Comparison of different regimens of proton pump inhibitors for acute peptic ulcer bleeding

Ignacio Neumann; Luz M Letelier; Gabriel Rada; Juan Carlos Claro; Janet Martin; Colin W Howden; Yuhong Yuan; Grigorios I Leontiadis

doi:10.1002/14651858.CD007999.pub2

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Figure 1

Study flow diagram.

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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

Funnel plot of comparison: 1 High vs. non‐high (medium or low) dose regimen, outcome: 1.1 Mortality.

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Figure 5

Funnel plot of comparison: 1 High vs. non‐high (medium or low) dose regimen, outcome: 1.2 Rebleeding.

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Figure 6

Funnel plot of comparison: 1 High vs. non‐high (medium or low) dose regimen, outcome: 1.3 Surgery.

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Figure 7

Funnel plot of comparison: 13 Post hoc analysis: studies that compared at least two PPI regimens with different cumulative 72 hour doses, outcome: 13.1 Mortality.

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Figure 8

Funnel plot of comparison: 13 Post hoc analysis: studies that compared at least two PPI regimens with different cumulative 72 hour doses, outcome: 13.2 Rebleeding.

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Figure 9

Funnel plot of comparison: 13 Post hoc analysis: studies that compared at least two PPI regimens with different cumulative 72 hour doses, outcome: 13.3 Surgery.

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Figure 10

Meta‐regression (univariate) for dose ratio and mortality logOR

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Figure 11

Meta‐regression (univariate) for dose ratio and rebleeding logOR

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Figure 12

Post hoc analysis: Meta‐regression (univariate) for dose ratio and rebleeding logOR for all studies that compared at least two doses of PPIs

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Analysis 1.1

Comparison 1 High vs. non‐high (medium or low) dose regimen, Outcome 1 Mortality.

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Analysis 1.2

Comparison 1 High vs. non‐high (medium or low) dose regimen, Outcome 2 Rebleeding.

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Analysis 1.3

Comparison 1 High vs. non‐high (medium or low) dose regimen, Outcome 3 Surgery.

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Analysis 1.4

Comparison 1 High vs. non‐high (medium or low) dose regimen, Outcome 4 Further EHT.

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Analysis 1.5

Comparison 1 High vs. non‐high (medium or low) dose regimen, Outcome 5 Length of hospital stay.

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Analysis 1.6

Comparison 1 High vs. non‐high (medium or low) dose regimen, Outcome 6 Blood transfusions.

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Analysis 2.1

Comparison 2 Subgroup analysis: Risk of bias, Outcome 1 Mortality.

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Analysis 2.2

Comparison 2 Subgroup analysis: Risk of bias, Outcome 2 Rebleeding.

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Analysis 2.3

Comparison 2 Subgroup analysis: Risk of bias, Outcome 3 Surgery.

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Analysis 2.4

Comparison 2 Subgroup analysis: Risk of bias, Outcome 4 Further EHT.

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Analysis 2.5

Comparison 2 Subgroup analysis: Risk of bias, Outcome 5 LOS.

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Analysis 2.6

Comparison 2 Subgroup analysis: Risk of bias, Outcome 6 Blood transfusions.

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Analysis 3.1

Comparison 3 Subgroup analysis: Geographical location, Outcome 1 Mortality.

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Analysis 3.2

Comparison 3 Subgroup analysis: Geographical location, Outcome 2 Rebleeding.

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Analysis 3.3

Comparison 3 Subgroup analysis: Geographical location, Outcome 3 Surgery.

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Analysis 3.4

Comparison 3 Subgroup analysis: Geographical location, Outcome 4 Further EHT.

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Analysis 3.5

Comparison 3 Subgroup analysis: Geographical location, Outcome 5 LOS.

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Analysis 3.6

Comparison 3 Subgroup analysis: Geographical location, Outcome 6 Blood transfusions.

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Analysis 4.1

Comparison 4 Subgroup analysis: Route of administration in non‐high dose regimen, Outcome 1 Mortality.

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Analysis 4.2

Comparison 4 Subgroup analysis: Route of administration in non‐high dose regimen, Outcome 2 Rebleeding.

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Analysis 4.3

Comparison 4 Subgroup analysis: Route of administration in non‐high dose regimen, Outcome 3 Surgery.

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Analysis 4.4

Comparison 4 Subgroup analysis: Route of administration in non‐high dose regimen, Outcome 4 Further EHT.

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Analysis 4.5

Comparison 4 Subgroup analysis: Route of administration in non‐high dose regimen, Outcome 5 LOS.

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Analysis 4.6

Comparison 4 Subgroup analysis: Route of administration in non‐high dose regimen, Outcome 6 Blood transfusions.

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Analysis 5.1

Comparison 5 Subgroup analysis: IV bolus vs. IV infusion in non‐high dose regimen, Outcome 1 Mortality.

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Analysis 5.2

Comparison 5 Subgroup analysis: IV bolus vs. IV infusion in non‐high dose regimen, Outcome 2 Rebleeding.

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Analysis 5.3

Comparison 5 Subgroup analysis: IV bolus vs. IV infusion in non‐high dose regimen, Outcome 3 Surgery.

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Analysis 5.4

Comparison 5 Subgroup analysis: IV bolus vs. IV infusion in non‐high dose regimen, Outcome 4 Further EHT.

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Analysis 5.5

Comparison 5 Subgroup analysis: IV bolus vs. IV infusion in non‐high dose regimen, Outcome 5 LOS.

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Analysis 5.6

Comparison 5 Subgroup analysis: IV bolus vs. IV infusion in non‐high dose regimen, Outcome 6 Blood transfusions.

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Analysis 6.1

Comparison 6 Subgroup analysis: Type of PPI in high dose regimen, Outcome 1 Mortality.

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Analysis 6.2

Comparison 6 Subgroup analysis: Type of PPI in high dose regimen, Outcome 2 Rebleeding.

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Analysis 6.3

Comparison 6 Subgroup analysis: Type of PPI in high dose regimen, Outcome 3 Surgery.

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Analysis 6.4

Comparison 6 Subgroup analysis: Type of PPI in high dose regimen, Outcome 4 Further EHT.

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Analysis 6.5

Comparison 6 Subgroup analysis: Type of PPI in high dose regimen, Outcome 5 LOS.

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Analysis 6.6

Comparison 6 Subgroup analysis: Type of PPI in high dose regimen, Outcome 6 Blood transfusions.

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Analysis 7.1

Comparison 7 Subgroup analysis: Ulcer site, Outcome 1 Mortality.

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Analysis 7.2

Comparison 7 Subgroup analysis: Ulcer site, Outcome 2 Rebleeding.

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Analysis 7.3

Comparison 7 Subgroup analysis: Ulcer site, Outcome 3 Surgery.

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Analysis 8.1

Comparison 8 Sensitivity analysis: High vs. low dose, Outcome 1 Mortality.

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Analysis 8.2

Comparison 8 Sensitivity analysis: High vs. low dose, Outcome 2 Rebleeding.

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Analysis 8.3

Comparison 8 Sensitivity analysis: High vs. low dose, Outcome 3 Surgery.

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Analysis 9.1

Comparison 9 Sensitivity analysis: High vs. medium dose, Outcome 1 Mortality.

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Analysis 9.2

Comparison 9 Sensitivity analysis: High vs. medium dose, Outcome 2 Rebleeding.

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Analysis 9.3

Comparison 9 Sensitivity analysis: High vs. medium dose, Outcome 3 Surgery.

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Analysis 10.1

Comparison 10 Sensitivity analysis: Medium vs. low dose, Outcome 1 Mortality.

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Analysis 10.2

Comparison 10 Sensitivity analysis: Medium vs. low dose, Outcome 2 Rebleeding.

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Analysis 10.3

Comparison 10 Sensitivity analysis: Medium vs. low dose, Outcome 3 Surgery.

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Analysis 11.1

Comparison 11 Sensitivity analysis: Non‐low (high or medium) dose vs. low dose, Outcome 1 Mortality.

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Analysis 11.2

Comparison 11 Sensitivity analysis: Non‐low (high or medium) dose vs. low dose, Outcome 2 Rebleeding.

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Analysis 11.3

Comparison 11 Sensitivity analysis: Non‐low (high or medium) dose vs. low dose, Outcome 3 Surgery.

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Analysis 12.1

Comparison 12 Sensitivity analysis: High vs. non‐high dose; patients with high risk SRH, Outcome 1 Mortality.

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Analysis 12.2

Comparison 12 Sensitivity analysis: High vs. non‐high dose; patients with high risk SRH, Outcome 2 Rebleeding.

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Analysis 12.3

Comparison 12 Sensitivity analysis: High vs. non‐high dose; patients with high risk SRH, Outcome 3 Surgery.

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Analysis 13.1

Comparison 13 Post hoc analysis: Studies that compared at least two PPI regimens with different 72‐hour cumulative dose, Outcome 1 Mortality.

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Analysis 13.2

Comparison 13 Post hoc analysis: Studies that compared at least two PPI regimens with different 72‐hour cumulative dose, Outcome 2 Rebleeding.

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Analysis 13.3

Comparison 13 Post hoc analysis: Studies that compared at least two PPI regimens with different 72‐hour cumulative dose, Outcome 3 Surgery.

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Analysis 13.4

Comparison 13 Post hoc analysis: Studies that compared at least two PPI regimens with different 72‐hour cumulative dose, Outcome 4 Further EHT.

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Analysis 13.5

Comparison 13 Post hoc analysis: Studies that compared at least two PPI regimens with different 72‐hour cumulative dose, Outcome 5 LOS.

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Analysis 13.6

Comparison 13 Post hoc analysis: Studies that compared at least two PPI regimens with different 72‐hour cumulative dose, Outcome 6 Blood transfusions.

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Analysis 14.1

Comparison 14 Post hoc analysis: Studies that compared at least two PPI regimens with different 72‐hour cumulative dose; high risk SRH, Outcome 1 Mortality.

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Analysis 14.2

Comparison 14 Post hoc analysis: Studies that compared at least two PPI regimens with different 72‐hour cumulative dose; high risk SRH, Outcome 2 Rebleeding.

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Analysis 14.3

Comparison 14 Post hoc analysis: Studies that compared at least two PPI regimens with different 72‐hour cumulative dose; high risk SRH, Outcome 3 Surgery.

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Analysis 15.1

Comparison 15 Post hoc analysis: Comparison of regimens with the same 72‐hour cumulative dose, but different route or frequency, Outcome 1 Rebleeding.

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Analysis 16.1

Comparison 16 Post hoc analysis: IV regimen vs. PO regimen, Outcome 1 Mortality.

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Analysis 16.2

Comparison 16 Post hoc analysis: IV regimen vs. PO regimen, Outcome 2 Rebleeding.

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Analysis 16.3

Comparison 16 Post hoc analysis: IV regimen vs. PO regimen, Outcome 3 Surgery.

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Analysis 16.4

Comparison 16 Post hoc analysis: IV regimen vs. PO regimen, Outcome 4 Further EHT.

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Analysis 16.5

Comparison 16 Post hoc analysis: IV regimen vs. PO regimen, Outcome 5 LOS.

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Analysis 16.6

Comparison 16 Post hoc analysis: IV regimen vs. PO regimen, Outcome 6 Blood transfusions.

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Summary of findings for the main comparison. High compared to non‐high (medium or low) dose regimen for acute peptic ulcer bleeding

High compared to non‐high (medium or low) dose regimen for acute peptic ulcer bleeding
Patient or population: patients with acute peptic ulcer bleeding Settings: hospital Intervention: high dose regimen Comparison: non‐high (medium or low) dose regimen
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Non‐high (medium or low) dose regimen	High
Mortality	3 per 100	3 per 100 (2 to 5)¹	RR 0.85 (0.47 to 1.54)	1667 (12 studies)	⊕⊕⊝⊝ low^2,3
Rebleeding	9 per 100	11 per 100 (9 to 14)¹	RR 1.27 (0.96 to 1.67)	1716 (13 studies)	⊕⊕⊝⊝ low^2,3
Surgery	2 per 100	3 per 100 (1 to 4)¹	RR 1.33 (0.63 to 2.77)	1270 (9 studies)	⊕⊕⊝⊝ low^2,3
Further EHT	7 per 100	9 per 100 (6 to 12)	RR 1.39 (0.88 to 2.18)	902 (6 studies)	⊕⊕⊝⊝ low²
Length of hospital stay		The mean length of hospital stay in the intervention group was 0.26 higher (0.08 lower to 0.6 higher)		1069 (6 studies)	⊕⊕⊕⊝ moderate²
Blood transfusions		The mean blood transfusions in the intervention group was 0.05 higher (0.21 lower to 0.3 higher)		1069 (6 studies)	⊕⊕⊕⊝ moderate²
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (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; EHT: endoscopic haemostatic treatment
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
¹ Pooled risk difference. ² Of the 22 trials included in this review, 17 had high risk of bias, 5 had unclear risk of bias and none had low risk of bias. The main limitation was the lack of blinding in 16 trials. ³ It is not possible to exclude a clinically relevant benefit or harm.

Summary of findings for the main comparison. High compared to non‐high (medium or low) dose regimen for acute peptic ulcer bleeding

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Table 1. Timing of outcome assessment

Study ID	Mortality	Rebleeding	Surgery	Further endoscopic haemostatic treatment
Andriulli 2008	During hospitalization	During hospitalization; 24 h; 3 d; 7 d	During hospitalization	During hospitalization
Bajaj 2007	30 d	30 h; 4 d; 30 d	30 d	U
Cheng 2005	U	3 d; 7 d; 14 d; 28 d	U	X
Cheng 2009	U	7 d; 28 d	X	X
Choi 2009	X	72 h; 7 d; 30 d	X	U
Costamagna 1998	X	48 h; 7 d	X	X
Dokas 2004	U	U	U	X
Focareta 2004	X	U	U	U
Garrido 2008	U	U	U	X
Hsu 2010	14 d	14 d	U	X
Hung 2007	30 d	30 d	30 d	U
Jang 2006	U	30 d	U	X
Lin 1997	U	U	U	U
Lin 2006	U	24 h; 3 d; 14 d	U	U
Mesihovic 2009	U	U	U	U
Oh 2007	U	X	X	X
Schonekas 1999	14 d	72 h	U	X
Sha 2001	U	U	U	X
Tsai 2009	14 d; 30 d	3 d; 14 d	14 d; 30 d	14 d
Udd 2001	30 d	U	U	U
Yilmaz 2006	30 d	During hospitalization; 30 d	U	During hospitalization
Yüksel 2008	U	U	U	U
U: unclear timing of outcome assessment X: outcome not reported or not calculable h: hours d: days

Table 1. Timing of outcome assessment

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Table 2. Subgroup and sensitivity analyses

Analysis 2. High vs. non‐high dose regimen: Subgroup analysis according to risk of bias
Outcome	Subgroup	Studies	Participants	Summary statistic	Effect estimate [95% CI]	Significant heterogeneity: Yes or No (P value; I²)	Test for subgroup differences: P value
Mortality	Unclear	5	1041	RR	1.05 [0.50, 2.20]	No (P = 0.84; I² = 0%)	P = 0.36
Mortality	High	7	626	RR	0.61 [0.24, 1.52]	No (P = 0.84; I² = 0%)	P = 0.36
Rebleeding	Unclear	13	1037	RR	1.26 [0.89, 1.76]	No (P = 0.96; I² = 0%)	P = 0.92
Rebleeding	High	5	679	RR	1.29 [0.80, 2.07]	No (P = 0.88; I² = 0%)	P = 0.92
Surgery	Unclear	4	944	RR	1.35 [0.58, 3.14]	No (P = 0.90; I² = 0%)	P = 0.94
Surgery	High	5	326	RR	1.26 [0.28, 5.73]	No (P = 0.72; I² = 0%)	P = 0.94
Further EHT	Unclear	3	713	RR	1.39 [0.86, 2.25]	No (P = 0.91; I² = 0%)	P = 0.96
Further EHT	High	3	189	RR	1.35 [0.36, 5.07]	No (P = 0.64; I² = 0%)	P = 0.96
LOS	Unclear	4	924	MD	0.28 [‐0.07, 0.63]	No (P = 0.64; I² = 0%)	P = 0.84
LOS	High	2	145	MD	0.10 [‐1.60, 1.80]	No (P = 0.27; I² = 16%)	P = 0.84
Blood transfusions	Unclear	4	924	MD	0.05 [‐0.21, 0.30]	No (P = 0.42; I² = 0%)	P = 0.95
Blood transfusions	High	2	145	MD	0.10 [‐1.60, 1.80]	No (P = 0.82; I² = 0%)	P = 0.95
Analysis 3. High vs. non‐high dose regimen: Subgroup analysis according to geographical location
Outcome	Subgroup	Studies	Participants	Summary statistic	Effect estimate [95% CI]	Significant heterogeneity: Yes or No (P value; I²)	Test for subgroup differences: P value
Mortality	Asian studies	7	807	RR	0.74 [0.33, 1.68]	No (P = 0.45; I² = 0%)	P = 0.66
Mortality	Other	5	860	RR	0.96 [0.43, 2.18]	No (P = 0.87; I² = 0%)	P = 0.66
Rebleeding	Asian studies	8	864	RR	1.24 [0.85, 1.80]	No (P = 0.95; I² = 0%)	P = 0.85
Rebleeding	Other	5	852	RR	1.31 [0.87, 1.96]	No (P = 0.81; I² = 0%)	P = 0.85
Surgery	Asian studies	5	568	RR	1.12 [0.36, 3.44]	No (P = 0.79; I² = 0%)	P = 0.69
Surgery	Other	4	702	RR	1.51 [0.57, 4.01]	No (P = 0.87; I² = 0%)	P = 0.69
Further EHT	Asian studies	3	261	RR	1.16 [0.41, 3.27]	No (P = 0.95; I² = 0%)	P = 0.71
Further EHT	Other	3	641	RR	1.44 [0.87, 2.39]	No (P = 0.67; I² = 0%)	P = 0.71
LOS	Asian studies	3	428	MD	0.10 [‐0.33, 0.54]	No (P = 0.80; I² = 0%)	P = 0.24
LOS	Other	3	641	MD	0.52 [‐0.03, 1.07]	No (P = 0.55; I² = 0%)	P = 0.24
Blood transfusions	Asian studies	3	428	MD	‐0.10 [‐0.45, 0.26]	No (P = 0.46; I² = 0%)	P = 0.25
Blood transfusions	Other	3	641	MD	0.20 [‐0.17, 0.57]	No (P = 1.00; I² = 0%)	P = 0.25
Analysis 4. High vs. non‐high dose regimen: Subgroup analysis according to route of administration for the non‐high dose regimen
Outcome	Subgroup	Studies	Participants	Summary statistic	Effect estimate [95% CI]	Significant heterogeneity: Yes or No (P value; I²)	Test for subgroup differences: P value
Mortality	IV	9	1394	RR	0.84 [0.45, 1.56]	No (P = 0.67; I² = 0%)	P = 0.92
Mortality	PO	3	273	RR	0.92 [0.20, 4.28]	No (P = 0.40; I² = 0%)	P = 0.92
Rebleeding	IV	10	1443	RR	1.24 [0.93, 1.65]	No (P = 0.99; I² = 0%)	P = 0.59
Rebleeding	PO	3	273	RR	1.64 [0.61, 4.40]	No (P = 0.56; I² = 0%)	P = 0.59
Surgery	IV	6	997	RR	1.26 [0.54, 2.91]	No (P = 0.89; I² = 0%)	P = 0.79
Surgery	PO	3	273	RR	1.59 [0.34, 7.40]	No (P = 0.68; I² = 0%)	P = 0.79
Further EHT	IV	5	877	RR	1.35 [0.85, 2.13]	No (P = 0.98; I² = 0%)	P = 0.41
Further EHT	PO	1	25	RR	4.64 [0.25, 87.91]	No (P = 0.96; I² = 0%)	P = 0.41
LOS	IV	4	833	MD	0.32 [‐0.10, 0.74]	No (P = 0.57; I² = 0)%	P = 0.63
LOS	PO	2	236	MD	0.15 [‐0.43, 0.73]	No (P = 0.37; I² = 0%)	P = 0.63
Blood transfusions	IV	4	833	MD	0.22 [‐0.11, 0.56]	No (P = 0.97; I² = 0%)	P = 0.12
Blood transfusions	PO	2	236	MD	‐0.19 [‐0.57, 0.20]	No (P = 0.69; I² = 0%)	P = 0.12
Analysis 5. High vs. non‐high dose regimen: Subgroup analysis according to whether in non‐high dose regimen PPI was administered as IV bolus or IV infusion
Outcome	Subgroup	Studies	Participants	Summary statistic	Effect estimate [95% CI]	Significant heterogeneity: Yes or No (P value; I²)	Test for subgroup differences: P value
Mortality	Bolus	7	1155	RR	1.15 [0.53, 2.47]	No (P = 0.82; I² = 0%)	P = 0.16
Mortality	Infusion	2	239	RR	0.45 [0.16, 1.32]	No (P = 0.37; I² = 0%)	P = 0.16
Rebleeding	Bolus	8	1178	RR	1.24 [0.86, 1.77]	No (P = 0.99; I² = 0%)	P = 0.95
Rebleeding	Infusion	3	265	RR	1.26 [0.75, 2.13]	No (P = 0.29; I² = 12%)	P = 0.95
Surgery	Bolus	6	997	RR	1.26 [0.54, 2.91]	No (P = 0.89; I² = 0%)	Not applicable
Surgery	Infusion	0	0	RR	Not estimable	Not applicable	Not applicable
Further EHT	Bolus	5	847	RR	1.34 [0.85, 2.12]	No (P = 0.98; I² = 0%)	Not applicable
Further EHT	Infusion	1	30	RR	Not estimable	Not applicable	Not applicable
LOS	Bolus	4	833	MD	0.32 [‐0.10, 0.74]	No (P = 0.57; I² = 0%)	Not applicable
LOS	Infusion	0	0	MD	Not estimable	Not applicable	Not applicable
Blood transfusions	Bolus	4	833	MD	0.22 [‐0.11, 0.56]	No (P = 0.97; I² = 0%)	Not applicable
Blood transfusions	Infusion	0	0	MD	Not estimable	Not applicable	Not applicable
Analysis 6. High vs. non‐high dose regimen: Subgroup analysis according to type of PPI in high dose regimen
Outcome	Subgroup	Studies	Participants	Summary statistic	Effect estimate [95% CI]	Significant heterogeneity: Yes or No (P value; I²)	Test for subgroup differences: P value
Mortality	Omeprazole	4	612	RR	0.63 [0.29, 1.37]	No (P = 0.60; I² = 0%)	P = 0.49
	Pantoprazole	7	581	RR	1.49 [0.44, 5.01]	No (P = 0.68; I² = 0%)
	Either omeprazole or pantoprazole	1	474	RR	0.99 [0.29, 3.38]	Not applicable
Rebleeding	Omeprazole	4	608	RR	1.25 [0.83, 1.87]	No (P = 0.60; I² = 0%)	P = 0.49
	Pantoprazole	8	634	RR	1.15 [0.69, 1.93]	No (P = 0.68; I² = 0%)
	Either omeprazole or pantoprazole	1	474	RR	1.46 [0.84, 2.54]	Not applicable
Surgery	Omeprazole	2	373	RR	1.23 [0.44, 3.48]	No (P = 0.92; I² = 0%)	P = 0.76
	Pantoprazole	6	423	RR	1.17 [0.36, 3.82]	No (P = 0.85; I² = 0%)
	Either omeprazole or pantoprazole	1	474	RR	2.97 [0.31, 28.39]	Not applicable
Further EHT	Omeprazole	1	142	RR	1.06 [0.28, 4.07]	Not applicable	P = 0.91
	Pantoprazole	4	286	RR	1.35 [0.51, 3.59]	No (P = 0.83; I² = 0%)
	Either omeprazole or pantoprazole	1	474	RR	1.46 [0.84, 2.54]	Not applicable
LOS	Omeprazole	2	353	MD	0.13 [‐0.35, 0.62]	No (P = 0.85; I² = 0%)	P = 0.42
	Pantoprazole	3	242	MD	0.16 [‐0.46, 0.79]	No (P = 0.54; I² = 0%)
	Either omeprazole or pantoprazole	1	474	MD	0.70 [‐0.03, 1.43]	Not applicable
Blood transfusions	Omeprazole	2	353	MD	‐0.19 [‐0.57, 0.20]	No (P = 0.72; I² = 0%)	P = 0.27
	Pantoprazole	3	242	MD	0.34 [‐0.43, 1.11]	No (P = 0.93; I² = 0%)
	Either omeprazole or pantoprazole	1	474	MD	0.20 [‐0.18, 0.58]	Not applicable
Analysis 7. High vs. non‐high dose regimen: Subgroup analysis according to ulcer site
Outcome	Subgroup	Studies	Participants	Summary statistic	Effect estimate [95% CI]	Significant heterogeneity: Yes or No (P value; I²)	Test for subgroup differences: P value
Mortality	Gastric ulcer	1	15	RR	Not estimable	Not applicable	Not applicable
Mortality	Duodenal ulcer	1	13	RR	Not estimable	Not applicable	Not applicable
Rebleeding	Gastric ulcer	2	196	RR	1.52 [0.66, 3.49]	No (P = 0.71; I² = 0%)	P = 1.00
Rebleeding	Duodenal ulcer	2	306	RR	1.52 [0.75, 3.07]	No (P = 0.72; I² = 0%)	P = 1.00
Surgery	Gastric ulcer	1	15	RR	2.67 [0.13, 56.63]	Not applicable	Not applicable
Surgery	Duodenal ulcer	1	13	RR	Not estimable	Not applicable	Not applicable
Analysis 8. Sensitivity analysis: High vs. low dose regimen
Outcome		Studies	Participants	Summary statistic	Effect estimate [95% CI]	Significant heterogeneity: Yes or No (P value: I²)
Mortality		4	835	RR	0.96 [0.43, 2.18]	No (P = 0.87; I² = 0%)
Rebleeding		5	867	RR	1.22 [0.82, 1.82]	No (P = 0.72; I² = 0%)
Surgery		3	677	RR	1.41 [0.51, 3.95]	No (P = 0.76; I² = 0%)
Analysis 9. Sensitivity analysis: High vs. medium dose regimen
Outcome		Studies	Participants	Summary statistic	Effect estimate [95% CI]	Significant heterogeneity: Yes or No (P value: I²)
Mortality		8	832	RR	0.74 [0.33, 1.68]	No (P = 0.45; I² = 0%)
Rebleeding		9	868	RR	1.30 [0.89, 1.90]	No (P = 0.93; I² = 0%)
Surgery		6	593	RR	1.24 [0.43, 3.57]	No (P = 0.85; I² = 0%)
Analysis 10. Sensitivity analysis: Medium vs. low dose regimen
Outcome		Studies	Participants	Summary statistic	Effect estimate [95% CI]	Significant heterogeneity: Yes or No (P value: I²)
Mortality		3	275	RR	0.42 [0.06, 2.80]	No (P = 0.81; I² = 0%)
Rebleeding		5	320	RR	0.69 [0.33, 1.43]	No (P = 0.28; I² = 21%)
Surgery		3	249	RR	0.48 [0.09, 2.55]	No (P = 0.96; I² = 0%)
Analysis 11. Sensitivity analysis: Non‐low (high or medium) dose vs. low dose regimen
Outcome		Studies	Participants	Summary statistic	Effect estimate [95% CI]	Significant heterogeneity: Yes or No (P value: I²)
Mortality		4	835	RR	0.96 [0.43, 2.18]	No (P = 0.87; I² = 0%)
Rebleeding		6	917	RR	1.22 [0.82, 1.82]	No (P = 0.47; I² = 0%)
Surgery		4	702	RR	1.51 [0.57, 4.01]	No (P = 0.87; I² = 0%)
Analysis 12. Sensitivity analysis: High vs. non‐high dose regimen, restricted to patients with high risk SRH
Outcome	Subgroup	Studies	Participants	Summary statistic	Effect estimate [95% CI]	Significant heterogeneity: Yes or No (P value: I²)	Test for subgroup differences (P value)
Mortality	All patients with HR SRH received initial EHT	3	292	RR	1.10 [0.26, 4.67]	No (P = 0.42; I² = 0%)	Not applicable
Mortality	Not all patients with HR SRH received initial EHT	1	14	RR	Not estimable	Not applicable	Not applicable
Rebleeding	All patients with HR SRH received initial EHT	4	655	RR	1.24 [0.79, 1.94]	No (P = 0.85; I² = 0%)	P = 0.64
Rebleeding	Not all patients with HR SRH received initial EHT	2	96	RR	1.75 [0.45, 6.85]	Not applicable	P = 0.64
Surgery	All patients with HR SRH received initial EHT	2	134	RR	1.02 [0.15, 6.96]	1.02 [0.15, 6.96]	Not applicable
Surgery	Not all patients with HR SRH received initial EHT	1	14	RR	Not estimable	Not applicable	Not applicable
Analysis 13. Post hoc analysis: Studies that compared at least two PPI regimens with different 72‐hour cumulative dose (highest vs. lowest dose)
Outcome		Studies	Participants	Summary statistic	Effect estimate [95% CI]	Significant heterogeneity: Yes or No (P value: I²)
Mortality		18	2197	RR	0.79 [0.47, 1.36]	No (P = 0.86; I² = 0%)
Rebleeding		21	2338	RR	1.02 [0.81, 1.29]	No (P = 0.67; I² = 0%)
Surgery		16	1884	RR	1.22 [0.64, 2.30]	No (P = 0.98; I² = 0%)
Further EHT		11	1352	RR	1.02 [0.74, 1.42]	No (P = 0.78; I² = 0%)
LOS		11	1503	MD	0.06 [‐0.28, 0.40]	No (P = 0.33; I² = 12%)
Blood transfusions		9	1425	MD	0.23 [‐0.25, 0.71]	Yes (P = 0.04; I² = 50%)
Analysis 14. Post hoc analysis: Studies that compared at least two PPI regimens with different 72‐hour cumulative dose (highest vs. lowest dose), restricted to patients with high risk SRH
Outcome	Subgroup	Studies	Participants	Summary statistic	Effect estimate [95% CI]	Significant heterogeneity: Yes or No (P value: I²)	Test for subgroup differences (P value)
Mortality	All patients with HR SRH received initial EHT	4	359	RR	0.88 [0.24, 3.28]	No (P = 0.52; I² = 0%)	Not applicable
Mortality	Not all patients with HR SRH received initial EHT	1	14	RR	Not estimable	Not applicable	Not applicable
Rebleeding	All patients with HR SRH received initial EHT	8	919	RR	0.97 [0.68, 1.39]	No (P = 0.40; I² = 4%)	P = 0.51
Rebleeding	Not all patients with HR SRH received initial EHT	3	122	RR	1.43 [0.48, 4.24]	No (P = 0.63; I² = 0%)	P = 0.51
Surgery	All patients with HR SRH received initial EHT	4	357	RR	0.66 [0.19, 2.34]	No (P = 0.84; I² = 0%)	Not applicable
Surgery	Not all patients with HR SRH received initial EHT	2	40	RR	Not estimable	Not applicable	Not applicable
Analysis 15. Post hoc analysis: Comparison of regimens with the same 72‐hour cumulative dose, but different route or frequency
Outcome		Studies	Participants	Summary statistic	Effect estimate [95% CI]	Significant heterogeneity: Yes or No (P value: I²)
Rebleeding		1	22	RR	0.30 [0.04, 2.27]	Not applicable
Analysis 16. Post hoc analysis: IV vs. PO regimen
Outcome		Studies	Participants	Summary statistic	Effect estimate [95% CI]	Significant heterogeneity: Yes or No (P value: I²)
Mortality		4	429	RR	0.77 [0.21, 2.79]	No (P = 0.65; I² = 0%)
Rebleeding		5	516	RR	1.08 [0.63, 1.84]	No (P = 0.70; I² = 0%)
Surgery		5	516	RR	1.13 [0.31, 4.11]	No (P = 0.67; I² = 0%)
Further EHT		3	268	RR	1.10 [0.57, 2.11]	No (P = 0.57; I² = 0%)
LOS		3	392	MD	0.09 [‐0.46, 0.63]	No (P = 0.55; I² = 0%)
Blood transfusions		3	392	MD	‐0.18 [‐0.56, 0.20]	No (P = 0.89; I² = 0%)

Table 2. Subgroup and sensitivity analyses

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Table 3. Meta‐regression analysis results

Outcome	Number of included studies	Covariate	Univariate meta‐regression		Multivariate meta‐regression: P
Outcome	Number of included studies	Covariate	Coefficient (95% CI)	P	Multivariate meta‐regression: P
Mortality	6	Dose ratio	0.04 (‐0.26 to 0.33)	0.759	0.995
		Geographical location	‐0.40 (‐2.24 to 1.43)	0.575	0.643
		Route for lower dose	‐0.68 (‐3.42 to 2.06)	0.529	0.406
Rebleeding	11	Dose ratio	0.01 (‐0.14 to 0.15)	0.997	1.000
		Geographical location	‐0.02 (‐0.77 to 0.74)	0.959	1.000
		Route for lower dose	0.04 (‐1.38 to 1.46)	0.948	0.999
Surgery	5	Dose ratio	‐0.01 (‐0.38 to 0.37)	0.956	1.000
		Geographical location	‐0.51 (‐.3.78 to 1.75)	0.651	0.621
		Route for lower dose	0.01 (‐3.31 to 3.32)	0.998	1.000
Dose ratio: ratio of higher dose to lower dose Geographical location: Asia vs. elsewhere Route for lower dose: intravenous or oral

Table 3. Meta‐regression analysis results

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Comparison 1. High vs. non‐high (medium or low) dose regimen

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Mortality Show forest plot	12	1667	Odds Ratio (M‐H, Random, 95% CI)	0.85 [0.47, 1.54]

2 Rebleeding Show forest plot	13	1716	Risk Ratio (M‐H, Random, 95% CI)	1.27 [0.96, 1.67]

3 Surgery Show forest plot	9	1270	Risk Ratio (M‐H, Random, 95% CI)	1.33 [0.63, 2.77]

4 Further EHT Show forest plot	6	902	Risk Ratio (M‐H, Random, 95% CI)	1.39 [0.88, 2.18]

5 Length of hospital stay Show forest plot	6	1069	Mean Difference (IV, Random, 95% CI)	0.26 [‐0.08, 0.60]

6 Blood transfusions Show forest plot	6	1069	Mean Difference (IV, Random, 95% CI)	0.05 [‐0.21, 0.30]

Comparison 1. High vs. non‐high (medium or low) dose regimen

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Comparison 2. Subgroup analysis: Risk of bias

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Mortality Show forest plot	12	1667	Risk Ratio (M‐H, Random, 95% CI)	0.85 [0.48, 1.51]

1.1 Risk of bias: Unclear	5	1041	Risk Ratio (M‐H, Random, 95% CI)	1.05 [0.50, 2.20]
1.2 Risk of bias: High	7	626	Risk Ratio (M‐H, Random, 95% CI)	0.61 [0.24, 1.52]
2 Rebleeding Show forest plot	13	1716	Risk Ratio (M‐H, Random, 95% CI)	1.27 [0.96, 1.67]

2.1 Risk of bias: Unclear	5	1037	Risk Ratio (M‐H, Random, 95% CI)	1.26 [0.89, 1.76]
2.2 Risk of bias: High	8	679	Risk Ratio (M‐H, Random, 95% CI)	1.29 [0.80, 2.07]
3 Surgery Show forest plot	9	1270	Risk Ratio (M‐H, Random, 95% CI)	1.33 [0.63, 2.77]

3.1 Risk of bias: Unclear	4	944	Risk Ratio (M‐H, Random, 95% CI)	1.35 [0.58, 3.14]
3.2 Risk of bias: High	5	326	Risk Ratio (M‐H, Random, 95% CI)	1.26 [0.28, 5.73]
4 Further EHT Show forest plot	6	902	Risk Ratio (M‐H, Random, 95% CI)	1.39 [0.88, 2.18]

4.1 RIsk of bias: Unclear	3	713	Risk Ratio (M‐H, Random, 95% CI)	1.39 [0.86, 2.25]
4.2 Risk of bias: High	3	189	Risk Ratio (M‐H, Random, 95% CI)	1.35 [0.36, 5.07]
5 LOS Show forest plot	6	1069	Mean Difference (IV, Random, 95% CI)	0.26 [‐0.08, 0.60]

5.1 Risk of bias: Unclear	4	924	Mean Difference (IV, Random, 95% CI)	0.28 [‐0.07, 0.63]
5.2 Risk of bias: High	2	145	Mean Difference (IV, Random, 95% CI)	0.10 [‐1.60, 1.80]
6 Blood transfusions Show forest plot	6	1069	Mean Difference (IV, Random, 95% CI)	0.05 [‐0.21, 0.30]

6.1 Risk of bias: Unclear	4	924	Mean Difference (IV, Random, 95% CI)	0.05 [‐0.21, 0.30]
6.2 Risk of bias: High	2	145	Mean Difference (IV, Random, 95% CI)	0.10 [‐1.60, 1.80]

Comparison 2. Subgroup analysis: Risk of bias

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Comparison 3. Subgroup analysis: Geographical location

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Mortality Show forest plot	12	1667	Risk Ratio (M‐H, Random, 95% CI)	0.85 [0.48, 1.51]

1.1 Asian	7	807	Risk Ratio (M‐H, Random, 95% CI)	0.74 [0.33, 1.68]
1.2 Others	5	860	Risk Ratio (M‐H, Random, 95% CI)	0.96 [0.43, 2.18]
2 Rebleeding Show forest plot	13	1716	Risk Ratio (M‐H, Random, 95% CI)	1.27 [0.96, 1.67]

2.1 Asian	8	864	Risk Ratio (M‐H, Random, 95% CI)	1.24 [0.85, 1.80]
2.2 Others	5	852	Risk Ratio (M‐H, Random, 95% CI)	1.31 [0.87, 1.96]
3 Surgery Show forest plot	9	1270	Risk Ratio (M‐H, Random, 95% CI)	1.33 [0.63, 2.77]

3.1 Asian	5	568	Risk Ratio (M‐H, Random, 95% CI)	1.12 [0.36, 3.44]
3.2 Others	4	702	Risk Ratio (M‐H, Random, 95% CI)	1.51 [0.57, 4.01]
4 Further EHT Show forest plot	6	902	Risk Ratio (M‐H, Random, 95% CI)	1.39 [0.88, 2.18]

4.1 Asian	3	261	Risk Ratio (M‐H, Random, 95% CI)	1.16 [0.41, 3.27]
4.2 Others	3	641	Risk Ratio (M‐H, Random, 95% CI)	1.44 [0.87, 2.39]
5 LOS Show forest plot	6	1069	Mean Difference (IV, Random, 95% CI)	0.26 [‐0.08, 0.60]

5.1 Asian	3	428	Mean Difference (IV, Random, 95% CI)	0.10 [‐0.33, 0.54]
5.2 Others	3	641	Mean Difference (IV, Random, 95% CI)	0.52 [‐0.03, 1.07]
6 Blood transfusions Show forest plot	6	1069	Mean Difference (IV, Random, 95% CI)	0.05 [‐0.21, 0.30]

6.1 Asian	3	428	Mean Difference (IV, Random, 95% CI)	‐0.10 [‐0.45, 0.26]
6.2 Others	3	641	Mean Difference (IV, Random, 95% CI)	0.20 [‐0.17, 0.57]

Comparison 3. Subgroup analysis: Geographical location

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Comparison 4. Subgroup analysis: Route of administration in non‐high dose regimen

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Mortality Show forest plot	12	1667	Risk Ratio (M‐H, Random, 95% CI)	0.85 [0.48, 1.51]

1.1 Intravenous	9	1394	Risk Ratio (M‐H, Random, 95% CI)	0.84 [0.45, 1.56]
1.2 Oral	3	273	Risk Ratio (M‐H, Random, 95% CI)	0.92 [0.20, 4.28]
2 Rebleeding Show forest plot	13	1716	Risk Ratio (M‐H, Random, 95% CI)	1.27 [0.96, 1.67]

2.1 Intravenous	10	1443	Risk Ratio (M‐H, Random, 95% CI)	1.24 [0.93, 1.65]
2.2 Oral	3	273	Risk Ratio (M‐H, Random, 95% CI)	1.64 [0.61, 4.40]
3 Surgery Show forest plot	9	1270	Risk Ratio (M‐H, Random, 95% CI)	1.33 [0.63, 2.77]

3.1 Intravenous	6	997	Risk Ratio (M‐H, Random, 95% CI)	1.26 [0.54, 2.91]
3.2 Oral	3	273	Risk Ratio (M‐H, Random, 95% CI)	1.59 [0.34, 7.40]
4 Further EHT Show forest plot	6	902	Risk Ratio (M‐H, Random, 95% CI)	1.39 [0.88, 2.18]

4.1 Intravenous	5	877	Risk Ratio (M‐H, Random, 95% CI)	1.35 [0.85, 2.13]
4.2 Oral	1	25	Risk Ratio (M‐H, Random, 95% CI)	4.64 [0.25, 87.91]
5 LOS Show forest plot	6	1069	Mean Difference (IV, Random, 95% CI)	0.26 [‐0.08, 0.60]

5.1 Intravenous	4	833	Mean Difference (IV, Random, 95% CI)	0.32 [‐0.10, 0.74]
5.2 Oral	2	236	Mean Difference (IV, Random, 95% CI)	0.15 [‐0.43, 0.73]
6 Blood transfusions Show forest plot	6	1069	Mean Difference (IV, Random, 95% CI)	0.05 [‐0.21, 0.30]

6.1 Intravenous	4	833	Mean Difference (IV, Random, 95% CI)	0.22 [‐0.11, 0.56]
6.2 Oral	2	236	Mean Difference (IV, Random, 95% CI)	‐0.19 [‐0.57, 0.20]

Comparison 4. Subgroup analysis: Route of administration in non‐high dose regimen

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Comparison 5. Subgroup analysis: IV bolus vs. IV infusion in non‐high dose regimen

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Mortality Show forest plot	9	1394	Risk Ratio (M‐H, Random, 95% CI)	0.84 [0.45, 1.56]

1.1 Bolus	7	1155	Risk Ratio (M‐H, Random, 95% CI)	1.15 [0.53, 2.47]
1.2 Infusion	2	239	Risk Ratio (M‐H, Random, 95% CI)	0.45 [0.16, 1.32]
2 Rebleeding Show forest plot	10	1443	Risk Ratio (M‐H, Random, 95% CI)	1.24 [0.93, 1.65]

2.1 Bolus	8	1178	Risk Ratio (M‐H, Random, 95% CI)	1.24 [0.86, 1.77]
2.2 Infusion	3	265	Risk Ratio (M‐H, Random, 95% CI)	1.26 [0.75, 2.13]
3 Surgery Show forest plot	6	997	Risk Ratio (M‐H, Random, 95% CI)	1.26 [0.54, 2.91]

3.1 Bolus	6	997	Risk Ratio (M‐H, Random, 95% CI)	1.26 [0.54, 2.91]
3.2 Infusion	0	0	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
4 Further EHT Show forest plot	5	877	Risk Ratio (M‐H, Random, 95% CI)	1.34 [0.85, 2.12]

4.1 Bolus	5	847	Risk Ratio (M‐H, Random, 95% CI)	1.34 [0.85, 2.12]
4.2 Infusion	1	30	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
5 LOS Show forest plot	4	833	Mean Difference (IV, Random, 95% CI)	0.32 [‐0.10, 0.74]

5.1 Bolus	4	833	Mean Difference (IV, Random, 95% CI)	0.32 [‐0.10, 0.74]
5.2 Infusion	0	0	Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]
6 Blood transfusions Show forest plot	4	833	Mean Difference (IV, Random, 95% CI)	0.22 [‐0.11, 0.56]

6.1 Bolus	4	833	Mean Difference (IV, Random, 95% CI)	0.22 [‐0.11, 0.56]
6.2 Infusion	0	0	Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]

Comparison 5. Subgroup analysis: IV bolus vs. IV infusion in non‐high dose regimen

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Comparison 6. Subgroup analysis: Type of PPI in high dose regimen

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Mortality Show forest plot	12	1667	Risk Ratio (M‐H, Random, 95% CI)	0.85 [0.48, 1.51]

1.1 Omeprazole	4	612	Risk Ratio (M‐H, Random, 95% CI)	0.63 [0.29, 1.37]
1.2 Pantoprazole	7	581	Risk Ratio (M‐H, Random, 95% CI)	1.49 [0.44, 5.01]
1.3 Either omeprazole or pantoprazole	1	474	Risk Ratio (M‐H, Random, 95% CI)	0.99 [0.29, 3.38]
2 Rebleeding Show forest plot	13	1716	Risk Ratio (M‐H, Random, 95% CI)	1.27 [0.96, 1.67]

2.1 Omeprazole	4	608	Risk Ratio (M‐H, Random, 95% CI)	1.25 [0.83, 1.87]
2.2 Pantoprazole	8	634	Risk Ratio (M‐H, Random, 95% CI)	1.15 [0.69, 1.93]
2.3 Either omeprazole or pantoprazole	1	474	Risk Ratio (M‐H, Random, 95% CI)	1.46 [0.84, 2.54]
3 Surgery Show forest plot	9	1270	Risk Ratio (M‐H, Random, 95% CI)	1.33 [0.63, 2.77]

3.1 Omeprazole	2	373	Risk Ratio (M‐H, Random, 95% CI)	1.23 [0.44, 3.48]
3.2 Pantoprazole	6	423	Risk Ratio (M‐H, Random, 95% CI)	1.17 [0.36, 3.82]
3.3 Either omeprazole or pantoprazole	1	474	Risk Ratio (M‐H, Random, 95% CI)	2.97 [0.31, 28.39]
4 Further EHT Show forest plot	6	902	Risk Ratio (M‐H, Random, 95% CI)	1.39 [0.88, 2.18]

4.1 Omeprazole	1	142	Risk Ratio (M‐H, Random, 95% CI)	1.06 [0.28, 4.07]
4.2 Pantoprazole	4	286	Risk Ratio (M‐H, Random, 95% CI)	1.35 [0.51, 3.59]
4.3 Either omeprazole or pantoprazole	1	474	Risk Ratio (M‐H, Random, 95% CI)	1.46 [0.84, 2.54]
5 LOS Show forest plot	6	1069	Mean Difference (IV, Random, 95% CI)	0.26 [‐0.08, 0.60]

5.1 Omeprazole	2	353	Mean Difference (IV, Random, 95% CI)	0.13 [‐0.35, 0.62]
5.2 Pantoprazole	3	242	Mean Difference (IV, Random, 95% CI)	0.16 [‐0.46, 0.79]
5.3 Either omeprazole or pantoprazole	1	474	Mean Difference (IV, Random, 95% CI)	0.70 [‐0.03, 1.43]
6 Blood transfusions Show forest plot	6	1069	Mean Difference (IV, Random, 95% CI)	0.05 [‐0.21, 0.30]

6.1 Omeprazole	2	353	Mean Difference (IV, Random, 95% CI)	‐0.19 [‐0.57, 0.20]
6.2 Pantoprazole	3	242	Mean Difference (IV, Random, 95% CI)	0.34 [‐0.43, 1.11]
6.3 Either omeprazole or pantoprazole	1	474	Mean Difference (IV, Random, 95% CI)	0.20 [‐0.18, 0.58]

Comparison 6. Subgroup analysis: Type of PPI in high dose regimen

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Comparison 7. Subgroup analysis: Ulcer site

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Mortality Show forest plot	1	28	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]

1.1 Gastric ulcer	1	15	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
1.2 Duodenal ulcer	1	13	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
2 Rebleeding Show forest plot	2	502	Risk Ratio (M‐H, Random, 95% CI)	1.52 [0.89, 2.60]

2.1 Gastric Ulcer	2	196	Risk Ratio (M‐H, Random, 95% CI)	1.52 [0.66, 3.49]
2.2 Duodenal Ulcer	2	306	Risk Ratio (M‐H, Random, 95% CI)	1.52 [0.75, 3.07]
3 Surgery Show forest plot	1	28	Risk Ratio (M‐H, Random, 95% CI)	2.67 [0.13, 56.63]

3.1 Gastric ulcer	1	15	Risk Ratio (M‐H, Random, 95% CI)	2.67 [0.13, 56.63]
3.2 Duodenal ulcer	1	13	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]

Comparison 7. Subgroup analysis: Ulcer site

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Comparison 8. Sensitivity analysis: High vs. low dose

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Mortality Show forest plot	4	835	Risk Ratio (M‐H, Random, 95% CI)	0.96 [0.43, 2.18]

2 Rebleeding Show forest plot	5	867	Risk Ratio (M‐H, Random, 95% CI)	1.22 [0.82, 1.82]

3 Surgery Show forest plot	3	677	Risk Ratio (M‐H, Random, 95% CI)	1.41 [0.51, 3.95]

Comparison 8. Sensitivity analysis: High vs. low dose

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Comparison 9. Sensitivity analysis: High vs. medium dose

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Mortality Show forest plot	8	832	Risk Ratio (M‐H, Random, 95% CI)	0.74 [0.33, 1.68]

2 Rebleeding Show forest plot	9	868	Risk Ratio (M‐H, Random, 95% CI)	1.30 [0.89, 1.90]

3 Surgery Show forest plot	6	593	Risk Ratio (M‐H, Random, 95% CI)	1.24 [0.43, 3.57]

Comparison 9. Sensitivity analysis: High vs. medium dose

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Comparison 10. Sensitivity analysis: Medium vs. low dose

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Mortality Show forest plot	3	275	Risk Ratio (M‐H, Random, 95% CI)	0.42 [0.06, 2.80]

2 Rebleeding Show forest plot	5	320	Risk Ratio (M‐H, Random, 95% CI)	0.69 [0.33, 1.43]

3 Surgery Show forest plot	3	249	Risk Ratio (M‐H, Random, 95% CI)	0.48 [0.09, 2.55]

Comparison 10. Sensitivity analysis: Medium vs. low dose

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Comparison 11. Sensitivity analysis: Non‐low (high or medium) dose vs. low dose

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Mortality Show forest plot	4	835	Risk Ratio (M‐H, Random, 95% CI)	0.96 [0.43, 2.18]

2 Rebleeding Show forest plot	6	917	Risk Ratio (M‐H, Random, 95% CI)	1.22 [0.82, 1.82]

3 Surgery Show forest plot	4	702	Risk Ratio (M‐H, Random, 95% CI)	1.51 [0.57, 4.01]

Comparison 11. Sensitivity analysis: Non‐low (high or medium) dose vs. low dose

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Comparison 12. Sensitivity analysis: High vs. non‐high dose; patients with high risk SRH

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Mortality Show forest plot	4	306	Odds Ratio (M‐H, Random, 95% CI)	1.11 [0.25, 4.91]

1.1 All patients with HR SRH received initial EHT	3	292	Odds Ratio (M‐H, Random, 95% CI)	1.11 [0.25, 4.91]
1.2 Not all patients with HR SRH received initial EHT	1	14	Odds Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
2 Rebleeding Show forest plot	6	751	Risk Ratio (M‐H, Random, 95% CI)	1.28 [0.84, 1.97]

2.1 All patients with HR SRH received initial EHT	4	655	Risk Ratio (M‐H, Random, 95% CI)	1.24 [0.79, 1.94]
2.2 Not all patients with HR SRH received initial EHT	2	96	Risk Ratio (M‐H, Random, 95% CI)	1.75 [0.45, 6.85]
3 Surgery Show forest plot	3	148	Risk Difference (M‐H, Random, 95% CI)	0.00 [‐0.06, 0.06]

3.1 All patients with HR SRH received initial EHT	2	134	Risk Difference (M‐H, Random, 95% CI)	0.00 [‐0.06, 0.06]
3.2 Not all patients with HR SRH received initial EHT	1	14	Risk Difference (M‐H, Random, 95% CI)	0.0 [‐0.24, 0.24]

Comparison 12. Sensitivity analysis: High vs. non‐high dose; patients with high risk SRH

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Comparison 13. Post hoc analysis: Studies that compared at least two PPI regimens with different 72‐hour cumulative dose

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Mortality Show forest plot	18	2197	Risk Ratio (M‐H, Random, 95% CI)	0.79 [0.47, 1.36]

2 Rebleeding Show forest plot	21	2338	Risk Ratio (M‐H, Random, 95% CI)	1.02 [0.81, 1.29]

3 Surgery Show forest plot	16	1884	Risk Ratio (M‐H, Random, 95% CI)	1.22 [0.64, 2.30]

4 Further EHT Show forest plot	11	1352	Risk Ratio (M‐H, Random, 95% CI)	1.02 [0.74, 1.42]

5 LOS Show forest plot	11	1570	Mean Difference (IV, Random, 95% CI)	‐0.41 [‐1.09, 0.27]

6 Blood transfusions Show forest plot	9	1425	Mean Difference (IV, Random, 95% CI)	0.23 [‐0.25, 0.71]

Comparison 13. Post hoc analysis: Studies that compared at least two PPI regimens with different 72‐hour cumulative dose

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Comparison 14. Post hoc analysis: Studies that compared at least two PPI regimens with different 72‐hour cumulative dose; high risk SRH

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Mortality Show forest plot	5	373	Risk Ratio (M‐H, Random, 95% CI)	0.88 [0.24, 3.28]

1.1 All patients with HR SRH received initial EHT	4	359	Risk Ratio (M‐H, Random, 95% CI)	0.88 [0.24, 3.28]
1.2 Not all patients with HR SRH received initial EHT	1	14	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
2 Rebleeding Show forest plot	11	1041	Risk Ratio (M‐H, Random, 95% CI)	1.01 [0.73, 1.41]

2.1 All patients with HR SRH received initial EHT	8	919	Risk Ratio (M‐H, Random, 95% CI)	0.97 [0.68, 1.39]
2.2 Not all patients with HR SRH received initial EHT	3	122	Risk Ratio (M‐H, Random, 95% CI)	1.43 [0.48, 4.24]
3 Surgery Show forest plot	6	397	Risk Ratio (M‐H, Random, 95% CI)	0.66 [0.19, 2.34]

3.1 All patients with HR SRH received initial EHT	4	357	Risk Ratio (M‐H, Random, 95% CI)	0.66 [0.19, 2.34]
3.2 Not all patients with HR SRH received initial EHT	2	40	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]

Comparison 14. Post hoc analysis: Studies that compared at least two PPI regimens with different 72‐hour cumulative dose; high risk SRH

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Comparison 15. Post hoc analysis: Comparison of regimens with the same 72‐hour cumulative dose, but different route or frequency

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Rebleeding Show forest plot	1	22	Risk Ratio (M‐H, Random, 95% CI)	0.30 [0.04, 2.27]

Comparison 15. Post hoc analysis: Comparison of regimens with the same 72‐hour cumulative dose, but different route or frequency

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Comparison 16. Post hoc analysis: IV regimen vs. PO regimen

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Mortality Show forest plot	4	429	Risk Ratio (M‐H, Random, 95% CI)	0.77 [0.21, 2.79]

2 Rebleeding Show forest plot	5	516	Risk Ratio (M‐H, Random, 95% CI)	1.08 [0.63, 1.84]

3 Surgery Show forest plot	5	516	Risk Ratio (M‐H, Random, 95% CI)	1.13 [0.31, 4.11]

4 Further EHT Show forest plot	3	268	Risk Ratio (M‐H, Random, 95% CI)	1.10 [0.57, 2.11]

5 LOS Show forest plot	3	392	Mean Difference (IV, Random, 95% CI)	0.09 [‐0.46, 0.63]

6 Blood transfusions Show forest plot	3	392	Mean Difference (IV, Random, 95% CI)	‐0.18 [‐0.56, 0.20]

Comparison 16. Post hoc analysis: IV regimen vs. PO regimen

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