Clinical Therapeutics/Volume xxx, Number xxx, xxxx
Pharmacologic Prophylaxis of Stress Ulcer in Non-
ICU Patients: A Systematic Review and Network
Meta-analysis of Randomized Controlled Trials
Yi Liu, PhD; Dandan Li, MD; and Aiping Wen, MD
Department of Pharmacy, Beijing Friendship Hospital, Capital Medical University, Beijing,
China
ABSTRACT
Purpose: Acid-suppressive medications are widely
used in noneintensive care unit (non-ICU) patients
for stress ulcer (SU) prophylaxis. However, SU
prophylaxis in this population is still controversial.
The purpose of this study was to systematically
evaluate the efficacy and tolerability of these agents
for SU prophylaxis in non-ICU patients.
Methods: Electronic databases including Cochrane,
ClinicalTrials.gov, Ovid-Medline, Embase, Chinese
CNKI, and Wanfang Data were systematically
searched on July 10, 2019, for randomized controlled
trials (RCTs) that evaluated acid-suppressive
medications in non-ICU patients. Network meta-
analysis and pairwise meta-analysis were performed
to calculate odds ratios (ORs) and 95% CIs. A
random-effects model was used for generating pooled
estimates. The primary outcome was occurrence of
SU bleeding, and the adverse drug events (ADEs)
were described as the secondary outcome.
Findings: A total of 17 RCTs involving 1985
patients were eligible. Meta-analysis results indicated
that the occurrence of SU bleeding was significantly
decreased with all acid-suppressive medications
compared with placebos (gastric mucosa protectants,
OR ¼ 0.29 [95% CI, 0.14e0.61]; H2-receptor
antagonists, OR ¼ 0.3 [95% CI, 0.18e0.50]; proton
pump inhibitors [PPIs]: OR ¼ 0.08 [95% CI,
0.04e0.16]). The occurrence of SU bleeding was
significantly decreased with PPIs compared with gastric
mucosa protectants (OR ¼ 0.29; 95% CI, 0.12e0.72)
and H2-receptor antagonists (OR ¼ 0.28; 95% CI,
0.16e0.48). There was no significant difference
between any 2 classes of PPIs on SU bleeding or any 2
acid-suppressive medications on ADEs.
Implications: PPIs could significantly decrease SU
bleeding risk without increasing ADEs than other
▪▪▪ xxxx
acid-suppressive medications for SU prophylaxis in
non-ICU patients. However, RCTs of high quality
were required to confirm the findings of this
investigation. (Clin Ther. xxxx;xxx:xxx) © 2020
Elsevier Inc. All rights reserved.
Key words: acid-suppressive medications, meta-
analysis, non-ICU, prophylaxis, stress ulcer.
INTRODUCTION
Stress ulcer (SU) is a stress-related mucosal injury
caused by mucosal ischemia, hypoperfusion, or
reperfusion damage under stress.1e4 Bleeding is a
common complication of SU, and it has been
confirmed to increase mortality, length of
hospitalization time, and hospitalization expenses in
critically ill patients.5e7 Acid-suppressive medicines,
including proton pump inhibitors (PPIs), H2-receptor
antagonists (H2RAs), and gastric mucosa protectants
(GMPs), are recommended for SU prophylaxis in
critically ill patients with risk factors.8
Acid-suppressive medications are also widely used
in inpatients.9 However, However, recent study has
shown that there is little evidence regarding the
benefit of SU prophylaxis outside the critical care
setting. Overuse of SU prophylaxis might lead to
increased health care expenditures and adverse drug
events (ADEs). Other studies have revealed that
>50% of patients were not hospitalized in the
intensive care unit (ICU) at the onset of SU
bleeding.10 Risk factors of SU bleeding such as major
surgery, severe trauma, and treatment with NSAIDs
Accepted for publication January 14, 2020
https://doi.org/10.1016/j.clinthera.2020.01.008
0149-2918/$ - see front matter
© 2020 Elsevier Inc. All rights reserved.
1
 Clinical Therapeutics
or anticoagulants are also common in non-ICU
patients.11e14 The SU guideline published by the
Eastern Association for the Surgery of Trauma
recommends using either a PPI or a H2RA for SU
prophylaxis.15 There is no consensus as to whether
SU prophylaxis is beneficial, and which agent is the
best choice for SU prophylaxis in non-ICU patients.
Furthermore, although different PPIs were discussed
in previous studies,16e19 no consensus has been
reached. Thus, this systematic review and network
meta-analysis of data from available randomized
controlled trials (RCTs) were carried out to
qualitatively assess the efficacy and tolerability of
acid-suppressive medications for SU prophylaxis in
non-ICU patients.
MATERIALS AND METHODS
This systematic review and network meta-analysis
were performed and reported according to the
PRISMA statement guidelines.
Searching Strategy
We systematically searched several electronic
databases including Cochrane (from 1944),
ClinicalTrials.gov, Ovid-Medline (from 1946) and
Embase (from 1974), Chinese CNKI (from 1979),
and Wanfang Data (from 1980) for all relevant
articles published through July 10, 2019, using SU
and relevant terms (see Supplemental Table S1 in the
online version at https://doi.org/10.1016/j.clinthera.
2020.01.008). We also screened reviews and relevant
meta-analyses for potential eligible RCTs.
Study Selection
We included RCTs with the following inclusion
criteria: comparisons acid-suppressive medications for
SU prophylaxis in non-ICU patients, assessments of
the prophylactic effect on SU bleeding, and full-text
publications.
SU bleeding was defined as any of the following
conditions: melena, brown/red gastric juice, frank
hematemesis, positive fecal/vomitus/gastric juice
occult blood, requirement of blood transfusion,
hemodynamic instability, and significant hemoglobin
decrease. Ulceration and/or erosions without bleeding
that were confirmed by endoscopy were excluded.
We excluded animal experiments, non-RCTs, RCTs
that evaluated efficacy of combination therapy or
enteral nutrition, and SU prophylaxis in patients with
2 Volume xxx Number xxx
acute coronary syndrome. Abstracts that were
presented at conferences and manufacturers' websites
were also excluded due to limited data. Studies in
both English and Chinese were searched. No
unpublished studies were used in our study. Study
selection was conducted by 2 reviewers independently
(Y.L. and D.L.), and any disagreement was resolved
by discussion with the third reviewer (A.W.).
Data Extraction and Quality Evaluation
Data were extracted into a standardized spreadsheet
by 2 reviewers (Y.L. and D.L.) independently. Any
discrepancy was discussed with the third reviewer
(A.W). The quality of selected RCTs was evaluated
by 2 authors (Y.L. and D.L.) independently following
the “low,” “high,” or “unclear” classification
according to the Cochrane risk for bias tools.20
Outcomes and Data Synthesis
There were 4 treatment groups in total: placebo,
PPI, H2RA, and GMP (including sucralfate and
aluminum hydroxide magnesium).
The primary outcome was the prevalence of SU
bleeding with the use of different acid-suppressive
medications and different PPI agents. The secondary
outcome was the occurrence of overall adverse events
during prophylactic treatment, including death,
infection, headache, diarrhea, nausea, myalgia,
dermatitis, and abnormal vision.
Statistical Analysis
First, we performed a random-effects network meta-
analysis by STATA version 13.1 (StataCorp, College
Station, Texas) using the mumeta21 and self-
programmed STATA routines assuming a common
heterogeneity variable for all comparisons.22 The
relative ranking of a specified outcome during
network meta-analysis was estimated by surface
under the cumulative ranking curve (SUCRA)
probabilities and mean ranks. In terms of zero events,
0.5 was added for correction prior to meta-
analysis.23 The dichotomous variables were presented
as odds ratios (ORs) with 95% CIs. Predictive
intervals of 95% were also examined to demonstrate
the uncertainty and magnitude of the heterogeneity in
the network meta-analysis.
Second, a standard pairwise meta-analysis with a
random-effects model by Review Manager version
5.1 was conducted for comparisons between at least

2 RCTs.24 The heterogeneity was assessed and
evaluated as high (>75%), moderate (25%e75%), or
low (<25%) using I2.
Inconsistency
A loop-specific approach was employed to evaluate
the inconsistency within each closed triangle or
quadratic loop. The inconsistency factors with 95%
CIs were calculated to determine their compatibility
with zero.25
Publication Bias
Publication bias was assessed to ensure the validity
of meta-analysis of the primary outcome by funnel
plot tests.26
RESULTS
We identified 2849 records including 2845 from
database searching, and 4 through checking reference
lists. After removing duplicates, and screening titles
and abstracts, 66 full RCTs met the inclusion criteria.
After reading full texts, 17 RCTs involving 1985
patients were finally included in this meta-analysis,
and the search flowchart is shown in Figure 1.
Characteristics and Quality
Table I shows the baseline characteristics of all
included studies. These studies were performed in
China,16e19,27e35 India,36,37 and Spain.38,39 The
number of patients in each study ranged from 40 to
320. The available follow-up periods ranged from 2
to 15 days. The age of included patients ranged from
5 to 92 years. The interventions involved PPIs, GMPs,
H2RAs, and placebo. These studies included patients
who received extracorporeal circulation,18,27,32 major
surgeries,16,17,28e31,33,34 or with other risk factors for
SU such as preoperative coma, inappropriate secretion
of antidiuretic hormone, and complications requiring
reoperation35e39 (see Supplemental Table S2 in the
online version at doi:10.1016/j.clinthera.2020.01.008).
Overall, the risk for bias was high or unclear for
random sequence generation in 10 trials (58.8%),
allocation concealment in 17 trials (100%),
blinding of participants and personnel in 12 trials
(70.6%), blinding of outcome assessment in 17
trials (100%), selective reporting in 1 trial (5.9%)
and other bias in 1 trial (5.9%). The bias of
incomplete data was found to be low for all trials
reviewed, meaning that the missing data from
▪▪▪ xxxx
Y. Liu et al.
follow-up analyses were acceptable and the
numbers of withdrawn patients were balanced
across intervention groups. A summary graph of
risks of bias is shown in Figure 2.
Network Meta-Analysis and Pairwise Meta-
Analysis of Different Acid-Suppressive Medications
on SU Bleeding
Network analysis of eligible comparisons for the
primary outcome is shown in Figure 3A. A total of
12 RCTs involving 1366 patients were available for
categorical analysis of different acid-suppressive
medications on SU bleeding. The prevalence of SU
bleeding among included patients was found to be
from 14.6% to 65.0% in the placebo group. A
network forest plot is shown in Supplemental
Figure S1A (see the online version at doi:10.1016/
j.clinthera.2020.01.008). All of these 3 prophylaxis
strategies significantly reduced the SU bleeding
compared with placebo (GMPs, OR ¼ 0.29 [95%
CI, 0.14e0.61]; H2RAs, OR ¼ 0.30 [95% CI,
0.18e0.50]; and PPIs, OR ¼ 0.08 [95% CI,
0.04e0.16]). In the meantime, PPIs were associated
with a significantly lower occurrence of SU bleeding
than either H2RAs or GMPs (H2RAs, OR ¼ 0.28
[95% CI, 0.16e0.48]; GMPs, OR ¼ 0.29 [95% CI,
0.12e0.72]). No other statistical differences were
detected in other comparisons (Table II).
Contributions of direct evidence for network
analyses are presented in Supplemental Figure S2A
(see the online version at doi:10.1016/
j.clinthera.2020.01.008). Furthermore, the
comparative effects of these 3 different acid-
suppressive medications against placebo with SUCRA
probabilities were ranked, and PPIs showed the
highest rank (see Supplemental Table S3 in the online
version at doi:10.1016/j.clinthera.2020.01.008). There
was no evidence of loop inconsistency from both
direct and indirect comparisons since 95% CIs all
included zero (see Supplemental Table S4 in the online
version at doi:10.1016/j.clinthera.2020.01.008). No
global inconsistency was observed in any treatment
networks. Underlying publication bias was shown in
the visual inspection of funnel plots (see Supplemental
Figure S3 in the online version at doi:10.1016/
j.clinthera.2020.01.008).
Pairwise meta-analysis showed similar results
with network comparisons (see Supplemental
Figure S4 in the online version at doi:10.1016/
3
 Clinical Therapeutics

Additional records Records identified through database

identified through searching (n=2845):

Identification reference lists Cochrane (n = 536); Ovid-Medline and

screened Embase (n=473); ClinicalTrials.gov (n=0); CNKI
(n = 4) (n=1161); ChianInfo (n=675)

Duplicates removed (n =286)

Screening

Records screened (n = 2563)

Articles excluded for irrelevant

articles, or not RCTs, or animal
experiment trials (n = 2497)

Full-text articles
assessed for eligibility
Eligibility

(n = 66)
Full texts excluded for intensive
care unit patients (n=46);
combination of drugs (n=1);
comparison of administration time
(n=1); ulceration/erosions without
bleeding confirmed by endoscopy
(n=1)
Included

17 RCTs were eligible for meta-analysis

Figure 1. PRISMA flow chart of articles included in this network meta-analysis.

j.clinthera.2020.01.008). I2 showed low or moderate Network Meta-Analysis of Different PPIs on SU

heterogeneity of these comparisons. GMP Bleeding
(OR ¼ 0.21; 95% CI, 0.05e0.78), H2RA Five RCTs involving 567 patients compared the
(OR ¼ 0.30; 95% CI, 0.17e0.52), and PPI occurrence of SU bleeding among different PPIs
(OR ¼ 0.10; 95% CI, 0.04e0.24) were associated (Figure 3B), including pantoprazole, omeprazole,
with a lower risk for SU bleeding compared to esomeprazole, and lansoprazole. Network meta-
placebo. analysis showed that there was no significant

4 Volume xxx Number xxx

▪▪▪ xxxx

Table I. Baseline characteristics and key data of included study.

Author Ref. Country Regimens Control Drug/ Intervention Number of Age, y Prevalence of Prevalence of Participants Random Method Blind Method Duration, Follow-Up,
of Study Compared Dosage Drug/Dosage Patients Stress Ulcer Adverse Effect d d
Bleeding,
%

HM Ge, 27 China PPI vs PLA PLA/e OME/40 mg for adult, PPI: 23; 5e53 PPI: 0; e Cardiac surgery Stratified Single-blind 6e10 2
2003 20 mg for child PO/ PLA: 22 PLA: 36.4 randomization method
IV.gtt once daily
CZ Zhou, 28 China PPI vs H2RA CIM/0.4 g OME/40 mg IV.gtt BID PPI: 160; e PPI: 5.6; PPI: 1.9; General surgery NA NA 7 7
2014 IV.gtt BID H2RA:160 H2RA: 14.4 H2RA: 3.1
WL Mai, 29 China PPI vs PLA PLA/e OME/40 mg PPI: 20; 41.71 ± 13.46 PPI: 30; e Brain surgery NA Double-blind 1 5
2010 IV gtt once daily PLA: 20 PLA: 65 method
Y Wu, 2013 30 China PPI vs H2RA FAM/40 mg PAN/40 mg PPI: 45; e PPI: 2.2; e Digestive surgery NA NA NA NA
IV.gtt once IV.gtt once daily H2RA: 13 H2RA: 30.8
daily
XS Ren, 31 China PPI vs H2RA CIM/0.4 g PAN/40 mg PPI: 54; 52.5 ± 19.4 PPI: 3.7; e General surgery Random number NA 14 14
2015 IV.gtt BID IV.gtt BID H2RA: 54 H2RA: 20.4 table
CH Pang, 16 China PPI vs PPI PAN/40 mg OME/60 mg PAN: 40; 55 ± 16 for PAN; PAN: 2.5; e General surgery Random number NA 5e7 14
2008 IV.gtt once IV.gtt once daily OME: 38 57 ± 20 for OME OME: 5.3 table
daily
D Rao, 32 China PPI vs PLA PLA/e ESO/40 mg PPI: 96; 48 ± 16 for PLA; PPI: 0.9; e Cardiac surgery NA NA 10 2
2013 PO/IV.gtt PLA: 112 46 ± 18 for PPI PLA: 16.7
once daily
MM Zheng, 17 China PPI vs PPI PAN/40 mg ESO/40 mg PAN: 40; 57.2 for ESO; PAN: 5.0; e Otorhinolaryngologic NA NA NA 7
2014 IV.gtt BID IV.gtt BID ESO:40 59.8 for PAN ESO: 2.5 surgical
YQ Huang, 18 China PPI vs PPI OME/20 mg or ESO/40 mg OME: 117; 48 ± 5 for OME; OME: 1.7; e Cardiac surgery NA NA 10 3
2013 40 mg IV once daily ESO: 112 49 ± 18 for ESO ESO: 0.9
PO/IV once
daily
H Wang, 19 China PPI vs PPI OME/40 mg, IV LAN/30 mg OME: 30; 65e83 OME: 6.7; OME: 6.7; Orthopedic surgery NA NA OME: 8 ± 3; NA
2016 BID IV BID LAN: 30 LAN: 33.3 LAN: 10.0 LAN: 7 ± 3
YP Hu, 2001 33 China PPI vs H2RA PLA/e OME/40 mg PLA: 30; 41 - 69 for PPI; PLA: 53.3; e Neurologic surgery NA NA 10 12
vs PLA IV.gtt QD; PPI: 29; 40 - 70 for H2RA; PPI: 6.9;
RAN/150 mg H2RA: 31 39 - 70 for PLA H2RA: 29.0
IV.gtt QD
XZ Chen, 34 China PPI vs PPI PAN/40 mg LAN/30 mg PAN: 60; 21.25e58.74 PAN: 10.0; PAN: 11.7; Digestive surgery Odd-even of NA 7 7
2017 IV.gtt QD IV once daily LAN: 60 LAN: 5.0 LAN: 5.0 registration
order
Kaushal S, 36 India GMP vs H2RA PLA/e FAM/20 mg PLA: 25; 36.34 ± 15.58 PLA: 44.0; e Neurologic surgery NA NA 15 15
2000 vs PLA PO BID; SUR/2 g H2RA: 24; for PLA; H2RA: 8.3;
PO BID GMP: 22 32.92 ± 10.93 GMP: 9.1
for H2RA;
32.7 ± 12.79
for GMP
Chan KH, 35 Hong Kong H2RA vs PLA PLA/e RAN/50 mg IV q6h; PLA: 49; 17e89 PLA: 42.9; PLA: 24.5; Neurologic surgery NA Double-blind NA NA
1995 of China or 150 mg PO BID H2RA: 52 H2RA: 17.3 H2RA: 34.6 method

Y. Liu et al.
Misra UK, 37 India GMP vs H2RA PLA/e RAN/50 mg IV q8h; PLA: 46; 25e91 PLA: 23.9; PLA: 39.1; Intracerebral Computer- Blinded NA NA
2005 vs PLA SUR/1 g PO q6h H2RA: 44; H2RA: 11.4; H2RA: 15.9; hemorrhage generated
GMP: 48 GMP: 14.6 GMP: 35.4 random table
number
5

(continued on next page)

Clinical Therapeutics

difference between any 2 PPIs (Table II). Network

CIM ¼ cimetidine; ESO ¼ esomeprazole; FAM ¼ famotidine; GMP ¼ gastric mucosa protectant; H2RA ¼ histamine-2 receptor antagonist; LAN ¼ lansoprazole;
MAG ¼ magaldrate; OME ¼ omeprazole; PAN ¼ pantoprazole; PLA ¼ placebo; PPI ¼ proton pump inhibitors; RAN ¼ ranitidine; SUR ¼ sucralfate. iv.gtt ¼
forest plot is shown in Supplemental Figure S1B (see
Follow-Up,
d

the online version at doi:10.1016/

NA

NA
j.clinthera.2020.01.008). Pairwise meta-analysis was
Duration,

not performed due to the limited numbers of RCTs.

d

Loop-specific inconsistency was detected in one loop

NA

from direct and indirect comparisons (see

Blind Method

Single-blind
method

Supplemental Table S4 in the online version at

doi:10.1016/j.clinthera.2020.01.008). Contributions
NA

of direct evidence to network analyses are presented

Random Method

General hospital ward Table of random

General hospital ward Table of random

in Supplemental Figure S2B (see the online version at

numbers

numbers

doi:10.1016/j.clinthera.2020.01.008).

Occurrence of ADEs
Regarding comparisons of different suppressive
Participants

medications, 6 RCTs reported the occurrence of

ADEs. The available prevalences of overall ADEs
were 1.9% with PPIs, 3.1%e34.6% with H2RAs,
Adverse Effect
Prevalence of

13.2%e35.4% with GMPs, and 24.5%e39.1% with

H2RA: 11.2;
GMP: 13.2

placebo. Gastrointestinal symptoms were mentioned

in 4 RCTs. Headache was reported in 1 RCT.
e

Dermatitis, infections or pneumonias, myalgia and

Prevalence of
Stress Ulcer
Bleeding,

H2RA: 71; 67 ± 12 for H2RA; H2RA: 2.8;

PLA: 22.9;

abnormal vision were mentioned in 2 RCTs,

GMP: 68 64 ± 13 for GMP GMP: 2.9

GMP: 1.9
%

respectively. The occurrence of death was stated in 3

RCTs. Among 14 cases of deaths in the placebo
group, 1 was reported to be directly related to SU
Age, y

bleeding. There were 8 cases of deaths reported in

20e92

the H2RA group, and 14 cases in the GMP group.

For different PPIs, 2 RCTs reported the overall
Number of
Patients

12, 16, 20 and 24 h GMP: 52

PLA: 48;

occurrence of ADEs, 5.0%e11.7%, including

myalgia, abnormal vision, dermatitis, and
gastrointestinal symptoms. No statistical analysis was
MAG/800 mg at 8,
Drug/Dosage
Intervention

CIM/800 mg qn

conducted on ADEs due to limited data in our analysis.

DISCUSSION
This study is the first systematic review and meta-
Control Drug/

GMP vs H2RA SUR/1 g q6h

analysis of SU prophylaxis in a non-ICU population,

Dosage

while most previous studies have focused on ICU

PLA/e

patients. Other reports have described the widespread

use of acid-suppressive medications with or without
Compared

GMP vs PLA
Regimens

indications.40,41 This study found that non-ICU

population might also need SU prophylaxis when
intravenously guttae.

indications existed.
of Study
Country

38 Spain

39 Spain

It is reported that acid suppression could reduce the

Table I. (Continued )

occurrence of SU by protecting the mucous layer from

Ref.

the diffusion of hydrogen ions across the gastric

GRAU JM,

Estruch R,
1993

1991

mucosa when usual gastric mucosal integrity

Author

mechanism is disrupted.42 Thus, prophylaxis of SU

bleeding in ICU patients is recommended.43e47

6 Volume xxx Number xxx

 Y. Liu et al.

Figure 2. Risk for bias graph: review authors' judgments about each risk-for-bias item presented as percentages
across all included studies.

Figure 3. Network meta-analysis results of category effect. A, different acid-suppressive medications on stress
ulcer (SU) bleeding; B, different PPIs on SU bleeding. ESO ¼ esomeprazole; GMP ¼ gastric mucosa
protectant; H2RA ¼ histamine-2 receptor antagonist; LAN ¼ lansoprazole; OME ¼ omeprazole;
PAN ¼ pantoprazole; PLA ¼ placebo; PPI ¼ proton pump inhibitors.

Although SU in non-ICU patients was not as common
as those in ICU, SU bleeding remained as a severe
complication that was associated with prolonged
hospitalization and increased mortality.
Acid-suppressive medications could prevent SU
bleeding through different mechanisms: GMPs
provide physical barriers by neutralizing gastric acid
or enhancing mucosal protection via stimulating
prostaglandin release.48 Both H2RAs and PPIs
protect the gastric mucosa by reducing gastric acid
secretion. H2RAs block the histamine H2 receptor,
which is 1 of the 3 pathways that activate proton
pump, while PPIs inactivate the final step in acid
secretion by binding covalently to cysteine residues
on the proton pump.49 Theoretically, PPIs could
provide much stronger acid suppression than H2RAs
because they are specifically and irreversibly bound
to proton pump.50 This reasoning was verified by our

▪▪▪ xxxx 7
 Clinical Therapeutics

Table II. Network meta-analysis results on stress ulcer bleeding. Data are given as odds ratios (95% Cl).

Category effect of acid suppressive medicines on stress ulcer bleeding

PPI 3.47 (1.40e8.61) 3.62 (2.07e6.33) 11.89 (6.33e22.34)

0.29 (0.12e0.72) GMP 1.04 (0.48e2.29) 3.43 (1.63e7.21)
0.28 (0.16e0.48) 0.96 (0.44e2.10) H2RA 3.29 (2.00e5.42)
0.08 (0.04e0.16) 0.29 (0.14e0.61) 0.30 (0.18e0.50) PLA

Category effect of different PPIs on stress ulcer bleeding

LAN 0.43 (0.04e4.27) 0.29 (0.01e6.22) 0.75 (0.08e7.24)

2.31 (0.23e22.70) OME 0.66 (0.05e9.20) 1.74 (0.17e17.40)
3.49 (0.16e75.65) 1.51 (0.11e21.03) ESO 2.63 (0.19e36.79)
1.33 (0.14e12.75) 0.58 (0.06e5.76) 0.38 (0.03e5.32) PAN

ESO ¼ esomeprazole; GMP ¼ gastric mucosa protectant; H2RA ¼ histamine-2 receptor antagonist; LAN ¼ lansoprazole;
OME ¼ omeprazole; PAN ¼ pantoprazole; PLA ¼ placebo; PPI ¼ proton pump inhibitors.

results that PPIs were associated with a significantly
lower occurrence of SU bleeding than the other 2
acid-suppressive medications. 95% Prediction
intervals in addition to the summary estimates and
CIs helped to illustrate the expected range of true
effects. The results of 95% prediction intervals (see
Supplemental Figure S1 in the online version at
doi:10.1016/j.clinthera.2020.01.008) showed the
potential advantages of acid-suppressive medications
in SU prophylaxis.
However, the results of this study should be
interpreted cautiously because of the relatively higher
risk for SU bleeding among included patients in this
study: the commonly reported occurrence of SU
bleeding was 0.4%e12.9% among non-ICU and ICU
patients in previous studies,51e53 yet the occurrence
of SU bleeding in our study was 16.7%e65.0% in
the placebo group. The included studies contained
patients with high risks, such as major surgeries,
serious infection, major organ damage, respiratory
failure, and fasting state. This meta-analysis revealed
that SU prophylaxis might be necessary and effective
in non-ICU patients with these risk factors.
Meanwhile, various risk factors might play an
important role in the development of SU. Respiratory
failure and coagulopathy were identified as 2
significantly independent risk factors recommended
by the Eastern Association for the Surgery of
Trauma.15 Major trauma, neurosurgery, multiple
organ failure, and surgical procedures were
recommended by the American Society of Health-
System Pharmacists as potential risk factors.54
Considering the significant difference among non-ICU
patients, a scoring system is required to stratify non-
ICU patients with SU bleeding risk. Furthermore,
even though PPIs appeared to be superior to other
medications in terms of efficacy, without a higher
risk for ADEs, more studies are required to explore
the noninferiority of H2RA among non-ICU patients
with a lower risk for SU bleeding, considering the
relatively lower cost of H2RAs.
Only overall ADEs were reported, including
gastrointestinal symptoms, abnormal vision,
dermatitis, myalgia, and chest infections. It was
found in previous studies that universal acid
suppression would increase the risk for nosocomial
pneumonia and Clostridium difficileeassociated
diarrhea in the intensive care population,55,56
especially in patients with mechanical ventilation.57
Although an association between PPI use and the
risks for developing chronic kidney disease and renal
failure was verified in a recent study.58 No kidney
disease or renal failure was reported in our included
RCTs, Which might due to the relatively short
follow-up of the included studies. It was reported
that chronic kidney disease and renal failure would
occur after 5e13.9 years of using PPIs.59 In order to
confirm the association of ADEs with the
prophylactic use of acid-suppressive medications,
further investigations are needed. The available

8 Volume xxx Number xxx


follow-up periods were different among our included
RCTs, ranging from 2 days to 2 weeks. Although
superficial lesions could occur within hours,60 the
onset of hemorrhage was variable (from 2 to 25
days).61 The effect of prophylaxis may be
exaggerated with extended follow-up periods.
It was assumed that the economic issues were not
related to SU prophylaxis strategies. It is still unclear
as to whether the reduction of SU prophylaxis would
generate overall economic benefits. This study is the
first systematic review and meta-analysis for SU
prophylaxis in a non-ICU population. Most previous
studies have focused only on ICU patients. Other
reports described the widespread use of acid-
suppressive medications with or without indications,
and there has been little evidence to support its use in
general wards. This study found that non-ICU
populations might also need SU prophylaxis when
indications exist.
Furthermore, several limitations are worthy of
discussion in this study. First, the funnel plot seemed to
be asymmetrical, indicating underlying bias in our
study. However, a comprehensive search strategy and a
systemic review were performed to reduce the
publication bias. Only trials in English and Chinese
were included, which may have increased the risk for
potential publication bias and selection bias. Our
analysis was limited by the quality of the included
RCTs. Only 2 RCTs used double-blinded methods and
6 RCTs stated a proper randomized method. The
effectiveness of SU prophylaxis might be overstated
without proper random allocation and allocation-
concealment methods. Conclusions should be
considered with caution in our study. More double-
blind, multicenter RCTs with high quality, large sample
size, and adequate follow-up are required for further
investigation. Second, a small bias may have existed
because our research has not been registered on
PROSPERO; however, this network meta-analysis was
performed strictly based on the process of systematic
evaluation. Third, we did entire-population research in
non-ICU patients. The ages of the included patients
ranged from 5 to 53 years in one RCT. Subgroup
analysis in pediatric patients should be considered in
further studies. Finally, we did not obtain raw data
from these trials to investigate individual analysis
caused by different risk factors. More attention should
be paid to identify the highest risk factor for SU
prophylaxis in non-ICU patients.
▪▪▪ xxxx
Y. Liu et al.
CONCLUSIONS
SU prophylaxis could reduce the occurrence of
bleeding without significantly increasing ADEs. PPIs
seemed to be the most effective agent for SU
prophylaxis. However, conclusions should be
considered with caution. More high-quality RCTs are
required for further investigation.
CONFLICTS OF INTEREST
The authors have indicated that they have no conflicts
of interest with regard to the content of this article.
ACKNOWLEDGMENTS
This study was supported by The Digestive Medical
Coordinated Development Center of Beijing
Municipal Administration of Hospitals (No.
XXZ0604).
We would like to express our appreciation to all
cooperating organizations. Special thanks to
XingGang Li, Wenjing Hou, Chao Zhang, Zhe Li,
Can Cui, Yao Song, and Yingming Zheng, who gave
valuable comments and suggestions on this
investigation.
Y.L. contributed writing of the original draft, review
and study investigation. D.L. contributed review and
editing, and methodology. A.W. contributed project
administration, software and review.
REFERENCES
1. Monnig AA, Prittie JE. A review of stress-related mucosal
disease. J Vet Emerg Crit Care. 2011;21:484e495.
2. Gyires K, Feher A. Stress, Neuropeptides and gastric
mucosa. Curr Pharm Des. 2017;23:3928e3940.
3. Fennerty MB. Pathophysiology of the upper gastrointestinal
tract in the critically ill patient: rationale for the therapeutic
benefits of acid suppression. Crit Care Med. 2002;30:
S351eS355.
4. Wilmer A, Tack J, Frans E, et al. Duodeno gastroesophageal
reflux and esophageal mucosal injury in mechanically
ventilated patients. Gastroenterology. 1999;116:1293e1299.
5. Duerksen DR. Stress-related mucosal disease in critically ill
patients. Best Pract Res Clin Gastroenterol. 2003;17:327e344.
6. Toews I, George AT, Peter JV, et al. Interventions for
preventing upper gastrointestinal bleeding in people
admitted to intensive care units. Cochrane Database Syst Rev.
2018;6:CD008687, 4.
7. Zuckerman GR, Shuman R. Therapeutic goals and
treatment options for prevention of stress ulcer syndrome.
Am J Med. 1987;83:29e35.
9
 Clinical Therapeutics
8. Armstrong TA, Coursin DB, Duke JS,
et al. ASHP therapeutic guidelines on
stress ulcer prophylaxis. Am J Health
Syst Pharm. 1999;56:347e379.
9. Jackson J, Okun JM, Paddu N. The
overuse of ulcer prophylaxis at a
tertiary care teaching hospital: an
observational study. J Investig Med.
2016;64:800e825.
10. Terdiman JP, Ostroff JW.
Gastrointestinal bleeding in the
hospitalized patient: a case-control
study to assess risk factors, causes,
and outcome. Am J Med. 1998;104:
349e354.
11. Lanas-Gimeno A, Lanas A. Risk of
gastrointestinal bleeding during
anticoagulant treatment. Expert Opin
Drug Saf. 2017;16:673e685.
12. Nithiwathanapong C,
Reungrongrat S, Ukarapol N.
Prevalence and risk factors of stress-
induced gastrointestinal bleeding in
critically ill children. World J
Gastroenterol. 2005;11:6839e6842.
13. Allen ME, Kopp BJ, Erstad BL. Stress
ulcer prophylaxis in the postoperative
period. Am J Health Syst Pharm.
2004;61:588e596.
14. Herzig SJ, Rothberg MB,
Feinbloom DB, et al. Risk factors for
nosocomial gastrointestinal bleeding
and use of acid-suppressive
medication in non-critically ill
patients. J Gen Intern Med. 2013;28:
683e690.
15. Guillamondegui OD, Gunter OL,
Bonadies JA, et al. Practice
Management Guidelines for Stress Ulcer
Prophylaxis. EAST Practice
Management Guidelines Committee;
2008. Available at: https://www.
east.org/education/practice-
management-guidelines/stress-ulcer-
prophylaxis. Accessed December,
2019.
16. Pang CH. Clinical study of
pantoprazole and omeprazole in the
prevention of stress ulcer after
surgery. China Mod Doctor. 2008:97
e102 [in Chinese].
17. Zheng MM, Guo X, Gao J. Study of
esomeprazole sodium on prevention
10
of stress ulcer hemorrhage caused by
laryngopharyngeal tumor surgery.
Chin Arch Otolaryngol Head Neck Surg.
2012;19:564 [in Chinese].
18. Huang YQ, Rao D, Hu D. Effect of
omeprazole and esomeprazole on
intragastric pH in patients in open-
heart surgery. Chin J
Pharmacoepidemiol. 2011;20:279e280
[in Chinese].
19. Wang H. Comparative analysis of
efficacy of omeprazole and
lansoprazole in preventing stress
ulcer after femoral head replacement
in the elderly, Chinese. J Trauma
Disabil Med. 2016:62e64 [in
Chinese].
20. Higgins JP. Cochrane handbook for
systematic reviews of interventions.
Cochrane Collaboration. Available
at: https://training.cochrane.org/
handbook#how to access. Accessed
December, 2019.
21. White IR, Barrett JK, Jackson D,
Higgins JP. Consistency and
inconsistency in network meta-
analysis model estimation using
multivariate meta-regression. Res Syn
Meth. 2012;3:111e125.
22. Li DD, Wang TS, Shen S, et al. Effects
of fluroquinolones in newly
diagnosed, sputum-positive
tuberculosis therapy: a systematic
review and network meta-analysis.
PLoS One. 2015:10.
23. Keus F, Wetterslev J, Gluud C,
Gooszen HG, van Laarhoven CJ.
Robustness assessments are needed to
reduce bias in meta-analyses that
include zero-event randomized trials.
Am J Gastroenterol. 2009;104:546e551.
24. DerSimonian R, Laird N. Meta-analysis
in clinical trials revisited. Contemp Clin
Trials. 2015;45:139e145.
25. Buti J, Glenny AM, Worthington HV,
Nieri M, Baccini M. Network meta-
analysis of randomised controlled
trials: direct and indirect treatment
comparisons. Eur J Oral Implantol.
2011;4:55e62.
26. Trinquart L, Chatellier G, Ravaud P.
Adjustment for reporting bias in
network meta-analysis of
antidepressant trials. BMC Med Res
Methodol. 2012;12:150.
27. Ge HM, Shen CS, Yan YZ, Cheng YD,
Ding CG, Zu XX. Prophylaxis of stress
ulcer with omeprazole (OME) after
cardiopulmonary bypass (CPB).
J Changzhi Med Coll. 2003;17:114
e115 [in Chinese].
28. Zhou CZ. To observe the curative
effect of omeprazole in preventing of
postoperative stress ulcer of acute
abdomen. Chin Community Doctors.
2014;30:53e55 [in Chinese].
29. Mai WL, Huang J, Chen ZS, Mo BH,
Zhang MS, Tang B. Clinical
Observation of Losec Injection in
Preventing Stress Ulcer in Craniocerebral
Surgery. China Medical Herald; 2010:
64e66 [in Chinese].
30. Wu Y, Cong-pin W. Efficacy
comparison of pantoprazole and
famotidine in prevention of stress
ulcer after hepatobiliary surgery. Clin J
Clin Rational Drug Use. 2013;6:23e24
[in Chinese].
31. Ren XS, Chen Y-f. Pantoproprazole
for prevention of post-traumatic
stress ulcer. World Chin J Digestol.
2015;23:1145e1148 [in Chinese].
32. Dan R, Qinbin Z, Yan W, Yuanqin H,
Nengzhen L, Xufa C. Clinical
observation on prevention of stress
ulcer with esomeprazole in cardio-
pulmonary bypass heart surgery.
J Cardiovasc Pulm Dis. 2011;30:17e19
[in Chinese].
33. Hu YP, Chen MJ. Clinical study of
omeprazole and ranitidine in
preventing stress ulcer hemorrhage
after operation for hypertensive
patients complicated with cerebral
hemorrhage. J New Med. 2001:598
e599 [in Chinese].
34. Chen ZX, Li GE. Efficacy and safety of
Ovega in preventing stress ulcer after
acute abdominal surgery. Health Care
Today. 2017;10:93e94 [in Chinese].
35. Chan KH, Lai EC, Tuen H, et al.
Prospective double-blind placebo-
controlled randomized trial on the
use of ranitidine in preventing
postoperative gastroduodenal
complications in high-risk
Volume xxx Number xxx

neurosurgical patients. J Neurosurg.
1995;82:413e417.
36. Kaushal S, Midha V, Sood A,
Chopra SC, Gupta C. A comparative
study of the effects of famotidine and
sucralfate in prevention of upper
gastro-intestinal bleeding in patients
of head injury. Indian J Pharmacol.
2000;32:246e249.
37. Misra UK, Kalita J, Pandey S,
Mandal SK, Srivastava M.
A randomized placebo controlled
trial of ranitidine versus sucralfate in
patients with spontaneous
intracerebral hemorrhage for
prevention of gastric hemorrhage.
J Neurol Sci. 2005;239:5e10.
38. Grau JM, Casademont J, Fernandez-
Sola J, Cardellach F, Urbano-
Marquez A. Prophylaxis of
gastrointestinal tract bleeding in
patients admitted to a general
hospital ward. Scand J Gastroenterol.
1993;28:244e248.
39. Estruch R, Pedrol E, Castells A,
Masanmorrhrdellach F, Urbano-
Marquez A. Prophylaxis o of
gastrointestinal tract bleeding with
magaldrate in patients admitted to a
general hospital ward. Scand J
Gastroenterol. 1991;26:819e826.
40. Parente F, Cucino C, Gallus S, et al.
Hospital use of acid-suppressive
medications and its fall-out on
prescribing in general practice: a 1-
month survey. Aliment Pharmacol Ther.
2003;17:1503e1506.
41. Nardino RJ, Vender RJ, Herbert PN.
Overuse of acid suppressive therapy
in hospitalized patients. Am J
Gastroenterol. 2000;95:3118e3122.
42. Cook DJ, Witt LG, Cook RJ,
Guyatt GH. Stress ulcer prophylaxis
in the critically ill: a meta-analysis.
Am J Med. 1991;91:519e527.
43. Lin Cc, Hsu YL, Chung CS, Lee TH.
Stress ulcer prophylaxis in patients
being weaned from the ventilator in a
respiratory care center: a randomized
▪▪▪ xxxx
control trial. J Formos Med Assoc.
2016;115:19e24.
44. Tryba M, Zevounou F, Torok M,
Zenz M. Prevention of acute stress
bleeding with sucralfate, antacids, or
cimetidine. A controlled study with
pirenzepine as a basic medication.
Am J Med. 1985;79:55e61.
45. Burgess P, Larson GM, Davidson P,
Brown J, Metz CA. Effect of ranitidine
on intragastric pH and stress-related
upper gastrointestinal bleeding in
patients with severe head injury. Dig
Dis Sci. 1995;40:645e650.
46. Liu BL, Li B, Zhang X, et al.
A randomized controlled study
comparing omeprazole and
cimetidine for the prophylaxis of
stress-related upper gastrointestinal
bleeding in patients with
intracerebral hemorrhage. J Neurosurg.
2013;118:115e120.
47. Peura DA, Johnson LF. Cimetidine for
prevention and treatment of
gastroduodenal mucosal lesions in
patients in an intensive care unit. Ann
Intern Med. 1985;103:173e177.
48. Triyba M, Cook D. Current guidelines
on stress ulcer prophylaxis. Drugs.
1997;54:581e596.
49. Welage LS. Overview of
pharmacologic agents for acid
suppression in critically ill patients.
Am J Health Syst Pharm. 2005;62:S4
eS10.
50. Savarino V, Di Mario F,
Scarpignato C. Proton pump
inhibitors in GORDan overview of
their pharmacology, efficacy and
safety. Pharmacol Res. 2009;59:135
e153.
51. Farsaei S, Ghorbani S, Adibi P.
Variables associated with adherence
to stress ulcer prophylaxis in patients
admitted to the general hospital
wards: a prospective study. Adv
Pharm Bull. 2017;7:73e80.
52. Wei J, Jiang R, Li L, et al. Stress-
related upper gastrointestinal
Address correspondence to: Aiping Wen, Department of Pharmacy, Beijing
Friendship Hospital, Capital Medical University, 95 Yongan Road,
Xicheng District, Beijing, 100050, China. E-mail: wenaiping@126.com
Y. Liu et al.
bleeding in adult neurocritical care
patients: a Chinese multicenter,
retrospective study. Curr Med Res
Opin. 2019;35:181e187.
53. Qadeer MA, Richter JE, Brotman DJ.
Hospital-acquired gastrointestinal
bleeding outside the critical care unit:
risk factors, role of acid suppression,
and endoscopy findings. J Hosp Med.
2006;1:13e20.
54. ASHP therapeutic guidelines on
stress ulcer prophylaxis. Am J Health
Syst Pharm. 1999;56:347e379.
55. Dial S, Delaney JA, Barkun AN,
Suissa S. Use of gastric acid-
suppressive agents and the risk of
community-acquired Clostridium
difficile-associated disease. JAMA.
2005;294:2989e2995.
56. Sasabuchi Y, Matsui H, Lefor AK,
Fushimi K, Yasunaga H. Risks and
benefits of stress ulcer prophylaxis for
patients with severe sepsis. Crit Care
Med. 2016;44:e464ee469.
57. Buendgens L, Koch A, Tacke F.
Prevention of stress-related ulcer
bleeding at the intensive care unit:
risks and benefits of stress ulcer
prophylaxis. World J Crit Care Med.
2016;5:57e64.
58. Klatte DCF, Gasparini A, Xu H, et al.
Association between proton pump
inhibitor use and risk of progression
of chronic kidney disease.
Gastroenterology. 2017;153:702e710.
59. Salman H, Ambrish S, Anwar H,
Abul KN. Proton pump inhibitors use
and risk of chronic kidney disease:
evidence-based meta-analysis of
observational studies. Clin Epidemiol
Glob Health. 2019;7:46e52.
60. Barletta JF, Bruno JJ, Buckley MS,
Cook DJ. Concise definitive review:
stress ulcer prophylaxis. Crit Care
Med. 2016;44:1395e1405.
61. Lucas CE, Sugawa C, Riddle J, et al.
Natural history and surgical dilemma
of “stress” gastric bleeding. Arch Surg.
1971;102:266e273.
11
Clinical Therapeutics

APPENDIX

Figure S1. Network forest plot of on SU bleeding. (A) different acid-suppressive medications on SU bleeding;
(B) different PPIs on SU bleeding. PLA ¼ placebo; GMP ¼ gastric mucosa protectant;
H2RA ¼ histamine-2 receptor antagonists; PPI ¼ proton pump inhibitors. PAN ¼ pantoprazole;
OME ¼ omeprazole; ESO ¼ esomeprazole; LAN ¼ lansoprazole. CI, confidence interval; PrI, pre-
diction interval.

Figure S2. Contribution figure of direct and indirect evidence to the networks of treatments. A: Category effects
of acid-suppressive medications on SUB. B: Category effects of different PPIs on SUB;
PLA ¼ placebo; GMP ¼ gastric mucosa protectant; H2RA ¼ histamine-2 receptor antagonists;
PPI ¼ proton pump inhibitors; PAN ¼ pantoprazole; OME ¼ omeprazole; ESO ¼ esomeprazole;
LAN ¼ lansoprazole.

11.e1 Volume xxx Number xxx

 Y. Liu et al.

Figure S3. Funnel plots of articles included for different acid-suppressive medications on SU bleeding.
PLA ¼ placebo; GMP ¼ gastric mucosa protectant; H2RA ¼ histamine-2 receptor antagonists;
PPI ¼ proton pump inhibitors.

▪▪▪ xxxx 11.e2

Clinical Therapeutics

Figure S4. Pairwise meta-analysis results of acid suppressive medicines on SU bleeding. PLA ¼ placebo;
GMP ¼ gastric mucosa protectant; H2RA ¼ histamine-2 receptor antagonists; PPI ¼ proton pump
inhibitors. A: GMP vs H2RA; B: GMP vs PLA; C: H2RA vs PLA; D: PPI vs H2RA; E: PPI vs PLA.

11.e3 Volume xxx Number xxx

 Y. Liu et al.

Table S1. Electronic search strategies (search data: July 10, 2019)

Cochrane search-536 citations:

#1 “stress ulcer”:ti,ab
#2 “stress ulcer bleeding”:ti,ab
#3 “acute gastric mucosal lesion”:ti,ab
#4 “curling ulcer”:ti,ab
#5 “cushing ulcer”:ti,ab
#6 stress mucosal disease:ti,ab
#7 stress gastro* bleeding:ti,ab
#8 stress ulcerat*:ti,ab
#9 *operat* adj10 gastro*:ti,ab
#10 hospital acquired gastro* bleed*:ti,ab
#11 nosocomial gastro* bleed*:ti,ab
#12 #1 or #2 or #3 or #4 or #5 or #6 or #7 or #8 or #9 or #10 or #11
#13 animals.sh. not (humans.sh. and animals.sh.)
#14 #12 not #13
limited to trials

ClinicalTrials.gov search-0 citations

(stress ulcer) OR (acute gastric mucosal lesion) or (curling ulcer) or (cushing ulcer)

Ovid-Medline and Embase search-473 citations

1 stress ulcer.ti,ab.
2 stress ulcer bleeding.ti,ab.
3 acute gastric mucosal lesion.ti,ab.
4 curling ulcer.ti,ab.
5 cushing ulcer.ti,ab.
6 (stress adj10 mucosal disease).ti,ab.
7 (stress adj15 gastro* bleeding).ti,ab.
8 (stress adj10 ulcerat*).ti,ab.
9 (?operat? adj20 gastro*).ti,ab.
10 (Hospital adj5 acquired gastro* bleed*).ti,ab.
11 Nosocomial Gastro* bleed*.ti,ab.
12 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11
13 random*.ti,ab.
14 (RCT or RCTs).ti,ab.
15 Randomized Controlled Trial.pt.
16 15 or 16 or 17
17 14 and 16

CNKI search-1161 citations

1 stress ulcer.ti,ab.
2 stress mucosal disease.ti,ab.
3 acute gastric mucosal lesion.ti,ab.
4 curling ulcer.ti,ab.
(continued on next page)

▪▪▪ xxxx 11.e4

Clinical Therapeutics

Table S1. (Continued )

Cochrane search-536 citations:

5 cushing ulcer.ti,ab.
6 stress ulcer bleeding.ti,ab.
7 stress ulcer bleeding.ti,ab.
8 (?operat? ulcer).ti,ab.
9 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8
10 random*.ti,ab.
11 (RCT or RCTs).ti,ab.
12 Randomized Controlled Trial.pt.
13 9 and 11

ChianInfo search-675

1 stress ulcer.ti,ab.
2 stress mucosal disease.ti,ab.
3 acute gastric mucosal lesion.ti,ab.
4 curling ulcer.ti,ab.
5 cushing ulcer.ti,ab.
6 gastric mucosa disease.ti,ab.
8 stress ulcer bleeding.ti,ab.
9 (?operat? ulcer).ti,ab.
10 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9
11 random*.ti,ab.
12 (RCT or RCTs).ti,ab.
13 Randomized Controlled Trial.pt.
14 10 and 12

Table S2. Risk factor and definition of bleeding of induced studies.

Author Ref. Risk factors Definition of bleeding

MH Ge, 2003 27 cardiopulmonary bypass melena or brown discolouration of

the gastric juice
CZ Zhou, 2014 28 Appendicitis, acute biliary infection, melena, frank hematemesis, or brown
strangulation intestinal obstruction, discolouration of the gastric juice
perforation of abdominal viscera,
traumatic rupture of liver and spleen
WL Mai, 2010 29 surgery duration >4 h positive fecal occult blood, melena,
brown gastric juice, frank
hematemesis, or requiring blood
transfusion
Y Wu, 2013 30 Hepatobiliary, duodenal or pancreatic positive gastric juice occult blood,
surgery positive fecal occult blood, melena,
or brown/red gastric juice

11.e5 Volume xxx Number xxx

 Y. Liu et al.

Table S2. (Continued )

Author Ref. Risk factors Definition of bleeding

CS Ren, 2015 31 brain trauma, multiple traumatic
fractures
CH Pang, 2008 16 prostate surgery, intrahepatic bile duct
stone reoperation, semi-hepatectomy,
radical cystectomy for bladder cancer,
and portal hypertension surgery
D Ran, 2013 32 cardiopulmonary bypass
MM Zheng, 2014 17 otorhinolaryngologic surgery
YQ Huang, 2013 18 cardiopulmonary bypass
H Wang, 2016 19 >65 years, combined with shock or
persistent hypotension, mechanical
ventilation >3 days, sepsis, use of
immunosuppressive agents, severe
jaundice, or parenteral nutrition
YP Hu, 2001 33 cerebral hemorrhage surgery
XZ Chen, 2017 34 acute abdominal surgery
Kaushal S, 2000 36 head injury in 24 h, GCS<10,
nasogastric intubation
Chan KH, 1995 35 preoperative coma, inappropriate
secretion of antidiuretic hormone,
complications requiring
reoperation, >60yrs, pyogenic central
nervous system infection
brown/red gastric juice, melena,
positive vomitus occult blood,
positive fecal occult blood, or
positive gastric juice occult blood
brown/red discolouration of the
gastric juice, positive gastric juice
occult blood, melena, or positive
fecal occult blood
frank hematemesis, melena, positive
fecal occult blood, or requiring
blood transfusion
coffee-ground/fresh-blood aspirate
from the nasogastric tube in 12 h,
strong positive gastric juice occult
blood for 3 times, melena, or strong
positive fecal occult blood
frank hematemesis, positive fecal
occult blood, melena, or requiring
blood transfusion
hematochezia, positive aspirate occult
blood, positive vomitus occult
blood, instability hemodynamic, or
hemoglobin decreased significantly
strong positive fecal/gastric juice
occult blood, melena, brown
discolouration of the gastric juice
strong positive fecal/vomitus gastric
juice occult blood, positive fecal
occult blood, visible blood in fecal/
vomitus, instability hemodynamic,
or hemoglobin decreased
significantly
instability hemodynamic, or
hemoglobin decreased significantly
coffee-ground and/or fresh-blood
aspirate from the nasogastric tube,
melena, hemorrhage, requiring
blood transfusion and/or surgery to
stop bleeding
(continued on next page)

▪▪▪ xxxx 11.e6

Clinical Therapeutics

Table S2. (Continued )

Author Ref. Risk factors Definition of bleeding

Misra UK, 2005 37 spontaneous intracerebral hemorrhage gross blood, coffee ground aspirate
from nasogastric tube, hematemesis
or malena
GRAU JM, 1993 38 respiratory failure (basal PO2, lower frank hematemesis or melena or when
than 60 mmHg at admission), heart a uniformly darkeblue reaction
failure (requiring inotropic treatment), with the hemoccult test on two
sepsis, thrombotic or hemorrhagic consecutive stool readings was
stroke, liver failure (encephalopathy or observed
jaundice), renal insufficiency (serum
creatinine above 350 mmol/L), or
treatment with corticosteroids (more
than 250 mg of prednisone/day),
heparin (1 mg/kg body weight14 h) or
coumarin; simplified Apache index
(SAPS) with a maximum score of 56.
Estruch R, 1991 39 respiratory failure (basal PO2, lower frank hematemesis or melena or
than 60 mmHg at admission), heart uniformly darkeblue reaction with
failure (requiring inotropic treatment), the hemoccult test on two
sepsis, thrombotic or hemorrhagic consecutive stool readings,
stroke, liver failure (encephalopathy or nasogastric aspirates demonstrated
jaundice), renal insufficiency (serum gastric hemorrhage
creatinine above 350 pmoL/l), or
treatment
with corticosteroids (more than 250 mg
of prednisone a day), heparin (1 mg/
kg body weight/4 h), or warfarin

11.e7 Volume xxx Number xxx

 Y. Liu et al.

Table S3. Results of the surface under the cu- Table S5. Acronyms table list.
mulative ranking curve (SUCRA) and
mean rank. Mean ranking indicates acronyms table list
the probability to be the most efficient ICU intensive care unit
SUP agent, the second efficient SUP
Non-ICU non-intensive care unit
agent, and so on, among the different
SU stress ulcer
interventions under evaluation.
OR odds ratio
SUCRA Mean Rank CI confidence interval
RCT randomized control trial
A: Category effects of SUP agents on SUB
PPI proton pump inhibitor
PLA 0 4
H2RA H2-receptor antagonist
GMP 51.5 2
GMP gastric mucosa protectant
H2RA 48.6 3
PLA placebo
PPI 99.9 1
SUCRA cumulative ranking curve
B: Category effects of different PPIs on SUB
PrIs predictive intervals
PAN 38.4 3
ADE adverse drug event
OME 60.9 2
ESO 72.6 1
LAN 28.2 4

PLA ¼ placebo; GMP ¼ gastric mucosa protectant;

H2RA ¼ histamine-2 receptor antagonists;
PPI ¼ proton pump inhibitors; PAN ¼ pantoprazole;
OME ¼ omeprazole; ESO ¼ esomeprazole;
LAN ¼ lansoprazole.

Table S4. Assessment of loop inconsistency in networks. 95% Cl across zero indicated no inconsistency.

Loop Inconsistency factor p-value 95% confidence interval Loop heterogeneity t2

A: Category effects of SUP agents on SUB

GMP-H2RA-PLA 0.309 0.670 0.00,1.73 0.000
PPI-H2RA-PLA 0.284 0.653 0.00,1.52 0.000
B: Category effects of different PPIs on SUB
PAN-OME-LAN 3.466 0.037 0.20, 6.73 0.000
PAN-OME-ESO 0.835 0.698 0.00, 5.05 0.000

PLA ¼ placebo; GMP ¼ gastric mucosa protectant; H2RA ¼ histamine-2 receptor antagonists; PPI ¼ proton pump inhibitors;
PAN ¼ pantoprazole; OME ¼ omeprazole; ESO ¼ esomeprazole; LAN ¼ lansoprazole.

▪▪▪ xxxx 11.e8