Supplementary Online Content

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1 Supplementary Online Content Sachar H, Vaidya K, Laine L. Intermittent vs continuous proton pump inhibitor therapy for highrisk bleeding ulcers: systematic review and meta-analysis. JAMA Intern Med. Published online September 8, doi: /jamainternmed efigure 1. Search strategies efigure 2. Risk of bias summary for individual studies in systematic review efigure 3. Forest plot of studies comparing intermittent PPI and bolus-continuous infusion PPI in patients with high-risk bleeding ulcers: rebleeding within 3 days in intention-to-treat population efigure 4. Forest plot of studies comparing intermittent PPI and bolus-continuous infusion PPI in patients with high-risk bleeding ulcers: rebleeding within 30 days in intention-to-treat population etable. Subgroup analyses for rebleeding within 7 days This supplementary material has been provided by the authors to give readers additional information about their work.

2 efigure 1. Search Strategies MEDLINE 1. exp Stomach/ 2. stomach.mp. 3. gastr$.mp. 4. exp Duodenum/ 5. duoden$.mp. 6. peptic$.mp. 7. exp Esophagus/ 8. esophagu$.mp. 9. oesopha$.mp. 10. exp Peptic Ulcer/ 11. (peptic adj5 ulcer$).mp. 12. (stomach adj5 ulcer$).mp. 13. (duoden$ adj5 ulcer$).mp. 14. (gastroduoden$ adj5 ulcer$).mp. 15. peptic ulcer hemorrhage.mp. 16. peptic ulcer haemorrhage.mp. 17. gastrointestinal hemorrhage.mp. 18. gastrointestinal haemorrhage.mp. 19. (bleed$ adj5 ulcer$).mp. 20. (rebleed$ adj5 ulcer$).mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept, rare disease supplementary concept, unique identifier] 21. (re-bleed$ adj5 ulcer$).mp. 22. (recurrent adj5 bleed$ adj5 ulcer$).mp. 23. (acute adj5 bleed$ adj5 ulcer$).mp. 24. (gastrointestinal adj5 bleed$).mp. 25. (gastrointestinal adj5 rebleed$).mp. 26. (gastrointestinal adj5 re-bleed$).mp. 27. (gastrointestinal adj5 hemorrhag$).mp. 28. (gastrointestinal adj5 haemorrhag$).mp. 29. (ulcer adj5 hemorrhag$).mp. 30. (ulcer adj5 haemorrhag$).mp. 31. exp Melena/ 32. melena.mp. 33. melaena.mp. 34. exp Hematemesis/ 35. hematemesis.mp. 36. haematemesis.mp. 37. (coffee adj1 ground).mp. 38. or/ acid suppression treatment.mp. 40. omeprazole.mp. or exp Omeprazole/

3 41. pantoprazole.mp. 42. lansoprazole.mp. 43. rabeprazole.mp. 44. esomeprazole.mp. or exp Esomeprazole Sodium/ 45. (proton adj5 pump adj5 inhibitor$).mp. 46. proton pump inhibitor.mp. or exp Anti-Ulcer Agents/ or exp Proton Pump Inhibitors/ 47. ppi$.mp. 48. or/ and limit 49 to randomized controlled trial limit 51 to humans 53. or/ or/ and and (animals not (humans and animals)).sh not randomized controlled trial.pt. 60. controlled clinical trial.pt. 61. randomized.ab. 62. placebo.ab. 63. drug therapy.fs. 64. randomly.ab. 65. trial.ab. 66. groups.ab. 67. or/ and benzimidazoles.mp. or exp Benzimidazoles/ or and 54 and not and 67

4 EMBASE 1. (random$ or placebo$).ti,ab. 2. ((single$ or double$ or triple$ or treble$) and (blind$ or mask$)).ti,ab. 3. controlled clinical trial$.ti,ab. 4. RETRACTED ARTICLE/ 5. (animal$ not human$).sh,hw. 6. or/ exp stomach/ 8. stomach.mp. 9. gastr$.mp. 10. exp duodenum/ 11. duoden$.mp. 12. peptic$.mp. 13. exp esophagus/ 14. esophag$.mp. 15. oesophag$.mp. 16. exp peptic ulcer/ 17. (peptic adj5 ulcer$).mp. 18. (stomach adj5 ulcer$).mp. 19. (duoden$ adj5 ulcer$).mp. 20. (gastroduoden$ adj5 ulcer$).mp. 21. or/ peptic ulcer hemorrhage.mp. 23. peptic ulcer haemorrhage.mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword] 24. gastrointestinal hemorrhage.mp. 25. gastrointestinal haemorrhage.mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword] 26. (bleed$ adj5 ulcer$).mp. 27. (rebleed$ adj5 ulcer$).mp. 28. (re-bleed$ adj5 ulcer$).mp. 29. (recurrent adj5 bleed$ adj5 ulcer$).mp. 30. (acute adj5 bleed$ adj5 ulcer$).mp. 31. (gastrointestinal adj5 bleed$).mp. 32. (gastrointestinal adj5 rebleed$).mp. 33. (gastrointestinal adj5 re-bleed$).mp. 34. (gastrointestinal adj5 hemorrhag$).mp. 35. (gastrointestinal adj5 haemorrhag$).mp. 36. (ulcer adj5 hemorrhag$).mp. 37. (ulcer adj5 haemorrhag$).mp. 38. exp melena/ 39. melena.mp.

5 40. melaena.mp. 41. exp hematemesis/ 42. haematemesis.mp. 43. hematemesis.mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword] 44. (coffee adj1 ground).mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword] 45. or/ acid suppression treatment.mp. 47. exp omeprazole/ 48. omeprazole.mp. 49. lansoprazole.mp. 50. pantoprazole.mp. 51. rabeprazole.mp. 52. esomeprazole.mp. 53. benzimidazoles.mp. 54. (proton adj5 pump adj5 inhibitor$).mp. 55. ppi$.mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword] 56. or/ not and 45 and and 58

6 CENTRAL ID Search #1 stomach:ti,ab,kw (Word variations have been searched) #2 stomach.mp. #3 gastr$.mp. #4 duodenum #5 duoden$.mp. #6 peptic$.mp. #7 peptic #8 esophagus #9 esophag$.mp. #10 oesophag$.mp. #11 peptic ulcer #12 (peptic adj5 ulcer$).mp. #13 (stomach adj5 ulcer$).mp. #14 (duoden$ adj5 ulcer$).mp. #15 (gastroduoden$ adj5 ulcer$).mp. #16 stomach ulcer #17 duodenal ulcer #18 gastroduodenal ulcer #19 stomach #20 gastro #21 #1 or #2 or #3 or #4 or #5 or #6 or #7 or #8 or #9 or #10 or #11 or #12 or #13 or #14 or #15 or #16 or #17 or #18 or #19 or #20 #22 peptic ulcer hemorrhage.mp. #23 peptic ulcer hemorrhage #24 peptic ulcer haemorrhage #25 peptic ulcer haemorrhage.mp #26 gastrointestinal hemorrhage #27 gastrointestinal hemorrhage.mp #28 gastrointestinal haemorrhage #29 gastrointestinal haemorrhage.mp #30 (bleed$ adj5 ulcer$).mp #31 (bleed$ adj5 ulcer$) #32 (rebleed$ adj5 ulcer$).mp. #33 (rebleed$ adj5 ulcer$) #34 (re-bleed$ adj5 ulcer$).mp. #35 (re-bleed$ adj5 ulcer$) #36 (recurrent adj5 bleed$ adj5 ulcer$).mp. #37 (recurrent adj5 bleed$ adj5 ulcer$) #38 (acute adj5 bleed$ adj5 ulcer$).mp. #39 (acute adj5 bleed$ adj5 ulcer$) #40 (gastrointestinal adj5 bleed$).mp #41 (gastrointestinal adj5 bleed$)

7 #42 (gastrointestinal adj5 rebleed$).mp #43 (gastrointestinal adj5 rebleed$) #44 (gastrointestinal adj5 re-bleed$).mp. #45 (gastrointestinal adj5 re-bleed$) #46 (gastrointestinal adj5 hemorrhag$).mp. #47 (gastrointestinal adj5 hemorrhag$) #48 (gastrointestinal adj5 haemorrhag$).mp. #49 (gastrointestinal adj5 haemorrhag$) #50 (ulcer adj5 hemorrhag$).mp. #51 (ulcer adj5 hemorrhag$) #52 (ulcer adj5 haemorrhag$).mp. #53 (ulcer adj5 haemorrhag$) #54 melena #55 melena.mp. #56 melaena #57 melaena.mp. #58 hematemesis #59 haematemesis #60 haematemesis.mp. #61 hematemesis.mp #62 (coffee adj1 ground).mp #63 (coffee adj1 ground) #64 coffee ground emesis #65 #22 or #23 or #24 or #25 or #26 or #27 or #28 or #29 or #30 or #31 or #32 or #33 or #34 or #35 or #36 or #37 or #38 or #39 or #40 or #41 or #42 or #43 or #44 or #45 or #46 or #47 or #48 or #49 or #50 or #51 or #52 or #53 or #54 or #55 or #56 or #57 or #58 or #59 or #60 or #61 or #62 or #63 or #64 #66 acid suppression treatment #67 acid suppression treatment.mp. #68 omeprazole #69 omeprazole.mp. #70 lansoprazole #71 lansoprazole.mp. #72 pantoprazole #73 proton pump inhibitor #74 proton pump inhibitor.mp #75 ppi #76 ppi$.mp #77 #66 or #67 or #68 or #69 or #70 or #71 or #72 or #73 or #74 or #75 or #76 #78 #21 and #65 and #77

8 efigure 2: Risk of Bias Summary for Individual Studies in Systematic Review

9 efigure 3: Forest Plot of Studies Comparing Intermittent PPI and Bolus-Continuous Infusion PPI in Patients with High-Risk Bleeding Ulcers: Rebleeding within 3 days in Intention-to-Treat Population

10 efigure 4: Forest Plot of Studies Comparing Intermittent PPI and Bolus-Continuous Infusion PPI in Patients with High-Risk Bleeding Ulcers: Rebleeding within 30 days in Intention-to-Treat Population

11 etable: Subgroup Analyses for Rebleeding within 7 Days Subgroups Studies Participants Relative Risk for Intermittent vs. Continuous- Infusion PPI (95% CI upper bound) 1. Risk of Bias Risk of Bias Abstract 2. Full Article (1.48) 0.62 (0.91) 0.47 (1.04) 0.78 (1.08) Heterogeneity P =.31 P = Initial Higher- Dose Bolus with Intermittent PPI 2. No Initial Higher-Dose Bolus with Intermittent PPI mg 2. >120mg (1.05) 0.77 (1.10) 0.78 (1.16) 0.63 (1.02) P =.54 P = mg 2. >240mg (1.15) 0.55 (0.95) P = IV 2. PO (0.94) 0.96 (2.02) P = Once Daily 2. >Once Daily (1.12) 0.69 (1.08) P = Asian 2. Non-Asian (1.55) 0.59 (0.88) P =.21