % 0.46 [ 0.23, 0.93 ]

Subtotal (95% CI) 474 454 100.0 % 0.46 [ 0.23, 0.93 ]

Total events: 11 (Misoprostol), 23 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 2.16 (P = 0.030)
3 High dose (800 ug)

0.01 0.1 1 10 100

Favours Misoprostol Favours Control
(Continued . . . )

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 (. . . Continued)
Study or subgroup Misoprostol Control Risk Ratio Weight Risk Ratio
n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
Elliot 1994 1/40 0/43 1.5 % 3.22 [ 0.13, 76.82 ]

Graham 1993 2/320 15/323 46.1 % 0.13 [ 0.03, 0.58 ]

Raskin 1995 2/228 23/454 47.5 % 0.17 [ 0.04, 0.73 ]

Roth 1993 0/60 1/53 4.9 % 0.30 [ 0.01, 7.09 ]

Subtotal (95% CI) 648 873 100.0 % 0.21 [ 0.09, 0.49 ]

Total events: 5 (Misoprostol), 39 (Control)
Heterogeneity: Chi2 = 3.31, df = 3 (P = 0.35); I2 =9%
Test for overall effect: Z = 3.55 (P = 0.00038)

0.01 0.1 1 10 100

Favours Misoprostol Favours Control

Analysis 4.7. Comparison 4 Misoprostol vs placebo - efficacy by dosage, Outcome 7 Total endoscopic ulcers
3-24 months.
Review: Prevention of NSAID-induced gastroduodenal ulcers

Comparison: 4 Misoprostol vs placebo - efficacy by dosage

Outcome: 7 Total endoscopic ulcers 3-24 months

Study or subgroup Misoprostol Control Risk Ratio Weight Risk Ratio

M- M-
H,Random,95% H,Random,95%
n/N n/N CI CI
1 Low dose (400-600 ug)
Agrawal 1995 15/193 32/191 44.8 % 0.46 [ 0.26, 0.83 ]

Chan 2001a 6/45 3/45 22.1 % 2.00 [ 0.53, 7.51 ]

Verdickt 1992 6/164 17/175 33.1 % 0.38 [ 0.15, 0.93 ]

Subtotal (95% CI) 402 411 100.0 % 0.60 [ 0.27, 1.31 ]

Total events: 27 (Misoprostol), 52 (Control)
Heterogeneity: Tau2 = 0.27; Chi2 = 4.62, df = 2 (P = 0.10); I2 =57%
Test for overall effect: Z = 1.29 (P = 0.20)
2 Mid-range dose (600 ug)
Subtotal (95% CI) 0 0 0.0 % 0.0 [ 0.0, 0.0 ]

0.005 0.1 1 10 200

Favours Misoprostol Favours Control
(Continued . . . )

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 (. . . Continued)
Study or subgroup Misoprostol Control Risk Ratio Weight Risk Ratio
M- M-
H,Random,95% H,Random,95%
n/N n/N CI CI
Total events: 0 (Misoprostol), 0 (Control)
Heterogeneity: not applicable
Test for overall effect: not applicable
3 High dose (800 ug)
Graham 1993 8/320 37/323 33.7 % 0.22 [ 0.10, 0.46 ]

Graham 2002 13/111 56/111 64.0 % 0.23 [ 0.13, 0.40 ]

Roth 1993 0/60 8/53 2.4 % 0.05 [ 0.00, 0.88 ]

Subtotal (95% CI) 491 487 100.0 % 0.22 [ 0.14, 0.34 ]

Total events: 21 (Misoprostol), 101 (Control)
Heterogeneity: Tau2 = 0.0; Chi2 = 1.07, df = 2 (P = 0.59); I2 =0.0%
Test for overall effect: Z = 6.84 (P < 0.00001)

0.005 0.1 1 10 200

Favours Misoprostol Favours Control

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 Analysis 4.8. Comparison 4 Misoprostol vs placebo - efficacy by dosage, Outcome 8 Clinical ulcers - 3-24
months.
Review: Prevention of NSAID-induced gastroduodenal ulcers

Comparison: 4 Misoprostol vs placebo - efficacy by dosage

Outcome: 8 Clinical ulcers - 3-24 months

Study or subgroup Misoprostol Control Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 Low dose (400-600 ug)

Melo Gomes 1993 0/216 1/217 100.0 % 0.33 [ 0.01, 8.17 ]

Subtotal (95% CI) 216 217 100.0 % 0.33 [ 0.01, 8.17 ]

Total events: 0 (Misoprostol), 1 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 0.67 (P = 0.50)
2 Mid-range dose (600 ug)
Subtotal (95% CI) 0 0 0.0 % 0.0 [ 0.0, 0.0 ]
Total events: 0 (Misoprostol), 0 (Control)
Heterogeneity: not applicable
Test for overall effect: not applicable
3 High dose (800 ug)
Silverstein 1995 16/4404 33/4439 100.0 % 0.49 [ 0.27, 0.89 ]

Subtotal (95% CI) 4404 4439 100.0 % 0.49 [ 0.27, 0.89 ]

Total events: 16 (Misoprostol), 33 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 2.36 (P = 0.018)

0.01 0.1 1 10 100

Favours Misoprostol Favours Control

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 Analysis 5.1. Comparison 5 Misoprostol vs placebo - toxicity causing withdrawal - by dose, Outcome 1
Nausea.
Review: Prevention of NSAID-induced gastroduodenal ulcers

Comparison: 5 Misoprostol vs placebo - toxicity causing withdrawal - by dose

Outcome: 1 Nausea

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio

M- M-
H,Random,95% H,Random,95%
n/N n/N CI CI

1 Misoprostol 400 ug/day

Agrawal 1995 0/193 2/191 5.2 % 0.20 [ 0.01, 4.10 ]

Bocanegra 1998 6/175 5/154 34.9 % 1.06 [ 0.33, 3.39 ]

Raskin 1995 9/462 10/454 59.9 % 0.88 [ 0.36, 2.16 ]

Subtotal (95% CI) 830 799 100.0 % 0.87 [ 0.44, 1.74 ]

Total events: 15 (Treatment), 17 (Control)
Heterogeneity: Tau2 = 0.0; Chi2 = 1.04, df = 2 (P = 0.60); I2 =0.0%
Test for overall effect: Z = 0.39 (P = 0.69)
2 Misoprostol 600 ug/day
Bocanegra 1998 0/152 5/154 29.9 % 0.09 [ 0.01, 1.65 ]

Raskin 1995 8/474 10/454 70.1 % 0.77 [ 0.31, 1.92 ]

Subtotal (95% CI) 626 608 100.0 % 0.41 [ 0.06, 2.93 ]

Total events: 8 (Treatment), 15 (Control)
Heterogeneity: Tau2 = 1.22; Chi2 = 2.02, df = 1 (P = 0.15); I2 =51%
Test for overall effect: Z = 0.89 (P = 0.37)
3 Misoprostol 800 ug/day
Graham 1993 7/320 6/323 3.2 % 1.18 [ 0.40, 3.47 ]

Raskin 1995 12/228 10/454 5.5 % 2.39 [ 1.05, 5.45 ]

Roth 1993 2/60 1/53 0.7 % 1.77 [ 0.16, 18.93 ]

Silverstein 1995 192/4404 166/4439 90.6 % 1.17 [ 0.95, 1.43 ]

Subtotal (95% CI) 5012 5269 100.0 % 1.22 [ 1.00, 1.48 ]

Total events: 213 (Treatment), 183 (Control)
Heterogeneity: Tau2 = 0.0; Chi2 = 2.85, df = 3 (P = 0.42); I2 =0.0%
Test for overall effect: Z = 1.99 (P = 0.047)

0.005 0.1 1 10 200

Favours treatment Favours control

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 Analysis 5.2. Comparison 5 Misoprostol vs placebo - toxicity causing withdrawal - by dose, Outcome 2
Dyspepsia.

Review: Prevention of NSAID-induced gastroduodenal ulcers

Comparison: 5 Misoprostol vs placebo - toxicity causing withdrawal - by dose

Outcome: 2 Dyspepsia

Study or subgroup Treatment Control Risk Ratio Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 Misoprostol 400 ug/day

Agrawal 1995 0/193 0/191 0.0 [ 0.0, 0.0 ]

Bocanegra 1998 3/175 3/154 0.88 [ 0.18, 4.30 ]

Raskin 1995 5/462 13/454 0.38 [ 0.14, 1.05 ]

Subtotal (95% CI) 830 799 0.48 [ 0.20, 1.11 ]

Total events: 8 (Treatment), 16 (Control)
Heterogeneity: Chi2 = 0.77, df = 1 (P = 0.38); I2 =0.0%
Test for overall effect: Z = 1.72 (P = 0.086)
2 Misoprostol 600 ug/day
Bocanegra 1998 4/152 3/154 1.35 [ 0.31, 5.93 ]

Raskin 1995 7/454 13/454 0.54 [ 0.22, 1.34 ]

Subtotal (95% CI) 606 608 0.69 [ 0.32, 1.47 ]

Total events: 11 (Treatment), 16 (Control)
Heterogeneity: Chi2 = 1.08, df = 1 (P = 0.30); I2 =7%
Test for overall effect: Z = 0.96 (P = 0.34)
3 Misoprostol 800 ug/day
Agrawal 1991 15/179 10/177 1.48 [ 0.68, 3.21 ]

Raskin 1995 8/225 13/454 1.24 [ 0.52, 2.95 ]

Roth 1993 1/60 0/53 2.66 [ 0.11, 63.84 ]

Saggioro 1991 3/82 1/84 3.07 [ 0.33, 28.94 ]

Silverstein 1995 202/4404 182/4439 1.12 [ 0.92, 1.36 ]

Subtotal (95% CI) 4950 5207 1.16 [ 0.96, 1.39 ]

Total events: 229 (Treatment), 206 (Control)
Heterogeneity: Chi2 = 1.53, df = 4 (P = 0.82); I2 =0.0%
Test for overall effect: Z = 1.54 (P = 0.12)

0.01 0.1 1 10 100

Favours treatment Favours control

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 Analysis 5.3. Comparison 5 Misoprostol vs placebo - toxicity causing withdrawal - by dose, Outcome 3
Constipation.

Review: Prevention of NSAID-induced gastroduodenal ulcers

Comparison: 5 Misoprostol vs placebo - toxicity causing withdrawal - by dose

Outcome: 3 Constipation

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 Misoprostol 400 ug/day

Subtotal (95% CI) 0 0 0.0 % 0.0 [ 0.0, 0.0 ]
Total events: 0 (Treatment), 0 (Control)
Heterogeneity: not applicable
Test for overall effect: not applicable
2 Misoprostol 600 ug/day
Subtotal (95% CI) 0 0 0.0 % 0.0 [ 0.0, 0.0 ]
Total events: 0 (Treatment), 0 (Control)
Heterogeneity: not applicable
Test for overall effect: not applicable
3 Misoprostol 800 ug/day
Agrawal 1991 1/179 1/177 2.7 % 0.99 [ 0.06, 15.69 ]

Silverstein 1995 23/4404 37/4439 97.3 % 0.63 [ 0.37, 1.05 ]

Subtotal (95% CI) 4583 4616 100.0 % 0.64 [ 0.38, 1.06 ]

Total events: 24 (Treatment), 38 (Control)
Heterogeneity: Chi2 = 0.10, df = 1 (P = 0.75); I2 =0.0%
Test for overall effect: Z = 1.74 (P = 0.082)

0.05 0.2 1 5 20
Favours treatment Favours control

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 Analysis 5.4. Comparison 5 Misoprostol vs placebo - toxicity causing withdrawal - by dose, Outcome 4
Diarrhea.
Review: Prevention of NSAID-induced gastroduodenal ulcers

Comparison: 5 Misoprostol vs placebo - toxicity causing withdrawal - by dose

Outcome: 4 Diarrhea

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 Misoprostol 400 ug/day

Agrawal 1995 0/193 3/191 23.9 % 0.14 [ 0.01, 2.72 ]

Bocanegra 1998 5/175 2/154 14.5 % 2.20 [ 0.43, 11.18 ]

Melo Gomes 1993 3/216 3/217 20.4 % 1.00 [ 0.21, 4.92 ]

Raskin 1995 14/462 6/454 41.2 % 2.29 [ 0.89, 5.91 ]

Subtotal (95% CI) 1046 1016 100.0 % 1.50 [ 0.78, 2.90 ]

Total events: 22 (Treatment), 14 (Control)
Heterogeneity: Chi2 = 3.68, df = 3 (P = 0.30); I2 =18%
Test for overall effect: Z = 1.21 (P = 0.22)
2 Misoprostol 600 ug/day
Bocanegra 1998 4/152 2/154 24.5 % 2.03 [ 0.38, 10.90 ]

Raskin 1995 18/474 6/454 75.5 % 2.87 [ 1.15, 7.17 ]

Subtotal (95% CI) 626 608 100.0 % 2.67 [ 1.20, 5.95 ]

Total events: 22 (Treatment), 8 (Control)
Heterogeneity: Chi2 = 0.13, df = 1 (P = 0.72); I2 =0.0%
Test for overall effect: Z = 2.40 (P = 0.017)
3 Misoprostol 800 ug/day
Agrawal 1991 5/179 1/177 0.5 % 4.94 [ 0.58, 41.89 ]

Elliot 1994 5/40 1/43 0.5 % 5.38 [ 0.66, 44.04 ]

Graham 1993 12/320 3/323 1.5 % 4.04 [ 1.15, 14.17 ]

Raskin 1995 8/228 6/454 2.1 % 2.65 [ 0.93, 7.56 ]

Roth 1993 3/60 1/53 0.5 % 2.65 [ 0.28, 24.71 ]

Saggioro 1991 2/82 0/84 0.3 % 5.12 [ 0.25, 105.06 ]

Silverstein 1995 438/4404 185/4439 94.6 % 2.39 [ 2.02, 2.82 ]

Subtotal (95% CI) 5313 5573 100.0 % 2.45 [ 2.09, 2.88 ]

Total events: 473 (Treatment), 197 (Control)
Heterogeneity: Chi2 = 1.91, df = 6 (P = 0.93); I2 =0.0%
Test for overall effect: Z = 10.89 (P < 0.00001)

0.01 0.1 1 10 100

Favours treatment Favours control

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 Analysis 5.5. Comparison 5 Misoprostol vs placebo - toxicity causing withdrawal - by dose, Outcome 5
Abdominal pain.

Review: Prevention of NSAID-induced gastroduodenal ulcers

Comparison: 5 Misoprostol vs placebo - toxicity causing withdrawal - by dose

Outcome: 5 Abdominal pain

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 Misoprostol 400 ug/day

Agrawal 1995 11/193 4/191 18.2 % 2.72 [ 0.88, 8.40 ]

Melo Gomes 1993 8/216 3/217 13.5 % 2.68 [ 0.72, 9.96 ]

Raskin 1995 15/462 15/454 68.3 % 0.98 [ 0.49, 1.99 ]

Subtotal (95% CI) 871 862 100.0 % 1.53 [ 0.90, 2.59 ]

Total events: 34 (Treatment), 22 (Control)
Heterogeneity: Chi2 = 3.22, df = 2 (P = 0.20); I2 =38%
Test for overall effect: Z = 1.57 (P = 0.12)
2 Misoprostol 600 ug/day
Raskin 1995 30/474 15/454 100.0 % 1.92 [ 1.04, 3.51 ]

Subtotal (95% CI) 474 454 100.0 % 1.92 [ 1.04, 3.51 ]

Total events: 30 (Treatment), 15 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 2.10 (P = 0.036)
3 Misoprostol 800 ug/day
Graham 1993 6/320 5/323 2.2 % 1.21 [ 0.37, 3.93 ]

Raskin 1995 19/228 15/454 4.4 % 2.52 [ 1.31, 4.87 ]

Roth 1993 1/60 2/63 0.8 % 0.53 [ 0.05, 5.64 ]

Silverstein 1995 284/4404 214/4439 92.6 % 1.34 [ 1.13, 1.59 ]

Subtotal (95% CI) 5012 5279 100.0 % 1.38 [ 1.17, 1.63 ]

Total events: 310 (Treatment), 236 (Control)
Heterogeneity: Chi2 = 4.04, df = 3 (P = 0.26); I2 =26%
Test for overall effect: Z = 3.84 (P = 0.00012)

0.05 0.2 1 5 20
Favours treatment Favours control

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 Analysis 5.6. Comparison 5 Misoprostol vs placebo - toxicity causing withdrawal - by dose, Outcome 6
Flatulence.
Review: Prevention of NSAID-induced gastroduodenal ulcers

Comparison: 5 Misoprostol vs placebo - toxicity causing withdrawal - by dose

Outcome: 6 Flatulence

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio

M- M-
H,Random,95% H,Random,95%
n/N n/N CI CI

1 Misoprostol 400 ug/day

Raskin 1995 8/462 4/454 100.0 % 1.97 [ 0.60, 6.48 ]

Subtotal (95% CI) 462 454 100.0 % 1.97 [ 0.60, 6.48 ]

Total events: 8 (Treatment), 4 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 1.11 (P = 0.27)
2 Misoprostol 600 ug/day
Raskin 1995 18/474 4/454 100.0 % 4.31 [ 1.47, 12.64 ]

Subtotal (95% CI) 474 454 100.0 % 4.31 [ 1.47, 12.64 ]

Total events: 18 (Treatment), 4 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 2.66 (P = 0.0078)
3 Misoprostol 800 ug/day
Raskin 1995 11/228 4/454 33.7 % 5.48 [ 1.76, 17.01 ]

Roth 1993 1/60 0/53 8.4 % 2.66 [ 0.11, 63.84 ]

Silverstein 1995 183/4404 121/4439 57.9 % 1.52 [ 1.22, 1.91 ]

Subtotal (95% CI) 4692 4946 100.0 % 2.46 [ 0.91, 6.65 ]

Total events: 195 (Treatment), 125 (Control)
Heterogeneity: Tau2 = 0.43; Chi2 = 4.80, df = 2 (P = 0.09); I2 =58%
Test for overall effect: Z = 1.77 (P = 0.077)

0.01 0.1 1 10 100

Favours treatment Favours control

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 Analysis 5.7. Comparison 5 Misoprostol vs placebo - toxicity causing withdrawal - by dose, Outcome 7
Vomiting.

Review: Prevention of NSAID-induced gastroduodenal ulcers

Comparison: 5 Misoprostol vs placebo - toxicity causing withdrawal - by dose

Outcome: 7 Vomiting

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio

M- M-
H,Random,95% H,Random,95%
n/N n/N CI CI

1 Misoprostol 400 ug/day

Raskin 1995 1/462 2/454 100.0 % 0.49 [ 0.04, 5.40 ]

Subtotal (95% CI) 462 454 100.0 % 0.49 [ 0.04, 5.40 ]

Total events: 1 (Treatment), 2 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 0.58 (P = 0.56)
2 Misoprostol 600 ug/day
Raskin 1995 3/474 2/454 100.0 % 1.44 [ 0.24, 8.56 ]

Subtotal (95% CI) 474 454 100.0 % 1.44 [ 0.24, 8.56 ]

Total events: 3 (Treatment), 2 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 0.40 (P = 0.69)
3 Misoprostol 800 ug/day
Raskin 1995 4/228 2/454 35.3 % 3.98 [ 0.73, 21.58 ]

Silverstein 1995 51/4404 61/4439 64.7 % 0.84 [ 0.58, 1.22 ]

Subtotal (95% CI) 4632 4893 100.0 % 1.46 [ 0.34, 6.25 ]

Total events: 55 (Treatment), 63 (Control)
Heterogeneity: Tau2 = 0.82; Chi2 = 3.10, df = 1 (P = 0.08); I2 =68%
Test for overall effect: Z = 0.51 (P = 0.61)

0.05 0.2 1 5 20
Favours treatment Favours control

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 Analysis 5.8. Comparison 5 Misoprostol vs placebo - toxicity causing withdrawal - by dose, Outcome 8
Dropouts due to side effects.

Review: Prevention of NSAID-induced gastroduodenal ulcers

Comparison: 5 Misoprostol vs placebo - toxicity causing withdrawal - by dose

Outcome: 8 Dropouts due to side effects

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio

M- M-
H,Random,95% H,Random,95%
n/N n/N CI CI
1 Misoprostol 400 ug/day
Agrawal 1995 11/193 9/191 10.0 % 1.21 [ 0.51, 2.85 ]

Bolten 1992 11/178 10/183 10.7 % 1.13 [ 0.49, 2.60 ]

Delmas 1994 5/73 6/103 5.6 % 1.18 [ 0.37, 3.71 ]

Raskin 1995 55/462 49/454 56.2 % 1.10 [ 0.77, 1.59 ]

Verdickt 1992 18/164 15/175 17.4 % 1.28 [ 0.67, 2.46 ]

Subtotal (95% CI) 1070 1106 100.0 % 1.15 [ 0.88, 1.51 ]

Total events: 100 (Treatment), 89 (Control)
Heterogeneity: Tau2 = 0.0; Chi2 = 0.17, df = 4 (P = 1.00); I2 =0.0%
Test for overall effect: Z = 1.01 (P = 0.31)
2 Misoprostol 600 ug/day
Raskin 1995 56/474 49/454 100.0 % 1.09 [ 0.76, 1.57 ]

Subtotal (95% CI) 474 454 100.0 % 1.09 [ 0.76, 1.57 ]

Total events: 56 (Treatment), 49 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 0.49 (P = 0.62)
3 Misoprostol 800 ug/day
Agrawal 1991 31/179 16/177 12.8 % 1.92 [ 1.09, 3.38 ]

Delmas 1994 10/80 6/103 5.7 % 2.15 [ 0.81, 5.66 ]

Elliot 1994 5/40 1/43 1.4 % 5.38 [ 0.66, 44.04 ]

Graham 1993 38/320 34/323 17.3 % 1.13 [ 0.73, 1.74 ]

Hawkey 1998 23/297 3/155 4.0 % 4.00 [ 1.22, 13.12 ]

Raskin 1995 46/228 49/454 20.2 % 1.87 [ 1.29, 2.71 ]

Roth 1993 9/60 2/53 2.7 % 3.98 [ 0.90, 17.58 ]

Saggioro 1991 6/82 1/84 1.4 % 6.15 [ 0.76, 49.94 ]

Silverstein 1995 1210/4404 896/4439 34.5 % 1.36 [ 1.26, 1.47 ]

Subtotal (95% CI) 5690 5831 100.0 % 1.68 [ 1.31, 2.17 ]

Total events: 1378 (Treatment), 1008 (Control)
Heterogeneity: Tau2 = 0.05; Chi2 = 14.18, df = 8 (P = 0.08); I2 =44%
Test for overall effect: Z = 4.05 (P = 0.000052)

0.02 0.1 1 10 50
Favours treatment Favours control

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 Analysis 5.9. Comparison 5 Misoprostol vs placebo - toxicity causing withdrawal - by dose, Outcome 9
Dropouts overall.

Review: Prevention of NSAID-induced gastroduodenal ulcers

Comparison: 5 Misoprostol vs placebo - toxicity causing withdrawal - by dose

Outcome: 9 Dropouts overall

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio

M- M-
H,Random,95% H,Random,95%
n/N n/N CI CI
1 Misoprostol 400 ug/day
Verdickt 1992 32/164 31/175 13.9 % 1.10 [ 0.71, 1.72 ]

Raskin 1995 101/462 115/454 50.6 % 0.86 [ 0.68, 1.09 ]

Bolten 1992 16/178 16/183 6.3 % 1.03 [ 0.53, 1.99 ]

Delmas 1994 14/73 16/103 6.5 % 1.23 [ 0.64, 2.37 ]

Graham 1988 45/143 42/138 22.6 % 1.03 [ 0.73, 1.47 ]

Subtotal (95% CI) 1020 1053 100.0 % 0.96 [ 0.82, 1.14 ]

Total events: 208 (Treatment), 220 (Control)
Heterogeneity: Tau2 = 0.0; Chi2 = 1.95, df = 4 (P = 0.75); I2 =0.0%
Test for overall effect: Z = 0.45 (P = 0.65)
2 Misoprostol 600 ug/day
Henriksson 1993 1/20 0/20 0.5 % 3.00 [ 0.13, 69.52 ]

Raskin 1995 131/474 115/454 99.5 % 1.09 [ 0.88, 1.35 ]

Subtotal (95% CI) 494 474 100.0 % 1.10 [ 0.88, 1.36 ]

Total events: 132 (Treatment), 115 (Control)
Heterogeneity: Tau2 = 0.0; Chi2 = 0.40, df = 1 (P = 0.53); I2 =0.0%
Test for overall effect: Z = 0.84 (P = 0.40)
3 Misoprostol 800 ug/day
Agrawal 1991 57/179 46/177 16.6 % 1.23 [ 0.88, 1.70 ]

Saggioro 1991 9/82 4/84 2.8 % 2.30 [ 0.74, 7.19 ]

Elliot 1994 13/40 5/43 4.0 % 2.80 [ 1.09, 7.14 ]

Raskin 1995 74/228 115/454 20.6 % 1.28 [ 1.00, 1.64 ]

Delmas 1994 31/80 16/103 9.8 % 2.49 [ 1.47, 4.23 ]

Graham 1988 41/139 42/138 15.3 % 0.97 [ 0.68, 1.39 ]

Roth 1993 9/60 2/53 1.7 % 3.98 [ 0.90, 17.58 ]

0.02 0.1 1 10 50
Favours treatment Favours control
(Continued . . . )

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 (. . .Continued)
Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio
M- M-
H,Random,95% H,Random,95%
n/N n/N CI CI
Silverstein 1995 1851/4404 1617/4439 29.1 % 1.15 [ 1.10, 1.22 ]

Subtotal (95% CI) 5212 5491 100.0 % 1.35 [ 1.10, 1.65 ]

Total events: 2085 (Treatment), 1847 (Control)
Heterogeneity: Tau2 = 0.04; Chi2 = 17.17, df = 7 (P = 0.02); I2 =59%
Test for overall effect: Z = 2.92 (P = 0.0035)

0.02 0.1 1 10 50
Favours treatment Favours control

Analysis 6.1. Comparison 6 Misoprostol vs placebo - symptoms - by dose, Outcome 1 Nausea.

Review: Prevention of NSAID-induced gastroduodenal ulcers

Comparison: 6 Misoprostol vs placebo - symptoms - by dose

Outcome: 1 Nausea

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio

M- M-
H,Random,95% H,Random,95%
n/N n/N CI CI
1 Misoprostol 400 ug/day
Agrawal 1995 19/193 14/191 11.7 % 1.34 [ 0.69, 2.60 ]

Bocanegra 1998 26/175 15/154 13.6 % 1.53 [ 0.84, 2.77 ]

Bolten 1992 19/178 2/183 3.0 % 9.77 [ 2.31, 41.32 ]

Graham 1988 24/143 21/138 15.9 % 1.10 [ 0.64, 1.89 ]

Melo Gomes 1993 18/216 11/217 10.1 % 1.64 [ 0.80, 3.40 ]

Raskin 1995 118/462 86/454 35.0 % 1.35 [ 1.05, 1.72 ]

Verdickt 1992 18/164 12/175 10.7 % 1.60 [ 0.80, 3.22 ]

Subtotal (95% CI) 1531 1512 100.0 % 1.46 [ 1.13, 1.89 ]

Total events: 242 (Treatment), 161 (Control)
Heterogeneity: Tau2 = 0.03; Chi2 = 8.45, df = 6 (P = 0.21); I2 =29%
Test for overall effect: Z = 2.91 (P = 0.0037)
2 Misoprostol 600 ug/day

0.005 0.1 1 10 200

Favours treatment Favours control
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 (. . .Continued)
Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio
M- M-
H,Random,95% H,Random,95%
n/N n/N CI CI
Bocanegra 1998 20/152 15/154 13.5 % 1.35 [ 0.72, 2.54 ]

Raskin 1995 113/474 86/454 86.5 % 1.26 [ 0.98, 1.61 ]

Subtotal (95% CI) 626 608 100.0 % 1.27 [ 1.01, 1.60 ]

Total events: 133 (Treatment), 101 (Control)
Heterogeneity: Tau2 = 0.0; Chi2 = 0.04, df = 1 (P = 0.84); I2 =0.0%
Test for overall effect: Z = 2.03 (P = 0.043)
3 Misoprostol 800 ug/day
Delmas 1994 12/80 31/103 23.3 % 0.50 [ 0.27, 0.91 ]

Graham 1988 22/139 21/138 24.2 % 1.04 [ 0.60, 1.80 ]

Graham 2002 6/134 0/134 3.7 % 13.00 [ 0.74, 228.49 ]

Raskin 1995 67/228 86/454 28.7 % 1.55 [ 1.18, 2.05 ]

Saggioro 1991 9/82 15/84 20.1 % 0.61 [ 0.29, 1.33 ]

Subtotal (95% CI) 663 913 100.0 % 0.97 [ 0.54, 1.75 ]

Total events: 116 (Treatment), 153 (Control)
Heterogeneity: Tau2 = 0.30; Chi2 = 17.38, df = 4 (P = 0.002); I2 =77%
Test for overall effect: Z = 0.10 (P = 0.92)

0.005 0.1 1 10 200

Favours treatment Favours control

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 Analysis 6.2. Comparison 6 Misoprostol vs placebo - symptoms - by dose, Outcome 2 Dyspepsia.

Review: Prevention of NSAID-induced gastroduodenal ulcers

Comparison: 6 Misoprostol vs placebo - symptoms - by dose

Outcome: 2 Dyspepsia

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio

M- M-
H,Random,95% H,Random,95%
n/N n/N CI CI
1 Misoprostol 400 ug/day
Agrawal 1995 23/193 15/191 9.1 % 1.52 [ 0.82, 2.82 ]

Bocanegra 1998 72/175 69/154 25.7 % 0.92 [ 0.72, 1.18 ]

Bolten 1992 16/178 8/183 5.7 % 2.06 [ 0.90, 4.68 ]

Delmas 1994 7/73 18/103 5.7 % 0.55 [ 0.24, 1.25 ]

Graham 1988 19/143 18/138 9.5 % 1.02 [ 0.56, 1.86 ]

Melo Gomes 1993 18/216 25/217 10.1 % 0.72 [ 0.41, 1.29 ]

Raskin 1995 99/462 111/454 26.5 % 0.88 [ 0.69, 1.11 ]

Verdickt 1992 18/164 12/175 7.5 % 1.60 [ 0.80, 3.22 ]

Subtotal (95% CI) 1604 1615 100.0 % 0.99 [ 0.80, 1.23 ]

Total events: 272 (Treatment), 276 (Control)
Heterogeneity: Tau2 = 0.03; Chi2 = 10.90, df = 7 (P = 0.14); I2 =36%
Test for overall effect: Z = 0.08 (P = 0.94)
2 Misoprostol 600 ug/day
Bocanegra 1998 52/152 69/154 34.6 % 0.76 [ 0.58, 1.01 ]

Chandresekaran 1991 11/45 13/45 5.8 % 0.85 [ 0.43, 1.68 ]

Delmas 1994 14/73 31/103 8.9 % 0.64 [ 0.37, 1.11 ]

Henriksson 1993 6/19 3/20 1.8 % 2.11 [ 0.61, 7.24 ]

Raskin 1995 101/474 111/454 48.9 % 0.87 [ 0.69, 1.10 ]

Subtotal (95% CI) 763 776 100.0 % 0.82 [ 0.70, 0.97 ]

Total events: 184 (Treatment), 227 (Control)
Heterogeneity: Tau2 = 0.0; Chi2 = 3.54, df = 4 (P = 0.47); I2 =0.0%
Test for overall effect: Z = 2.33 (P = 0.020)
3 Misoprostol 800 ug/day
Agrawal 1991 55/179 42/177 23.6 % 1.29 [ 0.92, 1.83 ]

Delmas 1994 12/80 18/103 15.7 % 0.86 [ 0.44, 1.68 ]

Elliot 1994 21/40 10/43 16.8 % 2.26 [ 1.22, 4.19 ]

Graham 1988 23/139 18/138 17.9 % 1.27 [ 0.72, 2.24 ]

0.05 0.2 1 5 20
Favours treatment Favours control
(Continued . . . )

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 (. . .Continued)
Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio
M- M-
H,Random,95% H,Random,95%
n/N n/N CI CI
Graham 2002 8/134 0/134 1.8 % 17.00 [ 0.99, 291.60 ]

Raskin 1995 43/228 111/454 24.3 % 0.77 [ 0.56, 1.06 ]

Subtotal (95% CI) 800 1049 100.0 % 1.23 [ 0.83, 1.82 ]

Total events: 162 (Treatment), 199 (Control)
Heterogeneity: Tau2 = 0.14; Chi2 = 15.33, df = 5 (P = 0.01); I2 =67%
Test for overall effect: Z = 1.02 (P = 0.31)

0.05 0.2 1 5 20
Favours treatment Favours control

Analysis 6.3. Comparison 6 Misoprostol vs placebo - symptoms - by dose, Outcome 3 Constipation.

Review: Prevention of NSAID-induced gastroduodenal ulcers

Comparison: 6 Misoprostol vs placebo - symptoms - by dose

Outcome: 3 Constipation

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 Misoprostol 400 ug/day

Subtotal (95% CI) 0 0 0.0 % 0.0 [ 0.0, 0.0 ]
Total events: 0 (Treatment), 0 (Control)
Heterogeneity: not applicable
Test for overall effect: not applicable
2 Misoprostol 600 ug/day
Agrawal 1991 5/179 8/177 79.1 % 0.62 [ 0.21, 1.85 ]

Roth 1993 1/60 2/53 20.9 % 0.44 [ 0.04, 4.73 ]

Subtotal (95% CI) 239 230 100.0 % 0.58 [ 0.22, 1.57 ]

Total events: 6 (Treatment), 10 (Control)
Heterogeneity: Chi2 = 0.06, df = 1 (P = 0.80); I2 =0.0%
Test for overall effect: Z = 1.07 (P = 0.28)
3 Misoprostol 800 ug/day
Subtotal (95% CI) 0 0 0.0 % 0.0 [ 0.0, 0.0 ]
Total events: 0 (Treatment), 0 (Control)
Heterogeneity: not applicable
Test for overall effect: not applicable

0.02 0.1 1 10 50
Favours treatment Favours control

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 Analysis 6.4. Comparison 6 Misoprostol vs placebo - symptoms - by dose, Outcome 4 Diarrhea.

Review: Prevention of NSAID-induced gastroduodenal ulcers

Comparison: 6 Misoprostol vs placebo - symptoms - by dose

Outcome: 4 Diarrhea

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio

M- M-
H,Random,95% H,Random,95%
n/N n/N CI CI
1 Misoprostol 400 ug/day
Agrawal 1995 23/193 15/191 10.8 % 1.52 [ 0.82, 2.82 ]

Bocanegra 1998 38/175 28/154 16.1 % 1.19 [ 0.77, 1.85 ]

Bolten 1992 32/178 22/183 14.0 % 1.50 [ 0.91, 2.47 ]

Delmas 1994 1/73 5/103 1.3 % 0.28 [ 0.03, 2.37 ]

Graham 1988 36/143 18/138 13.6 % 1.93 [ 1.15, 3.23 ]

Melo Gomes 1993 39/216 12/217 10.8 % 3.27 [ 1.76, 6.06 ]

Raskin 1995 100/462 45/454 20.6 % 2.18 [ 1.57, 3.03 ]

Verdickt 1992 30/164 18/175 12.7 % 1.78 [ 1.03, 3.06 ]

Subtotal (95% CI) 1604 1615 100.0 % 1.76 [ 1.37, 2.26 ]

Total events: 299 (Treatment), 163 (Control)
Heterogeneity: Tau2 = 0.05; Chi2 = 12.09, df = 7 (P = 0.10); I2 =42%
Test for overall effect: Z = 4.41 (P = 0.000010)
2 Misoprostol 600 ug/day
Bocanegra 1998 45/152 28/154 44.3 % 1.63 [ 1.08, 2.47 ]

Chandresekaran 1991 0/45 1/45 2.5 % 0.33 [ 0.01, 7.97 ]

Henriksson 1993 1/19 0/20 2.5 % 3.15 [ 0.14, 72.88 ]

Raskin 1995 136/474 45/454 50.7 % 2.89 [ 2.12, 3.95 ]

Subtotal (95% CI) 690 673 100.0 % 2.13 [ 1.28, 3.55 ]

Total events: 182 (Treatment), 74 (Control)
Heterogeneity: Tau2 = 0.11; Chi2 = 6.23, df = 3 (P = 0.10); I2 =52%
Test for overall effect: Z = 2.90 (P = 0.0037)
3 Misoprostol 800 ug/day
Agrawal 1991 45/179 9/177 13.3 % 4.94 [ 2.49, 9.81 ]

0.005 0.1 1 10 200

Favours treatment Favours control
(Continued . . . )

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 (. . .Continued)
Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio
M- M-
H,Random,95% H,Random,95%
n/N n/N CI CI
Delmas 1994 8/80 5/103 6.7 % 2.06 [ 0.70, 6.06 ]

Elliot 1994 8/40 5/43 7.2 % 1.72 [ 0.61, 4.82 ]

Graham 1988 54/139 18/138 20.2 % 2.98 [ 1.85, 4.81 ]

Graham 2002 29/134 4/134 7.4 % 7.25 [ 2.62, 20.06 ]

Hawkey 1998 25/297 7/155 10.4 % 1.86 [ 0.82, 4.21 ]

Raskin 1995 60/228 45/454 26.1 % 2.65 [ 1.87, 3.78 ]

Roth 1993 26/60 4/53 7.7 % 5.74 [ 2.14, 15.39 ]

Saggioro 1991 7/82 0/84 1.1 % 15.36 [ 0.89, 264.69 ]

Subtotal (95% CI) 1239 1341 100.0 % 3.16 [ 2.33, 4.29 ]

Total events: 262 (Treatment), 97 (Control)
Heterogeneity: Tau2 = 0.06; Chi2 = 11.57, df = 8 (P = 0.17); I2 =31%
Test for overall effect: Z = 7.38 (P < 0.00001)

0.005 0.1 1 10 200

Favours treatment Favours control

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 Analysis 6.5. Comparison 6 Misoprostol vs placebo - symptoms - by dose, Outcome 5 Abdominal pain.

Review: Prevention of NSAID-induced gastroduodenal ulcers

Comparison: 6 Misoprostol vs placebo - symptoms - by dose

Outcome: 5 Abdominal pain

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio

M- M-
H,Random,95% H,Random,95%
n/N n/N CI CI
1 Misoprostol 400 ug/day
Agrawal 1995 23/193 15/191 7.8 % 1.52 [ 0.82, 2.82 ]

Bocanegra 1998 51/175 45/154 15.8 % 1.00 [ 0.71, 1.40 ]

Bolten 1992 57/178 34/183 14.5 % 1.72 [ 1.19, 2.50 ]

Graham 1988 23/143 25/138 10.0 % 0.89 [ 0.53, 1.49 ]

Melo Gomes 1993 45/216 34/217 13.3 % 1.33 [ 0.89, 1.99 ]

Raskin 1995 195/462 168/454 23.9 % 1.14 [ 0.97, 1.34 ]

Verdickt 1992 31/64 44/175 14.9 % 1.93 [ 1.34, 2.76 ]

Subtotal (95% CI) 1431 1512 100.0 % 1.30 [ 1.07, 1.60 ]

Total events: 425 (Treatment), 365 (Control)
Heterogeneity: Tau2 = 0.04; Chi2 = 13.56, df = 6 (P = 0.03); I2 =56%
Test for overall effect: Z = 2.57 (P = 0.010)
2 Misoprostol 600 ug/day
Bocanegra 1998 48/152 45/154 38.4 % 1.08 [ 0.77, 1.52 ]

Henriksson 1993 8/19 1/20 2.4 % 8.42 [ 1.16, 61.10 ]

Raskin 1995 199/474 168/454 59.1 % 1.13 [ 0.97, 1.33 ]

Subtotal (95% CI) 645 628 100.0 % 1.17 [ 0.85, 1.60 ]

Total events: 255 (Treatment), 214 (Control)
Heterogeneity: Tau2 = 0.04; Chi2 = 4.06, df = 2 (P = 0.13); I2 =51%
Test for overall effect: Z = 0.97 (P = 0.33)
3 Misoprostol 800 ug/day
Graham 1988 25/139 25/138 23.8 % 0.99 [ 0.60, 1.64 ]

Graham 2002 8/134 0/134 3.1 % 17.00 [ 0.99, 291.60 ]

Hawkey 1998 14/297 9/155 17.6 % 0.81 [ 0.36, 1.83 ]

Raskin 1995 112/228 168/454 29.4 % 1.33 [ 1.11, 1.59 ]

Saggioro 1991 24/82 46/84 26.1 % 0.53 [ 0.36, 0.79 ]

Subtotal (95% CI) 880 965 100.0 % 0.97 [ 0.57, 1.64 ]

Total events: 183 (Treatment), 248 (Control)
Heterogeneity: Tau2 = 0.24; Chi2 = 21.75, df = 4 (P = 0.00022); I2 =82%
Test for overall effect: Z = 0.12 (P = 0.91)

0.005 0.1 1 10 200

Favours treatment Favours control

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 Analysis 6.6. Comparison 6 Misoprostol vs placebo - symptoms - by dose, Outcome 6 Flatulence.

Review: Prevention of NSAID-induced gastroduodenal ulcers

Comparison: 6 Misoprostol vs placebo - symptoms - by dose

Outcome: 6 Flatulence

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio

M- M-
H,Random,95% H,Random,95%
n/N n/N CI CI

1 Misoprostol 400 ug/day

Bolten 1992 16/178 6/183 15.4 % 2.74 [ 1.10, 6.85 ]

Graham 1988 26/143 19/138 27.8 % 1.32 [ 0.77, 2.27 ]

Raskin 1995 113/462 91/454 42.8 % 1.22 [ 0.96, 1.56 ]

Verdickt 1992 16/164 5/175 14.0 % 3.41 [ 1.28, 9.11 ]

Subtotal (95% CI) 947 950 100.0 % 1.63 [ 1.06, 2.52 ]

Total events: 171 (Treatment), 121 (Control)
Heterogeneity: Tau2 = 0.10; Chi2 = 6.49, df = 3 (P = 0.09); I2 =54%
Test for overall effect: Z = 2.22 (P = 0.027)
2 Misoprostol 600 ug/day
Raskin 1995 128/474 91/454 100.0 % 1.35 [ 1.06, 1.71 ]

Subtotal (95% CI) 474 454 100.0 % 1.35 [ 1.06, 1.71 ]

Total events: 128 (Treatment), 91 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 2.48 (P = 0.013)
3 Misoprostol 800 ug/day
Graham 1988 25/139 19/138 17.5 % 1.31 [ 0.76, 2.26 ]

Hawkey 1998 10/297 5/155 4.7 % 1.04 [ 0.36, 3.00 ]

Raskin 1995 76/228 91/454 77.8 % 1.66 [ 1.28, 2.16 ]

Subtotal (95% CI) 664 747 100.0 % 1.56 [ 1.24, 1.96 ]

Total events: 111 (Treatment), 115 (Control)
Heterogeneity: Tau2 = 0.0; Chi2 = 1.21, df = 2 (P = 0.55); I2 =0.0%
Test for overall effect: Z = 3.80 (P = 0.00014)

0.1 0.2 0.5 1 2 5 10

Favours treatment Favours control

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 Analysis 6.7. Comparison 6 Misoprostol vs placebo - symptoms - by dose, Outcome 7 Vomiting.

Review: Prevention of NSAID-induced gastroduodenal ulcers

Comparison: 6 Misoprostol vs placebo - symptoms - by dose

Outcome: 7 Vomiting

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio

M- M-
H,Random,95% H,Random,95%
n/N n/N CI CI

1 Misoprostol 400 ug/day

Raskin 1995 1/462 2/454 100.0 % 0.49 [ 0.04, 5.40 ]

Subtotal (95% CI) 462 454 100.0 % 0.49 [ 0.04, 5.40 ]

Total events: 1 (Treatment), 2 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 0.58 (P = 0.56)
2 Misoprostol 600 ug/day
Raskin 1995 3/474 2/454 100.0 % 1.44 [ 0.24, 8.56 ]

Subtotal (95% CI) 474 454 100.0 % 1.44 [ 0.24, 8.56 ]

Total events: 3 (Treatment), 2 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 0.40 (P = 0.69)
3 Misoprostol 800 ug/day
Raskin 1995 4/228 2/454 35.3 % 3.98 [ 0.73, 21.58 ]

Silverstein 1995 51/4404 61/4439 64.7 % 0.84 [ 0.58, 1.22 ]

Subtotal (95% CI) 4632 4893 100.0 % 1.46 [ 0.34, 6.25 ]

Total events: 55 (Treatment), 63 (Control)
Heterogeneity: Tau2 = 0.82; Chi2 = 3.10, df = 1 (P = 0.08); I2 =68%
Test for overall effect: Z = 0.51 (P = 0.61)

0.05 0.2 1 5 20
Favours treatment Favours control

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 Analysis 6.8. Comparison 6 Misoprostol vs placebo - symptoms - by dose, Outcome 8 Dropouts due to side
effects.
Review: Prevention of NSAID-induced gastroduodenal ulcers

Comparison: 6 Misoprostol vs placebo - symptoms - by dose

Outcome: 8 Dropouts due to side effects

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio

M- M-
H,Random,95% H,Random,95%
n/N n/N CI CI
1 Misoprostol 400 ug/day
Agrawal 1995 11/193 9/191 10.0 % 1.21 [ 0.51, 2.85 ]

Bolten 1992 11/178 10/183 10.7 % 1.13 [ 0.49, 2.60 ]

Delmas 1994 5/73 6/103 5.6 % 1.18 [ 0.37, 3.71 ]

Raskin 1995 55/462 49/454 56.2 % 1.10 [ 0.77, 1.59 ]

Verdickt 1992 18/164 15/175 17.4 % 1.28 [ 0.67, 2.46 ]

Subtotal (95% CI) 1070 1106 100.0 % 1.15 [ 0.88, 1.51 ]

Total events: 100 (Treatment), 89 (Control)
Heterogeneity: Tau2 = 0.0; Chi2 = 0.17, df = 4 (P = 1.00); I2 =0.0%
Test for overall effect: Z = 1.01 (P = 0.31)
2 Misoprostol 600 ug/day
Raskin 1995 56/474 49/454 100.0 % 1.09 [ 0.76, 1.57 ]

Subtotal (95% CI) 474 454 100.0 % 1.09 [ 0.76, 1.57 ]

Total events: 56 (Treatment), 49 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 0.49 (P = 0.62)
3 Misoprostol 800 ug/day
Agrawal 1991 31/179 16/177 12.8 % 1.92 [ 1.09, 3.38 ]

Delmas 1994 10/80 6/103 5.7 % 2.15 [ 0.81, 5.66 ]

Elliot 1994 5/40 1/43 1.4 % 5.38 [ 0.66, 44.04 ]

Graham 1993 38/320 34/323 17.3 % 1.13 [ 0.73, 1.74 ]

Hawkey 1998 23/297 3/155 4.0 % 4.00 [ 1.22, 13.12 ]

Raskin 1995 46/228 49/454 20.2 % 1.87 [ 1.29, 2.71 ]

Roth 1993 9/60 2/53 2.7 % 3.98 [ 0.90, 17.58 ]

Saggioro 1991 6/82 1/84 1.4 % 6.15 [ 0.76, 49.94 ]

Silverstein 1995 1210/4404 896/4439 34.5 % 1.36 [ 1.26, 1.47 ]

Subtotal (95% CI) 5690 5831 100.0 % 1.68 [ 1.31, 2.17 ]

Total events: 1378 (Treatment), 1008 (Control)
Heterogeneity: Tau2 = 0.05; Chi2 = 14.18, df = 8 (P = 0.08); I2 =44%
Test for overall effect: Z = 4.05 (P = 0.000052)

0.02 0.1 1 10 50
Favours treatment Favours control

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 Analysis 6.9. Comparison 6 Misoprostol vs placebo - symptoms - by dose, Outcome 9 Dropouts overall.

Review: Prevention of NSAID-induced gastroduodenal ulcers

Comparison: 6 Misoprostol vs placebo - symptoms - by dose

Outcome: 9 Dropouts overall

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio

M- M-
H,Random,95% H,Random,95%
n/N n/N CI CI
1 Misoprostol 400 ug/day
Verdickt 1992 32/164 31/175 13.9 % 1.10 [ 0.71, 1.72 ]

Raskin 1995 101/462 115/454 50.6 % 0.86 [ 0.68, 1.09 ]

Bolten 1992 16/178 16/183 6.3 % 1.03 [ 0.53, 1.99 ]

Delmas 1994 14/73 16/103 6.5 % 1.23 [ 0.64, 2.37 ]

Graham 1988 45/143 42/138 22.6 % 1.03 [ 0.73, 1.47 ]

Subtotal (95% CI) 1020 1053 100.0 % 0.96 [ 0.82, 1.14 ]

Total events: 208 (Treatment), 220 (Control)
Heterogeneity: Tau2 = 0.0; Chi2 = 1.95, df = 4 (P = 0.75); I2 =0.0%
Test for overall effect: Z = 0.45 (P = 0.65)
2 Misoprostol 600 ug/day
Henriksson 1993 1/20 0/20 0.5 % 3.00 [ 0.13, 69.52 ]

Raskin 1995 131/474 115/454 99.5 % 1.09 [ 0.88, 1.35 ]

Subtotal (95% CI) 494 474 100.0 % 1.10 [ 0.88, 1.36 ]

Total events: 132 (Treatment), 115 (Control)
Heterogeneity: Tau2 = 0.0; Chi2 = 0.40, df = 1 (P = 0.53); I2 =0.0%
Test for overall effect: Z = 0.84 (P = 0.40)
3 Misoprostol 800 ug/day
Agrawal 1991 57/179 46/177 16.6 % 1.23 [ 0.88, 1.70 ]

Saggioro 1991 9/82 4/84 2.8 % 2.30 [ 0.74, 7.19 ]

Elliot 1994 13/40 5/43 4.0 % 2.80 [ 1.09, 7.14 ]

Raskin 1995 74/228 115/454 20.6 % 1.28 [ 1.00, 1.64 ]

Delmas 1994 31/80 16/103 9.8 % 2.49 [ 1.47, 4.23 ]

Graham 1988 41/139 42/138 15.3 % 0.97 [ 0.68, 1.39 ]

Roth 1993 9/60 2/53 1.7 % 3.98 [ 0.90, 17.58 ]

Silverstein 1995 1851/4404 1617/4439 29.1 % 1.15 [ 1.10, 1.22 ]

Subtotal (95% CI) 5212 5491 100.0 % 1.35 [ 1.10, 1.65 ]

0.01 0.1 1 10 100

Favours treatment Favours control
(Continued . . . )

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 (. . . Continued)
Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio
M- M-
H,Random,95% H,Random,95%
n/N n/N CI CI
Total events: 2085 (Treatment), 1847 (Control)
Heterogeneity: Tau2 = 0.04; Chi2 = 17.17, df = 7 (P = 0.02); I2 =59%
Test for overall effect: Z = 2.92 (P = 0.0035)

0.01 0.1 1 10 100

Favours treatment Favours control

Analysis 6.10. Comparison 6 Misoprostol vs placebo - symptoms - by dose, Outcome 10 Headache.

Review: Prevention of NSAID-induced gastroduodenal ulcers

Comparison: 6 Misoprostol vs placebo - symptoms - by dose

Outcome: 10 Headache

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 Misoprostol 400 ug/day

Bolten 1992 12/178 20/183 56.0 % 0.62 [ 0.31, 1.22 ]

Verdickt 1992 10/164 16/175 44.0 % 0.67 [ 0.31, 1.43 ]

Subtotal (95% CI) 342 358 100.0 % 0.64 [ 0.38, 1.06 ]

Total events: 22 (Treatment), 36 (Control)
Heterogeneity: Chi2 = 0.02, df = 1 (P = 0.88); I2 =0.0%
Test for overall effect: Z = 1.72 (P = 0.085)
2 Misoprostol 600 ug/day
Subtotal (95% CI) 0 0 0.0 % 0.0 [ 0.0, 0.0 ]
Total events: 0 (Treatment), 0 (Control)
Heterogeneity: not applicable
Test for overall effect: not applicable
3 Misoprostol 800 ug/day
Subtotal (95% CI) 0 0 0.0 % 0.0 [ 0.0, 0.0 ]
Total events: 0 (Treatment), 0 (Control)
Heterogeneity: not applicable
Test for overall effect: not applicable

0.5 0.7 1 1.5 2

Favours treatment Favours control

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 Analysis 7.1. Comparison 7 H2 Receptor vs placebo - 4 - 11 week studies by dose, Outcome 1 Gastric ulcer.

Review: Prevention of NSAID-induced gastroduodenal ulcers

Comparison: 7 H2 Receptor vs placebo - 4 - 11 week studies by dose

Outcome: 1 Gastric ulcer

Study or subgroup Treatment Control Risk Ratio Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 High dose
Taha 1996 2/97 10/93 0.19 [ 0.04, 0.85 ]

Subtotal (95% CI) 97 93 0.19 [ 0.04, 0.85 ]

Total events: 2 (Treatment), 10 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 2.17 (P = 0.030)
2 Low dose
Berkowitz 1987 0/25 0/25 0.0 [ 0.0, 0.0 ]

Ehsanullah 1988 4/151 6/146 0.64 [ 0.19, 2.24 ]

Robinson 1989 3/72 4/72 0.75 [ 0.17, 3.23 ]

Taha 1996 6/95 10/93 0.59 [ 0.22, 1.55 ]

van Groenendaci 1996 0/18 2/18 0.20 [ 0.01, 3.89 ]

Subtotal (95% CI) 361 354 0.59 [ 0.31, 1.13 ]

Total events: 13 (Treatment), 22 (Control)
Heterogeneity: Chi2 = 0.63, df = 3 (P = 0.89); I2 =0.0%
Test for overall effect: Z = 1.58 (P = 0.11)

0.01 0.1 1 10 100

Favours treatment Favours control

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 Analysis 7.2. Comparison 7 H2 Receptor vs placebo - 4 - 11 week studies by dose, Outcome 2 Duodenal
ulcer.
Review: Prevention of NSAID-induced gastroduodenal ulcers

Comparison: 7 H2 Receptor vs placebo - 4 - 11 week studies by dose

Outcome: 2 Duodenal ulcer

Study or subgroup Treatment Control Risk Ratio Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 High dose
Taha 1996 1/97 6/93 0.16 [ 0.02, 1.30 ]

Subtotal (95% CI) 97 93 0.16 [ 0.02, 1.30 ]

Total events: 1 (Treatment), 6 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 1.71 (P = 0.087)
2 Low dose
Berkowitz 1987 0/25 1/25 0.33 [ 0.01, 7.81 ]

Ehsanullah 1988 2/151 10/146 0.19 [ 0.04, 0.87 ]

Robinson 1989 0/72 4/72 0.11 [ 0.01, 2.03 ]

Robinson 1991 2/112 3/115 0.68 [ 0.12, 4.02 ]

Taha 1996 1/95 6/93 0.16 [ 0.02, 1.33 ]

van Groenendaci 1996 0/18 0/18 0.0 [ 0.0, 0.0 ]

Subtotal (95% CI) 473 469 0.24 [ 0.10, 0.57 ]

Total events: 5 (Treatment), 24 (Control)
Heterogeneity: Chi2 = 1.88, df = 4 (P = 0.76); I2 =0.0%
Test for overall effect: Z = 3.20 (P = 0.0014)

0.005 0.1 1 10 200

Favours treatment Favours control

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 Analysis 7.3. Comparison 7 H2 Receptor vs placebo - 4 - 11 week studies by dose, Outcome 3 Total
endoscopic ulcers.

Review: Prevention of NSAID-induced gastroduodenal ulcers

Comparison: 7 H2 Receptor vs placebo - 4 - 11 week studies by dose

Outcome: 3 Total endoscopic ulcers

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 High dose
Hudson 1997 5/39 13/39 45.9 % 0.38 [ 0.15, 0.98 ]

Taha 1996 2/97 15/93 54.1 % 0.13 [ 0.03, 0.54 ]

Subtotal (95% CI) 136 132 100.0 % 0.25 [ 0.11, 0.53 ]

Total events: 7 (Treatment), 28 (Control)
Heterogeneity: Chi2 = 1.67, df = 1 (P = 0.20); I2 =40%
Test for overall effect: Z = 3.54 (P = 0.00041)
2 Low dose
Berkowitz 1987 0/25 1/25 4.0 % 0.33 [ 0.01, 7.81 ]

Ehsanullah 1988 6/151 16/146 43.6 % 0.36 [ 0.15, 0.90 ]

Roth 1987 2/12 2/14 5.0 % 1.17 [ 0.19, 7.07 ]

Taha 1996 6/95 15/93 40.7 % 0.39 [ 0.16, 0.97 ]

van Groenendaci 1996 0/18 2/18 6.7 % 0.20 [ 0.01, 3.89 ]

Subtotal (95% CI) 301 296 100.0 % 0.40 [ 0.23, 0.71 ]

Total events: 14 (Treatment), 36 (Control)
Heterogeneity: Chi2 = 1.62, df = 4 (P = 0.80); I2 =0.0%
Test for overall effect: Z = 3.11 (P = 0.0019)

0.01 0.1 1 10 100

Favours treatment Favours control

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 Analysis 8.1. Comparison 8 H2 Receptor vs placebo 12 weeks or longer - by dose, Outcome 1 Gastric ulcer.

Review: Prevention of NSAID-induced gastroduodenal ulcers

Comparison: 8 H2 Receptor vs placebo 12 weeks or longer - by dose

Outcome: 1 Gastric ulcer

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 High dose
Hudson 1997 7/39 16/39 41.7 % 0.44 [ 0.20, 0.94 ]

Taha 1996 7/97 16/93 42.6 % 0.42 [ 0.18, 0.97 ]

Ten Wolde 1996 3/15 6/15 15.7 % 0.50 [ 0.15, 1.64 ]

Subtotal (95% CI) 151 147 100.0 % 0.44 [ 0.26, 0.74 ]

Total events: 17 (Treatment), 38 (Control)
Heterogeneity: Chi2 = 0.06, df = 2 (P = 0.97); I2 =0.0%
Test for overall effect: Z = 3.13 (P = 0.0017)
2 Low dose
Ehsanullah 1988 8/151 7/146 13.4 % 1.11 [ 0.41, 2.97 ]

Levine 1993 20/248 28/248 52.6 % 0.71 [ 0.41, 1.23 ]

Swift 1989 0/16 1/8 3.7 % 0.18 [ 0.01, 3.91 ]

Taha 1996 11/95 16/93 30.4 % 0.67 [ 0.33, 1.37 ]

Subtotal (95% CI) 510 495 100.0 % 0.73 [ 0.50, 1.08 ]

Total events: 39 (Treatment), 52 (Control)
Heterogeneity: Chi2 = 1.54, df = 3 (P = 0.67); I2 =0.0%
Test for overall effect: Z = 1.55 (P = 0.12)

0.01 0.1 1 10 100

Favours treatment Favours control

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 Analysis 8.2. Comparison 8 H2 Receptor vs placebo 12 weeks or longer - by dose, Outcome 2 Duodenal
ulcer.
Review: Prevention of NSAID-induced gastroduodenal ulcers

Comparison: 8 H2 Receptor vs placebo 12 weeks or longer - by dose

Outcome: 2 Duodenal ulcer

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 High dose
Hudson 1997 3/39 6/39 29.0 % 0.50 [ 0.13, 1.86 ]

Taha 1996 2/97 10/93 49.3 % 0.19 [ 0.04, 0.85 ]

Ten Wolde 1996 0/15 4/15 21.7 % 0.11 [ 0.01, 1.90 ]

Subtotal (95% CI) 151 147 100.0 % 0.26 [ 0.11, 0.65 ]

Total events: 5 (Treatment), 20 (Control)
Heterogeneity: Chi2 = 1.44, df = 2 (P = 0.49); I2 =0.0%
Test for overall effect: Z = 2.87 (P = 0.0041)
2 Low dose
Ehsanullah 1988 2/151 10/146 37.3 % 0.19 [ 0.04, 0.87 ]

Levine 1993 5/248 7/248 25.7 % 0.71 [ 0.23, 2.22 ]

Taha 1996 3/95 10/93 37.1 % 0.29 [ 0.08, 1.03 ]

Subtotal (95% CI) 494 487 100.0 % 0.36 [ 0.18, 0.74 ]

Total events: 10 (Treatment), 27 (Control)
Heterogeneity: Chi2 = 2.15, df = 2 (P = 0.34); I2 =7%
Test for overall effect: Z = 2.78 (P = 0.0055)

0.01 0.1 1 10 100

Favours treatment Favours control

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 Analysis 8.3. Comparison 8 H2 Receptor vs placebo 12 weeks or longer - by dose, Outcome 3 Total
endoscopic ulcers.

Review: Prevention of NSAID-induced gastroduodenal ulcers

Comparison: 8 H2 Receptor vs placebo 12 weeks or longer - by dose

Outcome: 3 Total endoscopic ulcers

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 High dose
Hudson 1997 10/39 21/39 39.2 % 0.48 [ 0.26, 0.87 ]

Taha 1996 9/97 24/93 45.8 % 0.36 [ 0.18, 0.73 ]

Ten Wolde 1996 3/15 8/15 15.0 % 0.38 [ 0.12, 1.15 ]

Subtotal (95% CI) 151 147 100.0 % 0.41 [ 0.26, 0.63 ]

Total events: 22 (Treatment), 53 (Control)
Heterogeneity: Chi2 = 0.39, df = 2 (P = 0.82); I2 =0.0%
Test for overall effect: Z = 4.08 (P = 0.000045)
2 Low dose
Ehsanullah 1988 10/151 17/146 22.9 % 0.57 [ 0.27, 1.20 ]

Levine 1993 24/248 34/248 45.0 % 0.71 [ 0.43, 1.15 ]

Taha 1996 14/95 24/93 32.1 % 0.57 [ 0.32, 1.03 ]

Subtotal (95% CI) 494 487 100.0 % 0.63 [ 0.45, 0.88 ]

Total events: 48 (Treatment), 75 (Control)
Heterogeneity: Chi2 = 0.38, df = 2 (P = 0.83); I2 =0.0%
Test for overall effect: Z = 2.67 (P = 0.0076)

0.1 0.2 0.5 1 2 5 10

Favours treatment Favours control

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 Analysis 9.1. Comparison 9 H2 Receptor vs placebo - toxicity - by dose, Outcome 1 Total drop-outs.

Review: Prevention of NSAID-induced gastroduodenal ulcers

Comparison: 9 H2 Receptor vs placebo - toxicity - by dose

Outcome: 1 Total drop-outs

Study or subgroup Treatment Control Risk Ratio Risk Ratio

M- M-
H,Random,95% H,Random,95%
n/N n/N CI CI

1 High dose
Hudson 1997 8/39 14/39 0.57 [ 0.27, 1.21 ]

Swift 1989 0/16 0/8 0.0 [ 0.0, 0.0 ]

Taha 1996 16/97 13/93 1.18 [ 0.60, 2.32 ]

Subtotal (95% CI) 152 140 0.84 [ 0.41, 1.70 ]

Total events: 24 (Treatment), 27 (Control)
Heterogeneity: Tau2 = 0.13; Chi2 = 2.00, df = 1 (P = 0.16); I2 =50%
Test for overall effect: Z = 0.49 (P = 0.62)
2 Low dose
Berkowitz 1987 0/25 0/25 0.0 [ 0.0, 0.0 ]

Ehsanullah 1988 33/151 38/146 0.84 [ 0.56, 1.26 ]

Levine 1993 63/248 77/248 0.82 [ 0.62, 1.09 ]

Robinson 1989 11/72 18/72 0.61 [ 0.31, 1.20 ]

Swift 1989 0/16 0/8 0.0 [ 0.0, 0.0 ]

Taha 1996 14/95 13/93 1.05 [ 0.52, 2.12 ]

Subtotal (95% CI) 607 592 0.82 [ 0.66, 1.01 ]

Total events: 121 (Treatment), 146 (Control)
Heterogeneity: Tau2 = 0.0; Chi2 = 1.24, df = 3 (P = 0.74); I2 =0.0%
Test for overall effect: Z = 1.86 (P = 0.062)

0.5 0.7 1 1.5 2

Favours treatment Favours control

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 Analysis 9.2. Comparison 9 H2 Receptor vs placebo - toxicity - by dose, Outcome 2 Drop-outs due to side
effects.
Review: Prevention of NSAID-induced gastroduodenal ulcers

Comparison: 9 H2 Receptor vs placebo - toxicity - by dose

Outcome: 2 Drop-outs due to side effects

Study or subgroup Treatment Control Risk Ratio Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 High dose
Hudson 1997 3/39 3/39 1.00 [ 0.21, 4.65 ]

Swift 1989 0/16 0/8 0.0 [ 0.0, 0.0 ]

Subtotal (95% CI) 55 47 1.00 [ 0.21, 4.65 ]

Total events: 3 (Treatment), 3 (Control)
Heterogeneity: Chi2 = 0.0, df = 0 (P = 1.00); I2 =0.0%
Test for overall effect: Z = 0.0 (P = 1.0)
2 Low dose
Berkowitz 1987 0/25 0/25 0.0 [ 0.0, 0.0 ]

Ehsanullah 1988 19/151 18/146 1.02 [ 0.56, 1.87 ]

Levine 1993 19/248 25/248 0.76 [ 0.43, 1.34 ]

Robinson 1989 3/72 4/72 0.75 [ 0.17, 3.23 ]

Swift 1989 0/16 0/8 0.0 [ 0.0, 0.0 ]

Subtotal (95% CI) 512 499 0.86 [ 0.58, 1.28 ]

Total events: 41 (Treatment), 47 (Control)
Heterogeneity: Chi2 = 0.52, df = 2 (P = 0.77); I2 =0.0%
Test for overall effect: Z = 0.74 (P = 0.46)

0.2 0.5 1 2 5
Favours treatment Favours control

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 Analysis 9.3. Comparison 9 H2 Receptor vs placebo - toxicity - by dose, Outcome 3 Dropouts due to GI
symptoms.

Review: Prevention of NSAID-induced gastroduodenal ulcers

Comparison: 9 H2 Receptor vs placebo - toxicity - by dose

Outcome: 3 Dropouts due to GI symptoms

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 High dose
Subtotal (95% CI) 0 0 0.0 % 0.0 [ 0.0, 0.0 ]
Total events: 0 (Treatment), 0 (Control)
Heterogeneity: not applicable
Test for overall effect: not applicable
2 Low dose
Ehsanullah 1988 10/151 13/146 45.2 % 0.74 [ 0.34, 1.64 ]

Levine 1993 11/248 16/248 54.8 % 0.69 [ 0.33, 1.45 ]

Subtotal (95% CI) 399 394 100.0 % 0.71 [ 0.41, 1.23 ]

Total events: 21 (Treatment), 29 (Control)
Heterogeneity: Chi2 = 0.02, df = 1 (P = 0.89); I2 =0.0%
Test for overall effect: Z = 1.22 (P = 0.22)

0.5 0.7 1 1.5 2

Favours treatment Favours control

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 Analysis 9.4. Comparison 9 H2 Receptor vs placebo - toxicity - by dose, Outcome 4 Dropouts due to
abdominal pain.

Review: Prevention of NSAID-induced gastroduodenal ulcers

Comparison: 9 H2 Receptor vs placebo - toxicity - by dose

Outcome: 4 Dropouts due to abdominal pain

Study or subgroup Treatment Control Risk Ratio Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 High dose
Taha 1996 0/97 0/93 0.0 [ 0.0, 0.0 ]

Subtotal (95% CI) 97 93 0.0 [ 0.0, 0.0 ]

Total events: 0 (Treatment), 0 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 0.0 (P < 0.00001)
2 Low dose
Taha 1996 1/95 0/93 2.94 [ 0.12, 71.20 ]

Subtotal (95% CI) 95 93 2.94 [ 0.12, 71.20 ]

Total events: 1 (Treatment), 0 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 0.66 (P = 0.51)

0.01 0.1 1 10 100

Favours treatment Favours control

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 Analysis 9.5. Comparison 9 H2 Receptor vs placebo - toxicity - by dose, Outcome 5 Dropouts due to
diarrhea.
Review: Prevention of NSAID-induced gastroduodenal ulcers

Comparison: 9 H2 Receptor vs placebo - toxicity - by dose

Outcome: 5 Dropouts due to diarrhea

Study or subgroup Treatment Control Risk Ratio Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 High dose
Taha 1996 1/97 0/93 2.88 [ 0.12, 69.76 ]

Subtotal (95% CI) 97 93 2.88 [ 0.12, 69.76 ]

Total events: 1 (Treatment), 0 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 0.65 (P = 0.52)
2 Low dose
Taha 1996 0/95 0/93 0.0 [ 0.0, 0.0 ]

Subtotal (95% CI) 95 93 0.0 [ 0.0, 0.0 ]

Total events: 0 (Treatment), 0 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 0.0 (P < 0.00001)

0.01 0.1 1 10 100

Favours treatment Favours control

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 Analysis 9.6. Comparison 9 H2 Receptor vs placebo - toxicity - by dose, Outcome 6 Diarrhea.

Review: Prevention of NSAID-induced gastroduodenal ulcers

Comparison: 9 H2 Receptor vs placebo - toxicity - by dose

Outcome: 6 Diarrhea

Study or subgroup Treatment Control Risk Ratio Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 High dose
Taha 1996 1/97 0/93 2.88 [ 0.12, 69.76 ]

Subtotal (95% CI) 97 93 2.88 [ 0.12, 69.76 ]

Total events: 1 (Treatment), 0 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 0.65 (P = 0.52)
2 Low dose
Taha 1996 0/95 0/93 0.0 [ 0.0, 0.0 ]

Subtotal (95% CI) 95 93 0.0 [ 0.0, 0.0 ]

Total events: 0 (Treatment), 0 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 0.0 (P < 0.00001)

0.01 0.1 1 10 100

Favours treatment Favours control

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 Analysis 9.7. Comparison 9 H2 Receptor vs placebo - toxicity - by dose, Outcome 7 Abdominal pain.

Review: Prevention of NSAID-induced gastroduodenal ulcers

Comparison: 9 H2 Receptor vs placebo - toxicity - by dose

Outcome: 7 Abdominal pain

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 High dose
Taha 1996 16/97 27/93 100.0 % 0.57 [ 0.33, 0.98 ]

Subtotal (95% CI) 97 93 100.0 % 0.57 [ 0.33, 0.98 ]

Total events: 16 (Treatment), 27 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 2.02 (P = 0.044)
2 Low dose
Taha 1996 18/95 27/93 100.0 % 0.65 [ 0.39, 1.10 ]

Subtotal (95% CI) 95 93 100.0 % 0.65 [ 0.39, 1.10 ]

Total events: 18 (Treatment), 27 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 1.60 (P = 0.11)

0.5 0.7 1 1.5 2

Favours treatment Favours control

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 Analysis 9.8. Comparison 9 H2 Receptor vs placebo - toxicity - by dose, Outcome 8 GI symptoms.

Review: Prevention of NSAID-induced gastroduodenal ulcers

Comparison: 9 H2 Receptor vs placebo - toxicity - by dose

Outcome: 8 GI symptoms

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 High dose
Subtotal (95% CI) 0 0 0.0 % 0.0 [ 0.0, 0.0 ]
Total events: 0 (Treatment), 0 (Control)
Heterogeneity: not applicable
Test for overall effect: not applicable
2 Low dose
Levine 1993 11/248 16/248 83.0 % 0.69 [ 0.33, 1.45 ]

Swift 1989 0/16 2/8 17.0 % 0.11 [ 0.01, 1.98 ]

Subtotal (95% CI) 264 256 100.0 % 0.59 [ 0.29, 1.19 ]

Total events: 11 (Treatment), 18 (Control)
Heterogeneity: Chi2 = 1.49, df = 1 (P = 0.22); I2 =33%
Test for overall effect: Z = 1.48 (P = 0.14)

0.005 0.1 1 10 200

Favours treatment Favours control

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 Analysis 9.9. Comparison 9 H2 Receptor vs placebo - toxicity - by dose, Outcome 9 Flatulence.

Review: Prevention of NSAID-induced gastroduodenal ulcers

Comparison: 9 H2 Receptor vs placebo - toxicity - by dose

Outcome: 9 Flatulence

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 High dose
Subtotal (95% CI) 0 0 0.0 % 0.0 [ 0.0, 0.0 ]
Total events: 0 (Treatment), 0 (Control)
Heterogeneity: not applicable
Test for overall effect: not applicable
2 Low dose
Levine 1993 17/248 7/248 100.0 % 2.43 [ 1.03, 5.75 ]

Subtotal (95% CI) 248 248 100.0 % 2.43 [ 1.03, 5.75 ]

Total events: 17 (Treatment), 7 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 2.02 (P = 0.044)

0.1 0.2 0.5 1 2 5 10

Favours treatment Favours control

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 Analysis 9.10. Comparison 9 H2 Receptor vs placebo - toxicity - by dose, Outcome 10 Dyspepsia.

Review: Prevention of NSAID-induced gastroduodenal ulcers

Comparison: 9 H2 Receptor vs placebo - toxicity - by dose

Outcome: 10 Dyspepsia

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 High dose
Subtotal (95% CI) 0 0 0.0 % 0.0 [ 0.0, 0.0 ]
Total events: 0 (Treatment), 0 (Control)
Heterogeneity: not applicable
Test for overall effect: not applicable
2 Low dose
Levine 1993 11/248 16/248 83.0 % 0.69 [ 0.33, 1.45 ]

Swift 1989 0/16 2/8 17.0 % 0.11 [ 0.01, 1.98 ]

Subtotal (95% CI) 264 256 100.0 % 0.59 [ 0.29, 1.19 ]

Total events: 11 (Treatment), 18 (Control)
Heterogeneity: Chi2 = 1.49, df = 1 (P = 0.22); I2 =33%
Test for overall effect: Z = 1.48 (P = 0.14)

0.005 0.1 1 10 200

Favours treatment Favours control

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 Analysis 9.11. Comparison 9 H2 Receptor vs placebo - toxicity - by dose, Outcome 11 Rash.

Review: Prevention of NSAID-induced gastroduodenal ulcers

Comparison: 9 H2 Receptor vs placebo - toxicity - by dose

Outcome: 11 Rash

Study or subgroup Treatment Control Risk Ratio Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 High dose
Taha 1996 0/97 0/93 0.0 [ 0.0, 0.0 ]

Subtotal (95% CI) 97 93 0.0 [ 0.0, 0.0 ]

Total events: 0 (Treatment), 0 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 0.0 (P < 0.00001)
2 Low dose
Levine 1993 12/248 3/248 4.00 [ 1.14, 14.00 ]

Taha 1996 1/95 0/93 2.94 [ 0.12, 71.20 ]

Subtotal (95% CI) 343 341 3.85 [ 1.20, 12.33 ]

Total events: 13 (Treatment), 3 (Control)
Heterogeneity: Chi2 = 0.03, df = 1 (P = 0.86); I2 =0.0%
Test for overall effect: Z = 2.27 (P = 0.023)

0.01 0.1 1 10 100

Favours treatment Favours control

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 Analysis 10.1. Comparison 10 PPI vs placebo - 4 - 11 week studies, Outcome 1 Endoscopic gastric ulcer.

Review: Prevention of NSAID-induced gastroduodenal ulcers

Comparison: 10 PPI vs placebo - 4 - 11 week studies

Outcome: 1 Endoscopic gastric ulcer

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
Lai 2003 1/22 7/21 100.0 % 0.14 [ 0.02, 1.02 ]

Total (95% CI) 22 21 100.0 % 0.14 [ 0.02, 1.02 ]

Total events: 1 (Treatment), 7 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 1.94 (P = 0.052)
Test for subgroup differences: Not applicable

0.01 0.1 1 10 100

Favours treatment Favours control

Analysis 10.2. Comparison 10 PPI vs placebo - 4 - 11 week studies, Outcome 2 Endoscopic duodenal ulcer.

Review: Prevention of NSAID-induced gastroduodenal ulcers

Comparison: 10 PPI vs placebo - 4 - 11 week studies

Outcome: 2 Endoscopic duodenal ulcer

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
Lai 2003 1/22 2/21 100.0 % 0.48 [ 0.05, 4.88 ]

Total (95% CI) 22 21 100.0 % 0.48 [ 0.05, 4.88 ]

Total events: 1 (Treatment), 2 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 0.62 (P = 0.53)
Test for subgroup differences: Not applicable

0.02 0.1 1 10 50
Favours treatment Favours control

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 Analysis 10.3. Comparison 10 PPI vs placebo - 4 - 11 week studies, Outcome 3 Total endoscopic ulcers.

Review: Prevention of NSAID-induced gastroduodenal ulcers

Comparison: 10 PPI vs placebo - 4 - 11 week studies

Outcome: 3 Total endoscopic ulcers

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
Lai 2003 2/22 9/21 100.0 % 0.21 [ 0.05, 0.87 ]

Total (95% CI) 22 21 100.0 % 0.21 [ 0.05, 0.87 ]

Total events: 2 (Treatment), 9 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 2.15 (P = 0.031)
Test for subgroup differences: Not applicable

0.05 0.2 1 5 20
Favours treatment Favours control

Analysis 10.4. Comparison 10 PPI vs placebo - 4 - 11 week studies, Outcome 4 Clinical Ulcer (POB).

Review: Prevention of NSAID-induced gastroduodenal ulcers

Comparison: 10 PPI vs placebo - 4 - 11 week studies

Outcome: 4 Clinical Ulcer (POB)

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
Lai 2003 0/22 4/21 100.0 % 0.11 [ 0.01, 1.86 ]

Total (95% CI) 22 21 100.0 % 0.11 [ 0.01, 1.86 ]

Total events: 0 (Treatment), 4 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 1.53 (P = 0.12)
Test for subgroup differences: Not applicable

0.002 0.1 1 10 500

Favours experimental Favours control

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 Analysis 10.5. Comparison 10 PPI vs placebo - 4 - 11 week studies, Outcome 5 Clinical Ulcer - PUB (POB +
symptomatic ulcer).

Review: Prevention of NSAID-induced gastroduodenal ulcers

Comparison: 10 PPI vs placebo - 4 - 11 week studies

Outcome: 5 Clinical Ulcer - PUB (POB + symptomatic ulcer)

Study or subgroup Treatment Control Odds Ratio Weight Odds Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
Lai 2003 1/22 9/21 100.0 % 0.06 [ 0.01, 0.56 ]

Total (95% CI) 22 21 100.0 % 0.06 [ 0.01, 0.56 ]

Total events: 1 (Treatment), 9 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 2.47 (P = 0.013)
Test for subgroup differences: Not applicable

0.005 0.1 1 10 200

Favours experimental Favours control

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 Analysis 11.1. Comparison 11 PPI vs placebo - 8 weeks or longer studies, Outcome 1 Endoscopic gastric
ulcer.
Review: Prevention of NSAID-induced gastroduodenal ulcers

Comparison: 11 PPI vs placebo - 8 weeks or longer studies

Outcome: 1 Endoscopic gastric ulcer

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

Bianchi Porro 2000 7/43 5/23 3.9 % 0.75 [ 0.27, 2.10 ]

Cullen 1998 3/83 9/85 5.4 % 0.34 [ 0.10, 1.22 ]

Ekstrom 1996 2/86 6/91 3.5 % 0.35 [ 0.07, 1.70 ]

Graham 2002 45/236 54/111 44.3 % 0.39 [ 0.28, 0.54 ]

Hawkey 1998 35/274 50/155 38.5 % 0.40 [ 0.27, 0.58 ]

Lai 2003 1/22 7/21 4.3 % 0.14 [ 0.02, 1.02 ]

Total (95% CI) 744 486 100.0 % 0.39 [ 0.31, 0.50 ]

Total events: 93 (Treatment), 131 (Control)
Heterogeneity: Chi2 = 2.64, df = 5 (P = 0.75); I2 =0.0%
Test for overall effect: Z = 7.79 (P < 0.00001)
Test for subgroup differences: Not applicable

0.02 0.1 1 10 50
Favours treatment Favours control

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 Analysis 11.2. Comparison 11 PPI vs placebo - 8 weeks or longer studies, Outcome 2 Endoscopic duodenal
ulcer.
Review: Prevention of NSAID-induced gastroduodenal ulcers

Comparison: 11 PPI vs placebo - 8 weeks or longer studies

Outcome: 2 Endoscopic duodenal ulcer

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

Bianchi Porro 2000 0/43 2/23 7.2 % 0.11 [ 0.01, 2.18 ]

Cullen 1998 0/83 6/85 14.4 % 0.08 [ 0.00, 1.38 ]

Ekstrom 1996 2/86 9/91 19.6 % 0.24 [ 0.05, 1.06 ]

Hawkey 1998 7/274 19/155 54.3 % 0.21 [ 0.09, 0.48 ]

Lai 2003 1/22 2/21 4.6 % 0.48 [ 0.05, 4.88 ]

Total (95% CI) 508 375 100.0 % 0.20 [ 0.10, 0.39 ]

Total events: 10 (Treatment), 38 (Control)
Heterogeneity: Chi2 = 1.16, df = 4 (P = 0.89); I2 =0.0%
Test for overall effect: Z = 4.76 (P < 0.00001)
Test for subgroup differences: Not applicable

0.005 0.1 1 10 200

Favours treatment Favours control

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 Analysis 11.3. Comparison 11 PPI vs placebo - 8 weeks or longer studies, Outcome 3 Total endoscopic
ulcers.
Review: Prevention of NSAID-induced gastroduodenal ulcers

Comparison: 11 PPI vs placebo - 8 weeks or longer studies

Outcome: 3 Total endoscopic ulcers

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

Bianchi Porro 2000 12/65 14/30 8.7 % 0.40 [ 0.21, 0.75 ]

Cullen 1998 3/83 14/85 6.3 % 0.22 [ 0.07, 0.74 ]

Ekstrom 1996 4/86 15/91 6.6 % 0.28 [ 0.10, 0.82 ]

Graham 2002 45/236 56/111 34.5 % 0.38 [ 0.27, 0.52 ]

Hawkey 1998 42/274 69/155 39.9 % 0.34 [ 0.25, 0.48 ]

Lai 2003 2/22 9/21 4.2 % 0.21 [ 0.05, 0.87 ]

Total (95% CI) 766 493 100.0 % 0.34 [ 0.28, 0.42 ]

Total events: 108 (Treatment), 177 (Control)
Heterogeneity: Chi2 = 1.64, df = 5 (P = 0.90); I2 =0.0%
Test for overall effect: Z = 9.98 (P < 0.00001)
Test for subgroup differences: Not applicable

0.05 0.2 1 5 20
Favours treatment Favours control

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 Analysis 12.1. Comparison 12 PPI vs placebo - 12 weeks or longer studies, Outcome 1 Endoscopic gastric
ulcer.
Review: Prevention of NSAID-induced gastroduodenal ulcers

Comparison: 12 PPI vs placebo - 12 weeks or longer studies

Outcome: 1 Endoscopic gastric ulcer

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

Bianchi Porro 2000 7/43 5/23 4.1 % 0.75 [ 0.27, 2.10 ]

Cullen 1998 3/83 9/85 5.6 % 0.34 [ 0.10, 1.22 ]

Ekstrom 1996 2/86 6/91 3.7 % 0.35 [ 0.07, 1.70 ]

Graham 2002 45/236 54/111 46.3 % 0.39 [ 0.28, 0.54 ]

Hawkey 1998 35/274 50/155 40.3 % 0.40 [ 0.27, 0.58 ]

Total (95% CI) 722 465 100.0 % 0.40 [ 0.32, 0.51 ]

Total events: 92 (Treatment), 124 (Control)
Heterogeneity: Chi2 = 1.52, df = 4 (P = 0.82); I2 =0.0%
Test for overall effect: Z = 7.51 (P < 0.00001)
Test for subgroup differences: Not applicable

0.1 0.2 0.5 1 2 5 10

Favours treatment Favours control

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 Analysis 12.2. Comparison 12 PPI vs placebo - 12 weeks or longer studies, Outcome 2 Endoscopic duodenal
ulcer.
Review: Prevention of NSAID-induced gastroduodenal ulcers

Comparison: 12 PPI vs placebo - 12 weeks or longer studies

Outcome: 2 Endoscopic duodenal ulcer

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

Bianchi Porro 2000 0/43 2/23 7.6 % 0.11 [ 0.01, 2.18 ]

Cullen 1998 0/83 6/85 15.1 % 0.08 [ 0.00, 1.38 ]

Ekstrom 1996 2/86 9/91 20.5 % 0.24 [ 0.05, 1.06 ]

Hawkey 1998 7/274 19/155 56.9 % 0.21 [ 0.09, 0.48 ]

Total (95% CI) 486 354 100.0 % 0.19 [ 0.09, 0.37 ]

Total events: 9 (Treatment), 36 (Control)
Heterogeneity: Chi2 = 0.63, df = 3 (P = 0.89); I2 =0.0%
Test for overall effect: Z = 4.72 (P < 0.00001)
Test for subgroup differences: Not applicable

0.005 0.1 1 10 200

Favours treatment Favours control

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 Analysis 12.3. Comparison 12 PPI vs placebo - 12 weeks or longer studies, Outcome 3 Total endoscopic
ulcers.
Review: Prevention of NSAID-induced gastroduodenal ulcers

Comparison: 12 PPI vs placebo - 12 weeks or longer studies

Outcome: 3 Total endoscopic ulcers

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

Bianchi Porro 2000 12/65 14/30 9.0 % 0.40 [ 0.21, 0.75 ]

Cullen 1998 3/83 14/85 6.5 % 0.22 [ 0.07, 0.74 ]

Ekstrom 1996 4/86 15/91 6.9 % 0.28 [ 0.10, 0.82 ]

Graham 2002 45/236 56/111 36.0 % 0.38 [ 0.27, 0.52 ]

Hawkey 1998 42/274 69/155 41.6 % 0.34 [ 0.25, 0.48 ]

Total (95% CI) 744 472 100.0 % 0.35 [ 0.28, 0.43 ]

Total events: 106 (Treatment), 168 (Control)
Heterogeneity: Chi2 = 1.11, df = 4 (P = 0.89); I2 =0.0%
Test for overall effect: Z = 9.74 (P < 0.00001)
Test for subgroup differences: Not applicable

0.1 0.2 0.5 1 2 5 10

Favours treatment Favours control

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 Analysis 13.1. Comparison 13 PPI vs placebo - toxicity, Outcome 1 Dropouts overall.

Review: Prevention of NSAID-induced gastroduodenal ulcers

Comparison: 13 PPI vs placebo - toxicity

Outcome: 1 Dropouts overall

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
Graham 2002 33/269 23/134 60.0 % 0.71 [ 0.44, 1.17 ]

Hawkey 1998 33/275 16/155 40.0 % 1.16 [ 0.66, 2.04 ]

Total (95% CI) 544 289 100.0 % 0.89 [ 0.62, 1.29 ]

Total events: 66 (Treatment), 39 (Control)
Heterogeneity: Chi2 = 1.63, df = 1 (P = 0.20); I2 =39%
Test for overall effect: Z = 0.60 (P = 0.55)
Test for subgroup differences: Not applicable

0.5 0.7 1 1.5 2

Favours treatment Favours control

Analysis 13.2. Comparison 13 PPI vs placebo - toxicity, Outcome 2 Dropouts due to side effects.

Review: Prevention of NSAID-induced gastroduodenal ulcers

Comparison: 13 PPI vs placebo - toxicity

Outcome: 2 Dropouts due to side effects

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
Bianchi Porro 2000 3/70 2/34 13.8 % 0.73 [ 0.13, 4.16 ]

Ekstrom 1996 4/86 1/91 5.0 % 4.23 [ 0.48, 37.12 ]

Graham 2002 14/269 9/134 61.6 % 0.77 [ 0.34, 1.74 ]

Hawkey 1998 11/274 3/155 19.6 % 2.07 [ 0.59, 7.32 ]

Total (95% CI) 699 414 100.0 % 1.20 [ 0.66, 2.15 ]

Total events: 32 (Treatment), 15 (Control)
Heterogeneity: Chi2 = 3.44, df = 3 (P = 0.33); I2 =13%
Test for overall effect: Z = 0.60 (P = 0.55)
Test for subgroup differences: Not applicable

0.05 0.2 1 5 20
Favours treatment Favours control

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 Analysis 13.3. Comparison 13 PPI vs placebo - toxicity, Outcome 3 Diarrhea.

Review: Prevention of NSAID-induced gastroduodenal ulcers

Comparison: 13 PPI vs placebo - toxicity

Outcome: 3 Diarrhea

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
Graham 2002 13/269 4/133 37.4 % 1.61 [ 0.53, 4.83 ]

Hawkey 1998 21/275 7/155 62.6 % 1.69 [ 0.74, 3.89 ]

Total (95% CI) 544 288 100.0 % 1.66 [ 0.85, 3.22 ]

Total events: 34 (Treatment), 11 (Control)
Heterogeneity: Chi2 = 0.01, df = 1 (P = 0.94); I2 =0.0%
Test for overall effect: Z = 1.49 (P = 0.13)
Test for subgroup differences: Not applicable

0.2 0.5 1 2 5
Favours treatment Favours control

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 Analysis 13.4. Comparison 13 PPI vs placebo - toxicity, Outcome 4 Abdominal pain.

Review: Prevention of NSAID-induced gastroduodenal ulcers

Comparison: 13 PPI vs placebo - toxicity

Outcome: 4 Abdominal pain

Study or subgroup Treatment Control Risk Ratio Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
Graham 2002 0/269 0/133 0.0 [ 0.0, 0.0 ]

Hawkey 1998 14/275 9/155 0.88 [ 0.39, 1.98 ]

Total (95% CI) 544 288 0.88 [ 0.39, 1.98 ]

Total events: 14 (Treatment), 9 (Control)
Heterogeneity: Chi2 = 0.00, df = 0 (P<0.00001); I2 =100%
Test for overall effect: Z = 0.32 (P = 0.75)
Test for subgroup differences: Not applicable

0.5 0.7 1 1.5 2

Favours treatment Favours control

Analysis 13.5. Comparison 13 PPI vs placebo - toxicity, Outcome 5 Flatulence.

Review: Prevention of NSAID-induced gastroduodenal ulcers

Comparison: 13 PPI vs placebo - toxicity

Outcome: 5 Flatulence

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
Hawkey 1998 7/275 5/155 100.0 % 0.79 [ 0.25, 2.44 ]

Total (95% CI) 275 155 100.0 % 0.79 [ 0.25, 2.44 ]

Total events: 7 (Treatment), 5 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 0.41 (P = 0.68)
Test for subgroup differences: Not applicable

0.5 0.7 1 1.5 2

Favours treatment Favours control

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 Analysis 13.6. Comparison 13 PPI vs placebo - toxicity, Outcome 6 Dyspepsia.

Review: Prevention of NSAID-induced gastroduodenal ulcers

Comparison: 13 PPI vs placebo - toxicity

Outcome: 6 Dyspepsia

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
Cullen 1998 6/83 8/85 20.3 % 0.77 [ 0.28, 2.12 ]

Hawkey 1998 13/86 32/91 79.7 % 0.43 [ 0.24, 0.76 ]

Total (95% CI) 169 176 100.0 % 0.50 [ 0.30, 0.82 ]

Total events: 19 (Treatment), 40 (Control)
Heterogeneity: Chi2 = 0.95, df = 1 (P = 0.33); I2 =0.0%
Test for overall effect: Z = 2.76 (P = 0.0059)
Test for subgroup differences: Not applicable

0.1 0.2 0.5 1 2 5 10

Favours treatment Favours control

Analysis 14.1. Comparison 14 PPI vs H2-antagonist - 12 weeks or longer studies, Outcome 1 Endoscopic
gastric ulcers.

Review: Prevention of NSAID-induced gastroduodenal ulcers

Comparison: 14 PPI vs H2-antagonist - 12 weeks or longer studies

Outcome: 1 Endoscopic gastric ulcers

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
Yeomans 1998 11/210 35/215 100.0 % 0.32 [ 0.17, 0.62 ]

Total (95% CI) 210 215 100.0 % 0.32 [ 0.17, 0.62 ]

Total events: 11 (Treatment), 35 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 3.42 (P = 0.00063)
Test for subgroup differences: Not applicable

0.1 0.2 0.5 1 2 5 10

Favours treatment Favours control

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 Analysis 14.2. Comparison 14 PPI vs H2-antagonist - 12 weeks or longer studies, Outcome 2 Endoscopic
duodenal ulcers.
Review: Prevention of NSAID-induced gastroduodenal ulcers

Comparison: 14 PPI vs H2-antagonist - 12 weeks or longer studies

Outcome: 2 Endoscopic duodenal ulcers

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
Yeomans 1998 1/210 9/215 100.0 % 0.11 [ 0.01, 0.89 ]

Total (95% CI) 210 215 100.0 % 0.11 [ 0.01, 0.89 ]

Total events: 1 (Treatment), 9 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 2.07 (P = 0.038)
Test for subgroup differences: Not applicable

0.01 0.1 1 10 100

Favours treatment Favours control

Analysis 14.3. Comparison 14 PPI vs H2-antagonist - 12 weeks or longer studies, Outcome 3 Total
endoscopic ulcers.

Review: Prevention of NSAID-induced gastroduodenal ulcers

Comparison: 14 PPI vs H2-antagonist - 12 weeks or longer studies

Outcome: 3 Total endoscopic ulcers

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
Yeomans 1998 12/210 44/215 100.0 % 0.28 [ 0.15, 0.51 ]

Total (95% CI) 210 215 100.0 % 0.28 [ 0.15, 0.51 ]

Total events: 12 (Treatment), 44 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 4.10 (P = 0.000041)
Test for subgroup differences: Not applicable

0.1 0.2 0.5 1 2 5 10

Favours treatment Favours control

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 Analysis 14.4. Comparison 14 PPI vs H2-antagonist - 12 weeks or longer studies, Outcome 4 Total clinical
ulcers.
Review: Prevention of NSAID-induced gastroduodenal ulcers

Comparison: 14 PPI vs H2-antagonist - 12 weeks or longer studies

Outcome: 4 Total clinical ulcers

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
Yeomans 1998 1/210 0/215 100.0 % 3.07 [ 0.13, 74.96 ]

Total (95% CI) 210 215 100.0 % 3.07 [ 0.13, 74.96 ]

Total events: 1 (Treatment), 0 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 0.69 (P = 0.49)
Test for subgroup differences: Not applicable

0.01 0.1 1 10 100

Favours treatment Favours control

Analysis 14.5. Comparison 14 PPI vs H2-antagonist - 12 weeks or longer studies, Outcome 5 Toxicity-
dropouts due to side effects.

Review: Prevention of NSAID-induced gastroduodenal ulcers

Comparison: 14 PPI vs H2-antagonist - 12 weeks or longer studies

Outcome: 5 Toxicity- dropouts due to side effects

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
Yeomans 1998 13/210 7/215 100.0 % 1.90 [ 0.77, 4.67 ]

Total (95% CI) 210 215 100.0 % 1.90 [ 0.77, 4.67 ]

Total events: 13 (Treatment), 7 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 1.40 (P = 0.16)
Test for subgroup differences: Not applicable

0.1 0.2 0.5 1 2 5 10

Favours treatment Favours control

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 Analysis 14.6. Comparison 14 PPI vs H2-antagonist - 12 weeks or longer studies, Outcome 6 Vomiting.

Review: Prevention of NSAID-induced gastroduodenal ulcers

Comparison: 14 PPI vs H2-antagonist - 12 weeks or longer studies

Outcome: 6 Vomiting

Study or subgroup Treatment Control Risk Ratio Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
Yeomans 1998 0/1 0/1 0.0 [ 0.0, 0.0 ]

Total (95% CI) 1 1 0.0 [ 0.0, 0.0 ]

Total events: 0 (Treatment), 0 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 0.0 (P < 0.00001)
Test for subgroup differences: Not applicable

0.001 0.01 0.1 1 10 100 1000

Favours treatment Favours control

Analysis 14.7. Comparison 14 PPI vs H2-antagonist - 12 weeks or longer studies, Outcome 7 Abdominal
pain.

Review: Prevention of NSAID-induced gastroduodenal ulcers

Comparison: 14 PPI vs H2-antagonist - 12 weeks or longer studies

Outcome: 7 Abdominal pain

Study or subgroup Treatment Control Risk Ratio Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
Yeomans 1998 0/1 0/1 0.0 [ 0.0, 0.0 ]

Total (95% CI) 1 1 0.0 [ 0.0, 0.0 ]

Total events: 0 (Treatment), 0 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 0.0 (P < 0.00001)
Test for subgroup differences: Not applicable

0.1 0.2 0.5 1 2 5 10

Favours treatment Favours control

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 Analysis 14.8. Comparison 14 PPI vs H2-antagonist - 12 weeks or longer studies, Outcome 8 Diarrhea.

Review: Prevention of NSAID-induced gastroduodenal ulcers

Comparison: 14 PPI vs H2-antagonist - 12 weeks or longer studies

Outcome: 8 Diarrhea

Study or subgroup Treatment Control Risk Ratio Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
Yeomans 1998 0/1 0/1 0.0 [ 0.0, 0.0 ]

Total (95% CI) 1 1 0.0 [ 0.0, 0.0 ]

Total events: 0 (Treatment), 0 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 0.0 (P < 0.00001)
Test for subgroup differences: Not applicable

0.001 0.01 0.1 1 10 100 1000

Favours treatment Favours control

Analysis 15.1. Comparison 15 Misoprostol Vs PPI (as control) - 12 weeks or longer studies, Outcome 1
Endoscopic gastric ulcer.

Review: Prevention of NSAID-induced gastroduodenal ulcers

Comparison: 15 Misoprostol Vs PPI (as control) - 12 weeks or longer studies

Outcome: 1 Endoscopic gastric ulcer

Study or subgroup Misoprostol PPI Risk Ratio Weight Risk Ratio

M- M-
H,Random,95% H,Random,95%
n/N n/N CI CI
Graham 2002 9/111 45/236 42.4 % 0.43 [ 0.22, 0.84 ]

Hawkey 1998 31/296 35/274 57.6 % 0.82 [ 0.52, 1.29 ]

Total (95% CI) 407 510 100.0 % 0.62 [ 0.33, 1.18 ]

Total events: 40 (Misoprostol), 80 (PPI)
Heterogeneity: Tau2 = 0.13; Chi2 = 2.51, df = 1 (P = 0.11); I2 =60%
Test for overall effect: Z = 1.46 (P = 0.14)
Test for subgroup differences: Not applicable

0.2 0.5 1 2 5
Favours treatment Favours control

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 Analysis 15.2. Comparison 15 Misoprostol Vs PPI (as control) - 12 weeks or longer studies, Outcome 2
Endoscopic duodenal ulcer.

Review: Prevention of NSAID-induced gastroduodenal ulcers

Comparison: 15 Misoprostol Vs PPI (as control) - 12 weeks or longer studies

Outcome: 2 Endoscopic duodenal ulcer

Study or subgroup Misoprostol PPI Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
Hawkey 1998 30/296 7/274 100.0 % 3.97 [ 1.77, 8.88 ]

Total (95% CI) 296 274 100.0 % 3.97 [ 1.77, 8.88 ]

Total events: 30 (Misoprostol), 7 (PPI)
Heterogeneity: not applicable
Test for overall effect: Z = 3.35 (P = 0.00081)
Test for subgroup differences: Not applicable

0.1 0.2 0.5 1 2 5 10

Favours treatment Favours control

Analysis 15.3. Comparison 15 Misoprostol Vs PPI (as control) - 12 weeks or longer studies, Outcome 3
Total endoscopic ulcers.

Review: Prevention of NSAID-induced gastroduodenal ulcers

Comparison: 15 Misoprostol Vs PPI (as control) - 12 weeks or longer studies

Outcome: 3 Total endoscopic ulcers

Study or subgroup Misoprostol PPI Risk Ratio Weight Risk Ratio

M- M-
H,Random,95% H,Random,95%
n/N n/N CI CI
Graham 2002 13/111 45/236 38.4 % 0.61 [ 0.35, 1.09 ]

Hawkey 1998 61/296 42/274 47.1 % 1.34 [ 0.94, 1.92 ]

Jensen 2000 4/23 1/23 8.0 % 4.00 [ 0.48, 33.12 ]

Stupnicki 2003 2/258 1/257 6.5 % 1.99 [ 0.18, 21.83 ]

Total (95% CI) 688 790 100.0 % 1.11 [ 0.58, 2.13 ]

Total events: 80 (Misoprostol), 89 (PPI)
Heterogeneity: Tau2 = 0.20; Chi2 = 6.83, df = 3 (P = 0.08); I2 =56%
Test for overall effect: Z = 0.33 (P = 0.74)
Test for subgroup differences: Not applicable

0.05 0.2 1 5 20
Favours treatment Favours control

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 Analysis 16.1. Comparison 16 PPI Vs Misoprostol (as control) - 12 weeks or longer studies, Outcome 1
Endoscopic gastric ulcer.

Review: Prevention of NSAID-induced gastroduodenal ulcers

Comparison: 16 PPI Vs Misoprostol (as control) - 12 weeks or longer studies

Outcome: 1 Endoscopic gastric ulcer

Study or subgroup PPI Misoprostol Risk Ratio Weight Risk Ratio

M- M-
H,Random,95% H,Random,95%
n/N n/N CI CI
Graham 2002 45/236 9/111 42.4 % 2.35 [ 1.19, 4.64 ]

Hawkey 1998 35/274 31/296 57.6 % 1.22 [ 0.77, 1.92 ]

Total (95% CI) 510 407 100.0 % 1.61 [ 0.85, 3.06 ]

Total events: 80 (PPI), 40 (Misoprostol)
Heterogeneity: Tau2 = 0.13; Chi2 = 2.51, df = 1 (P = 0.11); I2 =60%
Test for overall effect: Z = 1.46 (P = 0.14)
Test for subgroup differences: Not applicable

0.2 0.5 1 2 5
Favours treatment Favours control

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 Analysis 16.2. Comparison 16 PPI Vs Misoprostol (as control) - 12 weeks or longer studies, Outcome 2
Endoscopic duodenal ulcer.

Review: Prevention of NSAID-induced gastroduodenal ulcers

Comparison: 16 PPI Vs Misoprostol (as control) - 12 weeks or longer studies

Outcome: 2 Endoscopic duodenal ulcer

Study or subgroup PPI Misoprostol Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
Hawkey 1998 7/274 30/296 100.0 % 0.25 [ 0.11, 0.56 ]

Total (95% CI) 274 296 100.0 % 0.25 [ 0.11, 0.56 ]

Total events: 7 (PPI), 30 (Misoprostol)
Heterogeneity: not applicable
Test for overall effect: Z = 3.35 (P = 0.00081)
Test for subgroup differences: Not applicable

0.1 0.2 0.5 1 2 5 10

Favours treatment Favours control

Analysis 16.3. Comparison 16 PPI Vs Misoprostol (as control) - 12 weeks or longer studies, Outcome 3
Total endoscopic ulcers.

Review: Prevention of NSAID-induced gastroduodenal ulcers

Comparison: 16 PPI Vs Misoprostol (as control) - 12 weeks or longer studies

Outcome: 3 Total endoscopic ulcers

Study or subgroup PPI Misoprostol Risk Ratio Weight Risk Ratio

M- M-
H,Random,95% H,Random,95%
n/N n/N CI CI
Graham 2002 45/236 13/111 38.4 % 1.63 [ 0.92, 2.89 ]

Hawkey 1998 42/274 61/296 47.1 % 0.74 [ 0.52, 1.06 ]

Jensen 2000 1/23 4/23 8.0 % 0.25 [ 0.03, 2.07 ]

Stupnicki 2003 1/257 2/258 6.5 % 0.50 [ 0.05, 5.50 ]

Total (95% CI) 790 688 100.0 % 0.90 [ 0.47, 1.72 ]

Total events: 89 (PPI), 80 (Misoprostol)
Heterogeneity: Tau2 = 0.20; Chi2 = 6.83, df = 3 (P = 0.08); I2 =56%
Test for overall effect: Z = 0.33 (P = 0.74)
Test for subgroup differences: Not applicable

0.05 0.2 1 5 20
Favours treatment Favours control

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 Analysis 17.1. Comparison 17 Misoprostol vs PPI - toxicity - 12 weeks or longer studies, Outcome 1
Dropouts overall.

Review: Prevention of NSAID-induced gastroduodenal ulcers

Comparison: 17 Misoprostol vs PPI - toxicity - 12 weeks or longer studies

Outcome: 1 Dropouts overall

Study or subgroup Favours treatment Control Risk Ratio Weight Risk Ratio
n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
Graham 2002 33/269 23/134 38.9 % 0.71 [ 0.44, 1.17 ]

Hawkey 1998 33/275 50/296 61.1 % 0.71 [ 0.47, 1.07 ]

Total (95% CI) 544 430 100.0 % 0.71 [ 0.52, 0.97 ]

Total events: 66 (Favours treatment), 73 (Control)
Heterogeneity: Chi2 = 0.00, df = 1 (P = 0.99); I2 =0.0%
Test for overall effect: Z = 2.12 (P = 0.034)
Test for subgroup differences: Not applicable

0.5 0.7 1 1.5 2

Favours treatment Favours control

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 Analysis 17.2. Comparison 17 Misoprostol vs PPI - toxicity - 12 weeks or longer studies, Outcome 2
Dropouts due to side effects.

Review: Prevention of NSAID-induced gastroduodenal ulcers

Comparison: 17 Misoprostol vs PPI - toxicity - 12 weeks or longer studies

Outcome: 2 Dropouts due to side effects

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
Graham 2002 14/269 14/134 42.2 % 0.50 [ 0.24, 1.01 ]

Hawkey 1998 11/274 23/296 49.9 % 0.52 [ 0.26, 1.04 ]

Jensen 2000 0/23 3/23 7.9 % 0.14 [ 0.01, 2.62 ]

Total (95% CI) 566 453 100.0 % 0.48 [ 0.29, 0.78 ]

Total events: 25 (Treatment), 40 (Control)
Heterogeneity: Chi2 = 0.72, df = 2 (P = 0.70); I2 =0.0%
Test for overall effect: Z = 2.94 (P = 0.0033)
Test for subgroup differences: Not applicable

0.01 0.1 1 10 100

Favours treatment Favours control

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 Analysis 18.1. Comparison 18 Misoprostol vs ranitidine 150 mg bid - 1-2 month, Outcome 1 Endoscopic
gastric ulcers.

Review: Prevention of NSAID-induced gastroduodenal ulcers

Comparison: 18 Misoprostol vs ranitidine 150 mg bid - 1-2 month

Outcome: 1 Endoscopic gastric ulcers

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
Raskin 1996 1/269 11/269 65.1 % 0.09 [ 0.01, 0.70 ]

Valentini 1995 1/30 6/31 34.9 % 0.17 [ 0.02, 1.35 ]

Total (95% CI) 299 300 100.0 % 0.12 [ 0.03, 0.51 ]

Total events: 2 (Treatment), 17 (Control)
Heterogeneity: Chi2 = 0.19, df = 1 (P = 0.66); I2 =0.0%
Test for overall effect: Z = 2.88 (P = 0.0039)
Test for subgroup differences: Not applicable

0.01 0.1 1 10 100

Favours treatment Favours control

Analysis 18.2. Comparison 18 Misoprostol vs ranitidine 150 mg bid - 1-2 month, Outcome 2 Endoscopic
duodenal ulcers.
Review: Prevention of NSAID-induced gastroduodenal ulcers

Comparison: 18 Misoprostol vs ranitidine 150 mg bid - 1-2 month

Outcome: 2 Endoscopic duodenal ulcers

Study or subgroup Treatment Control Risk Ratio Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
Raskin 1996 2/269 2/269 1.00 [ 0.14, 7.05 ]

Valentini 1995 0/30 0/31 0.0 [ 0.0, 0.0 ]

Total (95% CI) 299 300 1.00 [ 0.14, 7.05 ]

Total events: 2 (Treatment), 2 (Control)
Heterogeneity: Chi2 = 0.0, df = 0 (P = 1.00); I2 =0.0%
Test for overall effect: Z = 0.0 (P = 1.0)
Test for subgroup differences: Not applicable

0.1 0.2 0.5 1 2 5 10

Favours treatment Favours control

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 Analysis 18.3. Comparison 18 Misoprostol vs ranitidine 150 mg bid - 1-2 month, Outcome 3 Dropouts due
to side effects.
Review: Prevention of NSAID-induced gastroduodenal ulcers

Comparison: 18 Misoprostol vs ranitidine 150 mg bid - 1-2 month

Outcome: 3 Dropouts due to side effects

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
Raskin 1996 35/269 18/269 97.3 % 1.94 [ 1.13, 3.35 ]

Valentini 1995 1/30 0/31 2.7 % 3.10 [ 0.13, 73.16 ]

Total (95% CI) 299 300 100.0 % 1.98 [ 1.16, 3.37 ]

Total events: 36 (Treatment), 18 (Control)
Heterogeneity: Chi2 = 0.08, df = 1 (P = 0.78); I2 =0.0%
Test for overall effect: Z = 2.49 (P = 0.013)
Test for subgroup differences: Not applicable

0.01 0.1 1 10 100

Favours treatment Favours control

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 Analysis 18.4. Comparison 18 Misoprostol vs ranitidine 150 mg bid - 1-2 month, Outcome 4 Total
endoscopic ulcers.

Review: Prevention of NSAID-induced gastroduodenal ulcers

Comparison: 18 Misoprostol vs ranitidine 150 mg bid - 1-2 month

Outcome: 4 Total endoscopic ulcers

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
Raskin 1996 3/269 13/269 100.0 % 0.23 [ 0.07, 0.80 ]

Total (95% CI) 269 269 100.0 % 0.23 [ 0.07, 0.80 ]

Total events: 3 (Treatment), 13 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 2.31 (P = 0.021)
Test for subgroup differences: Not applicable

0.05 0.2 1 5 20
Favours treatment Favours control

Analysis 18.5. Comparison 18 Misoprostol vs ranitidine 150 mg bid - 1-2 month, Outcome 5 Dropouts
overall.
Review: Prevention of NSAID-induced gastroduodenal ulcers

Comparison: 18 Misoprostol vs ranitidine 150 mg bid - 1-2 month

Outcome: 5 Dropouts overall

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
Raskin 1996 89/269 75/269 93.8 % 1.19 [ 0.92, 1.53 ]

Valentini 1995 7/30 5/31 6.2 % 1.45 [ 0.52, 4.06 ]

Total (95% CI) 299 300 100.0 % 1.20 [ 0.94, 1.54 ]

Total events: 96 (Treatment), 80 (Control)
Heterogeneity: Chi2 = 0.13, df = 1 (P = 0.71); I2 =0.0%
Test for overall effect: Z = 1.45 (P = 0.15)
Test for subgroup differences: Not applicable

0.2 0.5 1 2 5
Favours treatment Favours control

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 Analysis 18.6. Comparison 18 Misoprostol vs ranitidine 150 mg bid - 1-2 month, Outcome 6 Dropouts due
to abdominal pain.

Review: Prevention of NSAID-induced gastroduodenal ulcers

Comparison: 18 Misoprostol vs ranitidine 150 mg bid - 1-2 month

Outcome: 6 Dropouts due to abdominal pain

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
Raskin 1996 15/269 5/269 100.0 % 3.00 [ 1.11, 8.14 ]

Total (95% CI) 269 269 100.0 % 3.00 [ 1.11, 8.14 ]

Total events: 15 (Treatment), 5 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 2.16 (P = 0.031)
Test for subgroup differences: Not applicable

0.1 0.2 0.5 1 2 5 10

Favours treatment Favours control

Analysis 18.7. Comparison 18 Misoprostol vs ranitidine 150 mg bid - 1-2 month, Outcome 7 Dropouts due
to nausea.
Review: Prevention of NSAID-induced gastroduodenal ulcers

Comparison: 18 Misoprostol vs ranitidine 150 mg bid - 1-2 month

Outcome: 7 Dropouts due to nausea

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
Raskin 1996 11/269 3/269 100.0 % 3.67 [ 1.03, 13.00 ]

Total (95% CI) 269 269 100.0 % 3.67 [ 1.03, 13.00 ]

Total events: 11 (Treatment), 3 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 2.01 (P = 0.044)
Test for subgroup differences: Not applicable

0.05 0.2 1 5 20
Favours treatment Favours control

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 Analysis 18.8. Comparison 18 Misoprostol vs ranitidine 150 mg bid - 1-2 month, Outcome 8 Dyspepsia.

Review: Prevention of NSAID-induced gastroduodenal ulcers

Comparison: 18 Misoprostol vs ranitidine 150 mg bid - 1-2 month

Outcome: 8 Dyspepsia

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio

M- M-
H,Random,95% H,Random,95%
n/N n/N CI CI
Raskin 1996 38/269 27/269 72.8 % 1.41 [ 0.89, 2.24 ]

Valentini 1995 5/30 0/31 27.2 % 11.35 [ 0.66, 196.81 ]

Total (95% CI) 299 300 100.0 % 2.49 [ 0.39, 15.92 ]

Total events: 43 (Treatment), 27 (Control)
Heterogeneity: Tau2 = 1.18; Chi2 = 2.08, df = 1 (P = 0.15); I2 =52%
Test for overall effect: Z = 0.96 (P = 0.34)
Test for subgroup differences: Not applicable

0.005 0.1 1 10 200

Favours treatment Favours control

Analysis 18.9. Comparison 18 Misoprostol vs ranitidine 150 mg bid - 1-2 month, Outcome 9 Abdominal pain
symptoms.

Review: Prevention of NSAID-induced gastroduodenal ulcers

Comparison: 18 Misoprostol vs ranitidine 150 mg bid - 1-2 month

Outcome: 9 Abdominal pain symptoms

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
Raskin 1996 124/269 100/269 100.0 % 1.24 [ 1.01, 1.52 ]

Total (95% CI) 269 269 100.0 % 1.24 [ 1.01, 1.52 ]

Total events: 124 (Treatment), 100 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 2.09 (P = 0.037)
Test for subgroup differences: Not applicable

0.5 0.7 1 1.5 2

Favours treatment Favours control

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 Analysis 18.10. Comparison 18 Misoprostol vs ranitidine 150 mg bid - 1-2 month, Outcome 10 Flatulence
symptoms.

Review: Prevention of NSAID-induced gastroduodenal ulcers

Comparison: 18 Misoprostol vs ranitidine 150 mg bid - 1-2 month

Outcome: 10 Flatulence symptoms

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
Raskin 1996 83/269 56/269 100.0 % 1.48 [ 1.10, 1.99 ]

Total (95% CI) 269 269 100.0 % 1.48 [ 1.10, 1.99 ]

Total events: 83 (Treatment), 56 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 2.62 (P = 0.0087)
Test for subgroup differences: Not applicable

0.5 0.7 1 1.5 2

Favours treatment Favours control

Analysis 18.11. Comparison 18 Misoprostol vs ranitidine 150 mg bid - 1-2 month, Outcome 11 Nausea
symptoms.

Review: Prevention of NSAID-induced gastroduodenal ulcers

Comparison: 18 Misoprostol vs ranitidine 150 mg bid - 1-2 month

Outcome: 11 Nausea symptoms

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
Raskin 1996 65/269 59/269 100.0 % 1.10 [ 0.81, 1.50 ]

Total (95% CI) 269 269 100.0 % 1.10 [ 0.81, 1.50 ]

Total events: 65 (Treatment), 59 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 0.61 (P = 0.54)
Test for subgroup differences: Not applicable

0.5 0.7 1 1.5 2

Favours treatment Favours control

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 Analysis 18.12. Comparison 18 Misoprostol vs ranitidine 150 mg bid - 1-2 month, Outcome 12 Diarrhea
symptoms.

Review: Prevention of NSAID-induced gastroduodenal ulcers

Comparison: 18 Misoprostol vs ranitidine 150 mg bid - 1-2 month

Outcome: 12 Diarrhea symptoms

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
Raskin 1996 65/269 32/269 100.0 % 2.03 [ 1.38, 2.99 ]

Total (95% CI) 269 269 100.0 % 2.03 [ 1.38, 2.99 ]

Total events: 65 (Treatment), 32 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 3.58 (P = 0.00034)
Test for subgroup differences: Not applicable

0.5 0.7 1 1.5 2

Favours treatment Favours control

Analysis 19.1. Comparison 19 Nizatidine 150 mg vs 300 mg efficacy, Outcome 1 Total endoscopic ulcers.

Review: Prevention of NSAID-induced gastroduodenal ulcers

Comparison: 19 Nizatidine 150 mg vs 300 mg efficacy

Outcome: 1 Total endoscopic ulcers

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
Simon 1994 6/121 2/116 100.0 % 2.88 [ 0.59, 13.96 ]

Total (95% CI) 121 116 100.0 % 2.88 [ 0.59, 13.96 ]

Total events: 6 (Treatment), 2 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 1.31 (P = 0.19)
Test for subgroup differences: Not applicable

0.05 0.2 1 5 20
Favours treatment Favours control

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 Analysis 19.2. Comparison 19 Nizatidine 150 mg vs 300 mg efficacy, Outcome 2 Dropouts overall.

Review: Prevention of NSAID-induced gastroduodenal ulcers

Comparison: 19 Nizatidine 150 mg vs 300 mg efficacy

Outcome: 2 Dropouts overall

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
Simon 1994 6/121 8/116 100.0 % 0.72 [ 0.26, 2.01 ]

Total (95% CI) 121 116 100.0 % 0.72 [ 0.26, 2.01 ]

Total events: 6 (Treatment), 8 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 0.63 (P = 0.53)
Test for subgroup differences: Not applicable

0.2 0.5 1 2 5
Favours treatment Favours control

Analysis 20.1. Comparison 20 NSAID + PPI vs COX 2, Outcome 1 Clinical Ulcer (POB).

Review: Prevention of NSAID-induced gastroduodenal ulcers

Comparison: 20 NSAID + PPI vs COX 2

Outcome: 1 Clinical Ulcer (POB)

Study or subgroup PPI + NSAID COX2 Odds Ratio Weight Odds Ratio
n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
Chan 2004 6/66 3/64 100.0 % 2.03 [ 0.49, 8.51 ]

Total (95% CI) 66 64 100.0 % 2.03 [ 0.49, 8.51 ]

Total events: 6 (PPI + NSAID), 3 (COX2)
Heterogeneity: not applicable
Test for overall effect: Z = 0.97 (P = 0.33)
Test for subgroup differences: Not applicable

0.1 0.2 0.5 1 2 5 10

Favours treatment Favours control

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APPENDICES

Appendix 1. MEDLINE search strategy

• RCT filter updated
• Lines 15-17 deleted: redundant (included in ‘exp peptic ulcer/’)
• Lines 27 and 28 deleted: redundant (see line 25)
• Line 37 amended to ‘(pylor$ adj3 stenosis).tw’ to pick up eg ‘stenosis of the pylorus’
• Line 45 amended to ‘lan?oprazole.tw’
• (After line 61) inserted ‘exp proton pump inhibitors/’
• Line 70 amended to ‘nonsteroid$ anti-inflammator$.tw’
• Line 71 amended to ‘non-steroid$ anti-inflammator$.tw’
• (After line 71) inserted ‘nonsteroid$ antiinflammator$.tw’ and ‘non-steroid$ antiinflammator$.tw’
• (After line 79) inserted ‘exp fenoprofen/’
• (After line 80) inserted ‘exp flurbiprofen/’
• Line 82 amended to ‘exp indomethacin/’ (correct spelling of subject heading)
• Line 83 amended to ‘indomet?acin$.tw’
• (After line 100) inserted ‘phenazone.tw’ (synonym for ‘antipyrine’)
• (After line 105) inserted ‘exp aminopyrine/’
• (After line 106) inserted ‘exp curcumin/’
• (After line 107) inserted ‘exp clofazimine/’
Search as run 07/05/09
RCT filter updated 26/03/09
1. randomized controlled trial.pt.
2. controlled clinical trial.pt.
3. randomized.ab.
4. placebo.ab.
5. drug therapy.fs.
6. randomly.ab.
7. trial.ab.
8. groups.ab.
9. 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8
10. humans.sh.
11. 9 and 10
12. exp peptic ulcer/
13. exp peptic ulcer hemorrhage/
14. (pep$ adj5 ulcer$).tw.
15. (stomach adj5 ulcer$).tw.
16. (duoden$ adj5 ulcer$).tw.
17. (gastr$ adj5 ulcer$).tw.
18. exp gastritis/
19. gastritis.tw.
20. gastropathy.tw.
21. (bleed$ adj5 ulcer$).tw.
22. (rebleed$ adj5 ulcer$).tw.
23. (gastrointestinal adj5 bleed$).tw.
24. (gastrointestinal adj5 rebleed$).tw.
25. (gastrointestinal adj5 hemorrhag$).tw.
26. (gastrointestinal adj5 haemorrhag$).tw.
27. (ulcer adj5 hemorrhag$).tw.
28. (ulcer adj5 haemorrhag$).tw.
29. (mucos$ adj5 injur$).tw.
30. exp pyloric stenosis/
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31. (pylor$ adj3 stenosis).tw.
32. (gastrointestinal adj3 perforat$).tw.
33. (gi adj3 perforat$).tw.
34. (ulcer$ adj3 perforat$).tw.
35. or/12-34
36. exp anti-ulcer agents/
37. exp omeprazole/
38. omeprazole.tw.
39. lan?oprazole.tw.
40. pantoprazole.tw.
41. rabeprazole.tw.
42. esomeprazole.tw.
43. exp histamine H2 antagonists/
44. exp cimetidine/
45. cimetidine.tw.
46. exp ranitidine/
47. ranitidine.tw.
48. exp famotidine/
49. famotidine.tw.
50. exp nizatidine/
51. nizatidine.tw.
52. (histamine adj3 H2 adj3 antagonist$).tw.
53. (antiulcer adj5 agent$).tw.
54. (anti$ adj3 ulcer$ adj3 agent$).tw.
55. (H2 adj5 receptor adj5 antagonist$).tw.
56. exp proton pump inhibitors/
57. (proton adj3 pump adj3 inhibitor$).tw.
58. exp misoprostol/
59. exp sucralfate/
60. misoprostol.tw.
61. sucralfate.tw.
62. or/36-61
63. Anti-inflammatory agents, non-steroidal/
64. nsaid$.tw.
65. nonsteroid$ anti-inflammator$.tw.
66. non-steroid$ anti-inflammator$.tw.
67. nonsteroid$ antiinflammator$.tw.
68. non-steroid$ antiinflammator$.tw.
69. exp ibuprofen/
70. ibuprofen$.tw.
71. aceclofenac$.tw.
72. acemetacin$.tw.
73. dexketoprofen$.tw.
74. exp diclofenac/
75. diclofenac$.tw.
76. fenbufen$.tw.
77. exp fenoprofen/
78. fenoprofen$.tw.
79. exp flurbiprofen/
80. flurbiprofen$.tw.
81. exp indomethacin/
82. indomet?acin$.tw.
83. exp ketoprofen/
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84. ketoprofen$.tw.
85. exp mefenamic acid/
86. (mefenamic adj3 acid$).tw.
87. nabumetone$.tw.
88. exp naproxen/
89. naproxen$.tw.
90. exp phenylbutazone/
91. phenylbutazone$.tw.
92. exp piroxicam/
93. piroxicam$.tw.
94. exp sulindac/
95. sulindac$.tw.
96. exp tolmetin/
97. tolmetin.tw.
98. exp antipyrine/
99. antipyrine.tw.
100. phenazone.tw.
101. tenoxicam$.tw.
102. (tiaprofenic adj3 acid$).tw.
103. exp aspirin/
104. aspirin$.tw.
105. (acetylsalicylic adj3 acid$).tw.
106. exp aminopyrine/
107. aminopyrine.tw.
108. exp curcumin/
109. curcumin.tw.
110. exp clofazimine/
111. clofazimine.tw.
112. or/63-111
113. 35 and 62 and 112
114. 11 and 113
115. limit 114 to yr=“2004-2009”

Appendix 2. CCOHTA Search Strategy

Literature Search Strategy
Search Legend
In Dialog®
De = descriptor, ie. Medical Subject Heading (a controlled, thesaurus term)
Ti = title (i.e. word has to occur in title field of the bibliographic record)
Ab = abstract (ie word has to occur in abstract field of bibliographic record)
! = explode; picks up narrower terms as well, i.e. terms which are conceptually
subsets of a broader term. For instance, gastritis! also retrieves gastritis,
atrophic and gastritis, hypertrophic
() = words must be adjacent
? = truncation symbol
DATABASES LIMITS KEY WORDS AND STRATEGY
Dialog® OneSearch®
MEDLINE® (File 155,
1966-2002/Apr W4);
ToxFile(File 156, 1966-
2002/Feb W4))
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2000-2002
for the update
of the
Cochrane
Review;
1990-2002
for the COX-
2/GI safety
review
Search done
May 3, 2002
1. gastritis!
2. (gastritis OR gastropathy)/ti,ab
3. gastrointestinal hemorrhage!
4. gi(w2)hemorrhage?/ti,ab
5. gi(w2)haemorrhage?/ti,ab
6. gastrointestinal(w2)hemorrhage?/ti,ab
7. gastrointestinal(w2)haemorrhage?/ti,ab
8. gi(w2)bleed?/ti,ab
9. gastrointestinal(w2)bleed?/ti,ab
10. ulcer(w2)hemorrhage?/ti,ab
11. ulcer(w2)haemorrhage?/ti,ab
12. peptic ulcer perforation/de
13. ulcer(w2)perforation?/ti,ab
14. gi(w2)perforation?/ti,ab
15. gastrointestinal(w2)perforation?/ti,ab
16. mucosa?(w2)injur?/ti,ab
17. peptic ulcer!
18. peptic(w2)ulcer?/ti,ab
19. stomach(w2)ulcer?/ti,ab
20. duodenal(w2)ulcer?/ti,ab
21. gastroduodenal(w2)ulcer?/ti,ab
22. gastric(w2)ulcer?/ti,ab
23. pyloric stenosis/de
24. pyloric(w)stenos?s/ti,ab
25. Set 1:Set 24
26. anti-inflammatory agents, non-steroidal/de
27. non()steroidal()antiflammator?ti,ab
28. nonsteroidal()antiflammator?/ti,ab
58
DATABASES LIMITS KEY WORDS AND STRATEGY
29. nsaid?/ti,ab
30. meclofenamic acid/de
31. meclofenamic()acid/ti,ab OR rn= 644-62-2
32. sulindac/de OR rn=38194-50-2 OR
sulindac/ti,ab
33. tolmetin/de OR tolmetin/ti,ab OR rn=26171-
23-3
34. naproxen/de OR naproxen/ti,ab OR
rn=22204-53-1
35. phenylbutazone! OR rn = 50-33-9 OR
phenylbutazone/ti,ab
36. rn=129-20-4 OR rn=30748-29-9 OR 57-96-5
Prevention of NSAID-induced gastroduodenal ulcers (Review) 159
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OR (oxyphenbutazone OR prenazone OR
sulfinpyrazone)/ti,ab
37. ketoprofen/de OR ketoprofen/ti,ab OR rn =
22071-15-4
38. indomethacin! OR indomethacin/ti,ab OR
rn=53-86-1
39. ketorolac/de OR ketorolac/ti,ab OR rn=66635-
83-4
40. ibuprofen/de OR ibuprofen/ti,ab OR
rn=15687-27-1
41. curcumin/de OR curcumin./ti,ab OR rn=458-
37-7
42. flurbiprofen/de OR flurbiprofen/ti,ab OR
rn=5104-49-4
43. diclofenac/de OR diclofenac/ti,ab OR
rn=15307-86-5
44. clofazimine/de OR clofazimine/ti,ab OR
rn=2030-63-9
45. aspirin/de OR [acetylsalicylic()acid OR
aspirin]/ti,ab OR
rn=50-78-2
46. antipyrine/de OR antipytrine/tia,b OR rn=60-
80-0
47. aminopyrine! OR (aminopyrine OR
dipyrone)/ti,ab OR rn=58-
15-1 OR rn= 68-89-3 OR dipyrone/de
48. oxaprozin/ti,ab OR rn=21256-18-8
49. diflunisal/de OR diflunisal/ti,ab OR
rn=22494-42-4
50. choline()magnesium()salicylate?/ti,ab OR
rn=64425-90-7
51. choline()salicylate?/ti,ab OR rn=2016-36-6
59
DATABASES LIMITS KEY WORDS AND STRATEGY
52. floctafenine/ti,ab OR rn=23779-99-9
53. piroxicam/de OR piroxicam/ti,ab OR
rn=36322-90-4
54. tenoxicam/ti,ab OR rn=59804-37-4
55. nabumetone/ti,ab OR rn=42924-53-8
56. tiaprofenic()acid?/ti,ab OR rn=33005-95-7
57. fenoprofen/de OR fenoprofen/ti,ab OR
rn=31879-05-7
58. mefenamic acid/de OR mefenamic()acid?/ti,ab
or rn= 61-68-7
59. etodolac/de OR etodolac/ti,ab OR rn=41340-
25-4
60. Set 26:Set 59
61. anti-ulcer agents/de
62. sucralfate/de OR sucralfate/ti,ab OR
rn=54182-58-0
63. Set 61:Set 62
64. prostaglandin antagonists/de
65. prostaglandin()antagonist?/ti,ab
Prevention of NSAID-induced gastroduodenal ulcers (Review) 160
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66. misoprostol/de OR misoprostol/ti,ab OR
rn=59122-46-2
67. Set 64:Set 66
68. proton pumps!(l)ai
69. proton()pump?()inhibit?/ti,ab OR PPI?/ti,ab
70. omeprazole/de OR omeprazole/ti,ab OR
rn=73590-58-6
71. pantoprazole/ti,ab OR rn=102625-70-7
72. lansoprazole/tia,b OR rn=103577-45-3
73. timoprazole?/ti,ab OR 57237-97-5
74. rabeprazole /ti,ab OR rn=117976-89-3
75. esomeprazole/ti,ab OR Nexium/ti,.ab
76. Set 68:Set 75
77. histamine H2 antagonists/de
78. histamine()H2()antagonist?/ti,ab OR
H2RA/ti,ab OR
[histamine()H2()receptor()antagonist? OR
histamine()type()2()receptor()antagonist?]/ti,
ab
79. cimetidine/de OR cimetidine/ti,ab OR rn=
51481-61-9
80. famotidine/de OR famotidine/ti,ab OR rn=
76824-35-6
81 nizatidine/de OR nizatidine/.ti,ab OR
82. ranitidine/de OR ranitidine/ti,ab OR
60
DATABASES LIMITS KEY WORDS AND STRATEGY
rn=66357-35-5
83. Set 77:Set 82
84. Set 25 AND Set 60
85. Set 84 AND (Set 63 OR Set 67 OR Set 76 OR
Set 83)
86. dt= (clinical trial OR clinical trial, phase i OR
clinical trial, phase ii OR clinical trial, phase
iii OR clinical trial, phase iv OR metaanalysis
OR controlled clinical trial OR
randomized controlled trial OR multicenter
study OR review)
87. clinical trials!
88. (comparative study OR double-blind method
OR random
allocation)/de
89. (random? OR controlled trial? OR controlled
clinical trial? OR clinical trial? OR double
blind?)/ti,ab
90. (multicent? trial? OR multi cent? trial? OR
meta analy? OR metaanaly? OR metaanalysis)/
ti,ab
91. (research integration OR research overview?
OR quantitative review? OR quantitative
overview? OR methodologic review?
OR methodologic overview?)/ti,ab
92. (systematic overview? OR systematic review?
Prevention of NSAID-induced gastroduodenal ulcers (Review) 161
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OR integrative research OR quantitative
synthesis OR comparative stud? OR
prospective stud? OR retrospective stud? OR
single blind? OR triple blind? OR treble
blind? OR dummy OR sham OR rct?)/ti,ab
93. Set 86:Set 92
94. Set 85 AND Set 93
95. Set 94/2000:2002
96. Set 95 from 155
97. Set 95 from 156
98. Set 94/1990:2002
99. Set 98 from 155
100. S98 from 156
101. [cyclo()oxygenase()2()inhibit? OR
cyclooxygenase()2()inhibit? OR
cox()2()inhibit?]/ti,ab
102. [celecoxib OR celebrex]/ti,ab OR rn=
169590-42-5
61
DATABASES LIMITS KEY WORDS AND STRATEGY
103. [rofecoxib OR vioxx]/ti,ab OR rn=162011-
90-7
104. (meloxicam OR mobic OR movalis OR
mobec OR movicox OR parocin OR uticox
OR mobicox)/ti,ab OR rn=71125-38-7
105. etodolac/de OR etodolac/ti,ab OR rn=41340-
25-4
106. Set 101:Set 105
107. Set 25 AND Set 106 AND Set 93
108. Set 107/1990:2002
109. Set 108 from 155
110. Set 109 from 156
EMBASE® (File 73,
1974-2002/Apr W4)
111. ulcer perforation/de
112. stomach mucosa injury/de
113. pylorus stenosis!
114. Set 111:Set 113
115. Set 1: 11
116. Set 13:16
117. Set 18:22
118. Set 114:Set 117
119. Set 17 OR Set 24 OR Set 118
120. nonsteroid antiinflammatory agent!
121. Set 120 OR Set 60
122. Set 119 AND Set 121
123. antiulcer agent! OR Set 62 OR
gastrointestinal mucosa protective agent!
124. prostaglandin receptor blocking agent!
125. stomach secretion inhibitor!
126. Set 123: Set 125
127. Set 69:Set 75
128. Set 65 OR Set 127 OR Set 83 OR Set 126
Prevention of NSAID-induced gastroduodenal ulcers (Review) 162
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129. Set 122 AND Set 128
130. (comparative study OR randomized
controlled trial OR prospective study OR
retrospective study OR meta analysis OR
clinical trial OR multicenter study OR phase
1 clinical trial OR phase 2 clinical trial OR
phase 3 clinical trial OR phase 4 clinical
trial OR prospective study OR retrospective
study OR double blind procedure OR
conference paper! OR longitudinal study /de
131. Set 129 AND (Set 130 OR Set 89 OR Set 90
OR Set 91 OR Set 92)
132. Set 131/2000:2001
62
DATABASES LIMITS KEY WORDS AND STRATEGY
133. Set 132 from Set 73
134. Set 131/1990:2002
135. cyclooxgenase 2 inhibitor! OR Set 106
136. Set 119 AND Set 135 AND (Set 130 OR
Set 89 OR Set 90 OR Set 91 OR Set 92)
137. Set 136/1990:2002
138. Set 137 from 73
BIOSIS Previews®
(File 5, 1969-2002/Apr
W4)
139. gastritis/de
140. gastrointestinal hemorrhage/de
141. gastrointestinal bleeding/de
142. gastric mucosal injury/de
143. gastric ulcer/de
144. gastroduodenal ulcer/de
145. duodenal ulcer/de
146. peptic ulcer/de
147. Set 139:Set 146
148. Set 4:Set 11
149. Set 13:16
150. Set 18:Set 22
151. Set 2 OR Set 24 OR Set 147 OR Set 148 OR
Set 149 OR Set 150
152. non-steroidal anti-inflammatory drugs/de
153. nonsteroidal anti-inflammatory drugs/de
154. Set 27:Set 59
155 acetylsalicylic acid/de
156. Set 152:Set 155
157. Set 151 AND Set 156
158. antiulcer-drug/de
159. Set 158 OR sucralfate/de OR sucralfate/ti,ab
OR rn=54182-58-0
160. Set 158:Set 159
161. Set 65 OR Set 66
162. proton pump inhibitors/de
163. Set 69 OR pantoprazole/de OR
lansoprazole/de
Prevention of NSAID-induced gastroduodenal ulcers (Review) 163
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164. Set 70:Set 75
165. Set 162 OR Set 163 OR S164
166. histamine H2-receptor antagonist-drug/de
167. Set 78:Set 82
168. Set 166:Set 167
169. Set 160 OR Set 161 OR Set 165 OR Set 168
170. Set 157 AND Set 169
171. (clinical trial OR randomized trial OR
prospective study OR randomized controlled
63
DATABASES LIMITS KEY WORDS AND STRATEGY
trial OR multicenter study OR randomized
clinical trial)/de
172. Set 171 OR Set 89 OR Set 90 OR Set 91 OR
Set 92
173. Set 170 AND Set 172
174. Set 173/2000:2002
175. Set 174 from 5
176. Set 151 AND Set 106 AND Set 172
177. Set 176/1990:2002
178. Set 177 from 5
Pharmaceutical News
Index (PNI®)(File 42,
1974-2002,Apr W4)
Current Contents
Search® (File 440,
1990-2002, May W3)
179. Set 4:Set 11
180. Set 13:Set 16
181. Set 18:Set 22
182. Set 2 OR Set 179 OR Set 180 OR Set 181
OR Set 24
183. Set 27:Set 29
184. [meclofenamic()acid OR
acetylsalicylic()acid OR
choline()magnesium()salicylate? OR
choline()salicylate? OR tiaprofenic()acid?
OR mefenamic()acid?]/ti,ab
185. (sulindac OR tolmetin OR naproxen OR
phenylbutazon OR oxyphenbutazone OR
prenazone OR sulfinpyrazone OR
ketoprofen OR indomethacin OR ketorolac
OR ibuprofen OR curcumin OR flurbiprofen
OR diclofenac OR clofazimine OR aspirin
OR antipytrine OR aminopyrine OR
dipyrone OR oxaprozin OR diflunisal
OR floctafenine OR piroxicam OR
tenoxicam OR nabumetone OR
fenoprofen)/ti,ab
186. Set 183:Set 185
187. Set 182 AND Set 186
188. [anti()ulcer()drug? OR antiulcer()drug? OR
sucralfate]/ti,ab
Prevention of NSAID-induced gastroduodenal ulcers (Review) 164
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189. [prostaglandin()antagonist? OR
misoprostol]/ti,ab
190. [proton()pump?()inhibit? OR PPI? OR
omeprazole OR pantoprazole OR
lansoprazole OR timoprazole OR
rabeprazole OR esomeprazole OR
Nexium]/ti,.ab
191. [histamine()H2()antagonist? OR H2RA OR
64
DATABASES LIMITS KEY WORDS AND STRATEGY
histamine()H2()receptor()antagonist? OR
histamine()type()2()receptor()antagonist?]/
ti,ab
192. [cimetidine OR famotidine OR
nizatidine]/ti,ab
193. Set 188:Set 192
194. Set 187 AND Set 193 AND (Set 89 OR Set
90 OR Set 91 OR Set 92)
195. Set 194/2000:2002
196. Set 195 from 42
197. Set 195 from 440
198. Set 195 from 173
199. [cyclo()oxygenase()2()inhibit? OR
cyclooxygenase()2()inhibit? OR
cox()2()inhibit?]/ti,ab
200. (celecoxib OR celebrex OR rofecoxib OR
vioxx OR meloxicam OR mobic OR
movalis OR mobec OR movicox OR
parocin OR uticox OR mobicox OR
etodolac)/ti,ab
201. Set 199:Set 200
202. Set 182 AND Set 201 AND (Set 89 OR Set
90 OR Set 91 OR Set 92)
203. Set 202/1990:2002
204. Set 203 from 42
205. Set 203 from 440
206. Set 203/from 173
207. Set 96 OR Set 97 OR Set 133 OR Set 175
OR Set 196 OR Set 197 OR Set 198
208. Reduce duplicates Set 207
209. type s208/4/all from
155,156,73,5,42,440,173 = CochraneUpdate
210. Set 109 OR Set 110 OR Set 138 OR Set 178
OR Set 204 OR Set 205 OR Set 206
211. Type S210/4/all from
155,156,73,5,42,440,173= Cox-2/GI safety
Cochrane Library on
CD-ROM (Cochrane
Collaboration and
Update Software);
Conference Papers
Index, CCOHTA HTA
Checklist; Google™
Prevention of NSAID-induced gastroduodenal ulcers (Review) 165
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Dialog® OneSearch® Search Using the strategy above which was devised to
65
DATABASES LIMITS KEY WORDS AND STRATEGY
on MEDLINE® (File
155), ToxFile(File 156),
EMBASE® (File 73),
BIOSIS Previews®
(File 5), Pharmaceutical
News Index
(PNI®)(File
42),Currrent Contents
Search® (File 440)
performed
May 3, 2002
update the original Cochrane search, an additional
search on gastroprotective agents under
investigation, was performed. These were
bioprazol, rebamipide, polaprezinc, nocloprost,
lafutidine, dosmalfate, and osutidine. Titles and
abstracts of articles were searched, registry
numbers, and earlier names, such as FRG 8813, F
3616, T 593
Dialog® Adis Clinical
Trials Insight (File
173), Biobase (File 71),
Biosis Previews®(File
5), SciSearch®(File 34),
Pharmaceutical News
Index (File 42), Inside
Conferences (File 65),
EMBASE (File 72),
Pascal (File 144),
MEDLINE®(File 154),
F-D-C Reports (File
187), Current Contents
(File 440). PubMed
was also searched.
Search
performed
April 7, 2003
Re: COX-2/GI safety, an additional search was
conducted during the course of the review to
identify whether the results of the SUCCESS-1
trial had been published in full.

Prevention of NSAID-induced gastroduodenal ulcers (Review) 166

Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Appendix 3. Embase Search Strategy
• RCT filter updated by translating Medline terminology to Embase terms
• Line 31 amended to ‘exp peptic ulcer bleeding/’
• Line 32 amended to ‘exp ulcer perforation/’
• Lines 33 and 34 deleted: redundant (included in ‘exp peptic ulcer/’)
• Lines 44 and 45 deleted: redundant (see line 42)
• Line 53 amended to ‘exp pylorus stenosis/’
• Line 54 amended to ‘(pylor$ adj3 stenosis).tw’
• Line 59 amended to ‘exp antiulcer agent/’
• Line 60 deleted: redundant (included in ‘exp antiulcer agent/’)
• Line 62 amended to ‘lan?oprazole.tw’
• Lines 66, 67, 69, 71 and 73 deleted: redundant (included in ‘exp antiulcer agent/’)
• (After line 78) inserted ‘exp proton pump inhibitor/’
• Lines 80 and 81 deleted: redundant (included in ‘exp antiulcer agent/’)
• Line 87 amended to ‘nonsteroid$ anti-inflammator$.tw’
• Line 88 amended to ‘non-steroid$ anti-inflammator$.tw’
• (After line 88) inserted ‘nonsteroid$ antiinflammator$.tw’ and ‘non-steroid$ antiinflammator$.tw’
• Line 116 amended to ‘exp phenazone/’
• (After line 116) inserted ‘phenazone.tw’
• Line 120 amended to ‘exp acetylsalicylic acid/’

Search as run 07/05/09

RCT filter updated 27/03/09
1. exp randomized controlled trial/
2. randomi?ed controlled trial$.tw.
3. exp randomization/
4. exp single blind procedure/
5. exp double blind procedure/
6. or/1-5
7. animal.hw.
8. human.hw.
9. 7 not (7 and 8)
10. 6 not 9
11. exp clinical trial/
12. (clin$ adj3 stud$).ti,ab,tw.
13. (clin$ adj3 trial$).ti,ab,tw.
14. ((singl$ or doubl$ or treb$ or tripl$) adj3 (blind$ or mask$)).ti,ab,tw.
15. exp placebo/
16. placebo$.ti,ab,tw.
17. random.ti,ab,tw.
18. (crossover$ or cross-over$).ti,ab,tw.
19. or/11-18
20. 19 not 9
21. 20 not 10
22. exp comparative study/
23. exp evaluation/
24. exp prospective study/
25. exp controlled study/
26. (control$ or prospective$ or volunteer$).ti,ab,tw.
27. or/22-26
28. 27 not 9
29. 10 or 21 or 28
30. exp peptic ulcer/
Prevention of NSAID-induced gastroduodenal ulcers (Review) 167
Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
31. exp peptic ulcer bleeding/
32. exp ulcer perforation/
33. (pep$ adj5 ulcer$).tw.
34. (stomach adj5 ulcer$).tw.
35. (duoden$ adj5 ulcer$).tw.
36. (gastr$ adj5 ulcer$).tw.
37. exp gastritis/
38. gastritis.tw.
39. gastropathy.tw.
40. (bleed$ adj5 ulcer$).tw.
41. (rebleed$ adj5 ulcer$).tw.
42. (gastrointestinal adj5 bleed$).tw.
43. (gastrointestinal adj5 rebleed$).tw.
44. (gastrointestinal adj5 hemorrhag$).tw.
45. (gastrointestinal adj5 haemorrhag$).tw.
46. (ulcer adj5 hemorrhag$).tw.
47. (ulcer adj5 haemorrhag$).tw.
48. (mucos$ adj5 injur$).tw.
49. exp pylorus stenosis/
50. (pylor$ adj3 stenosis).tw.
51. (gastrointestinal adj3 perforat$).tw.
52. (gi adj3 perforat$).tw.
53. (ulcer$ adj3 perforat$).tw.
54. or/30-53
55. exp antiulcer agent/
56. omeprazole.tw.
57. lan?oprazole.tw.
58. pantoprazole.tw.
59. rabeprazole.tw.
60. esomeprazole.tw.
61. cimetidine.tw.
62. ranitidine.tw.
63. famotidine.tw.
64. nizatidine.tw.
65. (histamine adj3 H2 adj3 antagonist$).tw.
66. (antiulcer adj5 agent$).tw.
67. (anti$ adj3 ulcer$ adj3 agent$).tw.
68. (H2 adj5 receptor adj5 antagonist$).tw.
69. exp proton pump inhibitor/
70. (proton adj3 pump adj3 inhibitor$).tw.
71. misoprostol.tw.
72. sucralfate.tw.
73. or/55-72
74. Anti-inflammatory agents, non-steroidal/
75. nsaid$.tw.
76. nonsteroid$ anti-inflammator$.tw.
77. non-steroid$ anti-inflammator$.tw.
78. nonsteroid$ antiinflammator$.tw.
79. non-steroid$ antiinflammator$.tw.
80. exp ibuprofen/
81. ibuprofen$.tw.
82. aceclofenac$.tw.
83. acemetacin$.tw.
Prevention of NSAID-induced gastroduodenal ulcers (Review) 168
Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
84. dexketoprofen$.tw.
85. exp diclofenac/
86. diclofenac$.tw.
87. fenbufen$.tw.
88. fenoprofen$.tw.
89. flurbiprofen$.tw.
90. exp indometacin/
91. indometacin$.tw.
92. exp ketoprofen/
93. ketoprofen$.tw.
94. exp mefenamic acid/
95. (mefenamic adj3 acid$).tw.
96. nabumetone$.tw.
97. exp naproxen/
98. naproxen$.tw.
99. exp phenylbutazone/
100. phenylbutazone$.tw.
101. exp piroxicam/
102. piroxicam$.tw.
103. exp sulindac/
104. sulindac$.tw.
105. exp tolmetin/
106. tolmetin.tw.
107. exp phenazone/
108. phenazone.tw.
109. antipyrine.tw.
110. tenoxicam$.tw.
111. (tiaprofenic adj3 acid$).tw.
112. exp acetylsalicylic acid/
113. aspirin$.tw.
114. (acetylsalicylic adj3 acid$).tw.
115. aminopyrine.tw.
116. curcumin.tw.
117. clofazimine.tw.
118. or/74-117
119. 54 and 73 and 118
120. 29 and 119
121. limit 120 to (“review” or short survey)
122. 120 not 121
123. limit 122 to yr=“2004-2009”

Appendix 4. EBMR Search Strategy

1. exp peptic ulcer/
2. exp peptic ulcer hemorrhage/
3. (pep$ adj5 ulcer$).ti,ab.
4. (stomach adj5 ulcer$).ti,ab.
5. (duoden$ adj5 ulcer$).ti,ab.
6. (gastr$ adj5 ulcer$).ti,ab.
7. exp gastritis/
8. gastritis.ti,ab.
9. gastropathy.ti,ab.
Prevention of NSAID-induced gastroduodenal ulcers (Review) 169
Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
10. (bleed$ adj5 ulcer$).ti,ab.
11. (rebleed$ adj5 ulcer$).ti,ab.
12. (gastrointestinal adj5 bleed$).ti,ab.
13. (gastrointestinal adj5 rebleed$).ti,ab.
14. (gastrointestinal adj5 hemorrhag$).ti,ab.
15. (gastrointestinal adj5 haemorrhag$).ti,ab.
16. (ulcer adj5 hemorrhag$).ti,ab.
17. (ulcer adj5 haemorrhag$).ti,ab.
18. (mucos$ adj5 injur$).ti,ab.
19. exp pyloric stenosis/
20. (pylor$ adj3 stenosis).ti,ab.
21. (gastrointestinal adj3 perforat$).ti,ab.
22. (gi adj3 perforat$).ti,ab.
23. (ulcer$ adj3 perforat$).ti,ab.
24. or/1-23
25. exp anti-ulcer agents/
26. exp omeprazole/
27. omeprazole.ti,ab.
28. lan?oprazole.ti,ab.
29. pantoprazole.ti,ab.
30. rabeprazole.ti,ab.
31. esomeprazole.ti,ab.
32. exp histamine H2 antagonists/
33. exp cimetidine/
34. cimetidine.ti,ab.
35. exp ranitidine/
36. ranitidine.ti,ab.
37. exp famotidine/
38. famotidine.ti,ab.
39. exp nizatidine/
40. nizatidine.ti,ab.
41. (histamine adj3 H2 adj3 antagonist$).ti,ab.
42. (antiulcer adj5 agent$).ti,ab.
43. (anti$ adj3 ulcer$ adj3 agent$).ti,ab.
44. (H2 adj5 receptor adj5 antagonist$).ti,ab.
45. exp proton pump inhibitors/
46. (proton adj3 pump adj3 inhibitor$).ti,ab.
47. exp misoprostol/
48. exp sucralfate/
49. misoprostol.ti,ab.
50. sucralfate.ti,ab.
51. or/25-50
52. Anti-inflammatory agents, non-steroidal/
53. nsaid$.ti,ab.
54. nonsteroid$ anti-inflammator$.ti,ab.
55. non-steroid$ anti-inflammator$.ti,ab.
56. nonsteroid$ antiinflammator$.ti,ab.
57. non-steroid$ antiinflammator$.ti,ab.
58. exp ibuprofen/
59. ibuprofen$.ti,ab.
60. aceclofenac$.ti,ab.
61. acemetacin$.ti,ab.
62. dexketoprofen$.ti,ab.
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Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
63. exp diclofenac/
64. diclofenac$.ti,ab.
65. fenbufen$.ti,ab.
66. exp fenoprofen/
67. fenoprofen$.ti,ab.
68. exp flurbiprofen/
69. flurbiprofen$.ti,ab.
70. exp indomethacin/
71. indomet?acin$.ti,ab.
72. exp ketoprofen/
73. ketoprofen$.ti,ab.
74. exp mefenamic acid/
75. (mefenamic adj3 acid$).ti,ab.
76. nabumetone$.ti,ab.
77. exp naproxen/
78. naproxen$.ti,ab.
79. exp phenylbutazone/
80. phenylbutazone$.ti,ab.
81. exp piroxicam/
82. piroxicam$.ti,ab.
83. exp sulindac/
84. sulindac$.ti,ab.
85. exp tolmetin/
86. tolmetin.ti,ab.
87. exp antipyrine/
88. antipyrine.ti,ab.
89. phenazone.ti,ab.
90. tenoxicam$.ti,ab.
91. (tiaprofenic adj3 acid$).ti,ab.
92. exp aspirin/
93. aspirin$.ti,ab.
94. (acetylsalicylic adj3 acid$).ti,ab.
95. exp aminopyrine/
96. aminopyrine.ti,ab.
97. exp curcumin/
98. curcumin.ti,ab.
99. exp clofazimine/
100. clofazimine.ti,ab.
101. or/52-100
102. 24 and 51 and 101
103. limit 102 to yr=“2004-2009”

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Appendix 5. Search used for Canadian NSAID Consensus Conference
1. exp stomach/
2. stomach.tw.
3. gastr$.tw.
4. exp duodenum/
5. duoden$.tw.
6. antrum.tw.
7. pylor$.tw.
8. gastroduoden$.tw.
9. or/1-8
10. exp peptic ulcer/
11. exp peptic ulcer hemorrhage/
12. (peptic adj5 ulcer$).tw.
13. (bleed$ adj5 ulcer$).tw.
14. (recurrent adj5 bleed$ adj5 ulcer$).tw.
15. (rebleed$ adj5 ulcer$).tw.
16. (ulcer$ adj5 hemo$).tw.
17. (ulcer$ adj5 haemo$).tw.
18. nonvaric$.tw.
19. (gastrointestinal adj5 bleed$).tw.
20. (gastrointestinal adj5 hemorrhag$).tw.
21. (gastrointestinal adj5 haemorrhag$).tw.
22. (GI adj5 bleed$).tw.
23. (GI adj5 hemorrhag$).tw.
24. (gi adj5 haemorrhag$).tw.
25. UGIB.tw.
26. (gastritis or gastropathy).ti,ab.
27. peptic ulcer perforation/
28. (ulcer adj5 perforation).ti,ab.
29. pyloric stenosis/
30. (pyloric adj5 stenosis).ti,ab.
31. (pyloric adj5 obstruction).ti,ab.
32. (endoscop$ adj5 ulcer).ti,ab.
33. (symptomatic adj5 ulcer).ti,ab.
34. nausea/
35. nausea.tw.
36. vomiting/
37. vomit$.tw.
38. abdominal pain/
39. abdominal pain.tw.
40. dyspepsia/
41. dyspepsia.tw.
42. or/10-33
43. 9 and 42
NSAIDS section
1. exp anti inflammatory agents non steroidal/
2. nonsteroidal anti-inflammator$.tw.
3. non-steroidal anti-inflammator$.tw.
4. NSAIDs/
5. NSAID$.tw.
6. diclofenac/ or diclofenac.ti,ab.
7. naproxen/ or naproxen.ti,ab.

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Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
 8. ibuprofen/ or ibuprofen.ti,ab.
9. ketoprofen/ or ketoprofen.ti,ab.
10. indomethacin/ or indomethacin.ti,ab.
11. ketorolac/ or ketorolac.ti,ab.
12. flurbiprofen/ or flurbiprofen.ti,ab.
13. clofazimine/ or clofazimine.ti,ab.
14. piroxicam/ or piroxicam.ti,ab.
15. tenoxicam/ or tenoxicam.ti,ab.
16. nabumetone/ or nabumetone.ti,ab.
17. fenoprofen/ or fenoprofen.ti,ab.
18. or/1-17
misoprostol
1. prostaglandin antagonists/
2. (prostaglandin adj2 antagonist?).ti,ab.
3. misoprostol/ or misoprostol.ti,ab.
4. or/1-3
H2RAs
1. histamine H2 antagonists/
2. (histamine adj3 “2” adj3 antagonist?).ti,ab.
3. (histamine adj2 “2” adj2 receptor adj2 antagonist?).ti,ab.
4. H2RA?.ti,ab.
5. cimetidine/ or cimetidine.ti,ab.
6. famotidine/ or famotidine.ti,ab.
7. nizatidine/ or nizatidine.ti,ab.
8. ranitidine/ or ranitidine.ti,ab.
9. or/1-8
RCT filter
1. randomized controlled trial.pt.
2. controlled clinical trial.pt.
3. randomized controlled trials/
4. random allocation/
5. double blind method/
6. single blind method/
7. or/1-6
8. (animals not human).sh.
9. 7 not 8
10. clinical trial.pt.
11. exp clinical trial/
12. (clin$ adj25 trial$).ti,ab.
13. ((singl$ or doubl$ or trebl$ or tripl$) adj25 (blind$ or mask$)).ti,ab.
14. placebos/
15. placebo$.ti,ab.
16. Random$.ti,ab.
17. research design/
18. or/10-17
19. 18 not 8
20. 19 not 9
21. comparative study/
22. exp evaluation studies/
23. follow-up studies/
24. prospective studies/
25. (control$ or prospectiv$ or volunteer$).ti,ab.
26. or/21-25
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Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
27. 26 not 8
28. 27 not (9 or 20)
29. 9 or 20 or 28

FEEDBACK

Endoscopic ulcers are not the same as clinical ulcers, 14 October 2010

Summary

Original feedback
We were pleased to read the review article as it addresses an important clinical question (Rostom 2002). We did however identify some
important issues that hinder our ability to apply the results in clinical practice.
Firstly, in the background, the authors noted that endoscopic ulcers can be found in approximately 40% of chronic NSAID users and up
to 85% of documented endoscopic ulcers do not become clinically apparent (Rostom 2002). However, in the results, we have concerns
about the lack of discussion regarding the use of surrogate endpoints, such as endoscopic ulcers, to predict meaningful endpoints such
as clinical ulcers (Moore 2009). Evidence showing a direct relationship in the same trial between endoscopic gastroduodenal ulcers
and clinically significant ulcer complications is lacking (Moore 2009). We would recommend including a discussion on the uncertain
clinical relevance of endoscopic ulcers (Graham 2009; Moore 2009).
Secondly, the overwhelming majority of trials included in the review (38/41) reported only on endoscopic ulcers; leaving a very small
sample of only three trials that reported on clinical ulcers and the subsequent complications. It is believed that selective outcome
reporting bias can have significant implications on the assessment of interventions (McGauran 2010). One way to address the issue of
selective outcome reporting bias is through contacting the authors of the individual trials and requesting to see their clinical outcome
data. In this review article, there was no indication of an attempt to contact the authors of the individual trials for information on
potential clinical events (i.e. symptomatic ulcers, bleeding, etc). The authors of the review discussed that the MUCOSA trial was the
only true clinical outcome trial; however, no attempt was made to highlight the potential dangers of drawing conclusions from a single
study without replication. In fact, the authors went on to summarize that “misoprostol at 800 ug daily reduces the occurrence of NSAID
related clinical ulcer complications” (Rostom 2002). We do not feel that this statement is justified.
Ninety three percent of trials did not report on clinical ulcers and this should have been emphasized in the review. Our interpretation of
the available literature is that there is insufficient evidence to determine if gastroprotection with any class of drugs reduces the incidence
of clinical complications that are important to patients on long-term NSAID therapy.
Lastly, we would like to note a potential transcription error on page 40 (Rostom 2002). In the list of characteristics of included studies,
the sample size described in the Silverstein 1995 trial appears to be missing the last numerical digit in the sample size at entry and
should read 4404 and 4439 instead of 440 and 443. As a reader, it’s helpful to understand all abbreviations used. In addition, the
authors did not define the abbreviations POB and PUB used in reference to proton pump inhibitor clinical endpoint trials.
Stephanie Halliday, BSc (Pharm)
Aaron Tejani, BSc (Pharm), PharmD, ACPR

Reply
Thank you for your letter and comments.
Your major concerns revolve around the usage of the endoscopic endpoint in the majority of the trials included in this review, and you
are also uncomfortable with the results of the mucosa study as it is a single clinical ulcer study.
Both these points were emphasised in our review including in the methods and discussion.
The feedback authors should be aware that the design and execution of a randomized controlled trial utilizing the endoscopic endpoint
is very different than for a trial utilizing the clinical ulcer composite endpoints (which typically include bleeding, perforation, or
obstruction). The common nature of endoscopic endpoints means that NSAID studies utilizing them can be small (few hundred
patients), short (4 to 12 weeks), and relatively inexpensive despite all patients undergoing endoscopy. These studies can be high
Prevention of NSAID-induced gastroduodenal ulcers (Review) 174
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quality and powered to detect significant changes in this endpoint. For example, proton pump inhibitors reduce the relative risk of
endoscopically detected duodenal ulcers by greater than 80% (Rostom 2009c; Rostom 2002). So it is no wonder that the vast majority
of researchers conducting NSAID studies, particularly the early traditional NSAID (tNSAID) trials and cyclo-oxygenase 2 inhibitors
(COX-2s) trials, utilized this endpoint.
NSAID trials that utilize clinical ulcer endpoints need to be very large (thousands of patients), quite long (6 months at least), and need
formal adjudication of potential endpoint events as not every patient undergoes endoscopy. The complexity and expense of these studies
limited their early usage until the COX-2 era arrived. Therefore, we feel the MUCOSA study (Silverstein 1995) can be considered
landmark in that it was the first to exercise this more complex design and subsequently was used as a model for the clinical ulcer trials
conducted for the COX-2s. Furthermore, the MUCOSA trial (Silverstein 1995) identified that clinical events occur at a rate of about
1.5% per 100 patient years amongst tNSAID users, a finding that was repeatedly identified in the COX-2 clinical ulcer studies (Rostom
2009c; Rostom 2002). MUCOSA was a high quality study and we have no reservation in the rating we gave it and as such in the
believability of its results (Rostom 2009c; Rostom 2002).
There is no question that the clinical ulcer studies are the preferred source of evidence over endoscopic studies particularly for the
evaluation of the safety of new agents as suggested by the FDA (FDA 2010). However at the same November 4th, 2010 FDA meeting,
the Gastrointestinal Drugs Advisory Committee agreed that endoscopic ulcers are “an adequate primary efficacy endpoint for evaluating
products intended to prevent NSAID-associated upper GI toxicity”. Therefore, it would be unwise to discount all the available data
from endoscopic studies. These studies demonstrated remarkable consistency in placebo arms event rates across the tNSAID and COX-
2 studies. Furthermore while there is not a one to one relationship between endoscopic ulcers and clinical ulcers, clearly there is a
relationship and few experts in the field would discount that today. In our own work, we have found that misoprostol and COX-2
inhibitors reduce the risk of clinical ulcers by about 50%, while the same agents reduce the risk of endoscopic ulcers by close to 80%
depending on whether one is speaking of endoscopic gastric or duodenal ulcers. Ironically, in previous versions of the review and in
our book chapters we discussed at length the relationship between endoscopic ulcers and clinical ulcers, but this was removed recently
as a relationship has become more accepted. So we feel that reporting on the endoscopic studies is valuable and appropriate (Rostom
2009c; Rostom 2002).
You also mention that one could contact authors for inclusion of unreported clinical events occurring within the endoscopic studies to
avoid bias. However, we purposely did not include this type of data even when a clinical event was occasionally mentioned in a paper.
The reason for this as detailed above is simply that these studies were not designed to look for these events in a systematic way, nor
were adjudication of such events described a priori and consistently among the endoscopic ulcer studies. We strongly feel that inclusion
of such reports would introduce multiple other sources of bias and would not improve our understanding in a tangible fashion. The
Hong Kong studies included in our review are of course different in that they were designed to report on both types of endpoints by
utilizing a very high risk NSAID population where clinical endpoints occur at a relatively high rate to allow for a relatively short, and
small study (Chan 2002; FDA 2010).
Lastly thank you for identifying the typos related to the MUCOSA study table.
In summary, we respect your opinion that “that there is insufficient evidence to determine if gastroprotection with any class of drugs
reduces the incidence of clinical complications that are important to patients on long-term NSAID therapy”, but we respectfully
disagree.
Alaa Rostom MD MSc FRCPC

Contributors
Stephanie Halliday, BSc (Pharm)
Aaron Tejani, BSc (Pharm), PharmD, ACPR
Alaa Rostom MD MSc FRCPC

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WHAT’S NEW
Last assessed as up-to-date: 11 May 2009.

Date Event Description

15 April 2011 Amended Correction of typos

HISTORY
Review first published: Issue 3, 2000

Date Event Description

12 April 2011 Feedback has been incorporated Endoscopic ulcers are not the same as clinical ulcers.

5 October 2010 Amended Contact details updated.

11 May 2009 New search has been performed 5 new studies have been added since the last update.

16 July 2008 Amended Converted to new review format.

25 July 2002 New citation required and conclusions have changed Substantive amendment.

CONTRIBUTIONS OF AUTHORS

Screening for titles and abstracts

Alaa Rostom, Catherine Dube, Vivian Welch, Emily Jolicoeur.

Assessment for inclusion

Alaa Rostom, Catherine Dube, Vivian Welch, Emily Jolicoeur.

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Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Quality assessment
Alaa Rostom, Catherine Dube, Vivian Welch.

Data extraction
Alaa Rostom, Catherine Dube, Vivian Welch.

Data entry into RevMan

Alaa Rostom, Vivian Welch.

Prepared the manuscript

Alaa Rostom, Catherine Dube.

Literature search
Jessie McGowen (original search) - subsequent searches performed by the Cochrane UGPD group.
Alaa Rostom.

Review statistics / data and manuscript review

Peter Tugwel, George Wells, Angel Lanas.

DECLARATIONS OF INTEREST
None.

SOURCES OF SUPPORT

Internal sources
• No sources of support supplied

External sources
• Canadian Coordinating Office for Health Technology Assessment, Canada.
August 2002 search update

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Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
DIFFERENCES BETWEEN PROTOCOL AND REVIEW
None.

NOTES
This is an updated version of the review first published in 2000. The changes include an updated search strategy, and new papers on
PPIs. We have also updated the Background and Discussion to reflect the changes in NSAID field related to COX-2 inhibitor market
withdrawals and new data on cardiovascular toxicity of COX-2s and NSAIDs.

INDEX TERMS

Medical Subject Headings (MeSH)

∗ Proton Pump Inhibitors; Anti-Inflammatory Agents, Non-Steroidal [∗ adverse effects]; Anti-Ulcer Agents [adverse effects; ∗ therapeutic
use]; Chronic Disease; Duodenal Ulcer [chemically induced; ∗ prevention & control]; Histamine H2 Antagonists [∗ therapeutic use];
Misoprostol [adverse effects; ∗ therapeutic use]; Randomized Controlled Trials as Topic; Stomach Ulcer [chemically induced; ∗prevention
& control]

MeSH check words

Humans

Prevention of NSAID-induced gastroduodenal ulcers (Review) 178

Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.