Proton pump inhibitor treatment initiated prior to endoscopic diagnosis in upper gastrointestinal bleeding

Takeshi Kanno; Yuhong Yuan; Frances Tse; Colin W Howden; Paul Moayyedi; Grigorios I Leontiadis

doi:10.1002/14651858.CD005415.pub4

Tratamiento con inhibidores de la bomba de protones iniciado antes del diagnóstico endoscópico en la hemorragia digestiva alta

Appendices

Appendix 1. CENTRAL search strategy

EBM Reviews ‐ CDSR (2005 to 11 October 2017) and CCRCT (September 2017)

exp Gastrointestinal Hemorrhage/
(UGIB or NVUGIB or upper GIB).tw,kw.
exp Stomach Ulcer/
exp duodenal ulcer/
exp gastroduodenal ulcer/
(stomach or fundus or fundal or antrum or antral or pyloric or pylorus or gastric or duodenum or duodenal).tw,kw.
(gastro* or oesophag* or esophag*).tw,kw.
exp Peptic Ulcer/
peptic ulcer*.tw,kw.
exp upper gastrointestinal tract/
(non‐variceal or non variceal or nonvariceal or upper GI or UGI).tw,kw.
or/3‐11
(bleed* or re‐bleed* or rebleed* or hemorrhag* or haemorrhag*).mp.
exp Hemorrhage/
(melena or melaena or hematemesis or heamatemesis).tw,kw.
or/13‐15
12 and 16
1 or 2 or 17
exp Proton Pump Inhibitors/
proton pump inhibitor*.mp.
(PPI or PPIs).tw,kw.
exp Omeprazole/
(omeprazole or h 16868 or losec or prilosec or rapinex or zegerid).mp.
exp Lansoprazole/
(lansoprazole or lanzoprazole or ag 1749 or agopton or bamalite or lanzor or monolitum or ogast or ogastro or opiren or prevacid or prezal or pro ulco or promeco or takepron or ulpax or zoton).mp.
(pantoprazole or by 1023 or protium or protonix or skf‐96022).mp.
exp esomeprazole/
(esomeprazole or nexium).mp.
exp Rabeprazole/
(rabeprazole or aciphex or dexrabeprazole or e 3810 or ly‐307640 or pariet).mp.
(dexlansoprazole or Kapidex or Dexilant or AGN 20194* or AGN20194* or dexrabeprazole).mp.
exp Dexlansoprazole/
(tenatoprazole or CAS 113712‐98‐4 or STU‐Na or TAK‐390* or TAK390* or TAK‐438 or TAK438 or AZD0865 or "AZD 0865").mp.
or/19‐33
18 and 34
remove duplicates from 35

Appendix 2. MEDLINE search strategy

Database: OVID Medline Epub Ahead of Print, In‐Process & Other Non‐Indexed Citations, Ovid MEDLINE(R) Daily and Ovid MEDLINE(R) 1946 to Present

randomized controlled trial.pt.
controlled clinical trial.pt.
random*.ab.
placebo.ab.
drug therapy.fs.
trial.ab.
groups.ab.
or/1‐7
exp animals/ not humans/
8 not 9
exp Gastrointestinal Hemorrhage/
(UGIB or NVUGIB or upper GIB or "PUB" or "PUBs").tw,kw.
(stomach or fundus or fundal or antrum or antral or pyloric or pylorus or gastric or duodenum or duodenal).tw,kw.
(gastro* or oesophag* or esophag*).tw,kw.
exp Peptic Ulcer/
peptic ulcer*.tw,kw.
exp upper gastrointestinal tract/
(non‐variceal or non variceal or nonvariceal or upper GI or UGI).tw,kw.
or/13‐18
(bleed* or re‐bleed* or rebleed* or hemorrhag* or haemorrhag*).mp.
exp Hemorrhage/
(melena or melaena or hematemesis or heamatemesis).tw,kw.
or/20‐22
19 and 23
11 or 12 or 24
exp Proton Pump Inhibitors/
proton pump inhibitor*.mp.
(PPI or PPIs).tw,kw.
(omeprazole or h 16868 or losec or prilosec or rapinex or zegerid).mp.
(lansoprazole or lanzoprazole or ag 1749 or agopton or bamalite or lanzor or monolitum or ogast or ogastro or opiren or prevacid or prezal or pro ulco or promeco or takepron or ulpax or zoton).mp.
(pantoprazole or by 1023 or protium or protonix or skf‐96022).mp.
(esomeprazole or nexium).mp.
(rabeprazole or aciphex or dexrabeprazole or e 3810 or ly‐307640 or pariet).mp.
(dexlansoprazole or Kapidex or Dexilant or AGN 20194* or AGN20194* or dexrabeprazole).mp.
(tenatoprazole or CAS 113712‐98‐4 or STU‐Na or TAK‐390* or TAK390* or TAK‐438 or TAK438 or AZD0865 or "AZD 0865").mp.
or/26‐35
25 and 36
10 and 37

Note: Lines 1‐10. “Cochrane Highly Sensitive Search Strategy for identifying randomized trials in MEDLINE: sensitivity‐maximizing version (2008 revision); Ovid format”. We made the following minor revisions: we used “random*” instead of “randomized.ab” or “randomly.ab.” to capture word variations such as “randomised, randomization, random”.

Appendix 3. Embase search strategy

random:.tw.
placebo:.mp.
double‐blind:.tw.
or/1‐3
exp animal/ not human/
4 not 5
exp gastrointestinal hemorrhage/
(UGIB or NVUGIB or upper GIB or "PUB" or "PUBs").tw,kw.
(stomach or fundus or fundal or antrum or antral or pyloric or pylorus or gastric or duodenum or duodenal).tw,kw.
(gastro* or oesophag* or esophag*).tw,kw.
exp peptic ulcer/
peptic ulcer*.tw,kw.
exp upper gastrointestinal tract/
(non‐variceal or non variceal or nonvariceal or upper GI or UGI).tw,kw.
or/9‐14
(bleed* or re‐bleed* or rebleed* or hemorrhag* or haemorrhag*).mp.
exp bleeding/
(melena or melaena or hematemesis or heamatemesis).tw,kw.
or/16‐18
15 and 19
7 or 8 or 20
exp proton pump inhibitor/
proton pump inhibitor*.mp.
(PPI or PPIs).tw,kw.
(omeprazole or h 16868 or losec or prilosec or rapinex or zegerid).mp.
(lansoprazole or lanzoprazole or ag 1749 or agopton or bamalite or lanzor or monolitum or ogast or ogastro or opiren or prevacid or prezal or pro ulco or promeco or takepron or ulpax or zoton).mp.
(pantoprazole or by 1023 or protium or protonix or skf‐96022).mp.
(esomeprazole or nexium).mp.
(rabeprazole or aciphex or dexrabeprazole or e 3810 or ly‐307640 or pariet).mp.
(dexlansoprazole or Kapidex or Dexilant or AGN 20194* or AGN20194* or dexrabeprazole).mp.
(tenatoprazole or CAS 113712‐98‐4 or STU‐Na or TAK‐390* or TAK390* or TAK‐438 or TAK438 or AZD0865 or "AZD 0865").mp.
or/22‐31
21 and 32
6 and 33

Note: Lines 1‐3. Hedge Best balance of sensitivity and specificity filter for identifying therapeutic trials in Embase. https://hiru.mcmaster.ca/hiru/HIRU_Hedges_EMBASE_Strategies.aspx

Figure 1

Study flow diagram: review update 03 June 2021

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Figure 2

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies

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Figure 3

Risk of bias summary: review authors' judgements about each risk of bias item for each included study

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Figure 4

Trial sequential analysis (TSA) for outcome mortality

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Figure 5

Trial sequential analysis (TSA) for outcome rebleeding

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Analysis 1.1

Comparison 1: Main analysis, Outcome 1: Mortality

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Analysis 1.2

Comparison 1: Main analysis, Outcome 2: Rebleeding

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Analysis 1.3

Comparison 1: Main analysis, Outcome 3: Surgery

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Analysis 1.4

Comparison 1: Main analysis, Outcome 4: Participants requiring blood transfusion

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Analysis 1.5

Comparison 1: Main analysis, Outcome 5: Proportion of participants with stigmata of recent haemorrhage

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Analysis 1.6

Comparison 1: Main analysis, Outcome 6: Proportion of participants with stigmata of recent haemorrhage plus Lau 2007

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Analysis 1.7

Comparison 1: Main analysis, Outcome 7: Proportion of participants with blood in stomach

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Analysis 1.8

Comparison 1: Main analysis, Outcome 8: Proportion of participants with active bleeding

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Analysis 1.9

Comparison 1: Main analysis, Outcome 9: Proportion of participants with active bleeding plus Lau 2007

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Analysis 1.10

Comparison 1: Main analysis, Outcome 10: Endoscopic haemostatic treatment at index endoscopy

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Analysis 2.1

Comparison 2: Subgroup analysis according to risk of bias, Outcome 1: Mortality

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Analysis 2.2

Comparison 2: Subgroup analysis according to risk of bias, Outcome 2: Rebleeding

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Analysis 2.3

Comparison 2: Subgroup analysis according to risk of bias, Outcome 3: Surgery

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Analysis 2.4

Comparison 2: Subgroup analysis according to risk of bias, Outcome 4: Proportion of participants with stigmata of recent haemorrhage

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Analysis 2.5

Comparison 2: Subgroup analysis according to risk of bias, Outcome 5: Endoscopic haemostatic treatment at index endoscopy

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Analysis 3.1

Comparison 3: Subgroup analysis according to geographic location, Outcome 1: Mortality

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Analysis 3.2

Comparison 3: Subgroup analysis according to geographic location, Outcome 2: Rebleeding

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Analysis 3.3

Comparison 3: Subgroup analysis according to geographic location, Outcome 3: Surgery

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Analysis 4.1

Comparison 4: Subgroup analysis according to route of PPI administration, Outcome 1: Mortality

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Analysis 4.2

Comparison 4: Subgroup analysis according to route of PPI administration, Outcome 2: Rebleeding

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Analysis 4.3

Comparison 4: Subgroup analysis according to route of PPI administration, Outcome 3: Surgery

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Analysis 5.1

Comparison 5: Subgroup analysis according to PPI dose (high dose versus non‐high dose), Outcome 1: Mortality

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Analysis 5.2

Comparison 5: Subgroup analysis according to PPI dose (high dose versus non‐high dose), Outcome 2: Rebleeding

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Analysis 5.3

Comparison 5: Subgroup analysis according to PPI dose (high dose versus non‐high dose), Outcome 3: Surgery

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Analysis 6.1

Comparison 6: Subgroup analysis according to control treatment, Outcome 1: Mortality

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Analysis 6.2

Comparison 6: Subgroup analysis according to control treatment, Outcome 2: Rebleeding

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Analysis 6.3

Comparison 6: Subgroup analysis according to control treatment, Outcome 3: Surgery

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Analysis 7.1

Comparison 7: Subgroup analysis according to use of endoscopic haemostatic treatment at index endoscopy, Outcome 1: Mortality

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Analysis 7.2

Comparison 7: Subgroup analysis according to use of endoscopic haemostatic treatment at index endoscopy, Outcome 2: Rebleeding

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Analysis 7.3

Comparison 7: Subgroup analysis according to use of endoscopic haemostatic treatment at index endoscopy, Outcome 3: Surgery

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Analysis 8.1

Comparison 8: Sensitivity analysis restricted to peptic ulcer participants, Outcome 1: Mortality

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Analysis 8.2

Comparison 8: Sensitivity analysis restricted to peptic ulcer participants, Outcome 2: Rebleeding

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Analysis 8.3

Comparison 8: Sensitivity analysis restricted to peptic ulcer participants, Outcome 3: Surgery

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Summary of findings 1. Proton pump inhibitor treatment compared to H2RA, placebo or no treatment in people with upper gastrointestinal bleeding prior to endoscopic diagnosis

Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)
Main analysis: proton pump inhibitor treatment compared to H₂RA, placebo or no treatment in people with upper gastrointestinal bleeding prior to endoscopic diagnosis
Patient or population: people with upper gastrointestinal bleeding prior to endoscopic diagnosis Setting: hospital setting (inpatients), any country (not limited to specific geographic locations or specific country income classifications) Intervention: proton pump inhibitor (PPI) Comparison: histamine‐2 receptor antagonist (H₂RA), placebo or no treatment
Outcomes	With control treatment	With PPI treatment (95% CI)	Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)
Mortality ‐ within 30 days	Study population		OR 1.14 (0.76 to 1.70)	2143 (5 RCTs)	⊕⊕⊝⊝ Low^a,b
Mortality ‐ within 30 days	45 per 1000	6 more per 1000 (from 6 less to 30 more)	OR 1.14 (0.76 to 1.70)	2143 (5 RCTs)	⊕⊕⊝⊝ Low^a,b
Rebleeding ‐ within 30 days	Study population		OR 0.81 (0.62 to 1.06)	2121 (5 RCTs)	⊕⊕⊝⊝ Low^c,d
Rebleeding ‐ within 30 days	131 per 1000	23 less per 1000 (from 45 less to 8 more)	OR 0.81 (0.62 to 1.06)	2121 (5 RCTs)	⊕⊕⊝⊝ Low^c,d
Surgery ‐ within 30 days	Study population		OR 0.91 (0.65 to 1.26)	2223 (6 RCTs)	⊕⊕⊝⊝ Low^e,f
Surgery ‐ within 30 days	77 per 1000	6 less per 1000 (from 24 less to 18 more)	OR 0.91 (0.65 to 1.26)	2223 (6 RCTs)	⊕⊕⊝⊝ Low^e,f
Proportion of participants with stigmata of recent haemorrhage at index endoscopy	Study population		OR 0.80 (0.52 to 1.21)	1332 (4 RCTs)	⊕⊕⊝⊝ Low^g,h
	465 per 1000	42 less per 1000 (from 135 less to 74 more)	OR 0.80 (0.52 to 1.21)	1332 (4 RCTs)	⊕⊕⊝⊝ Low^g,h
Endoscopic haemostatic treatment at index endoscopy	Study population		OR 0.68 (0.50 to 0.93)	1983 (3 RCTs)	⊕⊕⊕⊝ Moderateⁱ
Endoscopic haemostatic treatment at index endoscopy	118 per 1000	33 less per 1000 (52 less to 8 less)	OR 0.68 (0.50 to 0.93)	1983 (3 RCTs)	⊕⊕⊕⊝ Moderateⁱ
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; RR: risk ratio; OR: odds ratio
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
^aThe certainty of evidence for mortality was rated down one level due to serious study limitations. Two of the five studies had high risk of bias (high risk of performance bias due to lack of blinding; unclear risk of selection bias due to unclear random sequence generation and unclear allocation concealment), and two other studies had unclear risk of bias (unclear risk of selection bias due to unclear allocation concealment). Of note, if by a 'sensitivity approach' the above‐mentioned four studies were excluded, then all the evidence would be derived from one RCT at low risk of bias (Lau 2007): the effect estimate would remain similar, and there would be no study limitations, but the imprecision would further worsen and would be considered very serious (due to very wide 95% CI and only 15 events in total) requiring rating down by two levels for imprecision; therefore, the certainty of evidence would be low with either approach. ^bThe certainty of evidence for mortality was further downrated one level due to serious imprecision. The 95% CI of the pooled effect included no effect as well as clinically important benefit and clinically important harm. Small total number of events (102 in total). ^cThe certainty of evidence for rebleeding was rated down one level due to serious study limitations. Two of the five studies had high risk of bias (high risk of performance bias and detection bias due to lack of blinding; unclear risk of selection bias due to unclear random sequence generation or unclear allocation concealment, or both), and the other two studies had unclear risk of bias (unclear risk of selection bias due to unclear allocation concealment). Of note, if by a 'sensitivity approach' the above‐mentioned four studies were excluded, then all the evidence would be derived from one RCT at low risk of bias (Lau 2007): the effect estimate would include both clinically important benefit and clinically important harm), and there would be no study limitations, but the imprecision would further worsen and would be considered very serious (due to very wide 95% CI and only 18 events in total) requiring rating down by two levels for imprecision; therefore, the certainty of evidence would be low with either approach. ^dThe certainty of evidence for rebleeding was further downrated one level due to serious imprecision. The 95% CI of the pooled effect included no effect as well as clinically important benefit and small unimportant harm. Relatively small total number of events (255 in total). ^eThe certainty of evidence for surgery was rated down one level due to serious study limitations. Three of the five studies had high risk of bias (high risk of performance bias and detection bias due to lack of blinding; unclear risk of selection bias due to unclear random sequence generation or unclear allocation concealment, or both), and two other studies had unclear risk of bias (unclear risk of selection bias due to unclear allocation concealment). Of note, if by a 'sensitivity approach' the above‐mentioned four studies were excluded, then all the evidence would be derived from one RCT at low risk of bias (Lau 2007): the effect estimate would remain similar, and there would be no study limitations, but the imprecision would further worsen and would be considered very serious (due to very wide 95% CI and only 10 events in total) requiring downrating by two levels for imprecision; therefore, the certainty of evidence would be low with either approach. ^fThe certainty of evidence for surgery was further downrated one level due to serious imprecision. The 95% CI of the pooled effect included no effect as well as clinically important benefit and clinically important harm. Relatively small total number of events (163 in total). ^gThe certainty of evidence for the proportion of participants with stigmata of recent haemorrhage at index endoscopy was downrated one level due to serious study limitations. Two of the four studies had high risk of bias (high risk of performance bias and detection bias due to lack of blinding; unclear risk of selection bias due to unclear random sequence generation or unclear allocation concealment, or both), and the other two studies had unclear risk of bias (unclear risk of selection bias due to unclear allocation concealment). ^hThe certainty of evidence for the proportion of participants with stigmata of recent haemorrhage at index endoscopy was further downrated one level due to serious imprecision. The 95% CI of the pooled effect included no effect as well as clinically important benefit and clinically important harm. ⁱThe certainty of evidence for endoscopic haemostatic treatment at index endoscopy was downrated one level in total due to the combination of moderate study limitations, moderate indirectness and moderate imprecision. Two of the three studies had unclear risk of bias (unclear risk of selection bias due to unclear allocation concealment); the same two studies had indirectness because their criteria and technique for endoscopic haemostatic treatment were different from modern practice. However, these two studies contributed only a small proportion of the weight of the meta‐analysis (31% with random‐effects model, 26% with fixed‐effect model). If by a 'sensitivity approach' the above‐mentioned two studies were excluded, then all the evidence would be derived from one RCT at low risk of bias and without indirectness (Lau 2007): the effect estimate would remain identical, and there would be no study limitations, no indirectness but the imprecision would further worsen and would be considered serious (150 events in total) justifying downrating by one level for imprecision alone; therefore, the certainty of evidence would be moderate with either approach.

Summary of findings 1. Proton pump inhibitor treatment compared to H2RA, placebo or no treatment in people with upper gastrointestinal bleeding prior to endoscopic diagnosis

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Comparison 1. Main analysis

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1.1 Mortality Show forest plot	5	2143	Risk Ratio (M‐H, Random, 95% CI)	1.13 [0.77, 1.66]

1.2 Rebleeding Show forest plot	5	2121	Odds Ratio (M‐H, Random, 95% CI)	0.81 [0.62, 1.06]

1.3 Surgery Show forest plot	6	2223	Odds Ratio (M‐H, Random, 95% CI)	0.91 [0.65, 1.26]

1.4 Participants requiring blood transfusion Show forest plot	4	1512	Odds Ratio (M‐H, Random, 95% CI)	0.95 [0.75, 1.20]

1.5 Proportion of participants with stigmata of recent haemorrhage Show forest plot	4	1332	Odds Ratio (M‐H, Random, 95% CI)	0.80 [0.52, 1.21]

1.6 Proportion of participants with stigmata of recent haemorrhage plus Lau 2007 Show forest plot	5	1709	Odds Ratio (M‐H, Random, 95% CI)	0.68 [0.50, 0.93]

1.7 Proportion of participants with blood in stomach Show forest plot	3	1230	Odds Ratio (M‐H, Random, 95% CI)	0.64 [0.32, 1.30]

1.8 Proportion of participants with active bleeding Show forest plot	4	1332	Odds Ratio (M‐H, Random, 95% CI)	0.74 [0.53, 1.02]

1.9 Proportion of participants with active bleeding plus Lau 2007 Show forest plot	5	1709	Odds Ratio (M‐H, Random, 95% CI)	0.67 [0.47, 0.95]

1.10 Endoscopic haemostatic treatment at index endoscopy Show forest plot	3	1983	Odds Ratio (M‐H, Random, 95% CI)	0.68 [0.50, 0.93]

Comparison 1. Main analysis

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Comparison 2. Subgroup analysis according to risk of bias

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
2.1 Mortality Show forest plot	5	2143	Odds Ratio (M‐H, Random, 95% CI)	1.14 [0.76, 1.70]

2.1.1 low or unclear risk of bias	3	1983	Odds Ratio (M‐H, Random, 95% CI)	1.20 [0.79, 1.84]
2.1.2 high risk of bias	2	160	Odds Ratio (M‐H, Random, 95% CI)	0.66 [0.18, 2.46]
2.2 Rebleeding Show forest plot	5	2121	Odds Ratio (M‐H, Random, 95% CI)	0.81 [0.62, 1.06]

2.2.1 low or unclear risk of bias	3	1983	Odds Ratio (M‐H, Random, 95% CI)	0.87 [0.65, 1.16]
2.2.2 high risk of bias	2	138	Odds Ratio (M‐H, Random, 95% CI)	0.45 [0.19, 1.03]
2.3 Surgery Show forest plot	6	2223	Odds Ratio (M‐H, Random, 95% CI)	0.91 [0.65, 1.26]

2.3.1 low or unclear risk of bias	3	1983	Odds Ratio (M‐H, Random, 95% CI)	0.90 [0.64, 1.27]
2.3.2 high risk of bias	3	240	Odds Ratio (M‐H, Random, 95% CI)	0.85 [0.22, 3.37]
2.4 Proportion of participants with stigmata of recent haemorrhage Show forest plot	4	1332	Odds Ratio (M‐H, Random, 95% CI)	0.80 [0.52, 1.21]

2.4.1 low or unclear risk of bias	2	1172	Odds Ratio (M‐H, Random, 95% CI)	0.79 [0.40, 1.55]
2.4.2 high risk of bias	2	160	Odds Ratio (M‐H, Random, 95% CI)	1.01 [0.46, 2.19]
2.5 Endoscopic haemostatic treatment at index endoscopy Show forest plot	3	1983	Odds Ratio (M‐H, Random, 95% CI)	0.68 [0.50, 0.93]

2.5.1 low or unclear risk of bias	3	1983	Odds Ratio (M‐H, Random, 95% CI)	0.68 [0.50, 0.93]

Comparison 2. Subgroup analysis according to risk of bias

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Comparison 3. Subgroup analysis according to geographic location

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
3.1 Mortality Show forest plot	5	2143	Odds Ratio (M‐H, Random, 95% CI)	1.14 [0.76, 1.70]

3.1.1 Asian	2	689	Odds Ratio (M‐H, Random, 95% CI)	1.13 [0.43, 2.96]
3.1.2 Non‐Asian	3	1454	Odds Ratio (M‐H, Random, 95% CI)	0.96 [0.48, 1.94]
3.2 Rebleeding Show forest plot	5	2121	Odds Ratio (M‐H, Random, 95% CI)	0.81 [0.62, 1.06]

3.2.1 Asian	2	689	Odds Ratio (M‐H, Random, 95% CI)	1.04 [0.45, 2.40]
3.2.2 Non‐Asian	3	1432	Odds Ratio (M‐H, Random, 95% CI)	0.78 [0.59, 1.04]
3.3 Surgery Show forest plot	6	2223	Odds Ratio (M‐H, Random, 95% CI)	0.91 [0.65, 1.26]

3.3.1 Asian	2	689	Odds Ratio (M‐H, Random, 95% CI)	0.67 [0.19, 2.39]
3.3.2 Non‐Asian	4	1534	Odds Ratio (M‐H, Random, 95% CI)	0.93 [0.66, 1.30]

Comparison 3. Subgroup analysis according to geographic location

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Comparison 4. Subgroup analysis according to route of PPI administration

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
4.1 Mortality Show forest plot	5	2143	Odds Ratio (M‐H, Random, 95% CI)	1.14 [0.76, 1.70]

4.1.1 Oral PPI	1	205	Odds Ratio (M‐H, Random, 95% CI)	0.39 [0.07, 2.07]
4.1.2 Intravenous PPI	4	1938	Odds Ratio (M‐H, Random, 95% CI)	1.21 [0.80, 1.85]
4.2 Rebleeding Show forest plot	5	2121	Odds Ratio (M‐H, Random, 95% CI)	0.81 [0.62, 1.06]

4.2.1 Oral PPI	1	205	Odds Ratio (M‐H, Random, 95% CI)	1.01 [0.40, 2.54]
4.2.2 Intravenous PPI	4	1916	Odds Ratio (M‐H, Random, 95% CI)	0.79 [0.55, 1.13]
4.3 Surgery Show forest plot	6	2223	Odds Ratio (M‐H, Random, 95% CI)	0.91 [0.65, 1.26]

4.3.1 Oral PPI	1	205	Odds Ratio (M‐H, Random, 95% CI)	0.49 [0.12, 2.01]
4.3.2 Intravenous PPI	5	2018	Odds Ratio (M‐H, Random, 95% CI)	0.94 [0.67, 1.31]

Comparison 4. Subgroup analysis according to route of PPI administration

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Comparison 5. Subgroup analysis according to PPI dose (high dose versus non‐high dose)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
5.1 Mortality Show forest plot	5	2143	Odds Ratio (M‐H, Random, 95% CI)	1.14 [0.76, 1.70]

5.1.1 High dose PPI	1	631	Odds Ratio (M‐H, Random, 95% CI)	1.16 [0.41, 3.23]
5.1.2 Non‐high dose PPI	4	1512	Odds Ratio (M‐H, Random, 95% CI)	1.13 [0.73, 1.76]
5.2 Rebleeding Show forest plot	5	2121	Odds Ratio (M‐H, Random, 95% CI)	0.81 [0.62, 1.06]

5.2.1 High dose PPI	1	631	Odds Ratio (M‐H, Random, 95% CI)	1.40 [0.56, 3.53]
5.2.2 Non‐high dose PPI	4	1490	Odds Ratio (M‐H, Random, 95% CI)	0.77 [0.58, 1.02]
5.3 Surgery Show forest plot	6	2223	Odds Ratio (M‐H, Random, 95% CI)	0.91 [0.65, 1.26]

5.3.1 High dose PPI	1	631	Odds Ratio (M‐H, Random, 95% CI)	0.67 [0.19, 2.39]
5.3.2 Non‐high dose PPI	5	1592	Odds Ratio (M‐H, Random, 95% CI)	0.93 [0.66, 1.30]

Comparison 5. Subgroup analysis according to PPI dose (high dose versus non‐high dose)

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Comparison 6. Subgroup analysis according to control treatment

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
6.1 Mortality Show forest plot	5	2143	Odds Ratio (M‐H, Random, 95% CI)	1.14 [0.76, 1.70]

6.1.1 PPI versus placebo	3	1983	Odds Ratio (M‐H, Random, 95% CI)	1.20 [0.79, 1.84]
6.1.2 PPI versus H2RA	2	160	Odds Ratio (M‐H, Random, 95% CI)	0.66 [0.18, 2.46]
6.2 Rebleeding Show forest plot	5	2121	Odds Ratio (M‐H, Random, 95% CI)	0.81 [0.62, 1.06]

6.2.1 PPI versus placebo	3	1983	Odds Ratio (M‐H, Random, 95% CI)	0.87 [0.65, 1.16]
6.2.2 PPI versus H2RA	1	58	Odds Ratio (M‐H, Random, 95% CI)	0.56 [0.14, 2.26]
6.2.3 PPI versus no treatment	1	80	Odds Ratio (M‐H, Random, 95% CI)	0.39 [0.14, 1.12]
6.3 Surgery Show forest plot	6	2223	Odds Ratio (M‐H, Random, 95% CI)	0.91 [0.65, 1.26]

6.3.1 PPI versus placebo	3	1983	Odds Ratio (M‐H, Random, 95% CI)	0.90 [0.64, 1.27]
6.3.2 PPI versus H2RA	2	160	Odds Ratio (M‐H, Random, 95% CI)	1.53 [0.45, 5.18]
6.3.3 PPI versus no treatment	1	80	Odds Ratio (M‐H, Random, 95% CI)	0.37 [0.07, 2.02]

Comparison 6. Subgroup analysis according to control treatment

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Comparison 7. Subgroup analysis according to use of endoscopic haemostatic treatment at index endoscopy

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
7.1 Mortality Show forest plot	5	2143	Odds Ratio (M‐H, Random, 95% CI)	1.14 [0.76, 1.70]

7.1.1 Reported use of endoscopic haemostatic treatment at index endoscopy	4	2041	Odds Ratio (M‐H, Random, 95% CI)	1.20 [0.78, 1.82]
7.1.2 No mention of endoscopic haemostatic treatment at index endoscopy	1	102	Odds Ratio (M‐H, Random, 95% CI)	0.60 [0.14, 2.66]
7.2 Rebleeding Show forest plot	5	2121	Odds Ratio (M‐H, Random, 95% CI)	0.81 [0.62, 1.06]

7.2.1 Reported use of endoscopic haemostatic treatment at index endoscopy	4	2041	Odds Ratio (M‐H, Random, 95% CI)	0.85 [0.65, 1.13]
7.2.2 No mention of endoscopic haemostatic treatment at index endoscopy	1	80	Odds Ratio (M‐H, Random, 95% CI)	0.39 [0.14, 1.12]
7.3 Surgery Show forest plot	6	2223	Odds Ratio (M‐H, Random, 95% CI)	0.91 [0.65, 1.26]

7.3.1 Reported use of endoscopic haemostatic treatment at index endoscopy	4	2041	Odds Ratio (M‐H, Random, 95% CI)	0.90 [0.64, 1.27]
7.3.2 No mention of endoscopic haemostatic treatment at index endoscopy	2	182	Odds Ratio (M‐H, Random, 95% CI)	0.85 [0.22, 3.37]

Comparison 7. Subgroup analysis according to use of endoscopic haemostatic treatment at index endoscopy

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Comparison 8. Sensitivity analysis restricted to peptic ulcer participants

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
8.1 Mortality Show forest plot	2	580	Odds Ratio (M‐H, Random, 95% CI)	1.39 [0.52, 3.70]

8.2 Rebleeding Show forest plot	2	880	Odds Ratio (M‐H, Fixed, 95% CI)	0.86 [0.59, 1.26]

8.3 Surgery Show forest plot	2	880	Odds Ratio (M‐H, Random, 95% CI)	0.91 [0.59, 1.40]

Comparison 8. Sensitivity analysis restricted to peptic ulcer participants

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The Cochrane Library

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Tratamiento con inhibidores de la bomba de protones iniciado antes del diagnóstico endoscópico en la hemorragia digestiva alta

Appendices

Appendix 1. CENTRAL search strategy

Appendix 2. MEDLINE search strategy

Appendix 3. Embase search strategy

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Appendices

Appendix 1. CENTRAL search strategy

Appendix 2. MEDLINE search strategy

Appendix 3. Embase search strategy

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Instituciones a las que se accedió previamente

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