TUGAS UJIAN

GUIDELINE HEMATEMESIS

DISUSUN OLEH:

INTAN ARDYLA MAHARDIKA G991903024

PENGUJI :
dr. COANA SUKMAGAUTAMA, Sp.PD, M.Kes

KEPANITERAAN KLINIK/ PROGRAM STUDI PROFESI DOKTER

BAGIAN ILMU PENYAKIT DALAM
FAKULTAS KEDOKTERAN UNIVERSITAS SEBELAS MARET/
RUMAH SAKIT UNIVERSITAS SEBELAS MARET
SURAKARTA
2020

For numbered affiliations see
end of article.
Correspondence to
Professor Joseph JY Sung,
Institute of Digestive Disease,
Prince of Wales Hospital, the
Chinese University of Hong
Kong, Hong Kong, China; ​
jjysung@​cuhk.​edu.h​ k
Received 14 February 2018
Revised 28 March 2018
Accepted 29 March 2018
To cite: Sung JJY, Chiu PWY,
Chan FKL, et al. Gut
2018;67:1757–1768.
Asia-Pacific working group consensus on non-variceal
upper gastrointestinal bleeding: an update 2018
Joseph JY Sung,1 Philip WY Chiu,1 Francis K L Chan,1 James YW Lau,1 Khean-lee Goh,2
Lawrence HY Ho,3 Hwoon-young Jung,4 Jose D Sollano,5 Takuji Gotoda,6
Nageshwar Reddy,7 Rajvinder Singh,8 Kentaro Sugano,9 Kai-chun Wu,10
Chun-Yin Wu,11 David J Bjorkman,12 Dennis M Jensen,13 Ernst J Kuipers,14
Angel Lanas15
Abstract
Non-variceal upper gastrointestinal bleeding remains an
important emergency condition, leading to significant
morbidity and mortality. As endoscopic therapy is
the ’gold standard’ of management, treatment of
these patients can be considered in three stages: pre-
endoscopic treatment, endoscopic haemostasis and post-
endoscopic management. Since publication of the Asia-
Pacific consensus on non-variceal upper gastrointestinal
bleeding (NVUGIB) 7 years ago, there have been
significant advancements in the clinical management of
patients in all three stages. These include pre-endoscopy
risk stratification scores, blood and platelet transfusion,
use of proton pump inhibitors; during endoscopy new
haemostasis techniques (haemostatic powder spray and
over-the-scope clips); and post-endoscopy management
by second-look endoscopy and medication strategies.
Emerging techniques, including capsule endoscopy
and Doppler endoscopic probe in assessing adequacy
of endoscopic therapy, and the pre-emptive use of
angiographic embolisation, are attracting new attention.
An emerging problem is the increasing use of dual
antiplatelet agents and direct oral anticoagulants in
patients with cardiac and cerebrovascular diseases.
Guidelines on the discontinuation and then resumption
of these agents in patients presenting with NVUGIB
are very much needed. The Asia-Pacific Working Group
examined recent evidence and recommends practical
management guidelines in this updated consensus
statement.
Background
Important advances in the management of non-var-
iceal upper gastrointestinal bleeding (NVUGIB)
have been made. The concept of pre-endoscopic
treatment has changed. New devices in endoscopic
haemostasis have been introduced. The increasing
use of antiplatelets and anticoagulants has compli-
cated the picture. Endoscopic interventions, such as
mucosectomy and endoscopic submucosal dissec-
tion, have become standard care. These procedures
are associated with marked risks of bleeding. For
these reasons, the Asia-Pacific Working Group felt
that it was necessary to update their consensus
recommendations for the management of NVUGIB.
Similar to the previous Asia-Pacific consensus
statements published in 2011,1 this update aims
to produce management guidelines for clinicians
Sung JJY, et al. Gut 2018;67:1757–1768. doi:10.1136/gutjnl-2018-316276
Guidelines
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practising in community or referral hospitals. The
Asia-Pacific Working Group decided that there
was no need to repeat guideline statements previ-
ously recommended unless there was a change of
view, but only to highlight recommendations based
on new evidence reported in the past 5–10 years.
Therefore, the 2011 consensus recommendations
that are not dealt with in this update are considered
to be still valid for the management of NVUGIB.
The working group continued to use the same
modified Delphi process as before1 but chose to
divide the updated consensus into three sections:
(1) pre-endoscopic management, (2) endoscopic
management and (3) post-endoscopic management
of NVUGIB.
Methods
The Asia-Pacific Working Group of upper gastro-
intestinal bleeding comprises key opinion leaders
in the region/countries of Asia and Australasia—
namely, Australia, China, Hong Kong, India,
Japan, Korea, Malaysia, Philippines, Singapore and
Taiwan. We also invited international experts from
Europe and North America to share new scientific
data and discuss the consensus statements. The
group met during the Asia-Pacific Digestive Week
2017 in Hong Kong.
Literature search include Medline, EMBASE,
the Cochrane Central Register of Controlled Trials
and ISI Web of Knowledge with manual searches
of bibliographies of key articles and abstracts of
major gastroenterology conferences held in the past
5 years, 2012–2017 (Asian Pacific Digestive Week
(APDW), Digestive Disease Week (DDW), United
European Gastroenterology Week (UEGW)). Key
words used included gastrointestinal bleeding,
peptic ulcer disease and Asia.
The working group members from the 10 coun-
tries and regions mentioned above were selected
from the scientific committee of the APDW 2017
for their expertise in areas of NVUGIB, evidence-
based medicine and continuing medical education.
The preparation committee in this working group
comprised JJYS, PCYC, FKLC and JYWL, who
drafted the initial statements based on the literature.
A modified Delphi process was used, and these
drafted statements were sent to all group members
for voting before the meeting, together with
evidence-based reviews and other pertinent
   1757
 Guidelines
literature. Each statement was assessed on a five-point Likert
scale: (1) accept completely, (2) accept with some reservation,
(3) accept with major reservation, (4) reject with reservation,
(5) reject completely. Results and comments were collated by
emails. A statement was accepted when supported by ≥80% of
the working group (ie, proportion of the working group voting
on the 5-point scale for 1 or 2). Statements that did not reach
consensus support during the first-round voting were modified.
These modified statements were discussed during the meeting
in Hong Kong, followed by a second round of voting with elec-
tronic keypads. Participants voted anonymously on statements
after discussion and provided comments on the wording of the
statements, which were progressively finalised through two
separate iterations. If this again failed to reach consensus, the
statement was rejected.
Each statement was then assessed for level of evidence by the
following criteria: (a) high level of evidence; further research
is very unlikely to change our confidence in the estimate of
effect, (b) moderate level of evidence; further research is likely
to have an important impact on our confidence in the estimate
of effect and may change the recommendation and (c) low level
of evidence; 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.
The conference was supported by an unrestrictive grant from
the GI Research Fund of the Institute of Digestive Disease of
the Chinese University of Hong Kong. Industry support was
not provided to avoid potential influence on the process of
consensus development. Mandatory written disclosure of finan-
cial conflicts of interest within 24 months before the meeting
was obtained from all voting participants.
In this updated consensus meeting, it was decided that the
statements should focus on guiding clinical management of
NVUGIB rather than on clarifying clinical concepts. There
should be minimal overlap or repetition between this updated
statement and the previous Asia-Pacific consensus on non-var-
iceal upper gastrointestinal bleeding1 unless new evidence had
arisen that might change the recommendation. The panel also
decided to report the statements that had not reached consensus
as these are also considered useful in providing guidelines for the
clinical management of such patients. Therefore, the first part of
this report consists of consensus statements categorised under (1)
pre-endoscopic management, (2) endoscopic management, (3)
post-endoscopic management. The second part consists of state-
ments that were rejected after deliberations and debate among
panel members. These latter statements point towards new
management concepts or strategies, but they are not accepted as
recommendations because of insufficient evidence in the existing
literature.
Consensus statements
Pre-endoscopic management
Statement 1: The Glasgow Blatchford Score (GBS) should be used
in predicting clinical outcome of all patients presenting with upper
gastrointestinal bleeding (Accept—agreement: 94.5%, level of
evidence: high)
The most widely validated scoring methods for prediction of
recurrent bleeding and mortality are the Rockall (RS), GBS and
AIMS65. Many studies in the past 5 years have compared the
performance of various scoring systems as a risk stratification
tool.
The largest study is a multicentre prospective cohort that
recruited over 3000 patients with UGIB from six hospitals in
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Europe, North America, Asia and Oceania. It compared the
pre-endoscopy (admission RS, AIMS65 and GBS) and post-en-
doscopy scores (full RS, and Progetto Nazionale Emorragia
Digestiva (PNED)) for their ability to predict clinical outcome.
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GBS was found to be the best of these scoring systems for
predicting the need for intervention and mortality.2 GBS also
out-performed admission RS and AIMS65 in predicting the need
for endoscopic treatment. GBS  ≥7 is the best score to predict
the requirement for endoscopic treatment. 
Among these four scoring systems, GBS most accurately
predicts the need for hospital admission and mortality. In
Korea, a study recruiting 523 patients with NVUGIB concluded
that GBS predicted the requirement of blood transfusion with
highest accuracy.3 It was comparable to the full RS and AIMS65
for predicting 30-day mortality and endoscopic intervention.
A multicentre cohort study from Korea comparing GBS and
RS confirmed that GBS was useful in predicting the need for
hospital-based intervention, and RS was useful for predicting
outcome.4
A smaller-scale study from Europe comparing GBS, AIMS65
and RS in 309 patients presenting with UGIB reported that GBS
was the best for predicting the need for transfusion, identical
to AIMS65 in predicting endoscopic intervention, and compa-
rable to AIMS65 and RS in predicting inpatient mortality.5
In Denmark, 831 patients with UGIB were enrolled to
compare the accuracy of GBS, the age-extended GBS, the Baylor
Bleeding Score and the Cedars-Sinai Medical Centre Predictive
Index using the outcome of (1) need for hospital-based inter-
vention or 30-day mortality, (2) likelihood of rebleeding and (3)
mortality.6 GBS accurately identified patients most likely to need
a hospital-based intervention, but none of these scores accu-
rately predicted mortality or rebleeding.
Two studies from Australia were reported. From Victoria, a
study comparing AIMS65, GBS and RS in 424 patients confirmed
that the three scores were comparable in predicting a composite
outcome of rebleeding and endoscopic/radiological intervention,
and mortality.7 GBS was the best for predicting blood transfu-
sion. The AIMS65 score was better than both the GBS (area
under the receiver operating characteristic curve (AUROC), 0.80
vs 0.76, P<0.027) and the pre-endoscopy RS (AUROC 0.74,
P=0.001) and equivalent to the full RS (AUROC 0.78, P=0.18)
in predicting inpatient mortality. The AIMS65 score was better
than all other scores in predicting the need for intensive care
unit (ICU) admission and length of hospital stay. In Adelaide,
comparing just GBS and RS, investigators confirmed that GBS
was superior in predicting blood transfusion and surgery, and
was equivalent to RS in predicting the need for endoscopic
therapy, rebleeding and death.8
A study from Thailand recruiting close to 1000 patients with
UGIB compared GBS, full RS and pre-endoscopic RS and found
that these scores were better in NVUGIB than variceal UGIB.9
In Iran, 200 patients were recruited to compare the prediction
value of GBS and full RS. GBS was more accurate than full RS
for need for blood transfusion, rebleeding, ICU admission and
endoscopic intervention. RS predicted 30-day mortality better
than GBS in this study.10
A systematic review identified 16 studies evaluating pre-en-
doscopic risk scores (GBS, RS and AIMS65) on a composite
outcome including recurrent bleeding, need for intervention
and 30-day mortality.11 The review concluded that GBS has
the highest sensitivity and specificity to predict this outcome
compared with the other scores. The results of these studies were
very consistent. Most confirmed that GBS was the best score
to predict which patients require a hospital-based intervention,
Sung JJY, et al. Gut 2018;67:1757–1768. doi:10.1136/gutjnl-2018-316276

including blood transfusion, endoscopic therapy and surgery.
There is still room for improvement for GBS in predicting
recurrent bleeding and 30-day or long-term mortality. With the
large amount of clinical data providing consistent results, The
working group recommend that GBS is used for predicting clin-
ical outcome of patients with NVUGIB. Patients with a score of
0–1 rarely need any clinical intervention, and can thus be safely
discharged, with elective endoscopy at a later stage. In contrast,
a high score (say 10–12) is associated with frequent need for
intervention such as transfusion and therapeutic endoscopy. The
level of evidence was graded as high.
Statement 2: Patients with a GBS of<1can be treated as an
outpatient
(Accept-agreement: 94.5%, level of evidence: high)
Most of the studies are very consistent in showing that GBS is
the best tool to predict which patients presenting with UGIB
are likely to require a hospital-based intervention. This first
pertains to blood transfusion and also to the need for endoscopic
treatment and surgery. Several studies also point to setting the
threshold of GBS <1–3 as an indicator for patients not requiring
hospitalisation.2 4–6 9–11
The Upper Gastrointestinal Haemorrhage International
Consortium has examined the subject of threshold of GBS in
managing UGIB. In their study recruiting patients from four
countries (Scotland, England, Denmark and New Zealand), they
found that the GBS at a cut-off point of <1 and <2 identified
low-risk patients with a higher level of specificity than setting
the cut-off value of GBS at 0 (40–49% vs 22%).12 The GBS at a
cut-off value of <2 had the highest specificity to detect adverse
outcomes but missed 3% of high-risk patients. Therefore, the
authors suggested that a GBS cut-off point at <1 was most suit-
able as a guide for outpatient management.12 Some argue that
even the GBS has a relatively low specificity to predict adverse
outcomes.11 This comment is primarily based on a systematic
review. The working group believe that by adopting a GBS
cut-off point <1, most hospitals can reduce the majority of
unnecessary hospital admissions without missing high-risk
patients. It will naturally translate into a significant reduction
in costs of managing UGIB. As we have pointed out in our
previous consensus statement,1 a low risk for recurrent bleeding
is not the same as low risk for mortality. Patients whose bleeding
is controlled might still die owing to non-bleeding related causes
such as cardiac and pulmonary decompensation.13 Therefore,
the GBS score and its cut-off threshold cannot be interpreted
as a score to predict mortality. The working group agreed that
existing published data support this statement with a level of
evidence graded as high.
Statement 3: Bloodtransfusion should be restricted in the
management of upper gastrointestinal bleeding
(Accept—agreement: 100%, level of evidence: moderate)
It would seem uncontroversial to replace blood loss in UGIB
by transfusion of red blood cell and plasma to restore and
preserve tissue perfusion and blood pressure. The earliest
study that suggested that blood transfusion might be harmful
to patients with gastrointestinal haemorrhage was published
over 30 years ago. A small group of patients with severe UGIB
were randomised to receiving either a blood transfusion in
cases of a haemoglobin <8 g/dL or shock, or transfusion of at
least two units of blood regardless of haemoglobin level and
Sung JJY, et al. Gut 2018;67:1757–1768. doi:10.1136/gutjnl-2018-316276
Guidelines
haemodynamics.14 Early blood transfusion appeared to lead
to more recurrent bleeding in these patients, and the authors
suggested that this was due to reversal of hypercoagulable
response to haemorrhage thereby encouraging rebleeding and
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hence the need for surgery.
Almost three decades later, a study from Spain randomised
921 patients with severe acute UGIB to a restrictive blood
transfusion strategy (transfuse only when haemoglobin
level <7 g/dL) or a liberal transfusion strategy (transfuse
only when haemoglobin <9 g/dL).15 Significant differences
were demonstrated in the overall survival, further bleeding
and adverse events between the two groups in favour of
restrictive transfusion. The major difference, however, was
seen in the group of patients with cirrhosis and Child-Pugh
class A or B diseases.
A more recent study from the UK (TRIGGER Study) took
a cluster randomised feasibility trial approach in six hospi-
tals. A slightly different definition of restrictive transfusion
strategy (when haemoglobin  <8 g/dL) versus liberal transfu-
sion strategy (when haemoglobin <10 g/dL) was adopted.16
Comparison of centres using different transfusion strate-
gies showed that there was no significant difference in clin-
ical outcome, including mortality, thromboembolic events,
surgical or radiological intervention, therapeutic interven-
tion, length of hospital stay and serious adverse events.
In Asia, a study from Korea randomised patients to
receive  restrictive transfusion (haemoglobin  <8 g/dL) or
liberal transfusion (target haemoglobin >10 g/dL), 17 and
confirmed that restrictive transfusion was associated with
less recurrent bleeding. Pooling these four studies together,
a meta-analysis of randomised controlled trials concluded,
admitting moderate heterogeneity of studies and over 90%
of patients from two studies,15 16 that restrictive blood
transfusion conferred a lower mortality (relative risk 0.65,
95% CI 0.44 to 0.97) and lower rebleeding rate (relative
rate 0.58, 95% CI 0.40 to 0.84). 18 There was, however, no
difference in thromboembolic events associated with blood
transfusion.
A retrospective nationwide survey of 5861 hospital admis-
sions in Denmark showed that the number of units of red
blood cells is a predictor of the need for repeated endoscopy,
surgery and 30-day mortality.19 In Canada, a retrospective
cohort of 1677 patients with UGIB found that transfusion of
red blood cells within 24 hours of presentation was signifi-
cantly and independently associated with an increased risk
of recurrent bleeding.20 Another retrospective cohort from
Australia, which included 2228 patients with NVUGIB, also
reported that blood transfusion of more than four units is
associated with increased risk of further bleeding, but not
with higher mortality.21
It should be pointed out that the mechanisms explaining
why transfusion may lead to recurrent bleeding in NVUGIB
are not known. Based on existing published data, the Asia-Pa-
cific Working Group recommended a restrictive transfusion
strategy, without specifying whether the threshold should
be 7 g/dL or 8 g/dL. Clinical discretion should be exercised
when transfusion is given. In patients with active cardiovas-
cular disease, the role of transfusion needs to be individual-
ised based on assessment of blood loss and the cardiovascular
status. In patients with massive active bleeding with dropping
blood pressure, a more liberal transfusion strategy might be
necessary. There is also an expectation that more data will
allow a refinement of this recommendation. The level of
evidence was agreed to be moderate.
1759
 Guidelines
Statement 4: Platelet transfusion has no benefit for patients with
upper gastrointestinal bleeding taking antiplatelet agents
(Accept—agreement: 88.9%, level of evidence: low)
Antiplatelet agents, including aspirin and thienopyridines (eg,
clopidogrel), are increasingly used in patients with various
cardiovascular and cerebrovascular conditions as primary and
secondary prevention. As aspirin and thienopyridines cause
irreversible blockage of platelet function for the lifespan of the
platelet, approximately 8–10 days, their effects are expected to
last for days after discontinuation of this medication in patients
with acute UGIB. It is common practice to transfuse platelets
in patients with acute UGIB while receiving antiplatelet agents
despite having normal platelet count.
A case–control study compared patients with UGIB with or
without platelet transfusion irrespective of platelet counts. It
showed that platelet transfusion did not reduce bleeding but
probably increased the overall mortality.22 The use of platelet
transfusion was studied in another retrospective observational
study comparing a group of patients with UGIB in the ICU
for clinical outcome.23 There was no demonstrable differ-
ence in total hospital stay, amount of blood transfusion and
resulting haemoglobin levels between the platelet-transfused
and non-transfused group. The platelet-transfused patients,
however, were found to have had a shorter stay in the ICU. In
view of the absence of any demonstrable improvement in clin-
ical outcome, the working group did not recommend platelet
transfusion in UGIB even if patients are taking antiplatelet
agents. The working group considered the evidence for this
recommendation weak and remarked that this statement
applied only to patients with normal platelet counts.
Endoscopic management
Statement 5: Patients with haemodynamic shock and signs of upper
gastrointestinal bleeding should be offered urgent endoscopy after
resuscitation and stabilisation
(Accept—agreement: 100%, level of evidence: moderate)
The timing of endoscopy in patients with NVUGIB is a
matter of debate. The previous Asia-Pacific Working Group
consensus recommended ‘endoscopic intervention within
24 hours of onset of bleeding in patients at high risk”.1 A
systematic review concluded that endoscopy within 12 hours
did not improve clinical outcome.24 It has also been pointed
out that in patients at very high risk who are haemody-
namically unstable and in patients presenting with massive
haematemesis, endoscopy should be performed as soon as
they are stabilised with resuscitation.
Several studies examined the role of urgent endoscopy
(within 12 hours) in the management of NVUGIB. In a retro-
spective cohort of 361 patients, it was found that patients
who underwent urgent endoscopy had a greater than five-
fold increased risk of adverse outcome (death, inpatient
rebleeding, surgery or radiological intervention or repeated
endoscopic therapy). In a subgroup analysis from this study,
time to endoscopy was not significant as a predictor of worse
outcome, hence less prognostic in the high-risk patients than
in lower-risk patients.25 A nationwide cohort study included
12 601 patients with peptic ulcer disease. It suggested that
patients with haemodynamic instability or American Society of
Anesthesiology score of 3–5 had reduced in-hospital mortality
if receiving endoscopy within 6–24 hours after admission.26
However, the exact timing within 24 hours is still not clear.
1760
A nationwide survey from the UK included 4478 patients. It
showed that earlier endoscopy (<12 hours) was not associated
with a lower mortality, or need for surgery, compared with
endoscopy offered within 24 hours.27
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Two studies from Asia also examined this question. In Singa-
pore, a cohort study showed that in high-risk UGIB patients
with a GBS>12, timing of endoscopy is the most important
factor associated with all-cause in-hospital mortality.28 The
cut-off time of endoscopy that improved survival of such
patients was within 13 hours from presentation. In contrast, a
study from Hong Kong selected high-risk patients (GBS >12)
for randomisation to urgent (within 6 hours of presentation)
versus early (within 24 hours of presentation) endoscopy.
This study did not confirm the benefit of very early endos-
copy.29 With endoscopy within 6 hours, patients had more
active bleeding lesions requiring endoscopic haemostasis, but
this conferred no benefit in prevention of recurrent bleeding,
mortality, requirement of blood transfusion and duration of
hospital stay. Urgent endoscopy within 6 hours of presenta-
tion for all NVUGIB seems unnecessary. The working group
accepts that in some highly selected patients, such as those who
present with haemodynamic shock or instability, an urgent
endoscopy, say within 12 hours of admission, may benefit the
patient after initial resuscitation and stabilisation. However,
offering urgent endoscopy to all patients who present with
NVUGIB is not considered necessary. The level of evidence is
graded as moderate.
Statement 6: Endoscopic haemostatic powder spray (such as
Hemospray) is useful as a stop-gap treatment in NVUGIB
(Accept—agreement: 83.3%, level of evidence: low)
The first human study of endoscopic haemostatic power
spray in peptic ulcer disease was reported from Hong Kong.30
In a small series of 20 patients with peptic ulcer bleeding,
Hemospray stopped bleeding in 19 (95%) cases and recur-
rent bleeding occurred in 2 (10%). This initial success was
echoed by a number of case series, in which the haemo-
static spray was used either as a monotherapy, an adjunctive
therapy or as a salvage therapy.31–37 Most studies reported a
relatively high success rate (80–95%), but also a relatively
high recurrence rate of bleeding (range 10–40%). Endoscopic
haemostatic powder is easy to use and associated with few
adverse events. Haemostatic powder spray has also been used
in patients receiving oral anticoagulants and showed similar
success.38 When endoscopy is repeated on the next day, most
of the haemostatic power is washed away leaving a clean and
non-bleeding lesion for definitive treatment. Unfortunately, so
far there is no randomised controlled trial (RCT) comparing
the efficacy of haemostatic spray with any other endoscopic
modality. Only smaller series and retrospective cohort studies
are available. A RCT is eagerly awaited to confirm the efficacy
of this treatment.
The working group recommends endoscopic haemostatic
power spray as a useful treatment for temporary control of
bleeding in NVUGIB when definitive haemostasis cannot be
achieved. This includes situations such as lack of endoscopic
expertise or when despite attempts of endoscopic haemostasis,
bleeding still continues. Patients with bleeding from upper
gastrointestinal malignancy may also be benefit from haemo-
static powder spray treatment. In view of the lack of RCTs and
large-scale studies, the level of evidence was considered low.
Sung JJY, et al. Gut 2018;67:1757–1768. doi:10.1136/gutjnl-2018-316276

Statement 7: Over-the-scope-clipping devices (such as Ovesco) are
useful in treating lesions refractory to conventional endoscopic
haemostatic therapy
(Accept—agreement: 94.4%, level of evidence: moderate)
In contrast to haemostatic powder spray, the over-the-scope-clip
(OTSC), if successfully applied, appears to provide a firm and
definite control of bleeding in NVUGIB.
Made from nitinol alloy, the OTSC fits to the tip of the endo-
scope and can be deployed by tightening the thread with the
hand wheel using a mechanism similar to rubber band variceal
ligators. After being released from the applicator, the shape-
memory effect and elasticity of the alloy result in firm closure of
the clip. Compared with conventional clips, the OTSC can take
up much more tissue by grasping deeper layers of the gastroin-
testinal wall, and hence the device can be used to treat bleeding
and bowel perforation.
Several case series reported promising results of successful
haemostasis in the range of 70–100%.39–42 Recurrent bleeding
within 7 days occurred in 5–33%. This device, however, is tech-
nically slightly more demanding than other through-the-scope
haemostatic treatments. Deployment of the OTSC requires
accurate positioning and adequate retraction of tissue (either by
suction or retractor) into the cap of the OTSC before the clip can
be released properly. The retractor or anchor device is used in
hard fibrotic ulcers, especially those located in difficult positions
such as the high lesser curvature of the stomach. It punctures the
base of the lesion and allows tissue to be pulled into the cap. At
certain locations in the stomach (eg, proximal lesser curve of the
stomach) and duodenum (junction of the first and second part of
the duodenum), this can be technically challenging.
A multicentre randomised control trial comparing through-
the-scope clips (TTSC) with OTSC has recently been reported,43
In that study, 32 patients received TTSC and 33 received
OTSC. Initial haemostasis was reported in 62.5% of those who
received TTSC and 96.8% received OTSC (P=0.002). Recur-
rent bleeding within 7 days after treatment occurred at the same
rate in both groups (33.3% vs 24.4%). The interim results of this
study suggested that OTSC is a better haemostatic device than
haemoclips in the treatment of peptic ulcer bleeding. In view of
the promising interim results while waiting for a full report, the
working group recommends the use of OTSC in treating lesions
refractory to conventional endoscopic therapy, such as through-
the-scope haemoclips, thermal device or endoscopic injection.
There may be a role for OTSC in primary therapy, especially
in peptic ulcer bleeding with large vessels. This device will add
to the armamentarium for NVUGIB, with the level of evidence
graded as moderate.
Statement 8: Endoscopic treatment of delayed bleeding after
endoscopic mucosal resection or endoscopic submucosal dissection
is similar to that for bleeding peptic ulcers
(Accept—agreement: 89%, level of evidence: moderate)
As endoscopic mucosectomy (EMS) and endoscopic submu-
cosal dissection (ESD) are gaining popularity among tertiary
centres worldwide, complications such as delayed bleeding
require more guideline from experts. A meta-analysis which
pooled data from over 70 studies (15 RCTs, three prospec-
tive trials, five prospective cohort studies, and 48 retrospec-
tive cohort and case–control studies) depicted clearly the
risks associated with EMS and ESD.44 Post-ESD bleeding
occurred in 5.1% (95%  CI 4.5% to 5.7%) of patients. Risk
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Guidelines
factors identified included male gender, cardiac disease, the
use of antithrombotic agents, chronic liver or kidney disease,
tumour size >2 cm or resected specimen size >3 cm, lesions
on the lesser curve, flat or depressed lesion and invasive carci-
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noma. Procedure time was not a clear risk factor for post-ESD
bleeding but the need for endoscopic haemostasis was a factor.
Experienced practitioners of ESD stated that the management
of post-ESD bleeding did not differ from that for peptic ulcer
bleeding. Most post-ESD bleeding occurred within 24 hours
after the procedure. Endoscopic devices used in peptic ulcer
bleeding can also be used to treat post-ESD bleeding. Most
post-ESD bleeds come from a focal bleeding point and are
confined to mucosal and submucosal layers, without pene-
trating through the muscle layer. Hence, haemostasis in such
circumstances is relatively easy. There is no agreement on
whether proton pump inhibitors are better than histamine-2
receptor antagonists after ESD.45 46 Second-look endoscopy
has not been proved to be associated with less postproce-
dural bleeding,47 Overall, the working group concluded that
post-EMS and post-ESD bleeds can be managed like peptic
ulcer bleeds. The level of evidence was graded as moderate.
Post-endoscopic management
Statement 9: As an adjunct to endoscopic treatment, high-dose oral
proton pump inhibitors can be used to prevent rebleeding
(Accept—agreement: 88.9%, level of evidence: moderate)
The use of intravenous high-dose proton pump inhibitors
(PPIs) has become standard practice in the management of
upper gastrointestinal bleeding. At least three randomised
trials, all from South Asia, showed that oral PPIs, given with
or without endoscopic therapy, also reduce the risk of recur-
rent bleeding from peptic ulcer.48–50 New evidence suggests
that high-dose oral PPIs may have a similar effect to their
action in preventing recurrent bleeding from peptic ulcers.
A study from Hong Kong recruited 118 high-risk patients
with Forrest I or IIa/b peptic ulcer bleeding to receive
either IV esomeprazole plus oral placebo or oral esomepra-
zole (40 mg every 12 hours) plus IV PPI placebo.51 Recur-
rent bleeding within 30 days was reported in 7.7% in the
IV esomeprazole group and 6.4% in the oral esomeprazole
group. There was no difference in the requirement for blood
transfusion, repeated endoscopic therapy and hospital stay
between the two groups. It was noted that the study was
stopped prematurely and was not designed as an equivalent
trial. The trend suggests that the action of high-dose oral
PPI peptic ulcer bleeding is comparable to that of IV PPI. In
Taiwan, IV esomeprazole was compared with oral lansopra-
zole (30 mg four times a day for 3 days) in patients with peptic
ulcer bleeding.52 There was no difference in all the clinical
outcome parameters, except that those who received oral PPI
had a shorter hospital stay. In Korea, when IV omeprazole
was compared with oral rabeprazole (20 mg twice daily), the
recurrent bleeding rate, surgical intervention and mortality
between the two groups were comparable.53
There is no properly powered RCT to confirm that high-
dose oral PPI is as effective as IV PPI. The working group
accepted that high-dose oral PPI can be used to prevent recur-
rent bleeding, but emphasised that it has to be used as an
adjunct to endoscopic therapy. Only after endoscopic haemo-
stasis is achieved, can high-dose oral PPI be recommended
to prevent recurrent bleeding. The definition of high-dose
oral PPI has been stated as at least 80 mg of esomeprazole (or
1761
 Guidelines
equivalent dosage of other PPIs). The high oral dose should be
maintained for at least 3 days, which is the period of highest
risk of recurrent bleeding. If the patient’s condition remains
stable, standard dose oral PPI can be resumed afterwards. All
the reports were relatively small and underpowered, and thus
the level of evidence was graded as moderate, in the hope that
future studies might confirm this finding.
Statement 10: There is no special preference for a particular proton
pump inhibitor when used concomitantly with clopidogrel
(Accept—agreement: 94%, level of evidence: moderate)
Concern about a potential interaction between PPIs and
clopidogrel (a prodrug that requires CYP450 for metab-
olism) arose from a number of in vivo platelet aggregation
studies.54 55 Different PPIs may have unequal effects on
clopidogrel metabolism, which further intensifies the debate
about a potential interaction between PPIs and clopidogrel. It
has been suggested that PPIs such as lansoprazole, pantopra-
zole and rabeprazole have less interaction with clopidogrel
since they have fewer inhibitory effects on CYP2C19.56–59
More data suggest that concomitant use of a PPI with clopi-
dogrel increases the risk of major adverse cardiovascular
events (MACE) in patients with high cardiovascular risk.
A retrospective cohort study from China, including about
6200 patients who received aspirin plus clopidogrel with
a  PPI, reported that PPI users had a 3% increase in MACE
compared with non-users.60 Another retrospective cohort
from Italy reported an alarming 12% increase in MACE in
patients receiving a PPI in conjunction with clopidogrel.61
PPIs interact with clopidogrel in patients with coronary,
cerebrovascular and peripheral artery disease. This interac-
tion was implicated in the Factores de Riesgo y ENfermedad
Arterial (FRENA) Registry as leading to a doubling of the
incidence of myocardial infarction and ischaemic stroke.62
However, a number of studies showed otherwise. A Japa-
nese study of patients with coronary stenting receiving dual
antiplatelet agents showed no effect of PPIs on MACE or
mortality.63 The safety of prescribing a PPI with clopidogrel
was also suggested in a case–control study enrolling 23 655
patients from the Netherlands.64 Beside cardiovascular risk,
the safety profile of using a PPI concomitantly with clopido-
grel was also confirmed in group of 2765 patients who had
strokes.65
Finally, the strongest support came from the only RCT,
the Clopidogrel and the Optimisation of Gastrointestinal
Events Trial (COGENT).66 Patients receiving dual anti-
platelet therapy (aspirin and clopidogrel) were randomised
to receive omeprazole or placebo. Omeprazole significantly
reduced rates of composite gastrointestinal events from 2.7%
(without omeprazole) to 1.2% (with omeprazole). There was
no significant excess of cardiovascular events in 3759 high-
risk cardiovascular patients recruited in this study. Although
the trial was terminated prematurely, the follow-up period
was sufficient to demonstrate the rate of MACE related to
the medication. These data from COGENT, the only large-
scale RCT evaluating the effects of PPI on clinical endpoints
in patients requiring dual antiplatelet therapy, provided reas-
surance about the safety of PPIs in high-risk cardiovascular
subjects.67 Therefore, the working group recommended the
use of a PPI without preference for a particular type, in patients
requiring gastrointestinal protection against dual antiplatelet
1762
therapy. The level of evidence was considered moderate as
only one RCT has been carried out, with limitations.
Statement 11: Routine second-look endoscopy is not recommended
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for patients after gastric endoscopic submucosal dissection
(Accept—agreement: 88.9%, level of evidence: high)
Submucosal arterioles are often exposed after gastric ESD
just above the level of muscularis propria. As mentioned
above, the management of post-ESD haemorrhage is similar
to that for bleeding peptic ulcers. However, the pathology
is different as the artificial ulcers created by ESD have less
fibrosis and hence it is easier to stop bleeding using either
a thermal or mechanical device. In this situation, routine
second-look endoscopy may not be necessary.
A single-centre randomised trial comparing routine
second-look endoscopy with no second-look endoscopy
after gastric ESD in 155 patients demonstrated no differ-
ence in recurrent bleeding and need for transfusion.68 Two
prospective randomised trials including larger (>35 mm) arti-
ficial ulcers after gastric ESD also showed no difference in
outcome between those with and without second-look endos-
copy.69 70 Another large multicentre prospective randomised
trial conducted in Japan, including 262 patients, further
demonstrated that routine second-look endoscopy confers no
protection against recurrent haemorrhage.71 This result was
confirmed by a meta-analysis including four randomised trials
and four non-randomised trials. No difference in post-ESD
bleeding rate was shown by the pooled data between those
who did and did not receive second-look endoscopy.47 The
panel concurred with high agreement that based on current
evidence, routine second-look endoscopy is not recommended
for patients after gastric ESD, with a level of evidence graded
as high.
Statement 12: Among patients with high cardiothrombotic risk
receiving antiplatelet agents, these agents should be resumed as
soon as haemostasis can be established
(Accept—agreement: 100%, level of evidence: high)
Patients with NVUGIB taking antiplatelet agents face a
dilemma of discontinuing these drugs to facilitate controlling
of haemorrhage or to continue taking these drugs to avoid
thromboembolic complications. Using the UK primary care
database, a study reported the cardiovascular and UGIB conse-
quences of low-dose acetylsalicylic acid (ASA) in patients aged
50–84 years.72 Based on this dataset, the attributable risks
associated with ASA discontinuation for non-fatal myocar-
dial infarction/coronary death and ischaemic stroke were 17
and 11 per 1000 people, respectively. On the other hand, the
risk of UGIB with continued ASA was 1.6 per 1000 people.
This amounts to eight extra cardiovascular events for a reduc-
tion of 0.4 UGIB events per year.
The only RCT examining this subject was reported by the
Hong Kong group. It showed that immediate resumption of
aspirin for high-risk cardiac patients was critical as it did
not increase the risk of fatal haemorrhage but significantly
improved the 30-day survival.73 Subsequently, a retrospec-
tive analysis of 118 patients who received low-dose aspirin
with 40% of cases discontinuing the drug for 2 years showed
a sevenfold increase in risk for a cardiovascular event and
cardiac death.74 A study from Taiwan comparing 89 patients
receiving esomeprazole alone versus 89 patients receiving
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esomeprazole plus aspirin showed that the ulcer healing rate
between the groups was almost identical. There is no evidence
to suggest that aspirin would delay the healing of peptic ulcer
when treated with a PPI.75 It should be noted that these two
studies used a relative low dose of aspirin (80–100 mg daily).
Even at this dose, the cardioprotective effects of aspirin
are retained and haemorrhagic complications are not detri-
mental. Similarly, although data are lacking on non-aspirin
antiplatelet agents, the protective effects against thromboem-
bolic events in cardiovascular and cerebrovascular diseases
are considered more important than the increased risk of
gastrointestinal bleeding.
No study has investigated the optimal timing for the resump-
tion of antiplatelet agents, but one can consider resuming
these agents on day 1 if endoscopy shows a clean-based ulcer.
In patients who received endoscopic therapy for bleeding,
antiplatelet agents can be resumed 72 hours after the treat-
ment—that is, passing the period of highest risk for recur-
rent bleeding. The working group unanimously endorsed this
recommendation of resuming antiplatelet agents early when
UGIB is under control. The level of evidence of this statement
was considered as high.
Statement 13: In patients receiving dual antiplatelet agents, at
least one antiplatelet agent should be resumed in cases of upper
gastrointestinal bleeding
(Accept—agreement: 94.4%, level of evidence: low)
The most commonly used antiplatelet agents are ASA
(aspirin), a cyclo-oxygenase inhibitor and thienopyridines
that bind to P2Y12 component of the adenosine diphos-
phate receptors. After stopping ASA, 7–9 days are required
to regain full platelet function, whereas in the case of thien-
opyridines (such as clopidogrel or prasugrel), the minimum
duration to restore platelet function is 5–7 days. Use of dual
antiplatelet agents, often ASA plus a thienopyridine, may
confer a threefold increase in the risk of UGIB over single-
agent antithrombotic therapy.76 There are no data guiding the
management of these patients using dual antiplatelet therapy
when they develop UGIB. We do not recommend withholding
both antiplatelet drugs because the median time to coronary
stent thrombosis can be as short as 7 days with both drugs
withheld as compared with 122 days with only clopidogrel
withheld.77 Balancing the risk and benefit of discontinuation
of antiplatelet agents, the ASGE recommends that cessation
of all antiplatelet therapy after PCI should be avoided, and
furthermore, when only one antiplatelet agent is used, aspirin
should be continued as it is associated with a lower risk for
causing recurrent bleeding. On the other hand, for patients
with a high risk of thrombosis, such as those with drug-eluting
coronary stents, clopidogrel should not be discontinued for
more than 5 days.78
Cardiologists’ opinion should be sought for the commence-
ment of antiplatelet agents. In patients with low risk of recur-
rent bleeding from the gastrointestinal tract, antiplatelet
agents should not be discontinued at all. The working group
consider that this statement is primarily based on pharmaco-
logical characteristics of the antiplatelet agents. Clinical trials
to test the safety of this strategy are eagerly awaited. The
level of evidence was considered low.
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Guidelines
Statement 14: Among direct oral anticoagulant (DOAC) or warfarin
users with high cardiothrombotic risk who develop ulcer bleeding,
DOAC or warfarin should be resumed as soon as haemostasis is
established
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(Accept—agreement: 83.3%, level of evidence: low)
Clinical evidence is lacking to support strategies for managing
patients with NVUGIB and high cardiothrombotic risk who
receive DOAC or warfarin. For such patients with atrial fibril-
lation and/or valvular heart diseases, management should
depend on the balance between thrombotic risk and bleeding
risk. In acute NVUGIB, DOAC or warfarin should be with-
held to facilitate achievement of haemostasis.
If the patient is taking warfarin, four-factor prothrombin
complex concentrate (PCC) and vitamin K or fresh frozen
plasma can be given for life-threatening GI bleeding. Warfarin
reversal should be used for life-threatening bleeding irrespec-
tive of the international normalised ratio (INR). Current
evidence does not show any correlation between INR at
presentation and outcomes of GI bleeding.79 A combination
of PCC and vitamin K is preferred for urgent reversal of
warfarin. PCC has advantages over fresh-frozen plasma such
as faster onset of action and minimal risk of fluid overload.
Endoscopic therapy should not be delayed in patients with
serious UGIB. Warfarin and DOAC treatment should be with-
held in patients with ongoing NVUGIB.80
The Food and Drug Administration in October 2015
granted approval for idarucizumab, a potent monoclonal
antibody against dabigatran, for use in patients with uncon-
trolled bleeding. In a multicentre study of 503 patients with
uncontrolled bleeding who were about to undergo an urgent
procedure, 5 g of idarucizumab reversed the anticoagulant
effect of dabigatran within 4 hours in almost all patients.81
However, its true benefit in NVUGIB is still unclear because
of limited clinical data.
Once the bleeding is controlled, the decision to resume
anticoagulants should be made by a multidisciplinary team
with cardiologist, gastroenterologist, intensivist and, if
feasible, with patient’s participation. The CHA2DS2-VASC
and HAS-BLED score are useful in assessing the need for
continuing anticoagulation.82–84 In patients with high cardio-
vascular risk, resumption of anticoagulants should not be
delayed. A large prospective cohort study of patients with
atrial fibrillation in Denmark showed that resumption of
single anticoagulants was associated with lowest rate of
all-cause mortality85 Most data on vitamin K antagonists
show that resuming the oral anticoagulant is associated with
a lower mortality despite more frequent major bleeding.86 A
recent study suggested that dabigatran offers similar protec-
tion against thromboembolism with less rebleeding than
warfarin after major bleeding.87 The timing for resumption of
warfarin should be assessed on a patient-by-patient basis. Since
the time required for re-anticoagulation will be prolonged
after warfarin reversal with vitamin K, we recommend early
resumption of warfarin once haemostasis has been achieved,
especially in patients with high thromboembolic risk. With
DOAC, the effect should disappear in 1–2 days after stopping
the drug. Therefore, once bleeding is under control, DOAC
can be resumed earlier (within 1–2 days) bearing in mind that
anticoagulation is achieved rapidly within hours and there-
fore might increase the risk of rebleeding. If early anticoagu-
lation is indicated in patients with high thromboembolic risk,
a bridge approach with heparin or enoxaparin is useful. The
1763
 Guidelines
working group considered that this recommendation is based
primarily on expert opinion without data from RCTs, hence
the level of evidence was graded as low.
Rejected statements
Statement 1: Video capsule endoscopy can be considered as a triage
tool for patients who require early intervention
(Reject—agreement: 22.2%)
Modified: Capsule endoscopy can be considered as a triage tool for
hospitalisation
(Reject—agreement: 39%)
The first attempt to use video capsule endoscopy (VCE) in
assessment of patients with UGIB was conducted in a multi-
centre study in which patients received VCE, followed by naso-
gastric tube and then conventional endoscopy for evaluation of
UGIB.88 Blood was detected significantly more often by VCE
than by nasogastric tube aspiration. There was no difference in
identification of peptic or inflammatory lesions between VCE
and conventional endoscopy.
In view of this initial encouraging result, a prospective RCTwas
carried out. Seventy-one patients with UGIB were randomised
to receive either the standard-of-care treatment in hospital or a
VCE in the emergency room (ER). The need to admit to hospital
was determined by the findings of VCE.89 This study showed
a reduction of hospital admission in the VCE group of >70%
and with no serious adverse outcome. Comparison of the VCE
results with GBS evaluation, showed also a significant reduction
in hospital admission among the patients recruited to receive
VCE in this RCT. Based on this result, the authors considered
VCE in the ER a feasible triage tool to differentiate patients who
do or do not require hospital admission.
Comparison of VCE and GBS and RS was conducted in
another small-scale cohort study of 25 patients presenting with
UGIB.90 VCE accurately predicted high-risk endoscopic stigmata
and compared favourably with GBS and RS for risk stratifica-
tion. Training of ER physicians to interpret VCE images has
also been found to be feasible in a survey study involving 126
emergency department physicians.91 There are concerns about
the costs of VCE used in such circumstances, but a cost-effective-
ness analysis comparing VCE with other strategies for managing
UGIB showed that VCE was cost-effective for patients at low
and moderate risk presenting to the ER with UGIB.92
However, VCE may not be optimal in examination of the
duodenum. In a risk stratification study of UGIB from Australia,
authors found that because of low duodenal visualisation, there
was poor concordance between VCE and conventional endos-
copy in the findings of the bleeding source in patients with
UGIB.93
Although the initial data look promising, the Asia-Pacific
Working Group considered it premature at this stage to recom-
mend the use of VCE as a risk stratification method for UGIB or
as a triage tool to decide on hospital admission. There is so far
only one small-scale RCT supporting the use of VCE as a patient
triage tool. Besides inadequate duodenal visualisation, the possi-
bility of missing lesions in the fundus of the stomach and other
less accessible sites is a concern. The logistics of setting up VCE
in the ER, and of training personnel to interpret the video bring
further uncertainties. There were also concerns that VCE at the
ER might delay endoscopy for those who require endoscopic
intervention. The working group did not accept VCE as a triage
1764
tool and would like to await further clinical studies to prove its
value.
Statement 2: Pre-endoscopy intravenous proton pump inhibitors are
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recommended in stable patients awaiting endoscopy
(Reject—agreement: 72.2%)
Modified: Intravenous proton pump inhibitors are recommended
for patients with suspected gastrointestinal bleeding awaiting
endoscopy
(Reject—agreement: 66%)
There are now at least six RCTs, comprising 2223 patients with
UGIB being studied for the benefit of pre-endoscopy intravenous
PPIs.94–99 With PPIs, the stigmata of haemorrhage will be down-
graded and hence endoscopic therapy less frequently needed, yet
there is no reduction in recurrent bleeding, surgery and overall
mortality between PPI and control treatment. The Cochrane
review which pooled these six studies concluded that PPI treat-
ment before endoscopy might reduce the proportion of patients
requiring endoscopic therapy without affecting clinically signifi-
cant outcomes.100 It is possible that the overall costs of treatment
and the need for experienced endoscopists could be reduced;
however, the clinical impact is uncertain.
The working group noted that many physicians use intrave-
nous PPIs for patients presenting in stable conditions with symp-
toms suggestive of UGIB, while waiting for endoscopy. These are
commonly administered at the ER or at primary care clinics. This
statement pertains to patients who are ‘stable’ or ‘suspected’ of
UGIB waiting for endoscopy. The working group members voted
to reject indiscriminate use of IV PPIs in such circumstances as there
is no proven value. Indiscriminate use of IV PPIs will increase the
cost of managing NVUGIB. This statement should be read differ-
ently from the previous Asia-Pacific Working Group consensus
which stated that pre-endoscopy PPI is recommended where early
endoscopy or endoscopic expertise is not available within 24 hours.1
When endoscopy facilities or endoscopy expertise are not available
within 24 hours, downgrading stigmata of recent haemorrhage and
reducing the requirement for endoscopic intervention becomes
much more justified.
Statement 3: Angiographic embolisation should be applied in
patients with high-risk ulcers to prevent recurrent ulcer bleeding
(Reject—agreement: 38.9%)
When endoscopic haemostasis fails to control peptic ulcer bleeding,
repeated endoscopy and surgery are considered viable options to
control bleeding. There is little evidence to support the use of angio-
graphic embolisation as an alternative to surgery after endoscopic
treatment has failed except for two retrospective studies.101 102 A
Scandinavian study prospectively randomised 105 patients with
peptic ulcer bleeding to arterial embolisation after endoscopic
therapy or to standard treatment.103 The authors used a composite
endpoint which included transfusion requirement, development of
rebleeding, need for haemostatic intervention and mortality as the
primary endpoint. While there was a trend towards less rebleeding
for those who received angiography, the study reported no differ-
ence in the outcome of those who received angiography versus stan-
dard treatment.
More recently a prospective randomised trial in Hong Kong
tried to examine this by allocating patients with Forrest I/II
peptic ulcer bleeding to pre-emptive angiographic embolisation
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or standard-of-care management without embolisation.104 In the
intention-to-treat analysis, there was no demonstrable difference
between the two groups in recurrent bleeding within 30 days, need
for further endoscopic or surgical interventions, hospital stay, blood
transfusion requirement and mortality. In the per protocol analysis
of 90 patients who received angiographic embolisation compared
with 113 patients who did not, there a trend favouring angiography,
with a significant reduction in mortality. The size of ulcer (>1.5 cm)
is the best predictive parameter associated with benefit of angiog-
raphy. However, this is a single study with a marginal benefit. The
working group considered it premature to recommend angiography
to prevent recurrent bleeding from peptic ulcer after endoscopic
treatment. More evidence from future clinical trials is necessary.
Statement 4: A risk stratification score should be used to identify
high-risk bleeding ulcers after endoscopic therapy for second-look
endoscopy
(Reject—agreement: 55.6%)
Modified: A risk stratification score may be useful to identify
high-risk bleeding ulcers after endoscopic therapy for second-look
endoscopy
(Reject—agreement: 23%)
Recurrent bleeding occurs in 8–15% of patients with peptic ulcer
bleeding and is associated with a two- to fivefold increase in
mortality. The objective of routine second-look endoscopy, usually
performed within 24 hours after index endoscopy, is to pre-emp-
tively treat peptic ulcers with persistent stigmata of recent haemor-
rhage before they start bleeding again.
Second-look endoscopy was first investigated for its efficacy in
prevention of peptic ulcer rebleeding by a few prospective randomised
trials in the 1990s.105–108 The results from these randomised trials
were conflicting. Some showed that second-look endoscopy and
repeated endoscopic haemostasis were effective in preventing recur-
rent haemorrhage107 108 while others demonstrated no efficacy.105 106
The reasons for these conflicting results included recruitment of
patients with different levels of rebleeding risk, a non-standardised
method of primary haemostasis and variation in the performance of
second-look endoscopy. A meta-analysis based on eight prospective
randomised trials concluded that second-look endoscopy reduced
rebleeding in the absence of high-dose PPI especially in patients at
very high risk.109 Analysis of these pooled data also suggested that
second-look endoscopy reduced the need for surgery but had no
significant effect on mortality. However, after removing two trials
that included patients with a high risk of rebleeding, no benefit from
second-look endoscopy was found.109 110 A recent randomised trial
compared intravenous PPI infusion with second-look endoscopy in
patients after receiving endosocopic haemostasis for peptic ulcer
bleeding.110 It demonstrated no difference in recurrent bleeding,
need for surgery and mortality between the two treatment strat-
egies. Furthermore, second-look endoscopy did not appear to be
cost-effective when offered to all patients.
The question remains whether risk stratification with selection of
high-risk patients may lead to a benefit from second-look endoscopy
on the next day and with repeated treatment in case of persistent
stigmata. The Baylor Bleeding Score attempted to select high-risk
patients to receive second-look endoscopy versus controls and
found a 24% difference in rate of recurrent bleeding.111 A study
including 699 patients from Korea showed that use of a non-ste-
roidal anti-inflammatory drug, large transfusion volume and failure
to perform second-look endoscopy were risk factors for recurrent
Sung JJY, et al. Gut 2018;67:1757–1768. doi:10.1136/gutjnl-2018-316276
Guidelines
bleeding after endoscopic therapy.112 Another study from Taiwan
which enrolled 316 patients receiving a high-dose PPI after endo-
scopic therapy attempted to formulate a predictive score using
endoscopic monotherapy and serum albumin levels.113 By this
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score, the receiver operating characteristic curve to predict need
for second-look endoscopy appeared promising, but outcome data
were lacking. To date, there is still a lack of evidence to suggest
that any risk stratification method is effective in selecting patients
at high risk who would benefit from second-look endoscopy and
pre-emptive treatment.
The working group therefore rejected the statement that a risk
stratification score may be useful to identify high-risk bleeding
ulcers after endoscopic therapy for second-look endoscopy.
Future studies should be conducted to verify the use of a risk
stratification system.
Statement 5: A Doppler endoscopic probe should be used to guide
endoscopic therapy in order to ensure adequate haemostasis
(Reject—agreement: 66%)
The use of a Doppler endoscopic probe is not new. Previous studies
have shown that the technique requires skill and the results are often
irreproducible. A study from the CURE group has recently reported
that the Doppler endoscopic probe (DEP) can demonstrate major
stigmata of peptic ulcer bleeding (spurting ulcer, blood clot and
visible vessel) and had a significantly higher rate of detecting arterial
blood flow than oozing ulcer and ulcer with flat pigmented spot.69
The authors proposed that DEP can improve risk stratification in
the management of peptic ulcer bleeding. This DEP is a FDA-ap-
proved disposable probe (Vascular Technology, Nashua, New
Hampshire, USA) that can be inserted into the working channel of
the gastroscope. Subsequently, the same group compared the stan-
dard endoscopic treatment (using a thermal or mechanical device
with or without injection) with endoscopic treatment guided by
DEP.114 Endoscopic haemostasis was applied to peptic ulcers until
DEP showed no Doppler signal of residual blood flow. The results
showed that with DEP-guided therapy, recurrent bleeding can be
reduced from 26.3% to 11.1%. However, because of the small
number of patients with significant events, there was no difference
demonstrated in requirement for surgery or angiography to salvage
uncontrolled bleeding, and there was no reduction in mortality.
Although a remarkable RCT, the working group concluded that it
is too early to recommend DEP for the management of UGIB. This
is based on the argument that only a single study from a renowned
referral centre demonstrated the benefit of this skill-demanding
technique. The working group opined that more data, from other
centres recruiting more patients, are required to confirm the value
of DEP.
Conclusion
Since the last Asia-Pacific consensus on NVUGIB published 7 years
ago, significant advancement has been made in the clinical manage-
ment of patients before endoscopy (risk stratification scores, blood
and platelet transfusion, use of PPIs) and in the development of
endoscopic haemostasis (haemostatic powder spray and over-the-
scope clips). Emerging techniques, such as the use of capsule endos-
copy for patient triage, a Doppler endoscopic probe for assessing
adequacy of endoscopic therapy, and the pre-emptive use of angio-
graphic embolisation, look promising but require further evalua-
tion. The use of PPIs has been further clarified, showing that routine
use of IV PPI is unnecessary but high-dose oral PPI after endoscopy
may be beneficial. Experience in managing NVUGIB after EMR and
ESD is accumulating. An emerging problem is the increasing use of
1765
 Guidelines
double antiplatelet agents and direct oral anticoagulants in patients
with cardiac and cerebrovascular diseases, and clinical data to guide
management are still minimal. Resumption of antiplatelet agents or
anticoagulants is important but the timing and choice of drugs to
be resumed require further clinical trials for guidance.
Author affiliations
1 with upper gastrointestinal bleeding: a systematic review. Acad Emerg Med
Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong
2 2016;23:1218–27.
Department of Gastroenterology and Hepatology, University of Malaya, Kuala
Lumpur, Malaysia
3 Glasgow Blatchford score in managing patients with upper gastrointestinal bleeding.
Yong Loo Lin School of Medicine, National University of Singapore, Singapore
4 Clin Gastroenterol Hepatol 2015;13:115–21.
University of Ulsan College of Medicine, Ulsan, South Korea
5 13 Sung JJ, Tsoi KK, Ma TK, et al. Causes of mortality in patients with peptic ulcer
UST Hospital, University of Santo Tomas, Manila, Philippines
6 bleeding: a prospective cohort study of 10,428 cases. Am J Gastroenterol
Division of Gastroenterology and Hepatology, Nihon University School of Medicine,
Tokyo, Japan
7
Asian Institute of Gastroenterology, Asian Healthcare Foundation, Hyderabad, India
8
Department of Medicine, Lyell McEwin Hospital, University of Adelaide, Adelaide,
South Australia, Australia
9
Department of Medicine, Jichi Medical School, Shimotsuke, Japan
10
State Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, Xi’an,
China
11
China Medical University, Taichung, Taiwan
12
University of Utah College of Health, Salt Lake City, Utah, USA
13
University of California, Los Angeles, California, USA
14
Department of Gastroenterology and Hepatology, Erasmus University Medical
Center, Rotterdam, The Netherlands
15
Department of Gastroenterology, University Hospital, Zaragoza, Spain
Acknowledgements  Moe Kyaw, John Wong, Jessica Ching and Thomas Lam.
Contributors  Study design: JJYS; literature review: JJYS, PCYC, FKLC, JYWL, John
Wong and Moe Kyaw; draft of the manuscript: JJYS; revision of the manuscript: all
authors.
Funding  This research received no specific grant from any funding agency in the
public, commercial or not-for-profit sectors.
Competing interests  None declared.
Patient consent  Not required.
Provenance and peer review  Not commissioned; externally peer reviewed.
Open access  This is an open access article distributed in accordance with the
Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which
permits others to distribute, remix, adapt, build upon this work non-commercially,
and license their derivative works on different terms, provided the original work
is properly cited and the use is non-commercial. See: http://​creativecommons.​org/​
licenses/​by-​nc/​4.​0/
© Article author(s) (or their employer(s) unless otherwise stated in the text of the
article) 2018. All rights reserved. No commercial use is permitted unless otherwise
expressly granted.
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 STAT E O F T H E A RT R E V I E W

Management of acute upper

gastrointestinal bleeding

BMJ: first published as 10.1136/bmj.l536 on 25 March 2019. Downloaded from http://www.bmj.com/ on 3 June 2020 by guest. Protected by copyright.
Adrian J Stanley,1 Loren Laine2
1
Department of Gastroenterology,
Glasgow Royal Infirmary, Glasgow A B S T RAC T
G4 OSF, UK
2
Section of Digestive Diseases, Yale
Upper gastrointestinal bleeding (UGIB) is a common medical emergency, with a reported
School of Medicine, New Haven, mortality of 2-10%. Patients identified as being at very low risk of either needing an
and VA Connecticut Healthcare
System, West Haven, Connecticut, intervention or death can be managed as outpatients. For all other patients, intravenous
CT 06520, USA
Correspondence to: A J Stanley fluids as needed for resuscitation and red cell transfusion at a hemoglobin threshold of 70-80
adrian.stanley@ggc.scot.nhs.uk
and adrianstanley99@gmail.com
g/L are recommended. After resuscitation is initiated, proton pump inhibitors (PPIs) and the
Cite this as: BMJ 2019;364:l536 prokinetic agent erythromycin may be administered, with antibiotics and vasoactive drugs
doi: 10.1136/bmj.l536
recommended in patients who have cirrhosis. Endoscopy should be undertaken within 24
Series explanation: State of the
Art Reviews are commissioned hours, with earlier endoscopy considered after resuscitation in patients at high risk, such as
on the basis of their relevance to
academics and specialists in the US
those with hemodynamic instability. Endoscopic treatment is used for variceal bleeding (for
and internationally. For this reason example, ligation for esophageal varices and tissue glue for gastric varices) and for high risk
they are written predominantly by
US authors non-variceal bleeding (for example, injection, thermal probes, or clips for lesions with active
bleeding or non-bleeding visible vessel). Patients who require endoscopic therapy for ulcer
bleeding should receive high dose proton pump inhibitors after endoscopy, whereas those
who have variceal bleeding should continue taking antibiotics and vasoactive drugs. Recurrent
ulcer bleeding is treated with repeat endoscopic therapy, with subsequent bleeding managed
by interventional radiology or surgery. Recurrent variceal bleeding is generally treated with
transjugular intrahepatic portosystemic shunt. In patients who require antithrombotic agents,
outcomes appear to be better when these drugs are reintroduced early

Introduction summarizing evidence for risk assessment, resuscitation,

Upper gastrointestinal bleeding is a common medical
emergency worldwide and refers to bleeding from the
esophagus, stomach, or duodenum. Patients present with
hematemesis (bloody or coffee ground emesis) or melena,
although hematochezia can occur in the context of a major
bleed and is typically associated with hemodynamic insta-
bility. Patients with melena present with lower hemo-
globin values than patients with hematemesis, probably
because presentation is more likely to be delayed.1 There-
fore, patients with melena more often require transfusion,
although mortality is lower in patients with melena than
in those with hematemesis in some series.1 Numerous
improvements in the management of upper gastrointesti-
nal bleeding have been incorporated into clinical practice
in recent years. However, many patients now have risk
factors for a poorer outcome, including increasing age and
major medical comorbidities.2
Although the cause of a bleeding episode is uncertain
until endoscopy is undertaken, guidelines often separate
upper gastrointestinal bleeding into variceal and non-
variceal bleeding because management and outcomes
differ.3‑9 This article covers the acute management of
patients with overt upper gastrointestinal bleeding,
blood transfusion, medical and endoscopic therapy, and
early post-endoscopic management. We will not review
interventions for long term secondary prevention of
bleeding, such as testing for and treating Helicobacter
pylori infection, use of non-steroidal anti-inflammatory
drugs (NSAIDs), or maintenance antisecretory therapy.
Upper gastrointestinal bleeding is managed by many cli-
nicians across many specialties, including emergency room
physicians, hospitalists, internists, gastroenterologists,
surgeons, interventional radiologists, and hematologists.
A variety of topics—including risk assessment, the
threshold for blood transfusion, the timing of endoscopy,
and medical and endoscopic therapies—have continued to
evolve in recent years. In addition, it has become increas-
ingly important and complex to determine the appropriate
management of patients who need antithrombotic agents,
with gastroenterological, cardiovascular, and hematologi-
cal aspects needing to be considered.
This article provides a comprehensive and evidence based
summary of the assessment and management of patients
with acute upper gastrointestinal bleeding, which is relevant
to clinician specialists, academics, and clinical researchers.
A summary of management is provided in the box.

For personal use only 1 of 13

 STAT E O F T H E A RT R E V I E W
SUMMARY OF THE MANAGEMENT OF UPPER GASTROINTESTINAL BLEEDING
Pre-endoscopic management
• Hemodynamic assessment and resuscitation as needed
• Blood transfusion at a hemoglobin threshold of 70-80 g/L; higher threshold if severe
bleeding with hypotension
• Risk assessment:
-If Glasgow-Blatchford score ≤1 consider outpatient endoscopy and management
• Erythromycin (as a prokinetic agent) and proton pump inhibitor may be considered
• Patients with cirrhosis should receive vasoactive drugs and antibiotics
Endoscopic
• Endoscopy is generally recommended within 24 hours in patients admitted to hospital
––If the patient has severe bleeding with hemodynamic instability, urgent endoscopy
should be performed after resuscitation
• Ulcers with active bleeding and non-bleeding visible vessels should receive endoscopic
therapy; endoscopic therapy may also be used for ulcers with adherent clots
• Injection therapy (eg, epinephrine), thermal probes (eg, bipolar electrocoagulation, heater
probe), or clips should be used
• Epinephrine injection should always be followed by a second modality
• Recurrent bleeding should be treated with repeat endoscopic therapy but subsequent
bleeding by transarterial embolization or surgery
• Esophageal variceal bleeding should be treated with ligation and gastric varices with the
injection of tissue adhesive
• Refractory variceal bleeding should be treated with transjugular portosystemic shunt
• For massive refractory esophageal variceal bleeding a removable covered metal stent is
preferred to balloon tamponade as a temporizing measure
Post-endoscopic management
• Patients who have ulcers with high risk lesions (active bleeding, visible vessel, adherent clot)
should receive high dose proton pump inhibitors for 72 h
• Patients with cirrhosis should continue antibiotics for up to seven days regardless of the
bleeding source
• Variceal bleeding should be treated with vasoactive drugs for up to five days
• When used for secondary prevention, aspirin should be continued or reintroduced soon after
hemostasis is achieved
• Early reintroduction of other antithrombotic drugs is also recommended after hemostasis is
achieved to reduce thrombotic events and death
Overall quality of evidence
Numerous randomized controlled trials (RCTs) and
meta-analyses have assessed the use of medical and
endoscopic therapy, and the optimal blood transfusion
strategy in patients with acute upper gastrointestinal
bleeding, thereby providing high quality data to guide
management. Although the evidence regarding resuscita-
tion, risk assessment, timing of endoscopy, and reintro-
duction of antithrombotic drugs is of lower quality, large
recent studies in these areas have helped inform patient
management.
Incidence
The incidence of upper gastrointestinal bleeding in the
United Kingdom in the 1990s was 103-172/100 000
adults per year.10 11 Recent reports from the United States
using nationwide administrative databases indicate that
the incidence of hospital admission for the condition
was 61-78 per 100 000 persons in 2009-2012.12‑14 Peptic
ulcers are the most common cause of hospital admission
for upper gastrointestinal bleeding, accounting for just
over half of all cases.12 14 The incidence of hospital admis-
sion for the condition has decreased 21-23% during the
past 10 years.12 14 This decrease is largely accounted
for by decreases in peptic ulcer bleeding (and bleeding
For personal use only 2 of 13
ascribed to “gastritis”) probably because of the decreas-
ing prevalence of H pylori and increasing use of antisecre-
tory drugs. Case fatality rates from these database studies
BMJ: first published as 10.1136/bmj.l536 on 25 March 2019. Downloaded from http://www.bmj.com/ on 3 June 2020 by guest. Protected by copyright.
were low, in the range of 1.9-2.5%.12‑14 By contrast, large
observational cohort studies from Europe suggest higher
fatality rates of around 10%.15 16 The reason for these
differences is unknown but might be partly related to
reliance on coding in database studies and differences
in practice, such as low risk patients being more often
managed in outpatient settings in Europe.
Sources and selection criteria
We searched PubMed, Medline, and Cochrane databases
from 2010 to August 2018 using the search terms gastro-
intestinal hemorrhage, peptic ulcer bleeding, and variceal
bleeding. References were also identified from the inter-
national, UK, European, American, and Asia-Pacific
guidelines on upper gastrointestinal bleeding published
during this period in addition to relevant review articles.
We selected systematic reviews, meta-analyses, RCTs, and
observational studies (excluding case reports and small
(<15 cases) case series). We also excluded articles that
were not peer reviewed and those not published in Eng-
lish. Studies were prioritized by design, as noted above,
and by patient numbers, quality, and publication date.
Initial resuscitation
As with any new patient with a medical emergency, the
initial clinical evaluation of patients presenting with
upper gastrointestinal bleeding involves assessment of
the patient’s airway, breathing, and circulation. Many
patients are hemodynamically stable at presentation,
but for those with major bleeding, early resuscitation is
essential. In general, two large bore intravenous cannu-
lae are inserted, although central venous access may be
preferred in certain cases. Regular monitoring of pulse,
blood pressure, and oxygen saturations is crucial. Hypo-
tension is associated with increased mortality; a multi-
center observational study of 1882 patients reported an
odds ratio of 9.8 (95% confidence interval 5.1 to 19) with
systolic blood pressure <90 mm Hg versus ≥90 mm Hg.11
Tracheal intubation may be used to protect the airway in
patients with severe ongoing hematemesis, especially in
those at increased risk of aspiration (such as those with
an altered mental status or lack of gag reflex).
No RCTs have assessed fluid resuscitation in upper gas-
trointestinal bleeding. By contrast, a comparative study
and an RCT in patients with hemorrhagic shock as a result
of trauma suggest that a more restrictive fluid resuscita-
tion may be better (or not worse) than more intensive fluid
resuscitation.17 18 The choice of intravenous fluid for ini-
tial resuscitation is unclear, with crystalloids or colloids
often being used while the need for the transfusion of
blood products is assessed. A meta-analysis of 70 trials
with 22 392 patients found no difference in mortality
between colloid and crystalloid solutions for fluid resus-
citation in critically ill patients: relative risk 1.01 (0.93 to
1.10) for albumin or plasma proteins versus crystalloid
solutions, and similar negative results when other col-
loids were compared with crystalloids.19 An RCT of 15
802 critically ill hospital inpatients found reduced acute
 STAT E O F T H E A RT R E V I E W

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Fig 1 |  Blood transfusion meta-analysis: liberal versus restrictive transfusion for (A) mortality and (B) rebleeding.27 Reproduced
with permission from Elsevier. Abbreviations: CI=confidence interval; RR=relative risk.

kidney injury (odds ratio 0.91, 0.84 to 0.99) and a trend
towards reduced mortality in hospital (10.3% v 11.1%;
P=0.08) with balanced crystalloids versus saline.20
Whether these data can be fully extrapolated to upper
gastrointestinal bleeding is uncertain.
Red blood cell transfusion
A meta-analysis of 31 RCTs comprising 12 587 patients
in a variety of populations found that a more restrictive
approach to red cell transfusion (variably defined at
hemoglobin threshold 70-90 g/L) does not adversely affect
outcomes; hospital mortality was lower with a restrictive
strategy but 30 day mortality was not significantly differ-
ent (risk ratio 0.97, 0.81 to 1.16).21 This systematic review
concluded that a restrictive policy seemed to be safe in
patients with underlying cardiovascular disease but no
evidence was available for patients presenting with acute
coronary syndrome. On that basis, current US guidelines
recommend transfusion at a threshold of hemoglobin of
70 g/L for hemodynamically stable adult inpatients and
80 g/L for those undergoing orthopedic or cardiac surgery
or with pre-existing cardiovascular disease.22 Others have
suggested a threshold in patients with cardiovascular dis-
ease of ≥80 g/L.23
Importantly, results for the general populations
described above may not be applicable to those with upper
gastrointestinal bleeding. In such patients a restrictive
transfusion approach appears not only to be safe but also
to provide clinical benefit for rebleeding and mortality. A
small study in 1986 first showed reduced rebleeding with
restrictive transfusion.24 A large high quality Spanish RCT
in 921 patients found significantly lower mortality at six
weeks (hazard ratio 0.55, 0.33 to 0.92) and rebleeding
(0.68, 0.47 to 0.98) with a transfusion hemoglobin thresh-
old of 70 g/L versus 90 g/L.25 A subsequent six center
cluster randomized feasibility trial in the UK reported no
benefit from a liberal transfusion policy when hemoglobin
thresholds of 80 g/L versus 100 g/L were compared (mor-
tality difference −1%, −8% to 6% in 640 patients).26 A
meta-analysis of five RCTs comprising 1965 patients with
upper gastrointestinal bleeding reported that restrictive
transfusion was associated with lower mortality (relative
risk 0.65, 0.44 to 0.97) and reduced rebleeding (0.58,
0.40 to 0.84) (fig 1).27
Thus, in most patients with upper gastrointestinal
bleeding, red cell transfusion should be withheld until
a hemoglobin threshold of 70-80 g/L is reached.5 6 28
Patients with severe bleeding and hemodynamic com-
promise, who were generally excluded from the trials
described above, require transfusion at higher thresholds
because their hemoglobin will equilibrate to much lower
levels as their intravascular volume is repleted with fluid.
Transfusion thresholds in patients with cardiovascular
disease, especially those with acute coronary syndrome,
are less certain, but thresholds of 80 g/L or higher are vari-
ably recommended.22 23
Risk assessment
Many risk assessment scores have been developed for
patients with upper gastrointestinal bleeding, includ-
ing those that can be calculated early after presentation
(pre-endoscopy) and those that include endoscopic find-
ings.29‑34 They were designed to predict a variety of end-
points. We believe pre-endoscopy scores are of greater
practical use because it is probably most important to
predict risk soon after presentation to help direct man-
agement. The use of risk scores has been recommended to
stratify patients into those at higher or lower risk of poor

For personal use only 3 of 13

 STAT E O F T H E A RT R E V I E W

important to achieve a very high sensitivity so that almost

6HQVLWLYLW\


no patients who may come to harm are sent home.
A systematic review of 16 studies on the use of pre-

BMJ: first published as 10.1136/bmj.l536 on 25 March 2019. Downloaded from http://www.bmj.com/ on 3 June 2020 by guest. Protected by copyright.
endoscopy scores in emergency departments to predict
intervention, rebleeding, or death concluded that a GBS
of zero provided the highest sensitivity (0.99), although
 specificity was very low (0.08).39 In 2012, both US and UK
guidelines recommended that a GBS of zero could be used
to identify very low risk patients who could avoid admis-
sion and be offered outpatient endoscopy.4 28
Subsequently two large international comparative
 studies of risk assessment scores, with 3012 and 2305
patients, were published.35 40 These studies reported that
GBS ≤1 was the optimum low risk threshold, with a sen-
sitivity of 99% and specificity of 35-40%. The authors
suggested that this threshold could be used to identify
patients who could be safely discharged from the emer-

gency department for outpatient management, thereby
avoiding admission in 19-24% of patients presenting
with upper gastrointestinal bleeding. This approach has
been accepted by recent European and Asia-Pacific guide-
lines.5 6 No high quality interventional trial has assessed
 outcomes after the introduction of a risk score, although
a pre-post design study showed the safety of outpatient
    
management in 84 patients with a GBS score of zero.38
VSHFLƟFLW\

Management of patients taking antithrombotic drugs

*%6$852& $,06$852&
The increasing use of antiplatelet and anticoagulant
$56$852& 31('$852& (antithrombotic) medication in the management of car-
)56$852& 5HIHUHQFH
Fig 2 |  Comparison of five upper gastrointestinal bleeding risk scores in prediction of the need
for any intervention (transfusion, endoscopic therapy, interventional radiology, or surgery)
or 30 day mortality (n=1704).35 Abbreviations: AIMS65=see text; ARS=admission Rockall
score; AUROC=area under the receiver operating characteristic curve; FRS=full Rockall score;
GBS=Glasgow Blatchford score; PNED=Progetto Nazionale Emorragia digestive score.
outcome.3 6 This enables patients predicted to be high risk
to be managed in high dependency or intensive care units
and receive urgent endoscopy, whereas those at very low
risk can be managed as outpatients.
The most well established and commonly used pre-
endoscopic scores are the Glasgow Blatchford score
(GBS), the pre-endoscopic or “admission” Rockall score,
and the AIMS65score (Albumin <3 mg/dL, International
normalized ratio >1.5, altered Mental status, Systolic
blood pressure <90 mm Hg, age >65 years).29 32 34 The
GBS was developed to predict a composite of clinical
intervention or death, whereas the other two were
designed to predict death. Many studies have compared
these and other scores, and GBS seems to be superior at
predicting a combined endpoint of intervention or death
(fig 2).35‑37
These risk assessment scores cannot precisely identify
individual high risk patients who will definitely die if
they do not receive the intervention. Therefore, they have
limited clinical utility for predicting which patients are at
higher risk. However, risk scores do seem to have a clini-
cal role in identifying patients who are at very low risk.38
When aiming to identify a cohort of patients who are at
very low risk and could be managed as outpatients, it is
For personal use only 4 of 13
diovascular disease means that many patients now pre-
senting with upper gastrointestinal bleeding are taking
these drugs. A recent multicenter observational study
of 619 patients requiring endoscopic therapy for upper
gastrointestinal bleeding reported that 44% were taking
an antithrombotic drug at presentation, with 25% taking
more than one.41 Although these drugs are a recognized
risk factor for upper gastrointestinal bleeding,42 43 no
clear evidence indicates that their use worsens outcomes
after the bleed.41 44
The 2016 US guideline on management of antithrom-
botic agents for patients undergoing endoscopy suggests
that platelet transfusion is an option for life threaten-
ing or serious bleeding in patients taking antiplatelet
agents.45 However, observational studies have failed to
identify clinical benefit, and a cohort study with 408
patients showed significantly higher mortality with plate-
let transfusion (odds ratio 5.6, 1.5 to 27.1).46 This find-
ing led the recent Asia-Pacific guideline panel to suggest
that platelet transfusions should not be used in patients
taking antiplatelet agents who present with upper gas-
trointestinal bleeding.6 Platelet dysfunction may also be
present in patients on hemodialysis or those who have
had cardiac bypass surgery.47
Less information is available regarding the manage-
ment of anticoagulants, including warfarin and the newer
direct oral anticoagulants (DOACs), in patients with upper
gastrointestinal bleeding. For patients taking warfarin,
recent guidelines suggested the use of prothrombin com-
plex concentrate (PCC) along with vitamin K to prevent
rebound coagulopathy in patients with a life threatening
bleed or hemodynamic instability.5 6 PCC is preferable
 STAT E O F T H E A RT R E V I E W
to fresh frozen plasma because of the smaller volume
needed, its more rapid onset, lack of the need to check
the patient’s blood group, and the minimal infectious
risk.5 US guidelines suggest either four factor PCC plus
vitamin K or fresh frozen plasma.45
Guidelines also suggest that the international normal-
ized ratio (INR) should be corrected to <2.5 if possible
before undertaking endoscopy, with the potential need
for endoscopic therapy if the clinical situation allows.5 45
This suggestion is based on observational studies which
indicate that the outcome after endoscopic therapy is
similar in patients with an INR of 1.3-2.7 to that in those
not taking warfarin.48 49 Other studies report that the INR
value does not predict rebleeding.50
Data on DOACs are limited, but because of their short
half lives (5-17 h), anticoagulant activity wanes rapidly
over one to two days (in the absence of renal disease).
Thus, European guidelines state that “time is the most
important antidote against DOACs.”5 Although PCC may
be of some use in severe bleeding, particularly for Xa
inhibitors, neither vitamin K nor fresh frozen plasma
has been shown to be beneficial.5 51 Reversal agents for
dabigatran (idarucizumab)52 and the factor Xa inhibitors
(andexanet alfa)53 are now approved in the US. Their role
in patients with upper gastrointestinal bleeding is unclear
given the uncertain risk of thrombotic events and the
short half lives of DOACS. They would mainly be used in
patients with a severe ongoing bleed, especially if DOAC
ingestion was recent or if renal disease was present.
Coagulopathy and thrombocytopenia in patients with
cirrhosis
Interpretation of the complex clotting abnormalities seen
in cirrhosis can be difficult. Patients with cirrhosis have
parallel decreases in procoagulant and anticoagulant
factors.54 The prothrombin time measures procoagulant
activity only; therefore, prothrombin time or INR is not a
reliable indicator of coagulation status in patients with
cirrhosis.54 Fresh frozen plasma is often given to patients
with upper gastrointestinal bleeding, cirrhosis, and
raised prothrombin time, but it has not been shown to
provide benefit and could have adverse effects. For these
reasons, the most recent US guidelines on portal hyper-
tensive bleeding recommend against correcting INR with
fresh frozen plasma or recombinant factor VIIa in patients
with cirrhosis and acute variceal bleeding.9
Platelets from patients with cirrhosis generate throm-
bin in a similar way to those from healthy controls,
and patients with cirrhosis have pro-hemostatic fac-
tors (increased von-Willebrand factor and decreased
ADAMTS-13, a protease that cleaves von-Willebrand
factor).54 55 However, patients with cirrhosis often have
thrombocytopenia as a result of splenic sequestra-
tion. The experimental finding that a platelet count of
56×109/L leads to thrombin generation at the 10th centile
of healthy control values54 provides the basis for giving
platelet transfusions at around 50×109/L.4 7 However, no
studies have assessed platelet thresholds or results with
platelet transfusions, and some current guidelines state
that no recommendation can be made regarding platelet
transfusions.8 9
For personal use only 5 of 13
Pre-endoscopic medical therapy
The use of pre-endoscopic intravenous proton pump
inhibitors (PPIs) has been assessed in several studies. A
BMJ: first published as 10.1136/bmj.l536 on 25 March 2019. Downloaded from http://www.bmj.com/ on 3 June 2020 by guest. Protected by copyright.
meta-analysis of six RCTs comprising 2223 patients found
that the use of these drugs before endoscopy is associated
with both reduced high risk stigmata of bleeding and the
need for endoscopic therapy (odds ratio 0.68, 0.50 to
0.93) but has no effect on patient outcomes, including
rebleeding, need for surgery, or mortality (1.12, 0.72 to
1.73).56 As a result, UK National Institute for Health and
Care Excellence (NICE) guidelines do not support the
routine use of these drugs before endoscopy.4 However,
several other international guidelines suggest PPIs may
have a role before endoscopy, particularly for patients in
whom endoscopy may be delayed. 3 5 6 28 57
Prokinetic agents have been assessed for their ability
to improve gastric emptying, thereby improving visu-
alization at endoscopy. Erythromycin, usually given as a
250 mg infusion 30-120 minutes before endoscopy, has
been most widely studied. The most recent meta-analysis
of 598 patients in eight RCTs showed improved visuali-
zation, reduced need for second look endoscopy, and
reduced length of hospital stay (mean difference −1.75
days, 2.43 to −1.06) after erythromycin infusion before
endoscopy.58
Tranexamic acid (TXA) inhibits the fibrinolytic activity
of plasmin. A meta-analysis reported reduced mortality
with TXA in patients with upper gastrointestinal bleed-
ing, but many studies were of poor quality and had been
undertaken before the widespread use of PPIs and endo-
scopic therapy.59 Furthermore, other outcomes such as
bleeding episodes and transfusions were not reduced.
Therefore, it is difficult to draw firm conclusions from
these data. A meta-analysis of two RCTs comprising
40 138 patients with acute severe traumatic or postpar-
tum bleeding suggested even a short delay in the admin-
istration of TXA reduces benefit: immediate treatment
improved survival (odds ratio 1.72, 1.42 to 2.10), but
survival fell 10% with every 15 minutes delay, with no
benefit beyond three hours.60 A large international study
(HALT-IT) will finish recruitment shortly and the results
should help clarify the role of TXA in upper gastrointes-
tinal bleeding.61
Pre-endoscopic medical therapy in patients with cirrhosis
Vasoactive drugs (terlipressin, somatostatin, or its ana-
logs octreotide and vapreotide), which cause splanch-
nic artery vasoconstriction, are used in patients with
cirrhosis and variceal bleeding. When combined with
endoscopic therapy, the different vasoactive drugs seem
to have similar efficacy.62 Three double blind RCTs exam-
ined the use of vasoactive drugs (terlipressin, somatosta-
tin, and vapreotide) given before endoscopy in patients
with cirrhosis and upper gastrointestinal bleeding.63‑65
Two studies reported less active bleeding at endoscopy
in the active treatment group,64 65 and the third noted
significantly more control of bleeding (clear gastric lav-
age and stable hemoglobin) at 12 hours with vasoactive
drug therapy.63
Current guidelines recommend starting vasoactive
drugs as soon as variceal hemorrhage is suspected.7‑9
 STAT E O F T H E A RT R E V I E W

phy is used in patients who are not candidates for endos-

0RUWDOLW\

copy. However, these investigations are most commonly


used if no source of bleeding is identified at endoscopy

BMJ: first published as 10.1136/bmj.l536 on 25 March 2019. Downloaded from http://www.bmj.com/ on 3 June 2020 by guest. Protected by copyright.
in patients with melena. A technetium-99m labelled red
cell scan may also be used in this situation, but computed
 tomography angiography seems to be more accurate.70 71
Early use of capsule endoscopy has been reported, with
3  goals including stratifying risk and determining the timing
 of endoscopy,72 but more studies are needed to establish
any potential role.

 Timing of endoscopy

On the basis of improved outcomes in observational
studies,3 5 28 guidelines recommend that, after appropri-
 ate resuscitation, most patients who are admitted with
upper gastrointestinal bleeding should undergo endos-
    copy within 24 hours. Some guidelines suggest that
7LPLQJK patients with hemodynamic compromise and those with
$6$
)LWWHGYDOXHV
$6$
Fig 3 |  Association between timing of endoscopy and mortality in hospital patients with
hemodynamic instability after correction for confounding variables.76 Abbreviation:
ASA=American Society of Anesthesiologists score.
PPIs should not be given concurrently to patients who
are receiving somatostatin (or analogs) because somato-
statin provides inhibition of gastric acid secretion compa-
rable to that provided by PPIs.66 67 Recommended doses
are terlipressin 2 mg every four hours, somatostatin 250
μg bolus followed by 250-500 μg/h, and octreotide and
vapreotide 50 μg bolus followed by 50 μg/h.9 These drugs
are generally given for up to five days.7‑9
A meta-analysis of 12 RCTs compromising 1241
patients showed that antibiotics reduce infections,
rebleeding, and mortality (relative risk 0.79, 0.63 to
0.98) in patients with cirrhosis and upper gastrointestinal
bleeding.68 An RCT comparing intravenous ceftriaxone
versus oral norfloxacin for seven days in 111 patients
with advanced cirrhosis and gastrointestinal bleeding
showed reduced proven infections with ceftriaxone (11%
v 26%; P=0.03).69 However, the results may not be gener-
alizable to all patients with cirrhosis because only 9% of
screened patients were enrolled. Current guidelines sug-
gest that antibiotics should be given from admission for
up to seven days.7‑9 Intravenous ceftriaxone is preferred
in patients with advanced cirrhosis or those taking qui-
nolone prophylaxis and those in areas of high quinolone
resistance, although the choice of antibiotic is dependent
on local antimicrobial sensitivity patterns.7‑9
Role of non-endoscopic diagnostic modalities before
endoscopy
Because upper gastrointestinal bleeding can be diag-
nosed and treated with endoscopy, which is available in
most hospitals, the role of other diagnostic modalities
in patients presenting with an acute bleed is limited. In
almost all cases, the initial diagnostic test will be upper
endoscopy. Rarely, angiography or computed tomogra-
For personal use only 6 of 13
cirrhosis, who may have varices, undergo endoscopy
within 12 hours after presentation,5 6 8 9 28 because some
observational studies and subgroup analysis of an RCT
provided limited evidence of improved outcome in high
risk patients when endoscopy is performed within six to
13 hours.73‑75 Features that have been considered high
risk include GBS ≥8-12, bloody gastric lavage or persis-
tent bloody emesis in hospital, hypotension, tachycardia,
and comorbidities such as cirrhosis. However, evidence
that can precisely identify high risk patients who should
undergo early endoscopy is not available. In general,
patients with persistent hemodynamic instability despite
aggressive resuscitation will require urgent endoscopy.
Endoscopy should not be undertaken before the
patient’s hemodynamic status is dealt with by initiating
appropriate resuscitation and aiming to optimize comor-
bidities. This is illustrated by a recent observational study
of 12 601 Danish patients with upper gastrointestinal
bleeding secondary to peptic ulcers. This study suggested
a survival benefit from delaying endoscopy for 12 hours in
hemodynamically stable patients with American Society
of Anesthesiologists score 3-5 (odds ratio 0.48, 0.34 to
0.67), and for six hours in patients with hemodynamic
instability (0.73, 0.54 to 0.98) (fig 3).76 Most deaths after
upper gastrointestinal bleeding are caused by underlying
comorbidities rather than exsanguination, so attention to
other medical problems is key to patient management.77
Two small RCTs compared urgent (<2-6 h) with elective
(>48 h) endoscopy for patients presenting with upper gas-
trointestinal bleeding who were hemodynamically stable
and had no serious comorbidities.78 79 As expected in these
low risk patients, no difference in clinical outcomes was
identified. However, ~40-45% of patients had low risk
endoscopic findings that would allow for early discharge.
Thus, non-emergent endoscopy, undertaken as soon as
possible within routine business hours, is recommended
in low risk patients to allow safe early discharge in many
of these patients.80
Endoscopic therapy
Non-variceal bleeding
Recommended modalities for ulcer bleeding include
injection of epinephrine (eg, 1:10 000 dilution), injection
 STAT E O F T H E A RT R E V I E W
Fig 4 |  (A) Endoscopic view of a large posterior duodenal ulcer with intermittent bleeding from
a visible vessel. The patient, a middle aged man taking anticoagulant drugs, was admitted
with hematemesis, hemodynamic instability, and a hemoglobin concentration of 55 g/L.
After resuscitation, transfusion to hemoglobin 70-80 g/L, and correction of coagulopathy,
endoscopy was undertaken. (B) Through-the-scope clips were applied after dilute epinephrine
was injected into the four quadrants of the ulcer base. The fibrotic base made application of the
clips problematic. (C) There was ongoing intermittent oozing of blood. Given the high risk ulcer,
hemostatic powder spray was then applied to good effect. High dose intravenous proton pump
inhibitors (PPIs) were given and the patient was managed in the hospital high dependency unit.
Because of the clinical situation and the difficulty in providing endoscopic therapy to this large
fibrotic ulcer, the plan for urgent referral for radiological embolization—should early rebleeding
occur—was clearly documented by the endoscopist as a “rebleeding plan.” (D) Fifteen hours
later the patient rebled and became hemodynamically unstable. He was again resuscitated
appropriately, after which an interventional radiologist performed coil embolization of the
gastroduodenal artery. The patient had no further bleeding and was restarted on anticoagulants
on day 3. When he was discharged from hospital a week later he was still taking oral PPIs twice
daily, but when the 14 day course was finished, the dose was reduced to once daily.
of sclerosants such as absolute ethanol, thermal contact
devices such as bipolar electrocoagulation probes or
heater probes, and through-the-scope clips.5 28 RCT data
supporting efficacy in ulcer bleeding are more limited
for non-contact thermal devices such as argon plasma
coagulation.28 Vascular ectasias may also be treated
with thermal methods, commonly argon plasma coagu-
lation; radiofrequency ablation is another thermal con-
tact modality sometimes used for gastric antral vascular
ectasia.81
Endoscopic injection of epinephrine should not be
used as a single modality treatment. Meta-analyses have
reported lower rates of further bleeding with an alterna-
tive modality compared with epinephrine alone (relative
risk 0.58, 0.36 to 0.93) and with epinephrine combined
with a second modality versus epinephrine alone (relative
For personal use only 7 of 13
risk 0.34, 0.23 to 0.50).82 83 Epinephrine can be used for
temporary control of bleeding to aid visualization of the
lesion before definitive treatment with another modal-
BMJ: first published as 10.1136/bmj.l536 on 25 March 2019. Downloaded from http://www.bmj.com/ on 3 June 2020 by guest. Protected by copyright.
ity (such as a thermal or mechanical) or to decrease the
risk of inducing bleeding with the application of a second
modality.
Most data on non-variceal upper gastrointestinal bleed-
ing are from patients with peptic ulcer bleeding. The For-
rest classification of endoscopic stigmata is commonly
used by endoscopists to identify higher risk lesions that
require the application of endoscopic therapy.84 Endo-
scopic therapy significantly decreases further bleeding
and the need for urgent intervention in patients with
ulcers with spurting or oozing blood (Forrest 1a or 1b) or
with non-bleeding visible vessels (Forrest 2a; fig 4A).28
Patients with adherent clots (Forrest 2b) were not shown
to benefit from endoscopic therapy in a meta-analysis of
RCTs, but results of individual trials were very heteroge-
neous.80 This has led to guideline recommendations that
either endoscopic plus medical therapy or medical man-
agement alone may be used for patients with adherent
clots.5 28 Around 25-50% of patients admitted to hospital
with bleeding ulcers have Forrest 1a, 1b, 2a, or 2b stig-
mata.76 85 Endoscopic treatment is not needed for ulcers
with flat pigmented spots or a clean base (Forrest 2c or
3).5 28
Variceal bleeding
Variceal bleeding accounted for 11% of patients admit-
ted to hospital with acute upper gastrointestinal bleed-
ing in a nationwide UK audit.15 However, the proportion
of patients with variceal bleeding varies widely and is
related to the proportion of people with liver disease in
the population served. Patients with variceal bleeding
have a higher mortality than those with non-variceal
bleeding, and this is largely related to the severity of
underlying liver disease.14 86
The optimal endoscopic therapy for esophageal variceal
bleeding is variceal band ligation, which is associated
with less rebleeding and fewer side effects than sclero-
therapy.4 7 9 87 If gastric varices are found, ligation can be
used for gastroesophageal varices type-1, where esopha-
geal varices extend several centimeters distally along
the gastric lesser curve. Injection of tissue adhesive (eg,
N-butyl-cyanoacrylate) is the recommended endoscopic
approach for all other types of gastric varices, although
thrombin injection can be considered.7 9 88-90 Thrombin
injection has been described for gastric variceal bleeding
in cohort studies, but to date no RCTs have compared it
with other treatments.91‑93
Post-endoscopic management
PPI therapy
A meta-analysis of RCTs comparing PPIs to placebo or no
therapy in high risk patients undergoing successful endo-
scopic therapy showed that high dose PPIs, usually given
as an intravenous bolus of 80 mg followed by continu-
ous infusion at 8 mg/h for 72 hours, reduced rebleeding
(relative risk 0.40, 0.28 to 0.59) and mortality (0.41, 0.20
to 0.84). Intermittent intravenous or oral PPIs reduced
rebleeding (0.53, 0.35 to 0.78) but not mortality.82 A
 STAT E O F T H E A RT R E V I E W
meta-analysis of 13 studies found that a bolus followed
by intermittent doses of intravenous or oral PPIs was non-
inferior to continuous infusion (further bleeding risk ratio
0.72; one sided 95% confidence interval upper boundary
0.97), although most individual studies were relatively
small and not designed to answer this question.94 No
conclusions could be made regarding oral versus intra-
venous dosing,94 although oral administration provides
an antisecretory effect comparable to equivalent doses
of intravenous PPIs.95 Guidelines have recommended an
intravenous bolus followed by continuous infusion PPI
therapy,3 5 6 28 although recent guidelines also suggest con-
sidering intermittent high doses of oral or intravenous PPI
(eg, 80-160 mg daily in divided doses after an initial 80
mg bolus), rather than continuous infusion.5 6
Patients with peptic ulcer bleeding generally receive
four to eight weeks of once daily oral PPIs. Those with
low risk endoscopic lesions (clean base, flat spot) should
receive PPIs once a day from the time of diagnosis. Those
with high risk endoscopic lesions and clinical features
should receive high dose PPIs on days one to three as
above, followed by twice daily oral PPI on days four to
14. This regimen is based on an RCT of 187 patients that
showed significantly less rebleeding with twice daily ver-
sus once daily PPIs (relative risk 0.41, 0.18 to 0.93) during
this period.96
The benefits of PPIs outweigh potential risks when
used after bleeding from a peptic ulcer. Multiple phar-
macodynamics studies report that omeprazole reduces
the antiplatelet effect of clopidogrel, but a double blind
placebo controlled trial in 3761 clopidogrel users found
no evidence that omeprazole increased cardiovascular
events (hazard ratio 0.99, 0.68 to 1.44).97 The US Food
and Drug Administration recommends avoiding the use
of omeprazole or esomeprazole in patients who are taking
clopidogrel.98
Patients with cirrhosis and variceal bleeding
As noted above, in patients with cirrhosis and upper gas-
trointestinal bleeding, antibiotics should be continued
for up to seven days,7‑9 regardless of whether varices are
identified as the source of the bleeding. Patients who have
documented variceal bleeding at endoscopy should also
have their vasoactive drugs continued for up to five days.7‑9
Combined treatment with endoscopic ligation and vasoac-
tive drugs is superior to ligation alone or vasoactive drugs
alone in reducing further bleeding in hospital or during
the first seven days after treatment.99 100
Transjugular intrahepatic portosystemic shunt (TIPS)
may also be used after initial endoscopic therapy in the
first three days after presentation for the treatment of acute
esophageal variceal bleeding in patients with Child-Pugh
class C cirrhosis (score 10-13)8 9 A multicenter RCT com-
pared early (within 72 h) TIPS placement versus standard
treatment with variceal ligation plus drug therapy in 63
patients with Child-Pugh C cirrhosis or Child-Pugh B cir-
rhosis with active bleeding. It reported that more patients
were free from further bleeding at one year with early
TIPS (97% v 50%; P<0.001).101 One year survival was
also higher with early TIPS (86% v 61%; P<0.001) and
encephalopathy was not increased. Subsequent reports
For personal use only 8 of 13
suggest that the benefit is primarily in those with Child-
Pugh C disease.102 However the evidence for early TIPS
remains relatively limited and the practicalities may be
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challenging for many units.
Reintroduction of antithrombotic drugs
Several studies suggest a survival benefit from continuing
or reintroducing antithrombotic drugs after upper gastroin-
testinal bleeding.103 104 This is perhaps unsurprising given
that mortality after presentation with a bleed is more often
caused by underlying comorbidities, particularly cardio-
vascular disease, rather than the bleed itself.77 However,
balancing the risks and benefits of reintroducing these
drugs after a patient presents with upper gastrointestinal
bleeding can be challenging. If an antithrombotic drug is
reintroduced, a PPI is usually also administered.
Aspirin is the most widely studied antithrombotic drug
in patients with upper gastrointestinal bleeding. Strati-
fication of patients must be based on whether aspirin is
given for secondary or primary cardiovascular preven-
tion. This is because the benefit in secondary prevention
is far greater than that for primary prevention, with a
number needed to treat to prevent myocardial infarction,
stroke, or vascular death of 67 versus 1745.80
A randomized study of 156 patients with peptic ulcer
bleeding who had been taking aspirin for secondary
prevention reported reduced mortality at eight weeks in
those who continued aspirin compared with those who
discontinued the drug (1.3% v 12.9%; difference 11.6%,
3.7% to 19.5%).103 Therefore, current guidelines suggest
continuing aspirin (or reintroducing the drug within three
days for higher risk endoscopic lesions) once hemosta-
sis is achieved.4-6 105 106 It has been suggested that when
aspirin has been prescribed for primary prophylaxis, it
should be stopped in most patients because the bleed-
ing risk probably outweighs the cardiovascular benefit.28
If primary prevention is still clinically required after the
bleed, it can be reintroduced after the ulcer has healed,
or earlier depending on the clinical situation.5
No randomized studies are available to guide clinicians
on the reintroduction of thienopyridines (eg, clopidogrel)
or anticoagulants. Recent guidelines suggest that for
patients receiving dual antiplatelet therapy, at least one
drug, usually aspirin, should be reintroduced early as
above, with the second drug withheld for up to five days
after hemostasis, or the timing discussed with a cardio-
vascular specialist.5 6 105
Similar to the situation with antiplatelet agents, obser-
vational studies in patients who develop upper gastro-
intestinal bleeding while taking warfarin indicate that
those who restart warfarin have markedly lower rates of
death and thromboembolic events, without a higher rate
of recurrent bleeding, when compared with those whose
warfarin is not restarted.104 107 Recent guidelines suggest
restarting warfarin from “as soon as hemostasis is estab-
lished”6 to seven to 15 days after the bleeding event.5 The
indication for anticoagulation should be assessed at the
time of the bleed, with early reintroduction (zero to seven
days) recommended in patients with a higher thrombo-
embolic risk.5 6 However, robust data on the optimal tim-
ing of reintroduction are not available.
 STAT E O F T H E A RT R E V I E W
Data on the timing of the reintroduction of DOACs
after bleeding has been controlled are limited, and this
clearly depends on the balance of risk between rebleeding
and thromboembolic events. Use of the CHA2DS2-VASC
(Congestive heart failure, Hypertension, Age-2, Diabetes,
Stroke/TIA-2, Vascular disease) and HAS-BLED (Hyper-
tension, Abnormal renal and liver function, Stroke, prior
Bleeding, Labile INRs, Elderly (>65 years), Drugs and
alcohol) scores may help in this situation.108‑110 The recent
Asia-Pacific guidelines suggest reintroducing DOACs in
patients with a high thromboembolic risk as soon as
hemostasis is achieved, although others have suggested
that patients should have their anticoagulant restarted at
day 7, with possible bridging therapy with low molecu-
lar weight heparin from days 2 to 7 in those with a low
bleeding risk.6 In general, patients with an increased
thromboembolic risk should have early reintroduction
of antithrombotic drugs, because the risks and severity
of thromboembolic events generally outweigh those of
bleeding events.
Management of persistent or recurrent bleeding, including
role of interventional radiology and surgery
Non-variceal bleeding
The results of an RCT comparing repeat endoscopic ther-
apy with surgery in 92 patients with recurrent peptic
ulcer bleeding indicate that endoscopic therapy should
be repeated when bleeding recurs after initial endoscopic
control.111 This study reported similar mortality, although
more patients had complications with surgery (36.4% v
14.6%; P=0.03). For patients with persistent or refrac-
tory bleeding from non-variceal sources despite optimal
standard endoscopic and medical therapy, the addition
of hemostatic powder spray for temporary control (12-24
h) or over-the-scope clips (OTSC) as a rescue modality is
suggested, in parallel with ongoing resuscitation.5 6 112 113
For peptic ulcer bleeding not controlled by endoscopic
therapy, two recent meta-analyses of observational stud-
ies that compared surgery with radiological interven-
tion reported lower rebleeding with surgery, but similar
mortality and need for further interventions, although
patients receiving radiological intervention were older
and in worse general health.114 115 Because many patients
with recurrent bleeding are elderly with comorbidities,
interventional radiology is generally preferred if locally
available. Therefore, if bleeding continues despite opti-
mal endoscopic therapy, transarterial embolization is
recommended, although surgery should be considered if
radiological therapy is likely to be delayed.4 5
Prophylactic transarterial embolization of high risk
ulcers after endoscopic therapy is not recommended: it
did not significantly reduce rebleeding when compared
with standard treatment (10.2% v 11.4%) in an RCT of
241 patients.116
Variceal bleeding
Patients with rebleeding after initial endoscopic and
medical therapy for varices may have repeat endoscopic
therapy performed.8 TIPS is recommended for those with
persistent or severe recurrent bleeding.7‑9 For patients
with severe bleeding refractory to endoscopic therapy,
For personal use only 9 of 13
balloon tamponade has been recommended as a tempo-
rary bridge to definitive therapy.7 8 However, balloon tam-
ponade is associated with serious complications (such as
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esophageal rupture and aspiration pneumonia) in about
12% of patients and its use was lethal in 6% of patients
in a case series.117 Recently, removable self expanding
covered metal esophageal stents designed for the treat-
ment of severe esophageal variceal bleeding have become
available (although they are not approved in the US). An
RCT of 28 patients compared these stents with balloon
tamponade in patients with esophageal variceal bleed-
ing refractory to medical and endoscopic therapy and
showed that the stents led to improved bleeding control
(85% v 47%; Fisher’s exact test P=0.055), with similar
mortality.118
Emerging treatments
Hemostatic powder spray
Hemostatic powder spray provides high rates of initial
hemostasis for active non-variceal upper gastrointestinal
bleeding, but with relatively high rebleeding rates, sug-
gesting a temporary effect.119‑123 A systematic review of
195 cases reported initial hemostasis in 92% and a seven
day rebleeding rate of 21%.112 Currently, hemostatic
powder is often used as a temporary rescue treatment
for bleeding that cannot be controlled using established
methods, and it may have a role for the initial control
of diffuse bleeding from tumors.6 112 More limited data
are available on hemostatic powder spray for variceal
bleeding, often as a temporizing method until definitive
therapy is applied.124
Over-the-scope clips
Treatment with OTSC is another relatively new technique.
These clips are much larger than standard through-the-
scope clips so may be successful when applied to larger
fibrotic lesions or larger feeding vessels. A multicenter
RCT of 66 patients with recurrent ulcer bleeding after ini-
tial hemostasis showed that significantly fewer patients
treated with OTSC had further bleeding compared with
those on standard therapy (15% v 58%; difference 42%,
22% to 63%).125 Further data are awaited, but at present
OTSC may be considered as a rescue therapy when stand-
ard therapies do not achieve permanent hemostasis.
Doppler probes
Endoscopic Doppler probes have also been studied as a
guide to endoscopic therapy. A recent dual center RCT
of 148 patients with severe non-variceal upper gastro-
intestinal bleeding that compared endoscopic therapy
guided by Doppler probe positive signals with standard
endoscopic therapy guided by endoscopic stigmata found
reduced 30 day rebleeding with Doppler guided therapy
(11.1% v 26.3%; P=0.02).126 Further data on the clinical
utility and practicalities of this approach are needed, and
currently the use of these probes is not recommended by
guidelines.5 6
Guidelines
As already noted, international, UK (NICE), American,
European, and Asia-Pacific guidelines on upper gastro-
 STAT E O F T H E A RT R E V I E W

Recommendations from major published guidelines on non-variceal UGIB

Guideline Risk scoring Prokinetics Pre-endoscopy PPIs Timing of endoscopy Post-endoscopy PPIs
International, Prognostic scales recommended to Promotility agents May be considered but should not Within 24 h for most patients IV PPI bolus then infusion if

BMJ: first published as 10.1136/bmj.l536 on 25 March 2019. Downloaded from http://www.bmj.com/ on 3 June 2020 by guest. Protected by copyright.
20103 identify high and low risk groups should not be used delay endoscopy high risk stigmata and have had
routinely successful endoscopic therapy
US, ACG (ulcer Carry out risk assessment to stratify Consider IV IV PPIs may be considered Within 24 h after resuscitation. After successful endoscopic
bleeding only) into higher and lower risk groups. erythromycin Consider within 12 h if high risk hemostasis, give IV PPI bolus
201228 Consider discharge from ED if GBS=0 features (eg, hemodynamic instability, then infusion to those with active
bloody emesis in hospital) bleeding, NBVV, or adherent clot
US, ASGE No specific recommendation but Suggest IV prokinetic IV PPIs recommended Depends on clinical factors but IV PPI bolus then infusion after
201257 notes that GBS=0 identifies a very low if high probability of recommends within 24 h in the endoscopic therapy for ulcers with
risk group fresh blood or clot in presence of cancer, cirrhosis, high risk stigmata
stomach hematemesis, hypovolemia, or Hb
<80 g/L
UK, NICE 20124 Use GBS before endoscopy and Not assessed Do not give PPIs before endoscopy Within 24 h, but immediately after Offer PPIs if stigmata of recent
full Rockall score after endoscopy. resuscitation if unstable and severe bleeding seen at endoscopy
Consider early discharge if GBS=0 UGIB
Europe, ESGE Patients with GBS 0-1 do not require Recommend IV IV bolus then infusion but should Within 24 h of resuscitation, but IV PPI bolus then 72 h infusion for
20155 early endoscopy or admission erythromycin if not delay endoscopy consider within 12 h if high risk patients who receive endoscopic
clinically severe or features (eg, hemodynamic instability hemostasis and those with
ongoing active UGIB despite resuscitation, inpatient bloody adherent clots. Consider giving
emesis, contraindication to stopping PPIs as intermittent IV bolus or
anticoagulants) high dose oral
Asia-Pacific, Use GBS; adopting a cut off at GBS Not assessed IV PPIs recommended if suspected Within 24 h, but urgent (within 12 After endoscopic hemostasis is
20186 ≤1 allows most hospitals to reduce UGIB awaiting endoscopy h) if hemodynamic instability, after achieved high dose oral PPIs can
unnecessary admissions (especially if endoscopy is not resuscitation and stabilization be used for 72 h as an alternative
available within 24 h) to high dose IV PPIs
Abbreviations: ACG=American College of Gastroenterology; ASGE=American Society for Gastrointestinal Endoscopy; ED=emergency department; ESGE= European Society of Gastrointestinal Endoscopy;
GBS=Glasgow Blatchford score; Hb=hemoglobin; NBVV=non-bleeding visible vessel; NICE=National Institute for Health and Care Excellence; PPIs=proton pump inhibitors; IV=intravenous; UGIB=upper
gastrointestinal bleeding.

QUESTIONS FOR FUTURE RESEARCH
• What is the optimal approach to fluid resuscitation in
patients with acute upper gastrointestinal bleeding?
• Can risk assessment tools be developed to allow accurate
early identification of high risk patients with upper
gastrointestinal bleeding, such as those who require
endoscopic therapy or those with high mortality?
• What is the optimal timing of endoscopy after upper
gastrointestinal bleeding?
• What is the exact role of hemostatic powder spray,
over-the-scope clips, and Doppler ultrasound probes in
the endoscopic management of upper gastrointestinal
bleeding?
• When is the best time to reintroduce antithrombotic drugs
after upper gastrointestinal bleeding?
intestinal bleeding (non-variceal and variceal) have been
published over the past eight years. We have therefore
referenced them as appropriate throughout. The most
recent ones—the European (2015) and Asia-Pacific
(2018) guidelines on non-variceal bleeding, and the
UK, international, and US guidelines on variceal bleed-
ing—differ slightly from earlier ones, largely because they
assessed more recently published studies (table). These
guidelines have generally been written by experts in this
field, although methodology has varied.
Conclusions
Upper gastrointestinal bleeding remains a common cause
of presentation to hospitals worldwide, and many recent
studies have assessed the management of patients with
this condition. The evidence of improved outcomes from
a relatively restrictive approach to blood transfusion and
the ability to identify patients who are at very low risk and
suitable for outpatient management have recently altered
clinical practice, and these alterations to management are
now recommended by international guidelines. RCTs and
meta-analyses confirm a benefit from pre-endoscopy anti-
biotics and vasoactive drugs in patients with cirrhosis,
and post-endoscopy high dose PPIs for high risk peptic
ulcer bleeding.
Endoscopic therapy has advanced dramatically over the
past decades, with recent additions to the endoscopist’s
“toolkit,” including hemostatic powder spray, over-the-
scope clips, and Doppler probes. These join the estab-
lished and widely studied injection therapies, thermal
probes, and clips used for non-variceal bleeding, and
endoscopic band ligation and tissue adhesive injection
for variceal bleeding. However, the newer modalities
require further study to clarify their exact role in endo-
scopic management. Technical improvements and more
widely available services for interventional radiology have
led to it being the most commonly used rescue therapy
for persistent or recurrent upper gastrointestinal bleeding
that is refractory to endoscopic treatment. Surgery is now
typically reserved for situations in which interventional
radiology is unavailable, delayed, or unsuccessful.
The more widespread use of antiplatelet and anti-
coagulants drugs has led to uncertainty in managing
patients taking these medications who develop upper
gastrointestinal bleeding. However, recent data suggest
that relatively early reintroduction of these drugs once
hemostasis has been achieved is the best approach in
those with appropriate cardiovascular indications. New
approaches under investigation for managing upper
gastrointestinal bleeding include the early use of TXA
and novel endoscopic techniques to reduce rebleeding.
These and other developments will hopefully continue
to improve management and outcomes for patients with
upper gastrointestinal bleeding.

For personal use only 10 of 13

 STAT E O F T H E A RT R E V I E W
HOW PATIENTS WERE INVOLVED IN THE CREATION OF THIS
ARTICLE
After email communication from the UK Gastroenterology
Charity “Guts-UK” (previously CORE) to their members and
related charities, three patients kindly volunteered to review
the manuscript. In response to their comments, the sections
on blood transfusion and timing of endoscopy were revised.
Thanks to Deepak Vishwanath for help with the radiological image in fig 4.
Contributors: Both authors contributed equally to the planning and writing
of the article and both are responsible for the overall content as guarantors.
Competing interests: We have read and understood BMJ policy on
declaration of interests and declare the following interests: AJS, none; LL
has had single consultancies to Takeda and to Bayer and his full competing
interests are available from her on request.
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STAT E O F T H E A RT R E V I E W

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STAT E O F T H E A RT R E V I E W

For personal use only

 Guideline a1

Diagnosis and management of nonvariceal upper

gastrointestinal hemorrhage: European Society of
Gastrointestinal Endoscopy (ESGE) Guideline

Authors Ian M. Gralnek1, 2, Jean-Marc Dumonceau3, Ernst J. Kuipers4, Angel Lanas5, David S. Sanders6, Matthew Kurien6,
Gianluca Rotondano7, Tomas Hucl8, Mario Dinis-Ribeiro9, Riccardo Marmo10, Istvan Racz11, Alberto Arezzo12,
Ralf-Thorsten Hoffmann13, Gilles Lesur14, Roberto de Franchis15, Lars Aabakken16, Andrew Veitch17, Franco Radaelli18,
Paulo Salgueiro19, Ricardo Cardoso20, Luís Maia19, Angelo Zullo21, Livio Cipolletta22, Cesare Hassan23

This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
Institutions Institutions listed at end of article.

Bibliography
DOI http://dx.doi.org/
10.1055/s-0034-1393172
Published online: 0.0.
Endoscopy 2015; 47: 1–46
© Georg Thieme Verlag KG
Stuttgart · New York
ISSN 0013-726X
Corresponding author
Ian M. Gralnek, MD, MSHS
Institute of Gastroenterology
and Liver Diseases, Ha'Emek
Medical Center
Rappaport Faculty of Medicine,
Technion-Israel Institute of
Technology
Afula, Israel 18101
Fax: +972-4-6495314
ian_gr@clalit.org.il
This Guideline is an official statement of the European Society of Gastrointestinal Endoscopy (ESGE). It
addresses the diagnosis and management of nonvariceal upper gastrointestinal hemorrhage (NVUGIH).
Main Recommendations
MR1. ESGE recommends immediate assessment of
hemodynamic status in patients who present with
acute upper gastrointestinal hemorrhage (UGIH),
with prompt intravascular volume replacement
initially using crystalloid fluids if hemodynamic
instability exists (strong recommendation, mod-
erate quality evidence).
MR2. ESGE recommends a restrictive red blood cell
transfusion strategy that aims for a target hemo-
globin between 7 g/dL and 9 g/dL. A higher target
hemoglobin should be considered in patients
with significant co-morbidity (e. g., ischemic car-
diovascular disease) (strong recommendation,
moderate quality evidence).
MR3. ESGE recommends the use of the Glasgow-
Blatchford Score (GBS) for pre-endoscopy risk stra-
tification. Outpatients determined to be at very
low risk, based upon a GBS score of 0 – 1, do not re-
quire early endoscopy nor hospital admission. Dis-
charged patients should be informed of the risk of
recurrent bleeding and be advised to maintain
contact with the discharging hospital (strong re-
commendation, moderate quality evidence).
MR4. ESGE recommends initiating high dose intra-
venous proton pump inhibitors (PPI), intravenous
bolus followed by continuous infusion (80 mg
then 8 mg/hour), in patients presenting with acute
UGIH awaiting upper endoscopy. However, PPI in-
fusion should not delay the performance of early
endoscopy (strong recommendation, high quality
evidence).
MR5. ESGE does not recommend the routine use of
nasogastric or orogastric aspiration/lavage in pa-
tients presenting with acute UGIH (strong recom-
mendation, moderate quality evidence).
MR6. ESGE recommends intravenous erythromy-
cin (single dose, 250 mg given 30 – 120 minutes
prior to upper gastrointestinal [GI] endoscopy) in
patients with clinically severe or ongoing active
UGIH. In selected patients, pre-endoscopic infu-
sion of erythromycin significantly improves endo-
scopic visualization, reduces the need for second-
look endoscopy, decreases the number of units of
blood transfused, and reduces duration of hospital
stay (strong recommendation, high quality evi-
dence).
MR7. Following hemodynamic resuscitation, ESGE
recommends early (≤ 24 hours) upper GI endos-
copy. Very early (< 12 hours) upper GI endoscopy
may be considered in patients with high risk clini-
cal features, namely: hemodynamic instability (ta-
chycardia, hypotension) that persists despite on-
going attempts at volume resuscitation; in-hospi-
tal bloody emesis/nasogastric aspirate; or contra-
indication to the interruption of anticoagulation
(strong recommendation, moderate quality evi-
dence).
MR8. ESGE recommends that peptic ulcers with
spurting or oozing bleeding (Forrest classification
Ia and Ib, respectively) or with a nonbleeding visi-
ble vessel (Forrest classification IIa) receive endo-
scopic hemostasis because these lesions are at
high risk for persistent bleeding or rebleeding
(strong recommendation, high quality evidence).
MR9. ESGE recommends that peptic ulcers with an
adherent clot (Forrest classification IIb) be consid-
ered for endoscopic clot removal. Once the clot is
removed, any identified underlying active bleed-
ing (Forrest classification Ia or Ib) or nonbleeding
visible vessel (Forrest classification IIa) should re-
ceive endoscopic hemostasis (weak recommenda-
tion, moderate quality evidence).
MR10. In patients with peptic ulcers having a flat
pigmented spot (Forrest classification IIc) or clean
base (Forrest classification III), ESGE does not re-
commend endoscopic hemostasis as these stigma-

Gralnek Ian M et al. Nonvariceal upper gastrointestinal hemorrhage: ESGE Guideline … Endoscopy 2015; 47: a1–a46
a2 Guideline

ta present a low risk of recurrent bleeding. In selected clinical set-
tings, these patients may be discharged to home on standard PPI
therapy, e. g., oral PPI once-daily (strong recommendation, moder-
ate quality evidence).
MR11. ESGE recommends that epinephrine injection therapy not
be used as endoscopic monotherapy. If used, it should be combined
with a second endoscopic hemostasis modality (strong recom-
mendation, high quality evidence).
MR12. ESGE recommends PPI therapy for patients who receive
endoscopic hemostasis and for patients with adherent clot not re-
ceiving endoscopic hemostasis. PPI therapy should be high dose
and administered as an intravenous bolus followed by continuous
infusion (80 mg then 8 mg/hour) for 72 hours post endoscopy
(strong recommendation, high quality evidence).
MR13. ESGE does not recommend routine second-look endoscopy
sis if indicated. In the case of failure of this second attempt at he-
mostasis, transcatheter angiographic embolization (TAE) or sur-
gery should be considered (strong recommendation, high quality
evidence).
MR14. In patients with NVUGIH secondary to peptic ulcer, ESGE re-
commends investigating for the presence of Helicobacter pylori in
the acute setting with initiation of appropriate antibiotic therapy
when H. pylori is detected. Re-testing for H. pylori should be per-
formed in those patients with a negative test in the acute setting.
Documentation of successful H. pylori eradication is recommended
(strong recommendation, high quality evidence).
MR15. In patients receiving low dose aspirin for secondary cardio-
vascular prophylaxis who develop peptic ulcer bleeding, ESGE re-
commends aspirin be resumed immediately following index
endoscopy if the risk of rebleeding is low (e. g., FIIc, FIII). In patients

as part of the management of nonvariceal upper gastrointestinal
hemorrhage (NVUGIH). However, in patients with clinical evi-
dence of rebleeding following successful initial endoscopic hemo-
stasis, ESGE recommends repeat upper endoscopy with hemosta-
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
with high risk peptic ulcer (FIa, FIb, FIIa, FIIb), early reintroduction
of aspirin by day 3 after index endoscopy is recommended, provid-
ed that adequate hemostasis has been established (strong recom-
mendation, moderate quality evidence).

Abbreviations Introduction
! !
APC argon plasma coagulation Acute upper gastrointestinal hemorrhage (UGIH) is a common
ASA American Society of Anesthesiologists condition worldwide that has an estimated annual incidence of
DAPT dual antiplatelet therapy 40−150 cases per 100 000 population [1, 2], frequently leads to
CHADS2 congestive heart failure, hypertension, age ≥ 75 years, hospital admission, and has significant associated morbidity and
diabetes mellitus, and previous stroke or transient mortality, especially in the elderly. The most common causes of
ischemic attack [risk score] acute UGIH are nonvariceal [1, 2]. This includes peptic ulcers, 28
CI confidence interval % – 59 % (duodenal ulcer 17 % – 37 % and gastric ulcer 11 % – 24 %);
DOAC direct oral anticoagulant mucosal erosive disease of the esophagus/stomach/duodenum,
ESGE European Society of Gastrointestinal Endoscopy 1 % – 47 %; Mallory – Weiss syndrome, 4 % – 7 %; upper GI tract ma-
FFP fresh frozen plasma lignancy, 2 % – 4 %; other diagnosis, 2 % – 7 %; or no exact cause
GBS Glasgow-Blatchford Score identified, 7 % – 25 % [1, 2]. Moreover, in 16 % – 20 % of acute UGIH
GI gastrointestinal cases, more than one endoscopic diagnosis may be identified as
GRADE Grading of Recommendations Assessment, the cause of bleeding. The aim of this evidence-based consensus
Development and Evaluation guideline is to provide medical caregivers with a comprehensive
HR hazard ratio review and recommendations on the clinical and endoscopic
INR international normalized ratio management of NVUGIH.
NBVV nonbleeding visible vessel
NNT number needed to treat
NOAC non-VKA oral anticoagulant Methods
NVUGIH nonvariceal upper gastrointestinal hemorrhage !
PAR protease-activated receptor The ESGE commissioned this guideline on NVUGIH and appoin-
PCC prothrombin complex concentrate ted a guideline leader (I.M.G.) who in collaboration with the Chair
PICO patients, interventions, controls, outcomes of the ESGE Guidelines Committee (C.H.), invited the listed au-
PPI proton pump inhibitor thors to participate in the guideline development and review.
OR odds ratio Key questions were prepared by the coordinating team (I.M.G.
PUB peptic ulcer bleeding and C.H.) and reviewed and approved by all task force members.
RBC red blood cell The coordinating team formed four task force subgroups, each
RCT randomized controlled trial with its own coordinator, and divided the key topics/questions
RR relative risk or risk ratio amongst these four task force subgroups (see Appendix e1, on-
TAE transcatheter angiographic embolization line-only). Task force members included gastroenterologists/gas-
UGIH upper gastrointestinal hemorrhage trointestinal endoscopists, an interventional radiologist, and a
VCE videocapsule endoscopy surgeon. Clinical questions were formulated using the PICO (pa-
VKA vitamin K antagonist tients, interventions, controls, outcomes) methodology.
Each task force subgroup performed a systematic literature
search to identify the relevant literature that was subsequently
used to prepare evidence-based, well-balanced statements on
each of their assigned key questions. The Ovid MEDLINE, EM-
BASE, Google/Google Scholar, and the Cochrane Database of Sys-

Gralnek Ian M et al. Nonvariceal upper gastrointestinal hemorrhage: ESGE Guideline … Endoscopy 2015; 47: a1–a46

tematic Reviews were searched for English-language articles in-
cluding at a minimum the following key words: nonvariceal up-
per gastrointestinal (GI) hemorrhage/bleeding, peptic ulcer he-
morrhage/bleeding, fluid resuscitation, fluid therapy, critical ill-
ness, crystalloid solutions, colloid solutions, plasma transfusions,
red blood cell transfusion, platelet transfusion, hemoglobin, re-
strictive transfusion strategy, liberal transfusion strategy, risk
stratification, mortality, rebleeding, anti-thrombotic agent, anti-
platelet agent, aspirin, dual anti-platelet therapy (DAPT), anti-co-
agulation/anti-coagulant, direct/new oral anticoagulants
(DOACs), coagulopathy, vitamin K inhibitor/antagonist, prokinet-
ic agent, erythromycin, fresh frozen plasma, nasogastric tube, or-
ogastric tube, proton pump inhibitor, prokinetic agent, erythro-
mycin, endoscopic hemostasis, injection therapy, thermal ther-
apy (contact, non-contact), mechanical therapy/endoscopic clip-
ping, topical hemostasis therapy, second-look endoscopy, helico-
bacter pylori, H. pylori, transcatheter angiographic embolization
(TAE), and surgery. The hierarchy of studies included as part of
this evidence-based guideline was, in decreasing order of evi-
dence level, published systematic reviews/meta-analyses, ran-
domized controlled trials (RCTs), prospective and retrospective
observational studies. All selected articles were graded using the
Grading of Recommendations Assessment, Development and
Evaluation (GRADE) system [3, 4].
Each task force subgroup proposed statements for each of their
assigned key questions which were discussed and voted on dur-
ing the NVUGIH task force guideline meeting held in Berlin, Ger-
many in November 2014. In August 2015, a manuscript draft pre-
pared by I.M.G. was sent to all task force members. After agree-
ment on a final version, the manuscript was reviewed by two
members of the ESGE Governing Board and sent for further com-
ments to the National Societies and ESGE individual members.
After agreement on a final version, the manuscript was submit-
ted to the journal Endoscopy for publication. All authors agreed
on the final revised manuscript.
This NVUGIH guideline will be considered for review and updat-
ing in 2020, or sooner if new relevant evidence becomes avail-
able. Any updates to this guideline in the interim will be noted
on the ESGE website: http://www.esge.com/esge-guidelines.
html.
Statements and recommendations
! that aggressive volume resuscitation, including correction of coa-
See ●
" Table 1.
Initial patient evaluation and hemodynamic
resuscitation
ESGE recommends immediate assessment of hemodynamic status in patients
who present with acute upper gastrointestinal hemorrhage (UGIH), with
prompt intravascular volume replacement initially using crystalloid fluids if
hemodynamic instability exists (strong recommendation, moderate quality
evidence).
The goals of hemodynamic resuscitation are to correct intravas-
cular hypovolemia, restore adequate tissue perfusion, and pre-
vent multi-organ failure. Early intensive hemodynamic resuscita-
tion of patients with acute UGIH has been shown to significantly
decrease mortality [5]. In an observational study of patients with
acute UGIH and hemodynamic instability, patients who received
intensive hemodynamic resuscitation had significantly fewer
myocardial infarctions and lower mortality compared with those
Gralnek Ian M et al. Nonvariceal upper gastrointestinal hemorrhage: ESGE Guideline … Endoscopy 2015; 47: a1–a46
Guideline a3
in the “observation group” (P = 0.04 for both comparisons). How-
ever, there is no evidence from randomized controlled trials
(RCTs), for or against early or large-volume intravenous fluid ad-
ministration in uncontrolled hemorrhage [6, 7]. Moreover, the se-
lection of resuscitation fluid type in critically ill patients requires
careful consideration based on safety, effects on patient out-
comes, and costs. To date, there is ongoing uncertainty regarding
the ideal fluid administration strategy in this clinical setting [8,
9].
ESGE recommends a restrictive red blood cell transfusion strategy that aims
for a target hemoglobin between 7 g/dL and 9 g/dL. A higher target hemo-
globin should be considered in patients with significant co-morbidity (e. g.,
ischemic cardiovascular disease) (strong recommendation, moderate quality
evidence).
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
The use of red blood cell (RBC) transfusions may be lifesaving fol-
lowing massive UGIH. However, the role of RBC transfusion in
less torrential GI bleeding remains controversial, with uncertain-
ty existing regarding the hemoglobin level at which blood trans-
fusion should be initiated. This uncertainty reflects concerns
from both the critical care and gastroenterology literature sug-
gesting poorer outcomes in patients managed with a liberal RBC
transfusion strategy [2, 10, 11]. In a recent RCT that included 921
patients presenting with all causes of acute UGIH, a restrictive
RBC transfusion strategy (target hemoglobin, 7 to 9 g/dL) was
compared with a more liberal transfusion strategy (target hemo-
globin, 9 to 11 g/dL) [12]. The restrictive RBC transfusion group
had significantly improved 6-week survival (95 % vs. 91 %; hazard
ratio [HR] 0.55, 95 % confidence interval [CI] 0.33 – 0.92) and re-
duced rebleeding (10 % vs.16 %; HR 0.68, 95 %CI 0.47 – 0.98) [12].
In the subgroup of patients with NVUGIH (n = 699), there was a
statistical trend towards lower mortality in the restrictive vs. lib-
eral RBC transfusion strategy (3.7 % vs. 6.9 %, P = 0.065). Because
the study was not powered to specifically evaluate NVUGIH,
these findings should be interpreted with caution. Other limita-
tions of this study include the exclusion of patients with massive
exsanguinating bleeding and defined co-morbidities. Further-
more, all patients underwent endoscopy within 6 hours of pre-
sentation, which may not be feasible in everyday clinical practice.
Coagulopathy at the time of NVUGIH presentation is another fre-
quent and adverse prognostic factor [13]. Published data for the
management of coagulopathy are limited and inconclusive. One
small cohort study using an historical comparison group showed
gulopathy (international normalized ratio [INR] < 1.8), led to an
improvement in mortality outcomes [5]. In a systematic review
that evaluated the relevance of initial INR before correction in pa-
tients with NVUGIH, INR did not appear to predict rebleeding, yet
after adjusting for potential confounders, an initial INR > 1.5 pre-
dicted mortality (odds ratio [OR] 1.96, 95 %CI 1.13 – 3.41) [14].
This may in part reflect the presence of underlying liver disease.
There is however no available evidence to help guide coagulopa-
thy correction in critically ill patients and wide variation in man-
agement exists in this area, indicating clinical uncertainty re-
garding optimal practice [15]. Platelet count has not been shown
to be a predictor of either rebleeding or mortality. Currently,
there is no high quality evidence to guide platelet transfusion
thresholds, although a platelet transfusion threshold of 50 × 109/
L has been proposed for most patients, with a target of 10 × 109/L
for patients in whom platelet dysfunction is suspected [16].
a4 Guideline

Table 1 Summary of Guideline statements and recommendations. Diagnosis and management of nonvariceal upper gastrointestinal hemorrhage: European
Society of Gastrointestinal Endoscopy (ESGE) Guideline.

Initial patient evaluation and hemodynamic resuscitation

1 ESGE recommends immediate assessment of hemodynamic status in patients who present with acute upper gastrointestinal hemorrhage (UGIH), with
prompt intravascular volume replacement initially using crystalloid fluids if hemodynamic instability exists (strong recommendation, moderate quality
evidence).
2 ESGE recommends a restrictive red blood cell transfusion strategy that aims for a target hemoglobin between 7 g/dL and 9 g/dL. A higher target he-
moglobin should be considered in patients with significant co-morbidity (e. g., ischemic cardiovascular disease) (strong recommendation, moderate
quality evidence).
Risk stratification
3 ESGE recommends the use of a validated risk stratification tool to stratify patients into high and low risk groups. Risk stratification can aid clinical deci-
sion making regarding timing of endoscopy and hospital discharge (strong recommendation, moderate quality evidence).
4 ESGE recommends the use of the Glasgow-Blatchford Score (GBS) for pre-endoscopy risk stratification. Outpatients determined to be at very low risk,
based upon a GBS score of 0 – 1, do not require early endoscopy nor hospital admission. Discharged patients should be informed of the risk of recurrent
bleeding and be advised to maintain contact with the discharging hospital (strong recommendation, moderate quality evidence).

This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
Pre-endoscopy management
5 For patients taking vitamin K antagonists (VKAs), ESGE recommends withholding the VKA and correcting coagulopathy while taking into account the
patient's cardiovascular risk in consultation with a cardiologist. In patients with hemodynamic instability, administration of vitamin K, supplemented with
intravenous prothrombin complex concentrate (PCC) or fresh frozen plasma (FFP) if PCC is unavailable, is recommended (strong recommendation, low
quality evidence).
6 If the clinical situation allows, ESGE suggests an international normalized ratio (INR) value < 2.5 before performing endoscopy with or without endo-
scopic hemostasis (weak recommendation, moderate quality evidence).
7 ESGE recommends temporarily withholding new direct oral anticoagulants (DOACs) in patients with suspected acute NVUGIH in coordination/consul-
tation with the local hematologist/cardiologist (strong recommendation, very low quality evidence).
8 For patients using antiplatelet agents, ESGE recommends the management algorithm detailed in●
" Fig. 2 (strong recommendation, moderate quality

evidence).
9 ESGE recommends initiating high dose intravenous proton pump inhibitors (PPI), intravenous bolus followed by continuous infusion (80 mg then 8 mg/
hour), in patients presenting with acute UGIH awaiting upper endoscopy. However, PPI infusion should not delay the performance of early endoscopy
(strong recommendation, high quality evidence).
10 ESGE does not recommend the use of tranexamic acid in patients with NVUGIH (strong recommendation, low quality evidence).
11 ESGE does not recommend the use of somatostatin, or its analogue octreotide, in patients with NVUGIH (strong recommendation, low quality evi-
dence).
12 ESGE recommends intravenous erythromycin (single dose, 250 mg given 30 – 120 minutes prior to upper GI endoscopy) in patients with clinically se-
vere or ongoing active UGIH. In selected patients, pre-endoscopic infusion of erythromycin significantly improves endoscopic visualization, reduces the
need for second-look endoscopy, decreases the number of units of blood transfused, and reduces duration of hospital stay (strong recommendation, high
quality evidence).
13 ESGE does not recommend the routine use of nasogastric or orogastric aspiration/lavage in patients presenting with acute UGIH (strong recommen-
dation, moderate quality evidence).
14 In an effort to protect the patient's airway from potential aspiration of gastric contents, ESGE suggests endotracheal intubation prior to endoscopy in
patients with ongoing active hematemesis, encephalopathy, or agitation (weak recommendation, low quality evidence).
15 ESGE recommends adopting the following definitions regarding the timing of upper GI endoscopy in acute overt UGIH relative to patient presentation:
very early < 12 hours, early ≤ 24 hours, and delayed > 24 hours (strong recommendation, moderate quality evidence).
16 Following hemodynamic resuscitation, ESGE recommends early ( ≤ 24 hours) upper GI endoscopy. Very early ( < 12 hours) upper GI endoscopy may be
considered in patients with high risk clinical features, namely: hemodynamic instability (tachycardia, hypotension) that persists despite ongoing attempts
at volume resuscitation; in-hospital bloody emesis/nasogastric aspirate; or contraindication to the interruption of anticoagulation (strong recommenda-
tion, moderate quality evidence).
17 ESGE recommends the availability of both an on-call GI endoscopist proficient in endoscopic hemostasis and on-call nursing staff with technical ex-
pertise in the use of endoscopic devices to allow performance of endoscopy on a 24 /7 basis (strong recommendation, moderate quality evidence).
Endoscopic therapy (peptic ulcer bleeding)
18 ESGE recommends the Forrest (F) classification be used in all patients with peptic ulcer hemorrhage in order to differentiate low and high risk endo-
scopic stigmata (strong recommendation, high quality evidence).
19 ESGE recommends that peptic ulcers with spurting or oozing bleeding (Forrest classification Ia and Ib respectively), or with a nonbleeding visible vessel
(Forrest classification IIa) receive endoscopic hemostasis because these lesions are at high risk for persistent bleeding or rebleeding (strong recommen-
dation, high quality evidence).
20 ESGE recommends that peptic ulcers with an adherent clot (Forrest classification IIb) be considered for endoscopic clot removal. Once the clot is re-
moved, any identified underlying active bleeding (Forrest classification Ia or Ib) or nonbleeding visible vessel (Forrest classification IIa) should receive
endoscopic hemostasis (weak recommendation, moderate quality evidence).
21 In patients with peptic ulcers having a flat pigmented spot (Forrest classification IIc) or clean base (Forrest classification III), ESGE does not recommend
endoscopic hemostasis as these stigmata present a low risk of recurrent bleeding. In selected clinical settings, these patients may be discharged to home on
standard PPI therapy, e. g., oral PPI once-daily (strong recommendation, moderate quality evidence).
22 ESGE does not recommend the routine use of Doppler ultrasound or magnification endoscopy in the evaluation of endoscopic stigmata of peptic ulcer
bleeding (strong recommendation, low quality evidence).
23 For patients with actively bleeding ulcers (FIa, FIb), ESGE recommends combining epinephrine injection with a second hemostasis modality (contact
thermal, mechanical therapy, or injection of a sclerosing agent). ESGE recommends that epinephrine injection therapy not be used as endoscopic mono-
therapy (strong recommendation, high quality evidence).

Gralnek Ian M et al. Nonvariceal upper gastrointestinal hemorrhage: ESGE Guideline … Endoscopy 2015; 47: a1–a46
 Guideline a5

Table 1 (Continuation)

Initial patient evaluation and hemodynamic resuscitation

24 For patients with nonbleeding visible vessel (FIIa), ESGE recommends mechanical therapy, thermal therapy, or injection of a sclerosing agent as
monotherapy or in combination with epinephrine injection. ESGE recommends that epinephrine injection therapy not be used as endoscopic monotherapy
(strong recommendation, high quality evidence).
25 For patients with active NVUGIH bleeding not controlled by standard endoscopic hemostasis therapies, ESGE suggests the use of a topical hemostatic
spray or over-the-scope clip as salvage endoscopic therapy (weak recommendation, low quality evidence).
Endoscopic therapy (other causes of NVUGIH)
26 For patients with acid-related causes of NVUGIH different from peptic ulcers (e. g., erosive esophagitis, gastritis, duodenitis), ESGE recommends
treatment with high dose PPI. Endoscopic hemostasis is usually not required and selected patients may be discharged early (strong recommendation, low
quality evidence).
27 ESGE recommends that patients with a Mallory – Weiss lesion that is actively bleeding receive endoscopic hemostasis. There is currently inadequate
evidence to recommend a specific endoscopic hemostasis modality. Patients with a Mallory – Weiss lesion and no active bleeding can receive high dose PPI
therapy alone (strong recommendation, moderate quality evidence).
28 ESGE recommends that a Dieulafoy lesion receive endoscopic hemostasis using thermal, mechanical (hemoclip or band ligation), or combination
therapy (dilute epinephrine injection combined with contact thermal or mechanical therapy) (strong recommendation, moderate quality evidence).

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Transcatheter angiographic embolization (TAE) or surgery should be considered if endoscopic treatment fails or is not technically feasible (strong recom-
mendation, low quality evidence).
29 In patients bleeding from upper GI angioectasias, ESGE recommends endoscopic hemostasis therapy. However, there is currently inadequate evidence
to recommend a specific endoscopic hemostasis modality (strong recommendation, low quality evidence).
30 In patients bleeding from upper GI neoplasia, ESGE recommends considering endoscopic hemostasis in order to avert urgent surgery and reduce blood
transfusion requirements. However, no currently available endoscopic treatment appears to have long-term efficacy (weak recommendation, low quality
evidence).
Post endoscopy/endoscopic hemostasis management
31 ESGE recommends PPI therapy for patients who receive endoscopic hemostasis and for patients with adherent clot not receiving endoscopic hemo-
stasis. PPI therapy should be high dose and administered as an intravenous bolus followed by continuous infusion (80 mg then 8 mg /hour) for 72 hours post
endoscopy (strong recommendation, high quality evidence).
32 ESGE suggests considering PPI therapy as intermittent intravenous bolus dosing (at least twice-daily) for 72 hours post endoscopy for patients who
receive endoscopic hemostasis and for patients with adherent clot not receiving endoscopic hemostasis. If the patient’s condition permits, high dose oral
PPI may also be an option in those able to tolerate oral medications (weak recommendation, moderate quality evidence).
33 In patients with clinical evidence of rebleeding following successful initial endoscopic hemostasis, ESGE recommends repeat upper endoscopy with
hemostasis if indicated. In the case of failure of this second attempt at hemostasis, transcatheter angiographic embolization (TAE) or surgery should be
considered (strong recommendation, high quality evidence).
34 ESGE does not recommend routine second-look endoscopy as part of the management of NVUGIH. However, second-look endoscopy may be consid-
ered in selected patients at high risk for rebleeding (strong recommendation, high quality evidence).
35 In patients with NVUGIH secondary to peptic ulcer, ESGE recommends investigating for the presence of Helicobacter pylori in the acute setting with
initiation of appropriate antibiotic therapy when H. pylori is detected. Re-testing for H. pylori should be performed in those patients with a negative test in
the acute setting. Documentation of successful H. pylori eradication is recommended (strong recommendation, high quality evidence).
36 ESGE recommends restarting anticoagulant therapy following NVUGIH in patients with an indication for long-term anticoagulation. The timing for
resumption of anticoagulation should be assessed on a patient by patient basis. Resuming warfarin between 7 and 15 days following the bleeding event
appears safe and effective in preventing thromboembolic complications for most patients. Earlier resumption, within the first 7 days, may be indicated for
patients at high thrombotic risk (strong recommendation, moderate quality evidence).
37 In patients receiving low dose aspirin for primary cardiovascular prophylaxis who develop peptic ulcer bleeding, ESGE recommends withholding as-
pirin, re-evaluating the risks/benefits of ongoing aspirin use in consultation with a cardiologist, and resuming low dose aspirin following ulcer healing or
earlier if clinically indicated (strong recommendation, low quality evidence).
38 In patients receiving low dose aspirin for secondary cardiovascular prophylaxis who develop peptic ulcer bleeding, ESGE recommends aspirin be re-
sumed immediately following index endoscopy if the risk of rebleeding is low (e. g., FIIc, FIII). In patients with high risk peptic ulcer (FIa, FIb, FIIa, FIIb), early
reintroduction of aspirin by day 3 after index endoscopy is recommended, provided that adequate hemostasis has been established (strong recommen-
dation, moderate quality evidence).
39 In patients receiving dual antiplatelet therapy (DAPT) who develop peptic ulcer bleeding, ESGE recommends continuing low dose aspirin therapy. Early
cardiology consultation should be obtained regarding the timing of resuming the second antiplatelet agent (strong recommendation, low quality evi-
dence).
40 In patients requiring dual antiplatelet therapy (DAPT) and who have had NVUGIH, ESGE recommends the use of a PPI as co-therapy (strong recom-
mendation, moderate quality evidence).

admission. Discharged patients should be informed of the risk of recurrent

Risk stratification bleeding and be advised to maintain contact with the discharging hospital
(strong recommendation, moderate quality evidence).

Risk stratification of patients presenting with acute UGIH can as-

ESGE recommends the use of a validated risk stratification tool to stratify pa-
tients into high and low risk groups. Risk stratification can aid clinical decision
making regarding timing of endoscopy and hospital discharge (strong re-
commendation, moderate quality evidence).
ESGE recommends the use of the Glasgow-Blatchford Score (GBS) for pre-
sist in identifying those who may require more urgent interven-
tion and help triage patients to in-hospital vs. out-of-hospital
management. A number of scoring tools have been created for
predicting outcomes following acute UGIH, with the Glasgow-
Blatchford Score (GBS) (● " Table 2) and Rockall score being the

endoscopy risk stratification. Outpatients determined to be at very low risk, most widely evaluated and adopted [17 – 19]. However, no single
based upon a GBS score of 0 – 1, do not require early endoscopy nor hospital
scoring tool has been shown to excel at predicting all relevant

Gralnek Ian M et al. Nonvariceal upper gastrointestinal hemorrhage: ESGE Guideline … Endoscopy 2015; 47: a1–a46
a6 Guideline

Pre-endoscopy management
Table 2 Glasgow-Blatchford Score (GBS).
Initial management of antithrombotic agents
Points (anticoagulants and antiplatelet agents)
Systolic blood pressure, mmHg
100 – 109 1 For patients taking vitamin K antagonists (VKAs), ESGE recommends with-
90 – 99 2 holding the VKA and correcting coagulopathy while taking into account the
< 90 3 patient’s cardiovascular risk in consultation with a cardiologist. In patients
Blood urea nitrogen, mmol/L with hemodynamic instability, administration of vitamin K, supplemented
with intravenous prothrombin complex concentrate (PCC) or fresh frozen
6.5 – 7.9 2
plasma (FFP) if PCC is unavailable, is recommended (strong recommendation,
8.0 – 9.9 3 low quality evidence).
10.0 – 24.9 4
≥ 25.0 6
Hemoglobin for men, g/dL If the clinical situation allows, ESGE suggests an international normalized ratio
12.0 – 12.9 1 (INR) value < 2.5 before performing endoscopy with or without endoscopic
hemostasis (weak recommendation, moderate quality evidence).
10.0 – 11.9 3
< 10.0 6

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Hemoglobin for women, g/dL GI bleeding represents a serious complication of VKA therapy,
10.0 – 11.9 1 with an incidence of 1 % – 4 % per year [29, 30]. Discontinuation
< 10.0 6 of anticoagulants and correction of coagulopathy before endos-
Other risk variables copy is the “standard of practice” in patients with clinically sig-
Pulse ≥ 100 1 nificant GI bleeding [31 – 33]. Because data are limited, specific
Melena 1 strategies to reverse VKAs in a patient with acute overt UGIH
Syncope 2 vary [34]. Practice guidelines recommend urgent reversal in all
Hepatic disease 2 patients presenting with serious, life-threatening bleeding (i. e.,
Cardiac failure 2
hemodynamic instability or shock), either in the case of thera-
TOTAL GBS __________________ peutic or supratherapeutic INR elevations [32, 35]. For patients
GBS restricted for use only in nonhospitalized, ambulatory patients
Risk variables measured at time of patient presentation
who are not actively bleeding and are hemodynamically stable,
GBS = 0 – 1 denotes “low-risk” intravenous vitamin K administration may be an option. When
more urgent reversal is required, administration of prothrombin
complex concentrates (PCCs) or fresh frozen plasma (FFP) is nec-
outcomes in acute UGIH (e. g., rebleeding, need for intervention, essary, with concomitant intravenous administration of 5 – 10 mg
mortality) [19]. This is not surprising as the most validated risk vitamin K to prevent “rebound coagulopathy” once the trans-
scores were derived to assess a specific UGIH outcome: that for fused factors have been cleared. Prothrombin complex concen-
the Rockall score being mortality and for the GBS being the need trates contain clotting factors prepared from pooled and concen-
for intervention [17, 18]. trated human plasma and are preferred over FFP because of sev-
A recent systematic review evaluating the accuracy of the avail- eral advantages, including no need to check the patient’s blood
able UGIH risk stratification tools demonstrated substantial het- group, less risk for volume overload because of smaller transfu-
erogeneity in predicted outcomes and highlighted that methodo- sion volume, faster onset of action, similar thrombotic risk pro-
logical quality of the prediction scores was less than optimal [19]. file, and minimal risk of infectious transmission, albeit at a higher
Regarding the need for intervention, retrospective and prospec- cost [36 – 40]. A recent prospective, nonrandomized, comparative
tive studies have assessed the prognostic value of the GBS vs. the study of 40 warfarin users who presented with UGIH and an INR
Rockall score. These studies showed that the GBS correctly iden- > 2.1 reported that patients who received PCC had a near normal-
tified 98 % (95 %CI 89 % – 100 %) of those patients who did not re- ized INR at 2 hours following infusion (INR = 1.5) while those who
quire any subsequent intervention while 83 % (95 %CI 71 % – 91 %) received FFP had an INR of 2.4 at 6 hours following infusion [38].
of those patients were identified using the Rockall score. Ran- No patient in the PCC group had active bleeding at endoscopy
domized controlled trials and observational studies consistently compared with 7 in the FFP group (0 vs. 35 %, P < 0.01). The risk
indicate that clinical, endoscopic, and social factors may identify of thrombosis following PCC administration approximates 1 %,
patients who may be safely discharged for outpatient manage- and is similar to that reported with FFP [39, 40].
ment [20 – 28]. The most frequent adverse event reported is re-
bleeding ranging between 0.5 % and 4 %, with no deaths or hospi-
ESGE recommends temporarily withholding new direct oral anticoagulants
tal readmissions for surgery reported. Moreover, studies consis- (DOACs) in patients with suspected acute NVUGIH in coordination/consulta-
tently indicate that outpatient management of appropriately se- tion with the local hematologist/cardiologist (strong recommendation, very
low quality evidence).
lected patients with acute UGIH reduces resource utilization [20,
21, 27]. Emergency department discharge without inpatient As an alternative to heparin and VKAs, the new non-VKA oral an-
endoscopy (i. e., outpatient management) should be considered ticoagulants (NOACs; also referred to as direct oral anticoagulants
for patients if: systolic blood pressure ≥ 110 mmHg, pulse < 100 [DOACs]) are being rapidly adopted worldwide, primarily for
beats/minute, hemoglobin ≥ 13.0 g/dL for men or ≥ 12.0 g/dL for thromboembolic prevention in patients with nonvalvular atrial
women, blood urea nitrogen < 18.2 mg/dL, along with the absence fibrillation and for prophylaxis or treatment of venous throm-
of melena, syncope, hepatic disease, and cardiac failure [18]. (See boembolism [41]. These pharmacological agents do however,
Appendix e2, online-only.) present a risk of significant GI bleeding similar to or greater than
that reported with warfarin [42, 43]. Moreover, DOACs differ in
comparison with heparin and VKA. Specifically, in the absence
of renal or hepatic failure, DOAC clearance and the subsequent

Gralnek Ian M et al. Nonvariceal upper gastrointestinal hemorrhage: ESGE Guideline … Endoscopy 2015; 47: a1–a46
 Guideline a7

Acute upper GI hemorrhage in a patient using antiplatelet agent(s) (APA) Fig. 1 Algorithm for the management of patients
with acute upper gastrointestinal hemorrhage who
are using antiplatelet agent(s): European Society of
Upper GI endoscopy demonstrates a nonvariceal source of bleeding (e.g. peptic ulcer bleed) Gastrointestinal Endoscopy (ESGE) Guideline.

High risk endoscopic stigmata identified Low risk endoscopic stigmata identified
(FIa, FIb, FIIa, FIIb) (FIIc, FIII)

APA used for primary prophylaxis
▪ Withhold low dose acetylsalicylic acid
(ASA)
▪ Re-evaluate risks and benefits of
ongoing low dose ASA use
▪ Resume low dose ASA after ulcer
healing or earlier if clinically indicated
APA used for primary prophylaxis
▪ Withhold low dose ASA
▪ Re-evaluate risks and benefits of
ongoing low dose ASA use
▪ Resume low dose ASA at hospital
discharge if clinically indicated

APA used for secondary prophylaxis
(known cardiovascular disease)
1 Patients on low dose ASA alone
▪ Resume low dose ASA by day 3 following
index endoscopy
▪ Second-look endoscopy at the discretion of
the endoscopist may be considered
2 Patients on dual antiplatelet therapy (DAPT)
▪ Continue low dose ASA without interruption
▪ Early cardiology consultation for
recommendation on resumption/
continuation of second APA
▪ Second-look endoscopy at the discretion of
the endoscopist may be considered
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APA used for secondary prophylaxis
(known cardiovascular disease)
1 Patients on low dose ASA alone
▪ Continue low dose ASA without interruption
2 Patients on dual antiplatelet therapy (DAPT)
▪ Continue DAPT without interruption
For patients using a non-ASA APA as monotherapy
(e.g., thienopyridine alone), low-dose ASA may be
given as substitute for interval period in patients
with no contraindication or allergy to ASA.
Early cardiology consultation should be obtained
for further APA recommendations.

loss of anticoagulation effect is rapid and predictable (occurring
gradually over 12 – 24 hours), routine laboratory tests are not
sensitive for the quantitative assessment of their anticoagulant
activity, and there is currently no specific reversal agent/antidote
for emergency use with any DOAC, although potential agents are
in development and may be commercially available in the next
1 – 2 years [44 – 46]. As there are no published clinical trials ad-
dressing the management of GI bleeding in patients using DOAC,
current recommendations are based on expert opinion or labora-
tory end-points [47 – 49].
At the time of patient presentation with acute UGIH, DOACs
should be temporarily withheld. Given their relatively short
half-life, time is the most important antidote against DOACs.
Strategies to accelerate anticoagulation reversal are supported
only by data collected from healthy human volunteers, animal
models, and in vitro studies [50]. Based on those data, vitamin K
or FFP have no place as reversal agents for DOACs. Prothrombin
complex concentrates or activated PCC may be considered in pa-
tients with severe or life-threatening bleeding, and hemodialysis
can be used to reduce the blood concentration of dabigatran, but
not that of rivaroxaban and apixaban which are more tightly
bound to plasma proteins [48, 49, 51]. Additional data on the clin-
ical effectiveness of these strategies in acutely bleeding patients
are urgently needed.
For patients using antiplatelet agents, ESGE recommends the management
algorithm detailed in●" Fig. 1 (strong recommendation, moderate quality
evidence).
Antiplatelet agents include low dose aspirin and thienopyridines
(e. g., clopidogrel, prasugrel, ticlopidine) that irreversibly inhibit
platelet aggregation, ticagrelor a reversible P2Y12 receptor an-
tagonist, and vorapaxar, a protease-activated receptor (PAR-1)
antagonist that inhibits thrombin. The minimum duration of an-
tiplatelet agent discontinuation that allows for restoration of nor-
mal platelet aggregation is 5 – 7 days [52].
Studies have shown that in patients taking low dose aspirin for
secondary cardiovascular prophylaxis, all-cause mortality was
lower if aspirin was not discontinued following peptic ulcer
bleeding [53, 54]. In an RCT, 156 recipients of low dose aspirin
for secondary prophylaxis who had peptic ulcer bleeding were
randomized to receive continuous aspirin or placebo [53]. At 8-
week follow up, all-cause mortality was lower in the patients
randomized to aspirin compared with placebo (1.3 % vs. 12.9 %,
95 %CI 3.7 % – 19.5 %; hazard ratio [HR] 0.20), with the difference
being attributable to cardiovascular, cerebrovascular, or GI com-
plications. The 30-day ulcer rebleeding rate was not significantly
greater in the aspirin group. Patients who required dual antipla-
telet therapy (DAPT) were excluded from this study. In a subse-
quent retrospective analysis that included 118 low dose aspirin
recipients who had been treated for peptic ulcer bleeding and fol-
lowed-up for a median of 2 years, 47 (40 %) patients stopped as-
pirin [54]. Patients who discontinued aspirin and those who con-
tinued aspirin had similar mortality rates (31 %). However, in a
subgroup analysis limited to patients with cardiovascular co-
morbidities, those patients who discontinued aspirin had an al-
most fourfold increase in the risk of death or acute cardiovascular
event (P < 0.01) [54]. Randomized controlled trials have shown
that neither aspirin nor clopidogrel use impede ulcer healing
promoted by proton pump inhibitors (PPI) [55, 56].
Pharmacological therapy
ESGE recommends initiating high dose intravenous proton pump inhibitors
(PPI), intravenous bolus followed by continuous infusion (80 mg then 8 mg/
hour), in patients presenting with acute UGIH awaiting upper endoscopy.

Gralnek Ian M et al. Nonvariceal upper gastrointestinal hemorrhage: ESGE Guideline … Endoscopy 2015; 47: a1–a46
a8 Guideline
However, PPI infusion should not delay the performance of early endoscopy
(strong recommendation, high quality evidence).
A Cochrane meta-analysis of 6 RCTs (n = 2223 patients) showed
that administering PPIs before endoscopy significantly decreases
the incidence of high risk stigmata of hemorrhage at the time of
index endoscopy (37.2 % vs. 46.5 %; OR 0.67, 95 %CI 0.54 – 0.84)
and the need for endoscopic hemostasis (8.6 % vs. 11.7 %; OR
0.68, 95 %CI 0.50 – 0.93), but has no effect on rebleeding, need for
surgery, or mortality [57].
Cost– effectiveness studies suggest that high dose PPI infusion
prior to endoscopy for patients with UGIH is more effective and
less costly than placebo [58, 59]. (See Appendix e3, online-only.)
ESGE does not recommend the use of tranexamic acid in patients with NVU-
GIH (strong recommendation, low quality evidence).
Tranexamic acid reduces clot breakdown by inhibiting the fibri-
nolytic action of plasmin. A recent RCT demonstrated that tra-
nexamic acid significantly reduces bleeding-related and all-cause
mortality in trauma patients with significant hemorrhage [60]. A
Cochrane meta-analysis evaluating the use of tranexamic acid in
1654 UGIH patients showed a beneficial effect of tranexamic acid
on mortality when compared with placebo (relative risk [RR]
0.61, 95 %CI 0.42 – 0.89), but not on other patient outcomes in-
cluding bleeding, surgery, or transfusion requirements [61].
However, the beneficial effect on mortality did not persist in sub-
group analysis. The studies included in this meta-analysis have
important limitations that affect their generalizability including
their methodological quality and the fact that the majority were
conducted before the widespread use of therapeutic endoscopy
and PPIs. To date, no controlled trial assessing the role of alterna-
tive antifibrinolytic agents (e. g., aminocaproic acid, aprotinin) in
patients with acute UGIH has been reported. (See Appendix e4,
online-only.)
ESGE does not recommend the use of somatostatin, or its analogue octreo-
tide, in patients with NVUGIH (strong recommendation, low quality evi-
dence).
Somatostatin, and its analogue octreotide, inhibit both acid and
pepsin secretion while also reducing gastroduodenal mucosal
blood flow [62]. However, they are not routinely recommended
in NVUGIH (e. g., peptic ulcer bleeding), either pre-endoscopy or
as an adjunctive therapy post endoscopy, since published data
show little or no benefit attributable to these pharmacological
agents. (See Appendix e5, online-only.)
ESGE recommends intravenous erythromycin (single dose, 250 mg given 30 –
120 minutes prior to upper GI endoscopy) in patients with clinically severe or
ongoing active UGIH. In selected patients, pre-endoscopic infusion of ery-
thromycin significantly improves endoscopic visualization, reduces the need
for second-look endoscopy, decreases the number of units of blood trans-
fused, and reduces duration of hospital stay (strong recommendation, high
quality evidence).
It has been reported that in 3 % to 19 % of UGIH cases, no obvious
cause of bleeding is identified [63, 64]. This may in part be related
to the presence of blood and clots impairing endoscopic visuali-
zation. There are four published meta-analyses evaluating the
role of prokinetic agent infusion prior to upper GI endoscopy in
patients presenting with acute UGIH [65 – 68]. The most recently
published meta-analysis (n = 558 patients) showed that erythro-
mycin infusion prior to endoscopy significantly improved gastric
Gralnek Ian M et al. Nonvariceal upper gastrointestinal hemorrhage: ESGE Guideline … Endoscopy 2015; 47: a1–a46
mucosa visualization (OR 3.43, 95 %CI 1.81 – 6.50; P < 0.01), and
decreased the need for second-look endoscopy (OR 0.47, 95 %CI
0.26−0.83, P = 0.01), RBC units transfused (weighted mean differ-
ence −0.41, 95 %CI −0.82 to −0.01, P = 0.04), and duration of hospi-
tal stay (weighted mean difference −1.51 days, 95 %CI −2.45 to
−0.56, P < 0.01) [68].
A single intravenous dose of erythromycin is safe and generally
well tolerated, with no adverse events reported in the meta-ana-
lyses. Studies that found a significant improvement in endoscopic
visualization with pre-endoscopic erythromycin infusion includ-
ed patients admitted to the intensive care unit because of UGIH
with clinical evidence of active bleeding or hematemesis or blood
seen on nasogastric lavage. These patients are most likely to ben-
efit from erythromycin infusion prior to endoscopy. The dose of
erythromycin most commonly used is 250 mg and is infused 30
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to 120 minutes prior to upper GI endoscopy. A cost– effectiveness
study found that pre-endoscopy erythromycin infusion in UGIH
was cost-effective, primarily due to a reduction in the need for
second-look endoscopies [69]. Contraindications to erythromy-
cin administration include sensitivity to macrolide antibiotics
and prolonged QT interval.
Metoclopramide has been less studied, it has been assigned a
“black box warning” by the United States Food and Drug Admin-
istration because of the risk of neurologic side effects, and cau-
tion should therefore be advised with the use of this prokinetic
agent.
(See Appendix e6, online-only.)
Role of gastric lavage and prophylactic endotracheal
intubation
ESGE does not recommend the routine use of nasogastric or orogastric as-
piration/lavage in patients presenting with acute UGIH (strong recommenda-
tion, moderate quality evidence).
A number of studies, including a meta-analysis, have evaluated
the role of nasogastric aspiration/lavage in patients presenting
with acute UGIH [70 – 73]. In distinguishing upper from lower GI
bleeding, nasogastric aspiration has low sensitivity 44 % (95 %CI
39 % – 48 %) yet high specificity 95 % (95 %CI 90 % – 98 %). In identi-
fying severe UGIH, its sensitivity and specificity are 77 % (95 %CI
57 % – 90 %) and 76 % (95 %CI 32 % – 95 %), respectively [70]. This
meta-analysis also found that as compared to nasogastric aspira-
tion/lavage, clinical signs and laboratory findings (e. g., hemody-
namic shock and hemoglobin < 8 g/dL) had similar ability to iden-
tify severe UGIH [70]. Others have reported that nasogastric as-
piration/lavage failed to assist clinicians in correctly predicting
the need for endoscopic hemostasis, did not improve visualiza-
tion of the stomach at endoscopy, or improve clinically relevant
outcomes such as rebleeding, need for second-look endoscopy,
or blood transfusion requirements [71 – 73]. It also should be no-
ted that nasogastric aspiration/lavage is a very uncomfortable
procedure that is not well tolerated or desired by patients [74].
In an effort to protect the patient’s airway from potential aspiration of gastric
contents, ESGE suggests endotracheal intubation prior to endoscopy in pa-
tients with ongoing active hematemesis, encephalopathy, or agitation (weak
recommendation, low quality evidence).
It has been hypothesized that pre-endoscopic endotracheal intu-
bation may prevent cardiorespiratory adverse events in patients
with acute UGIH. However, between those patients who were
prophylactically intubated prior to upper GI endoscopy as com-

pared to those patients not intubated, published data show no
significant difference in patient outcomes (e. g., pulmonary as-
piration, in-hospital mortality) [75 – 77]. One study suggested
that aspiration was actually more frequent in those patients
who had undergone endotracheal intubation prior to upper GI
endoscopy [75]. At this time, endotracheal intubation prior to
upper GI endoscopy in patients with UGIH does not seem to
make a difference in patient outcome but published data are lim-
ited with small numbers of subjects and low methodological
quality.
Timing of endoscopy
ESGE recommends adopting the following definitions regarding the timing of
upper GI endoscopy in acute overt UGIH relative to patient presentation: very
early < 12 hours, early ≤ 24 hours, and delayed > 24 hours (strong recommen-
dation, moderate quality evidence).
Following hemodynamic resuscitation, ESGE recommends early ( ≤ 24 hours)
upper GI endoscopy. Very early ( < 12 hours) upper GI endoscopy may be
considered in patients with high risk clinical features, namely: hemodynamic
instability (tachycardia, hypotension) that persists despite ongoing attempts
at volume resuscitation; in-hospital bloody emesis/nasogastric aspirate; or
contraindication to the interruption of anticoagulation (strong recommenda-
tion, moderate quality evidence).
ESGE recommends the availability of both an on-call GI endoscopist proficient
in endoscopic hemostasis and on-call nursing staff with technical expertise in
the use of endoscopic devices to allow performance of endoscopy on a 24 /7
basis (strong recommendation, moderate quality evidence).
Performance of upper GI endoscopy within 24 hours of patient
presentation with suspected NVUGIH and no contraindication to
endoscopy has been proposed as a key quality indicator in the
management of upper GI bleeding [78]. In a large European ob-
servational study that included 123 centers in 7 countries, there
was wide variation in practice where anywhere from 70 % to 93 %
of 2660 unselected patients with UGIH underwent upper endos-
copy within 24 hours of hospital admission [79].
Two systematic reviews evaluating the timing of upper GI endos-
copy demonstrated improved risk assessment and reduction in
hospital length of stay if endoscopy was performed within 24
hours of patient presentation, yet the impact on need for surgery
and in-hospital mortality was variable [80, 81]. More recently, a
retrospective analysis of risk factors for mortality in more than
400 000 patients with NVUGIH found an increased mortality in
patients who failed to receive upper endoscopy within 1 day of
hospital admission (OR 1.32, 95 %CI 1.26 – 1.38) [82]. (See Appen-
dix e7, online-only.)
With respect to very early upper GI endoscopy, an RCT that in-
cluded 325 patients with peptic ulcer bleeding showed that up-
per GI endoscopy performed within 12 hours of admission (as
compared with 12 – 24 hours) resulted in a significant reduction
in transfusion requirements in patients with bloody nasogastric
lavage (P < 0.001). No such reduction was observed in patients
with “coffee grounds” or clear lavage [83]. A retrospective analy-
sis that included 934 UGIH patients showed that in the subset of
patients having a GBS ≥ 12 (n = 97, 10.4 %), the time lapse between
presentation to endoscopy was the lone independent risk factor
associated with all-cause in-hospital mortality [84]. In this study,
a cutoff time of 13 hours in delay to endoscopy best discrimina-
ted between patient survival and nonsurvival.
In patients who are hemodynamically stable and without serious
co-morbidities, RCTs have shown that performing endoscopy
Gralnek Ian M et al. Nonvariceal upper gastrointestinal hemorrhage: ESGE Guideline … Endoscopy 2015; 47: a1–a46
Guideline a9
without hospital admission facilitates discharge in up to 46 % of
patients and reduces costs/resource utilization [20, 85]. Dischar-
ging low risk suspected NVUGIH patients (GBS = 0) directly from
the emergency department without undergoing upper GI endos-
copy has been proposed as a safe and cost-saving option in multi-
ple studies in various clinical settings [18, 86 – 89]. Some investi-
gators have suggested that using a GBS ≤ 1 (see ● " Table 2) could
double the number of patients eligible for ambulatory manage-
ment while maintaining safety [89].
There are four published studies, one RCT and three prospective
case series, that have evaluated the test characteristics and accu-
racy parameters of video capsule endoscopy (VCE) in risk stratifi-
cation of patients presenting with acute UGIH [90 – 93]. The over-
all sensitivity, specificity, positive predictive value, and negative
predictive value of VCE for detecting blood in the upper GI tract
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in patients suspected of acute UGIH are 75 %, 76 %, 67 %, and 82 %
respectively. Because the data are limited, at this time there is no
role for VCE in the emergency department setting in evaluating
acute upper GIH. However, additional studies are needed to fur-
ther assess VCE in this patient population since, for low to mod-
erate risk UGIH patients, VCE may be a cost-effective modality if
post-VCE low risk patients are discharged directly home from the
emergency department and hospital admission is avoided
[94, 95].
Endoscopic management
Endoscopic diagnosis
ESGE recommends the Forrest (F) classification be used in all patients with
peptic ulcer hemorrhage in order to differentiate low and high risk endoscopic
stigmata (strong recommendation, high quality evidence).
ESGE recommends that peptic ulcers with spurting or oozing bleeding (Forr-
est classification Ia and Ib, respectively) or with a nonbleeding visible vessel
(Forrest classification IIa) receive endoscopic hemostasis because these le-
sions are at high risk for persistent bleeding or rebleeding (strong recom-
mendation, high quality evidence).
ESGE recommends that peptic ulcers with an adherent clot (Forrest classifica-
tion IIb) be considered for endoscopic clot removal. Once the clot is removed,
any identified underlying active bleeding (Forrest classification Ia or Ib) or
nonbleeding visible vessel (Forrest classification IIa) should receive endo-
scopic hemostasis (weak recommendation, moderate quality evidence).
In patients with peptic ulcers having a flat pigmented spot (Forrest classifica-
tion IIc) or clean base (Forrest classification III), ESGE does not recommend
endoscopic hemostasis as these stigmata present a low risk of recurrent
bleeding. In selected clinical settings, these patients may be discharged to
home on standard PPI therapy, e. g., oral PPI once-daily (strong recommen-
dation, moderate quality evidence).
The Forrest (F) classification was developed more than 40 years
ago in an attempt to standardize the characterization of peptic
ulcers [96]. The Forrest classification is defined as follows: FIa
spurting hemorrhage, FIb oozing hemorrhage, FIIa nonbleeding
visible vessel, FIIb an adherent clot, FIIc flat pigmented spot, and
FIII clean base ulcer [97 – 99]. This classification has been used in
numerous studies that aimed to identify patients at risk of per-
sistent ulcer bleeding, rebleeding and mortality. Most of these
studies have shown that the presence of an ulcer endoscopically
classified as FIa or FIb is an independent risk factor for persistent
bleeding or rebleeding [100 – 107]. A potential limitation of the
Forrest classification is that stigmata recognition and identifica-
a10 Guideline

Performance of upper GI endoscopy1

High risk stigmata FIIb (adherent clot) Low risk stigmata

FIa (active spurting) FIIc (flat pigmented spot)
FIb (active oozing) FIII (clean base)
FIIa (nonbleeding visible vessel)

Perform endoscopic hemostasis
Consider performing clot removal followed No endoscopic hemostasis required
by endoscopic hemostasis of underlying In select clinical settings, these patients may
high risk stigmata2 have expedited hospital discharge
OR
Medical management with high dose
intravenous PPI

For FIa and FIb stigmata For FIIa stigmata – Once daily oral PPI

Combination endoscopic therapy using
dilute epinephrine injection plus
a second hemostasis modality (contact
thermal3, mechanical, or sclerosant4)
Contact thermal4, mechanical, or
injection of a sclerosant can be used
alone as monotherapy or in combination
with dilute epinephrine injection
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– Start regular diet
– Test for Helicobacter pylori, treat if positive
– Document H. pylori eradication

▪ High dose intravenous PPI given as bolus + continuous infusion; If endoscopic hemostasis performed:
can consider intermittent intravenous bolus dosing (minimum ▪ Dilute epinephrine injection circumferential to base of clot
twice-daily) for 72 hours5 followed by clot removal using cold polyp snare guillotine technique
▪ May start clear liquids soon after endoscopy ▪ If underlying high risk stigmata identified after clot removal,
▪ Test for H. pylori, treat if positive apply endoscopic hemostasis as described for FIa, FIb, FIIa stigmata
▪ Document H. pylori eradication

If clinical evidence of ulcer rebleeding, repeat upper endoscopy with endoscopic hemostasis where indicated
If hemostasis not achieved or recurrent rebleeding following second attempt at endoscopic hemostasis,
▪ Consider endoscopic salvage therapy with topical hemostatic spray/over-the-scope clip
▪ Or refer for transcatheter angiographic embolization (TAE) or surgery

Fig. 2 Algorithm for the endoscopic management of patients with nonvariceal upper gastrointestinal hemorrhage (NVUGIH) secondary to peptic ulcer, stra-
tified by endoscopic stigmata: European Society of Gastrointestinal Endoscopy (ESGE) Guideline. GI, gastrointestinal; PPI, proton pump inhibitor.
1
Use of a large single-channel or double-channel therapeutic upper GI endoscope is recommended.
2
The benefit of endoscopic hemostasis may be greater in patients at higher risk for rebleeding, e. g., older age, co-morbidities, in-hospital UGIH.
3
Large size 10-Fr probe recommended.
4
Absolute alcohol, polidocanol, or ethanolamine injected in limited volumes.
5
High dose oral PPI may be an option in those able to tolerate oral medications.

tion, as well as interobserver agreement, may be less than opti-
mal, although the data are conflicting [108, 109].
In addition to the Forrest classification, there are other endo-
scopic features of peptic ulcers that can predict adverse outcomes
and/or endoscopic treatment failure. These include large-size ul-
cer (> 2 cm), large-size nonbleeding visible vessel, presence of
blood in the gastric lumen, and ulcer location on the posterior
duodenal wall or the proximal lesser curvature of the stomach
[100, 101, 103, 105, 110, 111].
A meta-analysis of RCTs that evaluated endoscopic hemostasis vs.
no endoscopic hemostasis demonstrated that endoscopic hemo-
stasis was effective in preventing persistent or recurrent bleeding
in actively bleeding ulcers (FIa, FIb: RR 0.29, 95 %CI 0.20 – 0.43;
number needed to treat [NNT] 2, 95 %CI 2 – 2) as well as in ulcers
with a nonbleeding visible vessel (FIIa: RR 0.49, 95 %CI 0.40 –
0.59; NNT 5, 95 %CI 4 – 6) [112].
●" Fig. 2 presents an algorithm for the endoscopic management of
bleeding peptic ulcer, stratified by endoscopic stigmata.
With respect to the incremental benefit of acid suppression in
addition to endoscopic hemostasis, an RCT and a subsequent
meta-analysis found a clear advantage for endoscopic hemostasis
combined with PPI therapy over PPI therapy alone in preventing
recurrent ulcer bleeding and need for surgery in patients with
FIIa and FIIb ulcers [113, 114].
The indication for endoscopic treatment of FIIb ulcers (adherent
clot) remains controversial because of conflicting data. In evalua-
tion of the natural history of FIIb ulcers (that did not receive
endoscopic hemostasis), it was found that 25 % of patients re-
bled within 30 days of follow-up [115]. In patients with FIIb ul-
cers, RCTs and a meta-analysis comparing medical therapy alone
with endoscopic hemostasis demonstrated a significant advan-
tage for endoscopic hemostasis in reducing ulcer rebleeding
(8.2 % vs. 24.7 %, P < 0.01, yet there was no difference in need for
surgery or mortality [116 – 118]. In contrast, in a separate RCT,
Sung and colleagues reported no ulcer rebleeding in those pa-
tients with adherent clots who received medical therapy alone;
however the numbers of such patients in the trial were quite
limited (n = 24) [113]. Moreover, a meta-analysis restricted only
to RCTs showed no benefit for endoscopic hemostasis in patients
with an adherent clot (RR 0.31, 95 %CI 0.06 – 1.77) [112].
In patients with peptic ulcers having a flat pigmented spot (FIIc)
or clean base (FIII), rebleeding is rare and therefore endoscopic
hemostasis does not provide a significant advantage [97 – 99].

Gralnek Ian M et al. Nonvariceal upper gastrointestinal hemorrhage: ESGE Guideline … Endoscopy 2015; 47: a1–a46

ESGE does not recommend the routine use of Doppler ultrasound or magni-
fication endoscopy in the evaluation of endoscopic stigmata of peptic ulcer
bleeding (strong recommendation, low quality evidence).
The persistence of a positive Doppler signal following endoscopic
hemostasis has been shown to predict recurrent bleeding [119].
The results of available studies have been disparate and limited
by their methodology, older endoscopic treatments applied, and
small numbers of subjects included; thus there is currently no
consensus as to the advantage for the routine use of Doppler ul-
trasound in patents with NVUGIH [120 – 123]. A cost-minimiza-
tion analysis did however demonstrate per-patient cost savings
with use of Doppler ultrasound in patients with peptic ulcer
bleeding [124].
With respect to magnification endoscopy, one study suggested
that FIIa ulcers can be classified as low risk or high risk and that
some visible vessels classified as low risk using conventional
endoscopy can be reclassified as high risk using magnification
endoscopy [125]. However, the classification used has not been
validated and no clinical benefit of this approach has been dem-
onstrated.
Endoscopic therapy
For patients with actively bleeding ulcers (FIa, FIb), ESGE recommends com-
bining epinephrine injection with a second hemostasis modality (contact
thermal, mechanical therapy, or injection of a sclerosing agent). ESGE re-
commends that epinephrine injection therapy not be used as endoscopic
monotherapy (strong recommendation, high quality evidence).
For patients with nonbleeding visible vessel (FIIa), ESGE recommends me-
chanical therapy, thermal therapy, or injection of a sclerosing agent as
monotherapy or in combination with epinephrine injection. ESGE recom-
mends that epinephrine injection therapy not be used as endoscopic mono-
therapy (strong recommendation, high quality evidence).
For patients with active NVUGIH bleeding not controlled by standard endo-
scopic hemostasis therapies, ESGE suggests the use of a topical hemostatic
spray or over-the-scope clip as salvage endoscopic therapy (weak recom-
mendation, low quality evidence).
Endoscopic hemostasis can be achieved using injection, thermal,
and mechanical modalities (see Box 1), and any endoscopic ther-
apy is superior to pharmacotherapy in patients with FIa, FIb and
FIIa ulcers [112, 126]. Meta-analyses show that thermal devices
(contact and noncontact), injectable agents other than epine-
phrine (i. e., sclerosing agents, thrombin/fibrin glue), and clips
are all effective methods for achieving hemostasis, with no single
modality being superior [112, 126, 137 – 141].
Epinephrine injection therapy is effective at achieving primary
hemostasis, but inferior to other endoscopic hemostasis mono-
therapies or combination therapy in preventing ulcer rebleeding
[112, 126, 139]. In the most recently published meta-analysis (19
RCTs, 2033 patients), epinephrine plus any second hemostasis
modality significantly reduced rebleeding (OR 0.53, 95 %CI
0.35 – 0.81) and emergency surgery (OR 0.68, 95 %CI 0.50 – 0.93)
but not mortality as compared with epinephrine injection mono-
therapy for high risk peptic ulcers [140]. Therefore, it is recom-
mended that if epinephrine is used to treat peptic ulcer bleeding
with high risk stigmata, it should only be used in combination
with a second endoscopic hemostasis modality [97 – 99, 141].
With respect to contact thermal therapy (e. g., bipolar electrocoa-
gulation, heater probe), a meta-analysis restricted only to RCTs
found that contact thermal therapy was significantly more effec-
Gralnek Ian M et al. Nonvariceal upper gastrointestinal hemorrhage: ESGE Guideline … Endoscopy 2015; 47: a1–a46
Guideline a11
tive than no endoscopic hemostasis in achieving primary hemo-
stasis (RR 11.7, 95 %CI 5.2 – 26.6), reducing recurrent bleeding (RR
0.44, 95 %CI 0.36 – 0.54; NNT = 4), need for urgent surgery (RR
0.39, 95 %CI 0.27 – 0.55; NNT = 8) and mortality (RR 0.58, 95 %CI
0.34 – 0.98) [112]. With respect to noncontact thermal therapy
(e. g., argon plasma coagulation), limited data from three small
RCTs suggest it is similar in efficacy to injection of a sclerosing
agent (polidocanol) or contact thermal therapy (heater probe)
[112].
Mechanical therapy using through-the-scope clips was found to
be superior to injection monotherapy in four of five meta-analy-
ses [112, 126, 137, 139, 142]. Mechanical therapy significantly re-
duced the risk of recurrent bleeding by 78 % (RR 0.22, 95 %CI
0.09 – 0.55) [112]. Compared with thermal coagulation, mechan-
ical therapy provided no significant improvement in definitive
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
hemostasis (RR 1.00, 95 %CI 0.77 – 1.31) [137]. However, a sepa-
rate meta-analysis [126] found through-the-scope clips to be sig-
nificantly more effective than thermal therapy in reducing the
risk of recurrent bleeding (OR 0.24, 95 %CI 0.06 – 0.95). Two small
studies from Japan compared the efficacy of clips versus hemo-
static forceps [143, 144]. The first was an RCT conducted in 96 pa-
tients with high risk bleeding gastric ulcers and showed that use
of monopolar, soft coagulation hemostatic forceps was as effec-
tive as clipping [143]. The second was an observational prospec-
tive cohort study on 50 patients in which use of bipolar hemo-
static forceps was more effective than endoscopic clipping for
both initial hemostasis (100 % vs. 78.2 %) and preventing recur-
rent bleeding (3.7 % vs. 22.2 %) [144]. Unlike thermal therapies
and sclerosing agents, mechanical therapy using clips has the
theoretical benefit of inducing only limited tissue injury, and
therefore may be preferred in patients on antithrombotic therapy
and those patients undergoing repeat endoscopic hemostasis for
rebleeding. A multidisciplinary expert panel developed an expli-
cit set of evidence-based quality indicators for NVUGIH [78].
Among them, it was felt that patients with ulcer-related bleeding
with high risk stigmata and elevated INR (> 1.5 – 2.0), should re-
ceive endoscopic hemostasis using endoscopic clips or a combi-
nation of epinephrine injection plus clips.
Meta-analyses have shown that combination endoscopic hemo-
stasis therapy (dilute epinephrine injection combined with a sec-
ond hemostasis modality including injectable, thermal contact
probe, or clips) is superior to injection therapy alone, but not to
clips or contact thermal therapy alone [126, 139]. There may be
practical reasons to pre-inject dilute epinephrine before other
therapies for high risk endoscopic stigmata. Injection of epine-
phrine may slow or stop bleeding allowing improved visualiza-
tion for application of subsequent therapy. Adverse events asso-
ciated with combination endoscopic hemostasis are low and in-
clude induction of bleeding (1.7 %) and perforation (0.6 %) [139].
Recent international consensus guidelines endorse combination
therapy (dilute epinephrine injection combined with contact
thermal therapy, clips, or injection of a sclerosant [e. g., absolute
ethanol]) as appropriate treatment in patients with peptic ulcer
bleeding with high risk endoscopic stigmata [98, 99, 145].
New endoscopic hemostasis modalities (topical hemostatic
sprays and over-the-scope clips) are emerging as possible alter-
native endotherapies for primary hemostasis when bleeding is
refractory or not amenable to standard endoscopic hemostasis
therapies [136, 146]. Moreover, several small retrospective stud-
ies have reported that an over-the-scope clip (OVESCO), may
have a role as rescue hemostasis therapy for severe NVUGIH
when conventional endoscopic treatment modalities fail [133,
a12 Guideline
134, 147]. An inert nanopowder (Hemospray) that causes im-
mediate hemostasis when sprayed onto active bleeding [136,
148] has recently been used as a primary hemostasis agent or as
a second-line salvage therapy. Several prospective uncontrolled
studies, a large European registry [149 – 154] and a systematic re-
view of the current limited data suggests that Hemospray is safe
and effective and may be best used in high risk cases as a tempor-
izing measure or a bridge toward more definitive treatment
[136]. Other topical agents, such as the starch-derived polysac-
charide hemostatic system (EndoClot) and the Ankaferd blood
stopper are also emerging [136]. However, RCTs directly compar-
ing topical agents with traditional hemostasis methods are re-
quired to better define their optimal role and safety in the endo-
scopic management of NVUGIH.
For patients with acid-related causes of NVUGIH different from peptic ulcers
(e. g., erosive esophagitis, gastritis, duodenitis), ESGE recommends treatment
with high dose PPI. Endoscopic hemostasis is usually not required and select-
ed patients may be discharged early (strong recommendation, low quality
evidence).
ESGE recommends that patients with a Mallory – Weiss lesion that is actively
bleeding receive endoscopic hemostasis. There is currently inadequate evi-
dence to recommend a specific endoscopic hemostasis modality. Patients
with a Mallory – Weiss lesion and no active bleeding can receive high dose PPI
therapy alone (strong recommendation, moderate quality evidence).
ESGE recommends that a Dieulafoy lesion receive endoscopic hemostasis
using thermal, mechanical (hemoclip or band ligation), or combination ther-
apy (dilute epinephrine injection combined with contact thermal or mechan-
ical therapy) (strong recommendation, moderate quality evidence). Trans-
catheter angiographic embolization (TAE) or surgery should be considered if
endoscopic treatment fails or is not technically feasible (strong recommen-
dation, low quality evidence).
In patients bleeding from upper GI angioectasias, ESGE recommends endo-
scopic hemostasis therapy. However, there is currently inadequate evidence
to recommend a specific endoscopic hemostasis modality (strong recom-
mendation, low quality evidence).
In patients bleeding from upper GI neoplasia, ESGE recommends considering
endoscopic hemostasis in order to avert urgent surgery and reduce blood
transfusion requirements. However, no currently available endoscopic treat-
ment appears to have long-term efficacy (weak recommendation, low quality
evidence).
Erosive esophagitis, gastritis and duodenitis are common causes
of NVUGIH and generally have a benign course and excellent
prognosis [2, 64, 155 – 158]. Meta-analyses show that acid sup-
pression therapy is effective, with high dose PPI therapy being
significantly more effective than H2-receptor antagonists and no
observed differences in effectiveness amongst PPIs [159, 160].
Endoscopic hemostasis is usually not required in this patient
population and selected patients are candidates for early hospital
discharge.
Although spontaneous resolution of bleeding is frequent, obser-
vational studies have demonstrated that acute UGIH secondary
to Mallory – Weiss syndrome has a mortality similar to that of
peptic ulcer bleeding [161, 162]. Risk factors for adverse out-
comes include older age, medical co-morbidities, and active
bleeding at the time of endoscopy. The latter supports early
endoscopy to stratify risk and to perform endoscopic hemostasis
if active bleeding is identified [162 – 166]. Despite suggestions
that mechanical methods (clips and band ligation) are more ef-
fective than epinephrine injection, this has not been found in all
Gralnek Ian M et al. Nonvariceal upper gastrointestinal hemorrhage: ESGE Guideline … Endoscopy 2015; 47: a1–a46
studies [164, 167, 168]. Mechanical therapy appears to be safe, yet
data are insufficient to make a clear recommendation of one he-
mostasis modality over another [164, 167, 169, 170].
The proximal stomach and duodenum are the most common lo-
cations for Dieulafoy lesions [171]. Endoscopic hemostasis is war-
ranted if technically feasible. Observational studies have reported
the superiority of combined, thermal and mechanical methods
over injection monotherapy, in achieving primary hemostasis,
preventing rebleeding, and in reducing the need for rescue ther-
apy, yet with no proven mortality benefit [172 – 180]. All endo-
scopic hemostasis modalities (e. g., band ligation, through-the-
scope clips, over-the-scope clips, contact thermal coagulation,
and argon plasma coagulation) appear safe and have similar re-
ported outcomes [171 – 180]. Selective TAE has been described
as an effective rescue therapy if endoscopic hemostasis fails or
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in patients who are poor surgical candidates [181, 182]. If both
endoscopic and angiographic therapies fail, surgery should be
considered.
Studies on endoscopic hemostasis therapy of angioectasias of the
upper GI tract are observational and include only a limited num-
ber of subjects. In two recent meta-analyses, endoscopic hemo-
stasis therapy (e. g., argon plasma coagulation, heater probe, bi-
polar coagulation, monopolar coagulation, band ligation, YAG la-
ser) is reported to be initially effective and safe, yet bleeding re-
currence rates are significant [183, 184]. Given the low quality of
evidence and scarcity of comparative data, a recommendation on
a specific endoscopic hemostasis treatment is not permitted at
this time.
There are limited published data on the role of endoscopic hemo-
stasis in bleeding due to upper GI tract neoplasia and evidence to
support a specific modality is scarce [185 – 188]. Numerous
endoscopic hemostasis modalities (e. g., injection, thermal, me-
chanical, topical spray/powder) have been reported, generally
with limited impact on primary hemostasis, prevention of re-
bleeding, or mortality. However, endoscopic treatment may avert
urgent surgery, reduce transfusion requirements, and may pro-
vide a temporary bridge to oncologic therapy and/or selective
embolization [185 – 188].
Management following endoscopy/
endoscopic hemostasis
ESGE recommends PPI therapy for patients who receive endoscopic hemo-
stasis and for patients with adherent clot not receiving endoscopic hemosta-
sis. PPI therapy should be high dose and administered as an intravenous bolus
followed by continuous infusion (80 mg then 8 mg/hour) for 72 hours post
endoscopy (strong recommendation, high quality evidence)
ESGE suggests considering PPI therapy as intermittent intravenous bolus
dosing (at least twice-daily) for 72 hours post endoscopy for patients who re-
ceive endoscopic hemostasis and for patients with adherent clot not receiving
endoscopic hemostasis. If the patient’s condition permits, high dose oral PPI
may also be an option in those able to tolerate oral medications (weak re-
commendation, moderate quality evidence).
Based upon previously published meta-analytic data, evidence-
based guidelines on NVUGIH have recommended that PPI ther-
apy be given as an 80 mg intravenous bolus followed by 8 mg/
hour continuous infusion to reduce rebleeding, surgery, and mor-
tality in patients with high risk ulcers that had undergone suc-
cessful endoscopic hemostasis [98, 99, 189, 190]. More recently
however, a meta-analysis of RCTs of high risk bleeding ulcers
treated with endoscopic hemostasis compared intermittent PPI
dosing (oral or intravenous) with the currently recommended

post hemostasis PPI regimen of 80 mg intravenous bolus followed
by 8 mg/hour continuous infusion [191]. In that meta-analysis,
Sachar et al reported that the risk ratio of recurrent ulcer bleed-
ing within 7 days for intermittent infusion of PPI vs. bolus plus
continuous infusion of PPI was 0.72 (upper boundary of one-si-
ded 95 %CI 0.97), with an absolute risk difference of −2.64 %. Risk
ratios for other outcomes, including radiologic/surgical interven-
tion and mortality, showed no differences between infusion regi-
mens. These meta-analytic data indicate that intermittent PPI
therapy appears comparable to the currently recommended regi-
men of intravenous bolus plus continuous PPI infusion post
endoscopic hemostasis. It should be noted however, that inter-
mittent PPI bolus dosing is associated with a somewhat higher
risk of rebleeding that in general can be managed endoscopically.
Given the pharmacodynamic profile of PPIs, consideration should
be given to use of high dose PPI infusion given at least twice-dai-
ly, and using high dose oral PPIs in patients able to tolerate oral
medications [191]. The concept of high dose PPI varies between
the different studies used in the meta-analysis conducted by Sa-
char et al. However, it appears that an 80 mg oral PPI dose fol-
lowed by 40 – 80 mg orally every 12 hours for 72 hours yields an
intragastric pH similar to that reported with continuous intrave-
nous PPI infusion following successful endoscopic hemostasis of
high risk peptic ulcers [192]. This is but one study, and therefore
we need more data to confirm these findings before drawing firm
practical conclusions for the post-endoscopy management of pa-
tients with NVUGIH. These data are in agreement with an RCT
that randomized patients to high dose continuous infusion of
esomeprazole vs. 40 mg of oral esomeprazole twice-daily for 72
hours (118 vs. 126 patients respectively) [193]. Recurrent bleed-
ing at 30 days was reported in 7.7 % and 6.4 % of patients, respec-
tively (difference −1.3 percentage points, 95 %CI −7.7 to 5.1 per-
centage points). However, this study was conducted in an Asian
population (e. g., PPI slow metabolizers) and its findings may not
be generalizable to Western NVUGIH populations. Moreover, this
study was stopped prematurely since it was not designed as an
equivalency trial, and based on the preliminary data, thousands
of patients would have been required in order to complete the
study. (See Appendix e8, online-only.)
In patients with clinical evidence of rebleeding following successful initial
endoscopic hemostasis, ESGE recommends repeat upper endoscopy with he-
mostasis if indicated. In the case of failure of this second attempt at hemo-
stasis, transcatheter angiographic embolization (TAE) or surgery should be
considered (strong recommendation, high quality evidence).
An RCT comparing endoscopic therapy with surgery for recurrent
peptic ulcer bleeding after successful initial endoscopic control of
bleeding showed that 35/48 (73 %) of patients randomized to
endoscopic re-treatment had long-term control of their peptic
ulcer bleeding, avoided surgery, and had a lower rate of adverse
events as compared to the surgery-treated patients [194]. The re-
maining 13 patients underwent salvage surgery because of failed
repeat endoscopic hemostasis (n = 11) or perforation due to con-
tact thermal therapy (n = 2).
If further bleeding occurs following a second endoscopic treat-
ment, surgery for low risk patients or interventional radiology
for high risk patients should be considered [195]. In recent sys-
tematic reviews and meta-analyses comparing TAE with surgery
for peptic ulcer bleeding after failed endoscopic hemostasis, a
higher rebleeding rate was observed following TAE. No signifi-
cant difference in mortality or need for additional interventions
was shown between treatments [196, 197]. Hemostatic powder
Gralnek Ian M et al. Nonvariceal upper gastrointestinal hemorrhage: ESGE Guideline … Endoscopy 2015; 47: a1–a46
Guideline a13
and over-the-scope clips may also be considered as rescue/sal-
vage therapy. Although limited, emerging data suggest that he-
mostatic powder may be successfully employed as salvage hemo-
stasis therapy [154, 198]. The over-the-scope clip (OTSC) has also
proven an effective and safe therapeutic option for severe acute
GI bleeding when conventional endoscopic treatment modalities
fail [134, 147].
(See Appendix e9, online-only.)
ESGE does not recommend routine second-look endoscopy as part of the
management of NVUGIH. However, second-look endoscopy may be consid-
ered in selected patients at high risk for rebleeding (strong recommendation,
high quality evidence).
Routine second-look endoscopy is defined as a scheduled repeat
endoscopic assessment of the previously diagnosed bleeding le-
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sion usually performed within 24 hours following the index
endoscopy [98]. This strategy employs repeat endoscopy regard-
less of the type of bleeding lesion, perceived rebleeding risk, or
clinical signs of rebleeding. A meta-analysis that evaluated the ef-
fectiveness of routine second-look endoscopy in NVUGIH report-
ed a significant reduction in rebleeding (OR 0.55, 95 %CI 0.37 –
0.81) and need for emergency surgery (OR 0.43, 95 %CI 0.19 –
0.96), but not mortality (OR 0.65, 95 %CI 0.26 – 1.62) [199]. How-
ever, only one included study in that meta-analysis utilized high
dose intravenous PPI, and in that study no benefit for second-
look endoscopy was observed, while any protective effect was
limited only to high risk patients (e. g., those with active bleeding
at index endoscopy). Similarly, scheduled second-look endoscopy
does not appear to be cost-effective outside the subgroup of pa-
tients thought to be at high risk for recurrent ulcer bleeding
[200]. Thus, the clinical utility and cost– efficiency of routine sec-
ond-look endoscopy in unselected patients remains to be proven.
In patients with NVUGIH secondary to peptic ulcer, ESGE recommends inves-
tigating for the presence of Helicobacter pylori in the acute setting with initia-
tion of appropriate antibiotic therapy when H. pylori is detected. Re-testing for
H. pylori should be performed in those patients with a negative test in the
acute setting. Documentation of successful H. pylori eradication is recom-
mended (strong recommendation, high quality evidence).
Peptic ulcer remains the most frequent cause of acute NVUGIH
with H. pylori infection remaining the primary cause of peptic ul-
cer disease [201, 202]. Indeed, when H. pylori is eradicated, the
risk of ulcer rebleeding is reported to be extremely low [203,
204]. However, the false-negative rate of H. pylori diagnostic test-
ing is higher if the test is performed at the time of the acute
bleeding episode as compared to later follow-up [205]. A meta-
regression analysis including 8496 bleeding peptic ulcer patients
found an H. pylori prevalence of 72 %, with the infection rate
being significantly higher when diagnostic testing was delayed
until at least 4 weeks following the bleeding event (OR 2.08, 95 %
CI 1.10 – 3.93; P = 0.024) [206]. Therefore, it is advisable to re-test
at a later time those patients who had a negative H. pylori test in
the acute setting.
When H. pylori infection is found, eradication therapy should be
initiated and guided by patient and local factors [98, 99]. Docu-
mentation of successful H. pylori eradication is strongly recom-
mended given the high risk of recurrent ulcer bleeding in the
presence of persistent H. pylori infection [98, 99]. (See Appendix
e10, online-only.)
ESGE recommends restarting anticoagulant therapy following NVUGIH in
patients with an indication for long-term anticoagulation. The timing for
a14 Guideline
resumption of anticoagulation should be assessed on a patient by patient ba-
sis. Resuming warfarin between 7 and 15 days following the bleeding event
appears safe and effective in preventing thromboembolic complications for
most patients. Earlier resumption, within the first 7 days, may be indicated for
patients at high thrombotic risk (strong recommendation, moderate quality
evidence).
Retrospective, observational data have shown that resuming an-
ticoagulation in patients with GI bleeding is associated with a
lower risk of thrombosis and death [207 – 209]. Restarting war-
farin therapy within 7 days of the index bleeding event was asso-
ciated with an approximately twofold increased risk of rebleed-
ing [207, 209]. Conversely, as compared with resuming warfarin
beyond 30 days, resuming warfarin between 7 and 30 days did
not increase the risk of rebleeding, but did significantly decrease
the risk of thromboembolism and improved survival [209]. These
data appear to support that resumption of anticoagulation after 7
days of interruption is safe and effective in preventing throm-
boembolic complications for most patients. However, in patients
at high thrombotic risk (e. g., chronic atrial fibrillation with pre-
vious embolic event, CHADS2 score ≥ 3, mechanical prosthetic
heart valve, recent [within past 3 months] deep venous thrombo-
sis or pulmonary embolism, and patients with known severe hy-
percoagulable state), for whom early resumption of anticoagula-
tion within the first week following an acute bleeding event
might be appropriate, bridging therapy using unfractionated or
low molecular weight heparin may be considered [210]. No data
are currently available to guide the management of DOACs fol-
lowing NVUGIH. Yet caution in the early resumption of DOACs is
required because of their rapid onset of action and the current
lack of reversal agents. (See Appendix 11, online-only.)
In patients receiving low dose aspirin for primary cardiovascular prophylaxis
who develop peptic ulcer bleeding, ESGE recommends withholding aspirin,
re-evaluating the risks/benefits of ongoing aspirin use in consultation with a
cardiologist, and resuming low dose aspirin following ulcer healing or earlier if
clinically indicated (strong recommendation, low quality evidence). See
●" Fig. 1.
In patients receiving low dose aspirin for secondary cardiovascular prophylaxis
who develop peptic ulcer bleeding, ESGE recommends aspirin be resumed
immediately following index endoscopy if the risk of rebleeding is low (e. g.,
FIIc, FIII). In patients with high risk peptic ulcer (FIa, FIb, FIIa, FIIb), early rein-
troduction of aspirin by day 3 after index endoscopy is recommended,
provided that adequate hemostasis has been established (strong recommen-
dation, moderate quality evidence). See● " Fig. 1.
In patients receiving dual antiplatelet therapy (DAPT) who develop peptic
ulcer bleeding, ESGE recommends continuing low dose aspirin therapy. Early
cardiology consultation should be obtained regarding the timing of resuming
the second antiplatelet agent (strong recommendation, low quality evi-
dence). See● " Fig. 1.
Discontinuing low dose aspirin therapy in the setting of second-
ary cardiovascular prophylaxis significantly increases the risk of
an adverse cardiovascular event, usually occurring within the
first week of discontinuation [211 – 214]. In a retrospective co-
hort study, patients with cardiovascular disease who discontin-
ued low dose aspirin following peptic ulcer bleeding had an al-
most twofold increase in risk for death or an acute cardiovascular
event in the first 6 months after hospital discharge, as compared
with patients who continued aspirin therapy [54]. In an RCT eval-
uating continuous vs. interrupted aspirin treatment in patients
with high risk peptic ulcers and at high cardiovascular risk, those
receiving continuous aspirin had a twofold increased risk of early,
nonfatal, recurrent bleeding (10.3 % vs. 5.4 % at 4 weeks; differ-
ence 4.9 percentage points, 95 %CI −3.6 to 13.4 percentage points;
Gralnek Ian M et al. Nonvariceal upper gastrointestinal hemorrhage: ESGE Guideline … Endoscopy 2015; 47: a1–a46
HR 1.9, 95 %CI 0.6 – 6.0), yet a 10-fold reduced risk of all-cause
mortality at 8 weeks (1.3 % vs. 12.9 %; difference 11.6 percentage
points, 95 %CI 3.7 – 19.5 percentage points; HR 0.2 95 %CI 0.06 –
0.60) and a lower mortality rate related to cardiovascular, cere-
brovascular, or gastrointestinal events (1.3 % vs. 10.3 %; difference
9 percentage points, 95 %CI 1.7 – 16.3 percentage points; HR 0.2,
95 %CI 0.05 – 0.70), compared with those patients in whom aspir-
in was withheld [53]. Patients who required DAPT were excluded
from this study. The antiplatelet effect of aspirin lasts for approxi-
mately 5 days (although new active platelets increase in number
each day), and the risk of early recurrent bleeding is high in the
first 3 days [53]. Therefore, restarting aspirin on day 3 in patients
with high risk endoscopic stigmata is a reasonable trade-off be-
tween the risks of rebleeding and thrombosis. In patients with
peptic ulcer bleeding with no high risk endoscopic stigmata, as-
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
pirin can be resumed immediately as RCTs have shown that nei-
ther aspirin nor clopidogrel use impede ulcer healing promoted
by PPIs [53, 55, 56]. No high level evidence helps guide the timing
for resumption of P2Y12 platelet receptor inhibitors (e. g., clopido-
grel) following NVUGIH. However, in view of its similar antiplate-
let activity, it seems reasonable to apply a similar management
strategy. Moreover, there is no evidence in the literature to help
guide the management of patients receiving DAPT in the setting
of NVUGIH. The overriding principle of balancing bleeding and
thrombotic event risks requires close collaboration between the
gastroenterology and cardiology teams.
In patients requiring dual antiplatelet therapy (DAPT) and who have had
NVUGIH, ESGE recommends the use of a PPI as co-therapy (strong recom-
mendation, moderate quality evidence.
Dual antiplatelet therapy, combining low dose aspirin and a
P2Y12 platelet receptor inhibitor (e. g., clopidogrel), is the corner-
stone of management of patients with acute coronary syndromes
and following coronary stent placement, but is associated with an
increased risk of GI bleeding [215 – 217]. Proton pump inhibitors
substantially reduce this risk and their use is recommended in
patients with a previous GI bleeding event [218 – 220]. Pharma-
codynamic studies have shown that the co-administration of
PPIs with clopidogrel reduces platelet inhibition, but the clinical
significance of this interaction has been extensively debated
[221 – 225]. Previous meta-analyses suggest that concomitant
clopidogrel and PPI use may be associated with increased adverse
cardiovascular events and myocardial infarction, but no effect on
mortality [226, 227]. However, the presence of significant hetero-
geneity in the included studies indicates that this evidence is at
best, inconsistent, and at worst, potentially biased or confoun-
ded. A recent meta-analysis included a subanalysis limited to
RCTs and propensity-matched studies evaluating the interaction
between PPI and clopidogrel; the subanalysis showed no signifi-
cant differences between patients using clopidogrel alone and
patients receiving the combination of clopidogrel and a PPI (n =
11 770) for all-cause mortality (OR 0.91, 95 %CI 0.58 – 1.40; P =
0.66), acute coronary syndrome (OR 0.96, 95 %CI 0.88 – 1.05; P =
0.35), myocardial infarction (OR 1.05, 95 %CI 0.86 – 1.28; P =
0.65), and cerebrovascular accident (OR 1.47, 95 %CI 0.660 – 3.25;
P = 0.34) [228]. The incidence of GI bleeding was significantly de-
creased in the group of patients who received a PPI (OR 0.24, 95 %
CI 0.09 – 0.62; P = 0.003). Current evidence does not support a
clinically relevant interaction between PPIs and clopidogrel. (See
Appendices e12 and e13, online-only.)

Box 1 Endoscopic hemostasis modalities: a primer
Injection therapy
The primary mechanism of action of injection therapy is local
tamponade resulting from a volume effect. Diluted epine-
phrine (1:10 000 or 1:20 000 with normal saline injected in
0.5 – 2-ml aliquots in and around the ulcer base) may also
have a secondary effect that produces local vasoconstriction
[126]. Sclerosing agents such as absolute ethanol, ethanola-
mine, and polidocanol produce hemostasis by causing direct
tissue injury and thrombosis. It should be noted that when
using a sclerosing agent in nonvariceal upper gastrointestinal
hemorrhage (NVUGIH), the volume injected should be limited
because of concerns about tissue necrosis, perforation, or pan-
creatitis. Another class of injectable agents is tissue adhesives
including thrombin, fibrin, and cyanoacrylate glues, which are
used to create a primary seal at the site of bleeding.
Endoscopic injection is performed using needles which con-
sist of an outer sheath and an inner hollow-core needle (19 –
25 gauge). The endoscopist or nursing assistant can retract the
needle into the sheath for safe passage through the working
channel of the endoscope. When the catheter is passed out of
the working channel and placed near the site of bleeding, the
needle is extended out of the sheath and the solution injected
into the submucosa using a syringe attached to the catheter
handle [126].
Thermal therapy
Thermal devices used in the treatment of upper gastrointesti-
nal (UGI) bleeding are divided into contact and noncontact
modalities. Contact thermal devices include heater probes
which generate heat directly and bipolar electrocautery
probes which generate heat indirectly by passage of an electri-
cal current through the tissue. Noncontact thermal devices in-
clude argon plasma coagulation (APC) tools. Heat generated
from these devices leads to edema, coagulation of tissue pro-
teins, contraction of vessels, and indirect activation of the co-
agulation cascade, resulting in a hemostatic bond [126, 127].
Contact thermal probes use local tamponade (mechanical
pressure of the probe tip directly onto the bleeding site) com-
bined with heat or electrical current to coagulate blood ves-
sels, a process known as “coaptive coagulation.” Heater probes
(available in 7-Fr and 10-Fr sizes) consist of a Teflon-coated
hollow aluminum cylinder with an inner heating coil com-
bined with a thermocoupling device at the tip of the probe to
maintain a constant energy output (measured in joules, com-
monly 15 – 30 joules of thermal energy are delivered). An
endoscopist-controlled foot pedal activates the heater probe
and provides waterjet irrigation. Multipolar/bipolar electro-
cautery contact probes (7-Fr and 10-Fr sizes) deliver thermal
energy by completion of an electrical local circuit (no ground-
ing pad required) between two electrodes on the tip of the
probe as current flows through nondesiccated tissue. As the
targeted tissue desiccates, there is a decrease in electrical con-
ductivity, limiting the maximum temperature, depth, and
area of tissue injury. An endoscopist-controlled foot pedal
controls the delivery of the energy [127]. The standard setting
for use in achieving hemostasis in peptic ulcer bleeding is 15 –
20 watts, which is delivered in 8 – 10-second applications
(commonly referred to as tamponade stations) [96].
APC, a noncontact thermal modality, uses high frequency,
monopolar alternating current conducted to the target tissue
Gralnek Ian M et al. Nonvariceal upper gastrointestinal hemorrhage: ESGE Guideline … Endoscopy 2015; 47: a1–a46
Guideline a15
through a stream of ionized gas, without mechanical contact,
resulting in coagulation of superficial tissue [128]. As the tis-
sue surface loses its electrical conductivity, the argon plasma
stream shifts to adjacent nondesiccated (conductive) tissue,
which again limits the depth of tissue injury [126]. If the APC
catheter is not near the target tissue, there is no ignition of the
gas and depression of the foot pedal results only in flow of in-
ert argon gas (flow rates of 0.5 – 0.7 L/min). Coagulation depth
is dependent on the generator power setting, duration of ap-
plication, and distance from the probe tip to the target tissue
(optimal distance, 2 – 8 mm) [129, 130].
Mechanical therapy
Endoscopic mechanical therapies include clips (through-the-
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
scope and over-the-scope) and band ligation devices. Endo-
scopic clips are deployed directly onto a bleeding site and ty-
pically slough off within days to weeks after placement [131].
Hemostasis is achieved by mechanical compression of the
bleeding site.
Clips are available in a variety of jaw lengths and opening
widths. The delivery catheter consists of a metal cable within
a sheath enclosed within a Teflon catheter. After insertion of
the catheter through the working channel of the endoscope,
the clip is extended out of the sheath, positioned over the tar-
get area and opened with the plunger handle. A rotation
mechanism on the handle is available on some commercially
available clips and this allows the endoscopist to change the
orientation of the clip at the site of bleeding. The jaws of the
clip are applied with pressure and closed onto the target tis-
sue by using the device handle. Some clips may be opened,
closed, and repositioned, whereas others are permanently de-
ployed and released upon clip closure. Some clips are provid-
ed with a reusable delivery sheath, greatly reducing costs. Si-
milarly, some clips are automatically released on deployment,
while others require repositioning of the plunger handle to re-
lease the deployed clip from the catheter [131].
The over-the-scope clip device includes an applicator cap, a
nitinol clip, and a hand wheel [132, 133]. The applicator cap,
with the mounted nitinol clip, is affixed to the tip of the endo-
scope in a manner similar to that of a variceal band ligation
device. Caps are available in three sizes to accommodate var-
ious endoscope diameters: 11 mm, 12 mm, and 14 mm. Caps
are also available in two lengths (3 mm and 6 mm) to allow
variation in the amount of tissue grasped. Clips come in three
different shapes of teeth: rounded, pointed and long-pointed.
Clips with rounded teeth are used where the goal is tissue
compression to achieve hemostasis. The applicator cap incor-
porates a clip release thread, which is pulled retrogradely
through the working channel of the endoscope and fixed
onto a hand wheel mounted on the working-channel access
port of the endoscope. The clip is released by turning the
hand wheel, in a manner similar to deploying a variceal liga-
tion band [134].
Last, endoscopic band ligation devices, commonly used in
esophageal variceal bleeding, have also been reported for
treatment of NVUGIH (e. g., for Dieulafoy lesion) and involve
the placement of elastic bands over tissue to produce mechan-
ical compression and tamponade.
a16 Guideline
Topical therapy
Topical hemostatic sprays have been used in acute NVUGIH
with promising results, but thus far in a limited number of pa-
tients and without any comparative data regarding standard
endoscopic hemostasis therapies [135, 136]. Advantages of
noncontact, spray catheter delivery of hemostatic agents in-
clude ease of use, lack of need for precise lesion targeting, ac-
cess to lesions in difficult locations, and the ability to treat a
large surface area.
Topical hemostatic sprays include TC-325, (Hemospray, Cook
Medical Inc, Winston-Salem, North Carolina, USA), which is a
proprietary, inorganic, absorbent powder that rapidly concen-
trates clotting factors at the bleeding site, forming a coagulum.
Hemospray comes in a hand-held device consisting of a pres-
surized CO2 canister, a through-the-scope delivery catheter,
and a reservoir for the powder cartridge. The powder is deliv-
ered via pushbutton in 1 – 2-second bursts until hemostasis is
achieved. The maximum amount of TC-325 that can be safely
administered during a single treatment session has not yet
been established [135, 136]. The coagulum typically sloughs
within 3 days and is naturally eliminated. Hemospray has re-
ceived regulatory clearance in some countries.
ESGE guidelines represent a consensus of best practice based on
the available evidence at the time of preparation. They may not
apply in all situations and should be interpreted in the light of
specific clinical situations and resource availability. Further con-
trolled clinical studies may be needed to clarify aspects of these
statements, and revision may be necessary as new data appear.
Clinical consideration may justify a course of action at variance
to these recommendations. ESGE guidelines are intended to be
an educational device to provide information that may assist
endoscopists in providing care to patients. They are not rules
and should not be construed as establishing a legal standard of
care or as encouraging, advocating, requiring, or discouraging
any particular treatment.
Competing interests: None
Institutions
1
Institute of Gastroenterology and Liver Diseases, Ha'Emek Medical Center,
Afula, Israel
2
Rappaport Faculty of Medicine Technion-Israel Institute of Technology,
Haifa, Israel
3
Gedyt Endoscopy Center, Buenos Aires, Argentina
4
Departments of Internal Medicine and Gastroenterology and Hepatology,
Erasmus MC University Medical Center, Rotterdam, The Netherlands
5
University of Zaragoza, Aragon Health Research Institute (IIS Aragon),
CIBERehd, Spain
6 tration for patients with bleeding. Cochrane Database Syst Rev 2014;
Department of Gastroenterology, Sheffield Teaching Hospitals, United
Kingdom
7
Division of Gastroenterology and Digestive Endoscopy, Maresca Hospital,
Torre del Greco, Italy
8
Department of Gastroenterology and Hepatology, Institute for Clinical and
Experimental Medicine, Prague, Czech Republic
9
Department of Gastroenterology, IPO Porto, Portugal and CINTESIS, Porto
Faculty of Medicine, Portgal
10
Division of Gastroenterology, Hospital Curto, Polla, Italy
11
First Department of Internal Medicine and Gastroenterology, Petz Aladar,
Hospital, Gyor, Hungary
12
Department of Surgical Sciences, University of Torino, Torino, Italy
13
Institute and Polyclinic for Diagnostic Radiology, University Hospital
Dresden-TU, Dresden, Germany
14
Department of Gastroenterology, Ambroise Paré Hospital, Boulogne, France
15
Department of Biomedical and Clinical Sciences, University of Milan,
Gastroenterology Unit, Luigi Sacco University Hospital, Milan, Italy
Gralnek Ian M et al. Nonvariceal upper gastrointestinal hemorrhage: ESGE Guideline … Endoscopy 2015; 47: a1–a46
Additional topical hemostatic sprays include EndoClot and the
Ankaferd Blood Stopper [135, 136]. EndoClot (EndoClot Plus
Inc, Santa Clara, California, USA) is a starch-derived compound
that rapidly absorbs water from serum and concentrates pla-
telets, red blood cells, and coagulation proteins at the bleeding
site to accelerate the clotting cascade. Hemostatic sprays de-
rived from plant products/extracts have also been evaluated.
Clinical experience with these agents for endoscopic hemosta-
sis is currently limited to the off-label use of the Ankaferd
Blood Stopper (Ankaferd Health Products Ltd, Istanbul, Tur-
key). This topical agent promotes formation of a protein
mesh that acts as an anchor for erythrocyte aggregation with-
out significantly altering coagulation factors or platelets and is
delivered onto the bleeding site via an endoscopic spray cath-
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
eter until an adherent coagulum is formed. The particles are
subsequently cleared from the bleeding site within hours to
days later. The overall efficacy of these topical agents is un-
known in brisk arterial bleeding and may be limited because
of the rapid “wash-away” effect of the hemostatic agent by on-
going blood flow.
16
Department of Medical Gastroenterology, Rikshospitalet University Hospital,
Oslo, Norway
17
Department of Gastroenterology, Royal Wolverhampton Hospitals NHS
Trust, Wolverhampton, United Kingdom
18
Department of Gastroenterology, Valduce Hospital, Como, Italy
19
Department of Gastroenterology, Centro Hospitalar do Porto, Portugal
20
Department of Gastroenterology, Centro Hospitalar e Universitário de
Coimbra, Portugal
21
Endoscopy Unit, Nuovo Regina Margherita Hospital, Rome, Italy
22
Gastroenterology and Endoscopy Department, Antonio Cardarelli Hospital,
Naples, Italy
23
Digestive Endoscopy Unit, Catholic University, Rome, Italy
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a22 Guideline

Appendix e1 Nonvariceal upper gastrointestinal hemorrhage (NVUGIH): task forces and key questions.

Topics and key questions Task forces

(leader in bold)
Task force 1: Initial patient evaluation/hemodynamic resuscitation/risk stratification David S. Sanders
How should the patient be initially hemodynamically resuscitated? Jean-Marc Dumonceau
Who should receive blood product transfusion? What target for hemoglobin? Matthew Kurien
How should patient risk stratification be used? Gilles Lesur
What risk stratification score(s) are reliable and valid? Pre-endoscopy risk score? Post-endoscopy risk score? Riccardo Marmo
How should risk stratification tools be applied?
Task force 2: Pre-endoscopic management Jean-Marc Dumonceau
How to manage the patient using antiplatelet and anticoagulant drugs (known collectively as antithrombotic agents) at the Ian Gralnek
time of acute upper gastrointestinal (UGI) bleeding? Cesare Hassan
Need to also consider the current data on potential adverse events related to antiplatelet/anticoagulant drug interruption Angel Lanas
(i. e. atrial fibrillation, cardiac stent thrombosis, cardiac ischemic event, neurovascular event) Gilles Lesur
What is the role of pre-endoscopy proton pump inhibitor (PPI) therapy? Istvan Racz

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What is the role of pre-endoscopy somatostatin therapy? Franco Radaelli
What is the role of naso-/orogastric tube aspiration/lavage? Gianluca Rotondano
What is the role of endotracheal intubation before upper endoscopy?
Is there a role for antifibrinolytic medications?
What is the role of prokinetic agents prior to upper endoscopy?
Is there a role for capsule endoscopy in the emergency department in evaluating acute UGI bleeding?
What is appropriate timing for upper endoscopy?
Task force 3: Endoscopic management Ernst J. Kuipers
Which endoscopic classification should be used for describing high and low risk endoscopic stigmata of recent hemorrhage Ricardo Cardoso
in peptic ulcer bleeding? What are high risk vs. low risk endoscopic stigmata and their importance in risk stratification? Livio Cipolletta
Is there a role for doppler ultrasonography, magnification endoscopy, chromoendoscopy in helping to better evaluate Mário Dinis-Ribeiro
endoscopic stigmata of recent hemorrhage for peptic ulcer bleeding? Luís Maia
Which ulcer stigmata require endoscopic hemostasis? Which do not? Gianluca Rotondano
Which endoscopic hemostasis modality should be used (with focus on peptic ulcer bleeding)? Paulo Salgueiro
Injection therapy?
Thermal contact therapy?
Thermal noncontact therapy?
Mechanical therapy?
Combination therapy?
Topical spray/powder therapy
What to do in situations of nonvariceal, nonulcer bleeding lesions?
Task force 4: Post-endoscopic management Angel Lanas
What is the medical management post endoscopic hemostasis? Lars Aabakken
What to do when rebleeding occurs? What is the role of repeat upper endoscopy? Alberto Arezzo
Is there a role for scheduled second-look endoscopy? Roberto de Franchis
Rebleeding/failed endoscopic hemostasis: When should the interventional radiologist be involved/when should the Cesare Hassan
surgeon be involved? Ralf-Thorsten Hoffmann
Diagnosis and treatment of Helicobacter pylori? When? In whom? What if testing for H. pylori in the acute setting of Tomas Hucl
bleeding is negative? Documentation of eradication? Gilles Lesur
How to manage the NVUGIH patient using antiplatelet and anticoagulant drugs (collectively known as antithrombotics Franco Radaelli
agents) post endoscopy? How and when to reinstitute these medications? Andrew Veitch
Angelo Zullo
When to discharge patients home?

Gralnek Ian M et al. Nonvariceal upper gastrointestinal hemorrhage: ESGE Guideline … Endoscopy 2015; 47: a1–a46
 Appendix e2 Criteria for outpatient management of patients with nonvariceal upper gastrointestinal hemorrhage (NVUGIH).

First author, Study design, Participants Patients, n (%) Outcomes

year [ref.] study objective
Observed Out- Transfusion Re-bleeding Need for Death
patients required surgery
Longstreth, Prospective Absolute criteria. 141 34 (24 %) 1 (2.9 %) 0 0
1995 [229] Absence of: high risk endoscopic findings (arterial bleeding, adherent
clot, or visible vessel); varices; and portal hypertensive gastropathy
Nonabsolute criteria.
No debilitation; no orthostatic vital sign change; no severe liver disease;
no serious concomitant disease; no anticoagulation therapy or coagulo-
pathy; no fresh, voluminous hematemesis or multiple episodes of mele-
na on the day of presentation; no severe anemia (hemoglobin < 8.0 g/dL);
adequate support at home
Longstreth, Retrospective As above Not done 176 1 (0.5 %) 0 0
1998 [230]
Cebollero- Prospective Clinical criteria. 84 24 (28 %) 1 (4.1 %) 0 0
Santamaria, Absence of: severe cardiac disease/recent myocardial infarction; severe
1999 [231] respiratory failure; decompensated cirrhosis; severe coagulopathy (in-
ternational normalized ratio [INR] ≥ 1.5); poor social support; require-
ment for blood transfusion; recent cerebrovascular accident
Endoscopic criteria.
Clean base ulcer < 1.5 cm in diameter; erosive mucosal disease (esopha-
gus, stomach, or duodenum); nonbleeding Mallory – Weiss tear; portal
hypertensive gastropathy
Brullet, 2004 RCT Clinical criteria. 297 endoscopi- 40 (13 %) 7 2 0 0
[232] Absence of signs of hypovolemia (defined as systolic blood pressure cally treated
< 100 mmHg and pulse rate > 100 beats/minute with peripheral signs of patients
circulatory failure);
Absence of severe associated diseases (defined as American Society of
Anesthesiologists [ASA] classification III – V);
No anticoagulant drug therapy; and
Appropriate sociofamilial support.
The latter was defined as the following: (i) living within a family whose
members were able to comprehend the clinical condition of the patient
and capable of providing adequate care; (ii) having a telephone; and (iii)
residing less than 20 minutes by car from the hospital.
Endoscopic criteria.
(1) peptic ulcer with an nonbleeding visible vessel;
(2) ulcer size smaller than 15 mm
Guideline

Gralnek Ian M et al. Nonvariceal upper gastrointestinal hemorrhage: ESGE Guideline … Endoscopy 2015; 47: a1–a46
a23

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 a24

Appendix e2 (Continuation)

First author, Study design, Participants Patients, n (%) Outcomes

year [ref.] study objective
Guideline

Observed Out- Transfusion Re-bleeding Need for Death

patients required surgery
Lai, 1997 Prospective Inclusion criteria were as follows: 305 75 (24 %) 0 0 0 0
[233] 1 (1) Presence of melena and/or hematemesis;
(2) Presence of duodenal ulcer and absence of other upper gastrointes-
tinal pathology to account for gastrointestinal bleeding;
(3) Hemoglobin level greater than 10 gm/dL on admission;
(4) Systolic blood pressure above 100 mmHg and pulse less than 100
beats/minute on admission before any resuscitation with fluids, and
orthostatic blood pressure drop of less than 10 mmHg (patient excluded
if abnormal vital signs developed after admission);
(5) No concurrent serious medical illness (absence of heart failure,
chronic obstructive airway disease, hepatic cirrhosis, hematologic
malignancies, chronic renal failure, and strokes);
(6) no stigmata of recent hemorrhage on endoscopy, which was carried
out within 24 h of admission;
(7) Age 60 years or younger; and
(8) Normal coagulation findings.
Lee, 1999 RCT Clinical criteria. 56 26 (46 %) 1 (3.8 %) 0 0
[234] 2 Absence of:
Co-morbid illness requiring intensive care (e. g., myocardial ischemia);
Hemodynamic instability after resuscitation by infusion of 2 L of fluid
(heart rate greater than 115 beats/min, systolic blood pressure less than
90 mmHg, or diastolic blood pressure less than 60 mmHg);
Known or suspected variceal source, coagulopathy (use of any anticoa-
gulant or thrombolytic agent within the preceding week, platelet count
less than 50 000, INR < 1.5, or any other known coagulopathy);
Upper GI bleeding within the preceding 1 month; and
Age less than 18 years.

Gralnek Ian M et al. Nonvariceal upper gastrointestinal hemorrhage: ESGE Guideline … Endoscopy 2015; 47: a1–a46
Endoscopic criteria.
No clot obscuring complete visualization;
Clean ulcer base;
Mallory-Weiss tear;
Esophagitis, gastritis, duodenitis, or other benign findings.
Hemodynamically stable, alert, wanted to go home
Gralnek, Retrospective Complete Rockall scores (after endoscopy) of ≤ 2 175 53 (30 %) 2 (3.7 %) 0 0
2004 [235]

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 Appendix e2 (Continuation)

First author, Study design, Participants Patients, n (%) Outcomes

year [ref.] study objective
Observed Out- Transfusion Re-bleeding Need for Death
patients required surgery
Cipolletta. RCT Clinical criteria. 244 95 (39 %) 2 (2.%) 0 0
2002 [236] 2 Absence of hypovolemic shock, orthostatic change in vital signs, and
need for blood transfusion;
Normal coagulation findings;
Absence of serious concurrent medical illness;
Easy accessibility to hospital; and
Adequate sociofamial support at home.
Endoscopic criteria.
Absence of varices and signs of portal hypertension, high risk stigmata of
recent hemorrhage (active bleeding, visible vessel, or adherent clot);
Patients having a clean ulcer base or flat spot, gastritis or duodenitis,
Mallory – Weiss tear, or other benign findings.
GI, gastrointestinal; INR, international normalized ratio; RCT, randomized controlled trial.
1
Only patients with peptic ulcer
2
The hospital stay and the costs of care were significantly less for early endoscopy
Guideline

Gralnek Ian M et al. Nonvariceal upper gastrointestinal hemorrhage: ESGE Guideline … Endoscopy 2015; 47: a1–a46
a25

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Appendix e3 Role of proton pump inhibitors (PPIs) prior to upper endoscopy in acute upper gastrointestinal hemorrhage.
First author, Study type Patient group
year [ref.]
Sreedharan, Cochrane meta- Total of 2223 patients were
2012 [237] analysis of 6 RCTs included with unselected
Searches were re-run upper GI bleeding.
in Feb 2006 and Oct Prior to endoscopy patients
2008 were given PPI (oral or
intravenous) or H2RA or
placebo
Lau, 2007 Double-blind, place- Omeprazole group (n =
[238] bo-controlled, 319): 80 mg omeprazole
randomized trial intravenous bolus + 8 mg/h
control infusion until
endoscopy
Placebo group (n = 319):
placebo bolus + placebo
infusion until endoscopy
Endoscopies were per-
formed next morning.
Mean duration of infusion
before endoscopy:
– Omeprazole group
Gralnek Ian M et al. Nonvariceal upper gastrointestinal hemorrhage: ESGE Guideline … Endoscopy 2015; 47: a1–a46
14.7 ± 6.3 h
– Placebo group
15.2 ± 6.2 h
Liu, 2012 Randomized, single- PPI parenteral (either ome-
[239] center, prospective, prazole or esomeprazole)
double-blind started prior to endoscopy
(“early” endoscopy ≤ 24 h,
“late” > 24 – 72 h)
Intensive regimen, 80 mg +
8 mg/h infusion:
410 patients
Standard regimen,
2 × 40 mg PPI/day: 456 pa-
tients
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Key outcomes
– 30-day mortality
– Rebleeding
– Surgery
– Stigmata of recent hemor-
rhage (SRH) at index endos-
copy
– Need for endoscopic therapy
– Need for transfusion
Primary:
– Need for endoscopic therapy
at the first endoscopic
examination
Secondary:
– Signs of bleeding
– Need for urgent endoscopy
– Emergency surgery
– Recurrent bleeding
Rebleeding rate
Need for endoscopic therapy at
first endoscopy
Key results
No significant difference between PPI
and control treatment for:
– Mortality: 6.1 % vs. 5.5 %; OR 1.12,
95 %CI 0.72 – 1.73
– Rebleeding rates: 13.9 % vs.
16.6 %; OR 0.81, 95 %CI 0.61 –
1.09
– Surgery: 9.9 % – 10.2 %; OR 0.96,
95 %CI 0.68 – 1.35
Significant reduction:
– Proportion with SRH:
37.2 % – 46.5 %; OR 0.67, 95 %CI
0.54 – 0.84
– Need for endoscopic therapy:
8.6 % – 11.7 %; OR 0.68, 95 %CI
0.50 – 0.93
Among patients with peptic ulcer
bleeding, endoscopic treatment re-
quired in:
– Omeprazole group 22.5 %
– Placebo group 36.8 %
– OR 0.61, 95 %CI 0.44 – 0.84;
P = 0.002
Active ulcer bleeding seen less
frequently in omeprazole group
than in placebo group:
6.4 % vs. 14.7 %; P = 0.001.
Rebleedings: 3.5 % in omeprazole
group vs. 2.5 % in placebo group;
P = 0.49
Rebleeding:
11 % in standard regimen group vs.
6.4 % in intensive regimen group
(P = 0.03)
Early endoscopy therapy need:
16.7 % vs. 10.0 % (P = 0.05)
Rebleeding rates at late endoscopies:
7.5 % in standard vs. 4.0 % in intensive
PPI group (P = 0.03)
Limitations
Oral and intravenous PPI studies
are mixed
– No data regarding the length
of pre-emptive PPI and place-
bo treatment
– Variceal and nonvariceal
bleeding sources are not
analyzed selectively
Long-term aspirin users were
excluded
Both omeprazole and esomepra-
zole were used
Endoscopic therapy was not
standardized
No detailed data about the timing
of endoscopy (how many hours
after the initiation of pre-emptive
PPI therapy)
a26
Conclusions
Guideline
PPI treatment initiated before
endoscopy for upper GI bleeding
might reduce the proportion of
patients with SRH at index endos-
copy and significantly reduces
requirement for endoscopic ther-
apy during index endoscopy.
However, there is no evidence
that PPI treatment affects clini-
cally important outcomes, name-
ly mortality or need for surgery.
Pre-emptive omeprazole appears
to accelerate the resolution of
signs of bleeding.
Fewer cases of actively bleeding
ulcers were seen among patients
receiving omeprazole than
among those who received
placebo.
In patients awaiting endoscopy
pre-emptive use of high dose in-
travenous omeprazole is recom-
mended.
High dose intravenous PPI initi-
ated before endoscopy reduces
rebleeding rates, blood transfu-
sion volume and hospital stay,
especially when endoscopy is
delayed beyond 24 h of presen-
tation.
No alteration on need for endo-
scopic treatment.
 Appendix e3 (Continuation)

First author, Study type Patient group Key outcomes Key results Limitations Conclusions
year [ref.]
Barkun, 2010 International Consen- NA Rebleeding Pre-endoscopic PPI treatment signifi- NA Pre-endoscopic PPI therapy may
[240] sus Guideline Patients receiving pre- Need for surgery cantly reduced the proportion of be considered in order to down-
emptive PPI before endos- Mortality patients with high risk stigmata (OR stage the endoscopic lesion and
copy. Need for intervention 0.67, CI 0.54 – 0.84), and the need for decrease the need for endoscopic
Supportive cost-effective analysis pre-endoscopic therapy (OR 0.68, intervention but should not delay
CI 0.50 – 0.93) compared with the endoscopy.
control group (placebo or H2RA). Comment: ESGE Board endorsed
Economic dominance of pre-endo- the consensus recommendation.
scopic high dose intravenous PPI
therapy.
Tsoi, 2008 Decision analysis Omeprazole group (80 mg Number of patients who avoided 248 patients in the PPI group and 227 The estimated values were based The use of high dose PPI before
[241] model bolus intravenous + 8 mg/h endoscopic therapy within the patients in the placebo group avoided on an assumed linear relationship an endoscopy is shown to be an
Cost-effectiveness infusion): follow-up period endoscopic therapy. effective and cost-saving way to
comparison n = 314 patients Direct costs of medical treat- Overall direct costs: 2813 US dollars treat patients with upper GI
187 peptic ulcer cases ment, diagnostic endoscopy, (USD) in the PPI group vs. 2948 USD in bleeding.
– initiated prior to hemostasis, emergency surgery, the placebo group
endoscopy hospitalization Costs were reduced by 7.4 % with
Placebo group: pre-emptive PPI therapy
n = 317 patients
190 peptic ulcer cases
– initiated prior to
endoscopy
Barkun, 2008 Editorial NA Key questions: NA NA The earlier the endoscopy is per-
[242] To contrast the pre-endoscopic formed, the less the cost-effec-
with post-endoscopic hemostatic tiveness of high dose intravenous
uses of PPI (in high dose intrave- PPI.
nous administration) in patients Pre-emptive PPI use should not
with peptic ulcer bleeding replace the performance of early
Almost no data about the time endoscopy.
elapsed until endoscopy (i. e., the
duration of intravenous PPI ad-
ministration before gastroscopy)
What is the optimal duration of
pre-emptive high dose intrave-
nous PPI therapy regarding
cost-effectiveness
Which subgroups of ulcer
patients benefits most from
pre-endoscopy PPI therapy
Guideline

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 a28

Appendix e3 (Continuation)

First author, Study type Patient group Key outcomes Key results Limitations Conclusions
year [ref.]
Guideline

Rácz, 2012 Single-center, retro- 240 PUB patients, panto- Active ulcer bleeding at the first Mean duration of infusion before Retrospective study Pre-emptive infusion of high dose
[243] spective, comparative prazole bolus 80 mg intra- endoscopy endoscopy: Aspirin, NSAIDs, and anticoagu- pantoprazole longer than 4 h
cohort study venous + 8 mg/h pantopra- Need for endoscopic hemostasis 5.4 ± 12.9 h in the saline group vs. 6.9 lants were discontinued at time of before endoscopy decreased the
zole infusion before endos- at the first endoscopy ± 13.2 h in the pantoprazole group hospital admission. ratio of active bleeding only in
copy Need for urgent endoscopy (P = 0.29). Only data from patients admitted gastric and not in duodenal ulcer
Control group: 93 PUB All outcomes were analyzed in Active bleeding at first endoscopy: during evening hours (6pm to patients.
patients received saline subgroups of patients with differ- 19.2 % in the pantoprazole group vs. 8am) were analyzed
infusion until endoscopy ent durations of intravenous pan- 24.7 % in the saline infusion group
toprazole before endoscopy. (P = 0.26).
Rebleeding rates Endoscopic treatment requirement at
Separate analyses in duodenal first endoscopy:
ulcer and gastric ulcer patients 61.3 % in the pantoprazole group vs.
56.9 % in the saline group (P = 0.82)
Lanas, 2013 Summary of main NA – – – It has been reported that the
[244] studies administration of a PPI prior to
endoscopy or the early perform-
ance of endoscopy within 6 h of
admission in patients with UGIB
does not improve the prognosis of
the event.
Sung, 2011 Consensus report NA NA – – A pre-endoscopy proton pump
[245] inhibitor (PPI) is recommended as
a stopgap treatment when
endoscopy within 24 h is not
available.
Al-Sabah, Decision model com- Cost-effectiveness – – Intravenous PPIs given before
2008 [246] pared high dose PPI in- endoscopy are slightly more ef-
itiated while awaiting fective than no administration.
endoscopy with ad-

Gralnek Ian M et al. Nonvariceal upper gastrointestinal hemorrhage: ESGE Guideline … Endoscopy 2015; 47: a1–a46
ministration on the
basis of endoscopic
findings
Ghassemi. Overview NA NA NA – Intravenous PPI therapy before
2009 [247] endoscopy seems reasonable in
patients presenting with severe
upper gastrointestinal bleeding
suspected from a peptic ulcer, if
a delay is anticipated in urgent
endoscopy.
Laursen, 2012 Guideline approved by NA NA NA – Treatment with PPI prior to
[248] the Society of Danish endoscopy cannot be recommen-
Society for Gastro- ded and must not delay the timing
enterology of upper endoscopy.
Lin, 2010 Overview NA NA NA – There was no evidence that PPI
[249] before endoscopy improves
clinical outcomes.
ESGE, European Society of Gastrointestinal Endoscopy; H2RA, histamine-2 receptor antagonist; trial; NA, not available; NSAID, nonsteroidal anti-inflammatory drug; PPI, proton pump inhibitor; PUB, peptic ulcer bleeding; RCT, randomized controlled trial;
UGIB, upper gastrointestinal bleeding.

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 Appendix e4 Role of tranexamic acid (TXA) in upper gastrointestinal hemorrhage.
First author, Study type Study population, Interven-
year [ref.] tions
Gluud, 2012 Cochrane meta-analysis of Patients admitted with sus-
[250] 7 RCTs vs. placebo pected upper gastrointestinal
1 RCT included also a treatment bleeding confirmed by gastric
arm with cimetidine (Ref. 5) lavage, hematemesis or melena
1 RCT included also a treatment Interventions:
arm with lansoprazole and – Oral TXA administration
lansoprazole + TXA (3 studies;
– Intravenous TXA adminis-
tration (4 studies.
Treatment duration (range):
2 – 7 days
Total daily TXA dose, range:
4 – 8 g (divided in four to six
daily doses)
1 RCT offered endoscopic
treatment to all randomized
patients
CI, confidence interval; NVUGIB, nonvariceal upper gastrointestinal bleeding; RCT, randomized controlled trial; RR, relative risk.
Gralnek Ian M et al. Nonvariceal upper gastrointestinal hemorrhage: ESGE Guideline … Endoscopy 2015; 47: a1–a46
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Key outcomes
– Mortality (1654 patients,
7 studies)
– Rebleeding or continued
bleeding (1604 patients,
6 studies)
– Surgery (1504 patients,
6 studies)
– Need for transfusion (1504
patients, 6 studies)
– Any thromboembolic event
(1048 patients, 3 studies
Key results Limitations Conclusion
TXA versus placebo: Methodological quality of stud- TXA cannot be recommended
Significant difference in ies included (unclear or high risk for routine use.
mortality: 5 % vs. 8.2 %; RR 0.61 of bias of selection bias in many Additional trials in which TXA is
(95 %CI 0.42 – 0.89) of them) used in combination with the
No significant difference in a Scarce applicability of evidence currently recommended inter-
subgroup analysis stratified for (most trials do not include the ventions are required.
quality of bias control (trials currently recommended inter-
with adequate allocation vention for management of
sequence generation or alloca- NVUGIB)
tion concealment included):
RR 0.78, 95 %CI 0.58 – 1.05)
No significant difference in:
– Rebleeding: RR 0.73,
95 %CI 0.5 – 1.07
– Surgery: RR 0.62,
95 %CI 0.35 – 1.09
– Need for transfusion: 1.02,
95 %CI 0.93 – 1.11
– Any thromboembolic
event: RR 1.86, 95 %CI
0.66 – 5.24
TXA versus cimetidine or
lansoprazole:
No significant difference in all
outcome variables
Guideline
a29

Appendix e5 Role of somatostatin in acute nonvariceal upper gastrointestinal hemorrhage (NVUGIH).
First author, year [ref.] Study type
Magnusson, 1985 [251] Randomized,
double‐blind
Choi, 2011 [252] Retrospective analysis of
a prospective database
Avgerinos, 2005 [253] Randomized,
double‐blind
Gralnek Ian M et al. Nonvariceal upper gastrointestinal hemorrhage: ESGE Guideline … Endoscopy 2015; 47: a1–a46
Archimandritis, 2000 [254] Prospective,
randomized, open
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Patient group
95 patients with acute non-
variceal GI bleeds with “mas-
sive” bleeding (clinical signs
of shock or preshock)
– 46 patients: 72 h soma-
tostatin infusion
– 49 patients: placebo
101 patients with acute ulcer
bleeding, high risk stigmata
(FIa,Ib, IIa)
Endoscopic therapy in all
patients
– 52 patients: pantopra-
zole 80-mg bolus + con-
tinuous infusion 8 mg/h
for 72 h
– 49 patients: pantopra-
zole as above, and also
somatostatin as 250-µg
bolus + continuous infu-
sion 250 µg/h for 72 h
Adult patients admitted
within 24 h of bleeding
Endoscopic stage IIc and III
peptic ulcer bleeding
Not on PPI or H2 blockers in
the previous week
No hypovolemia
Normal platelets, no
coagulopathy
14 somatostatin
14 PPI
15 placebo
84 patients with acute non-
variceal upper GI bleed
– 44 ranitidine
– 40 ranitidine +
octreotide
Key outcomes
Need for surgical treatment
(indication: > 6 units PRBC
needed to keep hemodyna-
mically stable
Evidence of active bleeding
1 day after treatment
Clinically significant early
rebleeding
Loss of endoscopic high risk
stigmata at second-look
endoscopy
Gastric pH compared with
patient baseline gastric pH
during drug infusion
Intragastric pH > 4 in the
fundus during the 24-h
infusion period
Need for surgical inter-
vention
Hospital stay length
Blood units transfused
a30
Key results Limitation Conclusion
Guideline
Patients who needed surgery Only included patients Somatostatin infusion was
(P < 0.04): with signs of shock superior to placebo regard-
– 14 placebo Endoscopic treatment ing surgical need in patients
– 5 somatostatin was not standardized with nonvariceal upper gas-
P < 0.04 trointestinal bleeding.
Rebleeding:
– 5 placebo
– 6 somatostatin
Rebleeding rates: Not randomized study Adjunctive somatostatin for
– PPI: 12.2 % management of nonvariceal
– 14.3 % PPI + somatostatin upper gastrointestinal
P = 0.766 bleeding did not show an ad-
Loss of stigmata: ditive effect in reducing early
– 94.2 % PPI rebleeding.
– 95.9 % PPI + somatostatin
P = 0.696
Successful maintenance of pH > 4.0 186 patients screened; During the first 12 h of the
in patients having somatostatin 143 excluded infusion somatostatin was
(P < 0.0001) and PPI (P < 0.0001) Patients with stigmata more effective than panto-
During first half of treatment, time of recent hemorrhage prazole maintaining high
with above pH 4.0 and 5.4, respec- were excluded intragastric pH.
tively, was higher with somatostatin Evaluation of rebleeding
than PPI (P < 0.005) and (P < 0.02) was only a secondary
end point
No difference between groups for: Small numbers
– Hospital stay length (P = 0.25) Not blinded
– Amount of blood units
(P = 0.16)
Need for emergency surgery did
not differ (P = 1.0)
 Appendix e5 (Continuation)
First author, year [ref.]
Lin, 1995 [255]
Kim, 2008 [256]
Antonioli, 1986 [257]
Tisbouris, 2007 [258]
Gralnek Ian M et al. Nonvariceal upper gastrointestinal hemorrhage: ESGE Guideline … Endoscopy 2015; 47: a1–a46
Study type
Randomized, open
Retrospective analysis
Multicenter, randomized,
prospective, controlled trial
Randomized, double-blind,
controlled trial
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Patient group
Patients with active peptic
ulcer bleeding, or Nonbleed-
ing visible vessel at ulcer
bases
– 42 octreotide
– 42 ranitidine
Patients with peptic ulcer
bleeding, Forrest Ia, b, II a,b
Group A: 45 patients; 48 h
pantoprazole infusion
Group B: 45 patients; 48 h
pantoprazole + 250 µg/h
infusion of somatostatin
56 PUB patients
Group A: 250 µg/h infusion
somatostatin for 48 h
Group B: 1600 µg/24 h cime-
tidine for 48 h after endos-
copy
Patients with peptic ulcer
bleeding, Forrest Ia, Ib, Iia
Group P: 82 patients, 8 mg/h
pantoprazole infusion for
48 h
Group S: 82 patients, 250 µg
somatostatin infusion for
48 h
Key outcomes Key results Limitation Conclusion
Hemostasis Hemostasis achieved in 35/42 Not blinded
Blood units transfused (83.3 %) octreotide group vs. 23/42
(54.8 %) in ranitidine group;
(P < 0.01)
Octreotide group had:
– Lower volume of blood
(P < 0.05)
– Fewer patients needing endo-
scopic hemostasis/surgery
(P < 0.05)
– Fewer days in hospital
(P < 0.001)
Rebleeding in: 72 h rebleeding: Not randomized Combined therapy with PPI
– 72 h, and – PPI alone: 11 % Endoscopic treatment and somatostatin did not re-
– 30 days – PPI + somatostatin: 13 % was not standardized sult in better outcomes than
Not significant PPI alone.
30-day rebleeding:
– 13 % vs. 16 %
Not significant
Secondary hemostasis Hemostasis: Small patient numbers Somatostatin infusion for
Transfusion requirement – Somatostatin group: 93.3 % Rebleeding rate was not 48 h is superior to cimetidine
– Cimetidine group: 61.5 % defined infusion regarding
P < 0.01 definitive hemostasis.
Blood requirement:
– Somatostatin: 1.14 PRBC
– Cimetidine: 2.46 PRBC
P < 0.05
Rebleeding 3 days after initial Rebleeding and need for endo- Endoscopic treatment Infusion of pantoprazole
hemostasis scopic re-treatment: was not standardized after initial hemostasis was
Need for endoscopic – Group P: 5 % vs. Not placebo-controlled superior to somatostatin
re-treatment – Group S: 17 % infusion to prevent bleeding
(P = 0.046) recurrence
Achieved pH > 6 for more than No difference in the need for
85 % of the time: surgery and in mortality.
– Group P: 56.7 % vs.
– Group S: 46.7 %
(P = 0.44)
Guideline
a31

Appendix e5 (Continuation)
First author, year [ref.]
Okan, 2000 [259]
Rutgeerts, 2006 [260]
PPI, proton pump inhibitor; PRBC, packed red blood cells; PUB, peptic ulcer bleeding.
Gralnek Ian M et al. Nonvariceal upper gastrointestinal hemorrhage: ESGE Guideline … Endoscopy 2015; 47: a1–a46
Study type
Prospective, randomized,
double-blind controlled
study
Double-blind randomized
controlled trial
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Patient group
Total of 48 patients with up-
per gastrointestinal bleeding
Group I: 15 Forrest Ib
patients
Group II: 30 Forrest II
patients
Randomly administered:
– Somatostatin 250 µg bo-
lus + continuous infusion
6 mg/day for 72 h, or
– Ranitidine 300 mg/day
continuous infusion for
72 h
369 PUB patients
Before endoscopy, random-
ized for intravenous treat-
ment:
– S group: 250 µg bolus +
12 mg/day somatostatin
for 72 h
– P group: placebo infu-
sion for 72 h
Diagnostic endoscopy within
8 h of randomization
Key outcomes
Blood transfusion require-
ment
Time to bleeding cessation
Rebleeding rate
Failure rate (Forrest Ia or Ib at
diagnostic endoscopy, clini-
cal signs of active bleeding
≥ 1 h after the start of infu-
sion
Use of rescue therapy (endo-
scopic treatment, surgery,
vasoactive drugs) to stop
bleeding
Key results
Transfusion requirement: no sign.
difference
In group I (Forrest Ib patients), time
to bleeding cessation was signifi-
cantly shorter in those receiving
somatostatin vs. those receiving
ranitidine (3.24 vs. 11.25 h,
P = 0.038)
No differences in rebleeding rate or
mortality
Failure rates in S and P groups:
– No statistically significant
difference, 34 % vs. 36 %
Stigmata of bleeding:
– Statistically significant effect in
favor of somatostatin
– P = 0.034
Rescue treatment:
– Significantly less in S vs. P group
P = 0.012
a32
Limitation Conclusion
Guideline
Low patient numbers Somatostatin is more effec-
tive than ranitidine in con-
trolling acute nonvariceal
upper gastrointestinal
bleeding in patients with
Forrest Ib bleeding activity.
No additional benefit with
Forrest II bleeding activity.
Unusual presentation of The results of this multicen-
results ter large trial were published
“Failure rate” is not an only in abstract form. How-
established measure of ever, the results appear to
results in studies support the use of intrave-
nous somatostatin adminis-
tered early and prior to diag-
nostic endoscopy and endo-
therapy to control bleeding
in patients with suspected
acute and severe PUB.
 Appendix e6 Role of prokinetic agents in acute overt upper gastrointestinal hemorrhage.
First author, year Study type Patient group
[ref.]
Carbonell, 2006, Prospective, random- Upper gastrointestinal bleeding
[261] ized, double-blind patients, all with nasogastric
tube
– 49 patients, 250 mg ery-
thromycin prior to endos-
copy
– 50 patients, placebo prior to
endoscopy
Coffin, 2002 [262] Prospective, random- Acute upper gastrointestinal
ized, endoscopist- bleeding within 12 h requiring
blinded, controlled esophagogastro-duodenoscopy
trial (EGD)
Before EGD patients were given:
– 3 mg/kg erythromycin in
125 mL saline as a 30-min-
ute infusion, or
– Observation without motili-
ty agent
EGD within 60 – 120 min follow-
ing erythromycin infusion
Erythromycin group:
19 patients
Control group: 22 patients
Frossard, 2002 Prospective, random- – Erythromycin intravenous
[263] ized, double-blind, 250 mg: 51 patients
monocentric – Placebo: 54 patients
20 minutes before endoscopy
Within 12 h after hematemesis
Theivanayagam, Meta-analysis of 558 patients with upper gastro-
2013 [264] 6 studies intestinal bleeding (patients
with variceal bleeds were also
included)
Gralnek Ian M et al. Nonvariceal upper gastrointestinal hemorrhage: ESGE Guideline … Endoscopy 2015; 47: a1–a46
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Key outcomes
Improvement of gastric cleans-
ing prior to endoscopy
Identification of bleeding point
Effectiveness of hemostasis
treatment
Quality of EGD examination
evaluated using a score
Need for second EGD
Effectiveness of endoscopy
therapy
Effect of intravenous erythro-
mycin on endoscopic yield
Need for second-look endos-
copy
Transfusion requirement
Visualization of gastric mucosa
Need for second endoscopy
Key results
– Better visualization of entire
gastric mucosa in erythro-
mycin patients: 65 % vs. 44 %
P < 0.05
– Clots in the stomach: 30 %
erythromycin vs. 52 % place-
bo
P < 0.05
– Hemostatic treatment: 67 %
erythromycin vs. 62 % place-
bo
P = 0.67
Significantly better visualization
during EGD in the erythromycin
group (P = 0.02)
No interference with the hemo-
static procedure
Need for second endoscopy:
erythromycin:15.8 % vs. con-
trol:45.4 % (P = 0.089)
Clear stomach found more often
in erythromycin group: 82 % vs.
33 %, P < 0.001
Erythromycin shortened the
endoscopy duration and the
need for second-look endoscopy
Erythromycin infusion before
endoscopy significantly im-
proved visualization vs. no ery-
thromycin:
OR 3.43, 95 %CI 1.81 – 6.50
Significant decrease in the need
for second endoscopy (P = 0.01)
Limitation
Low patient numbers
Subjective criteria based on the
endoscopist’s judgment
Low patient numbers
Qualitative evaluation of results
(by scoring system)
Low patient number with non-
variceal upper gastrointestinal
bleeding
Inclusion of variceal bleedings
Conclusion
Intravenous erythromycin
before endoscopy improves
stomach cleansing and the
quality of endoscopic examina-
tion.
Limited clinical benefit.
Erythromycin infusion before
endoscopy significantly im-
proved the quality of EGD.
Tendency to reduce the need for
second-look endoscopy.
Erythromycin infusion before
endoscopy in patients with
recent hematemesis makes
endoscopy shorter and easier,
and reduces the need for
second-look endoscopy.
Erythromycin infusion before
endoscopy in patients with up-
per gastrointestinal bleeding
significantly improves visuali-
zation of gastric mucosa and
decreases the need for a second
endoscopy.
Guideline
a33
 a34

Appendix e6 (Continuation)

First author, year Study type Patient group Key outcomes Key results Limitation Conclusion
[ref.]
Guideline

Sussman, 2008 Single-center, pro- Patients with overt hema- Mucosal visualization during Better visualization after meto- Low patient numbers Intravenous metoclopramide
[265] spective, random- temesis or melena EGD (Avgerinos score) clopramide, P = not significant Subjective quality score may increase visualization of the
ized, controlled study A total of 26 patients Duration of EGD No significant difference re- proximal stomach during EGD,
Intravenous metoclo- Rebleeding rate garding blood transfusion, re- but not significantly.
pramide bolus (10 mg peat EGD No translation into better
intravenous) clinical outcome.
Barkun, 2010 [266] Meta-analysis 3 erythromycin studies Primary: A prokinetic agent significantly Small numbers of patients Intravenous erythromycin or
3 fully published 2 metoclopramide studies – Need for repeat EGD reduced the need for repeat metoclopramide immediately
articles, 2 abstracts 316 patients Secondary: EGD: before EGD in patients with
– Blood transfusion OR 0.55, 95 %CI 0.32 – 0.94 acute upper gastrointestinal
– Need for surgery No significant alterations: bleeding decreases the need for
– Blood transfusion, and repeat EGD, but does not im-
– Need for surgery: prove clinical outcomes.
Habashi, 2007 [267] Prospective, random- 54 patients with hematemesis Visualization of the mucosa Gastric mucosa entirely Small sample sizes No significant difference be-
ized, controlled trial (42 % PUB patients) Quality of the EGD visualized: Subjective scores tween placebo and either medi-
– Intravenous erythromycin: – erythromycin group: 86 %, Dosage of prokinetics not cation regarding key outcomes.
15 patients vs. reported
– Intravenous metoclopra- – metoclopramide group:
mide: 15 patients 66 %
– Placebo: 15 patients Quality of EGD significantly
better in erythromycin group vs.
metoclopramide and placebo
groups
Winstead, 2007 Cost-effectiveness a- 3 RCTs were analyzed with a total Quality-adjusted life-years Intravenous erythromycin be- The estimates need for repeat Intravenous erythromycin
[268] nalysis of 126 patients (QALYs) fore endoscopy was cost-effec- endoscopy. before endoscopy in acute
(Frossard, Coffin and Carbonell Need for second-look endos- tive when the rate of second- The complex model may fail to upper gastrointestinal hemor-
studies) copy look endoscopy was less than capture all the slight variations rhage (UGIH) is cost-saving and
0.29 in patterns of care among dif- increases QALYs.
Intravenous erythromycin was ferent hospitals. Erythromycin is recommended

Gralnek Ian M et al. Nonvariceal upper gastrointestinal hemorrhage: ESGE Guideline … Endoscopy 2015; 47: a1–a46
cost-effective when the charges prior to EGD in UGIH.
for uncomplicated peptic ulcer
disease PUD were less than
8000 US dollars
CI, confidence interval; EGD, esophagogastroduodenoscopy; PUB, peptic ulcer bleeding; OR, odds ratio; RCT, randomized controlled trial.

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 Guideline a35

Appendix e7 Summary of the evidence regarding impact of early endoscopy (≤ 24 h) on the outcome of patients with nonvariceal upper gastrointestinal
hemorrhage (NVUGIH).

First author, Country Study type, Patients, n Major findings

year [ref.] Study period
Spiegel, – Systematic review 12 625 Early endoscopy ( ≤ 24 h) safe and effective in all risk groups.
2001 [269] 1980 – 2000 Low risk: allows safe and prompt discharge.
23 studies High risk: significantly reduces recurrent bleeding, transfusion require-
– 6 controlled in ments, need for surgery and length of hospital stay.
low risk patients
– 7 uncontrolled in
low risk patients
– 6 controlled in
high risk patients
– 4 comparing resource

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utilization
Tsoi, 2009 – Systematic review 5 677 Early endoscopy aids risk stratification and reduces the need for hospi-
[270] 1996 – 2007 talization; however it may increase the use of unnecessary therapeutic
8 studies procedures.
– 3 RCT Endoscopy performed ≤ 8 h of presentation has no advantage over
– 5 retrospective endoscopy performed within 12 – 24 h of presentation in reducing
recurrent bleeding or improving survival.
Sarin, 2009 Canada Retrospective 502 No advantage for early endoscopy (< 6 h) compared with endoscopy
[271] 2004 – 2006 within 24 h in terms of mortality, need for surgery, or transfusion
requirements.
Lim, 2011 Singapore Retrospective 837 low risk Endoscopy within 13 h of presentation is associated with lower mortality
[272] 97 high risk in high risk but not low-risk patients with NVUGIH.
Marmo, Italy Multicenter, prospective 3 207 Significant increase of mortality in high risk patients when endoscopy is
2011 [273] cohort studies (3 databases) performed ≤ 12 h compared with endoscopy performed 13 – 24 h after
2004 – 2009 presentation (14.3 % – 16.6 % vs. 5.2 %, P = 0.001).
Wysocki, US Retrospective 435 765 Increased mortality risk in patients who do not receive endoscopy within
2012 [274] Administrative data 1 day of admission: OR 1.32, 95 %CI 1.26 – 1.38.
NIS 2002 – 2007
Jairath, UK Multicenter, prospective 4 478 Compared with later endoscopy (> 24 to 48 h), endoscopy performed
2012 [275] cohort study ≤ 12 h did not affect mortality (OR 0.98, 95 %CI 0.88 – 1.09), but led to
2007 a decreased risk-adjusted length of hospital stay (1.7 days,
95 %CI 1.39 – 1.99).
CI, confidence interval; OR, odds ratio; RCT, randomized controlled trial.

Gralnek Ian M et al. Nonvariceal upper gastrointestinal hemorrhage: ESGE Guideline … Endoscopy 2015; 47: a1–a46

Appendix e8 Medical management following endoscopic hemostasis
First author, year Study design Intervention
[ref.]
Barkun, 2010 [240] International consensus After endoscopic therapy:
guideline – Proton pump inhibitor (PPI) vs.
– Placebo or H2RA
Sachar, 2014 [276] Systematic review After endoscopic therapy:
– PPI intravenous continuous
infusion (80 mg + 8 mg/h for
72 h) vs.
– Intermittent PPI
Sung, 2014 [277] Randomized, controlled After endoscopic therapy:
trial, double blind – Intravenous esomeprazole
bolus 80 mg + 8 mg/h for 72 h
vs.
– Oral esomeprazole 40 mg/12 h
Mostaghni, 2011 Randomized, open-label – Oral omeprazole (80 mg twice-
[278] daily for 3 days), or
– Intravenous pantoprazole
(80 mg bolus and 8 mg/hour
infusion for 3 days)
Followed in all patients by
omeprazole (20 mg each day
for 30 days).
Yen, 2012 [279] Randomized, open-label Esomeprazole group: 40 mg con-
tinuous infusion of esomeprazole
every 6 h for 3 days. Then oral
Gralnek Ian M et al. Nonvariceal upper gastrointestinal hemorrhage: ESGE Guideline … Endoscopy 2015; 47: a1–a46
esomeprazole 40 mg once-daily for
2 months.
Lansoprazole group: oral 30 mg
four times daily for 3 days followed
by once daily for 2 months.
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Participants Outcomes Results
Patients with endoscopic Mortality Rebleeding: OR 0.45, CI 0.36 – 0.57
signs of high risk of Rebleeding 3 – 7 days Surgery: OR 0.56, CI 0.45 – 0.70
rebleeding Mortality: OR 0.90 CI 0.67 – 1.19
Patients with endoscopic Rebleeding 7 days Rebleeding: risk ratio (RR) 0.72
signs of high risk of Mortality (upper boundary of 1-sided 95 %CI
rebleeding 0.97).
RRs for rebleeding 3 – 30 days,
mortality, urgent interventions
were less than 1.
Patients with endoscopic Rebleeding at 30 days Intravenous esomeprazole group:
signs of high risk of 118 patients
rebleeding Oral esomeprazole group:
126 patients
Recurrent bleeding:
– Intravenous group: 7.7 %, vs.
– Oral group: 6.4 %
Patients with endoscopic Rebleeding (30 days?; – Oral omeprazole: 44 patients
signs of high risk of timing not well-defined) – Intravenous pantoprazole: 41
rebleeding patients
Rebleeding:
– Oral omeprazole: 11.4 %, vs.
– Intravenous pantoprazole:
9.8 %
Mean hospital stay and blood
transfusion were not different
between the two groups.
Patients with endoscopic Rebleeding rate within 100 patients enrolled.
signs of high risk of 14 days. Rebleeding rates:
rebleeding Secondary outcomes – esomeprazole intravenous
included: group: 4 % (2 /50), and
– Hospital stay – Lansoprazole oral group: 4 %
– Volume of blood (2/50)
transfusion No difference between the two
– Surgical intervention, groups with regard to:
and – Hospital stay
– Mortality within – Volume of blood transfusion
1 month – Surgery, or
– Mortality rate
a36
Level of evidence, conclusions
Guideline
Intravenous PPI 80 mg bolus
+ 8 mg/h for 72 h recommended.
Evidence: High
No differences between intermit-
tent high dose PPI (all routes) vs.
intravenous PPI 80 mg bolus
+ 8 mg/h for 72 h.
Evidence: High
High dose oral esomeprazole may
be considered as a useful alterna-
tive to intravenous therapy.
Evidence: Moderate
Oral omeprazole and intravenous
pantoprazole had equal effects on
prevention of rebleeding after
endoscopic therapy in patients
with high risk bleeding peptic
ulcers.
Evidence: Low
There is no evidence of a difference
in clinical outcomes between oral
and intravenous PPI treatment.
(not powered to prove equivalence
or noninferiority). Patients receiv-
ing oral PPI have a shorter hospital
stay.
Evidence: Low
 Appendix e8 (Continuation)

First author, year Study design Intervention Participants Outcomes Results Level of evidence, conclusions
[ref.]
Tsai, 2008 [280] Randomized, open-label – Oral rabeprazole (20 mg twice- Patients with endoscopic Bleeding up to 14 days. 156 patients with 78 in each group Oral rabeprazole and intravenous
daily for 3 days), or signs of high risk of Also compared: Rebleeding: regular-dose omeprazole are
– Intravenous omeprazole rebleeding – Hospital stay – Omeprazole group: 12 patients equally effective in preventing re-
(40 mg intravenous infusion – Volume of blood (15.4 %) bleeding in patients with high risk
every 12 h for 3 days). transfusion – Rabeprazole group: bleeding peptic ulcers after suc-
– Surgery, and 13 patients (16.7 %) cessful endoscopic injection with
– Mortality within – 95 %CI of difference: epinephrine.
14 days 12.82 – 10.22 Evidence: Low
No differences in the other
evaluated outcomes
Wang, 2010 [281] Systematic review High dose PPIs (80 mg bolus + Patients with bleeding – Rebleeding 7 studies and 1157 patients Compared with non – high dose
8 mg/h for 3 days vs. peptic ulcer – Surgical intervention, – Rebleeding: OR 1.30, 95 %CI PPIs, high dose PPIs do not further
Non-high dose PPIs (40 mg160 mg/ and 0.88 – 1.91 reduce the rates of rebleeding,
day for 3 days) – Mortality – Surgical intervention: OR 1.49, surgical intervention, or mortality
0.66 – 3.37 after endoscopic treatment.
– Mortality: OR 0.89, 0.37 – 2.13 Evidence: High
Masjedizadeh, Randomized, open-label – High dose pantoprazole (80 mg Patients with endoscopic Rebleeding at 30 days 166 patients (83 patients per For controlling peptic ulcer bleed-
2014 [282] bolus, 8 mg per hour) infused signs of high risk of re- group) ing, there is no difference between
for 3 days vs. bleeding Rebleeding observed in: high dose and low dose pantopra-
– Low dose pantoprazole (40 mg – High dose group: 27 patients zole infusion.
bolus, 4 mg per hour) infused (32.53 %) Evidence: Low
for 3 days – Low dose group: 21 patients
(25.30 %)
P = 0.30
CI, confidence interval; H2RA, histamine-2 receptor antagonist; OR, odds ratio; PPI, proton pump inhibitor; RR, risk ratio.
Guideline

Gralnek Ian M et al. Nonvariceal upper gastrointestinal hemorrhage: ESGE Guideline … Endoscopy 2015; 47: a1–a46
a37

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 a38

Appendix e9 Salvage therapy in failed endoscopic hemostasis.

First author, Study type Patient group Key outcomes Key results Limitations Level of evidence, Conclusion
Guideline

year [ref.]
Lau, 1999 Prospective, random- Endoscopic re-treat- Definitive hemostasis Definitive hemostasis: 35 /48 Very high expertise center High quality
[283] ized trial ment with the same Complications Salvage surgery: 13 Not blinded In patients with peptic ulcers and
Comparison between device (epinephrine Surgery – Persistent bleeding: 11 2 perforations related to rebleeding after initial hemostatic suc-
immediate endo- injection + heater Mortality – Perforation: 2 re-treatment with heater cess, endoscopic re-treatment reduces
scopic re-treatment probe): Complications: probe the need for surgery without increasing
vs. surgery – n = 48 patients 7 patients in the endoscopy group (includ- risk of death and is associated with
Surgery: ing 6 who underwent salvage surgery) had fewer complications than surgery.
– n = 44 complications, as compared with 16 in the
surgery group (P = 0.03)
7
Mortality: n.s.
Hypotension at randomization and ulcer
> 2 cm were independent predictors of
re-treatment failure
Wong, 2011 Retrospective Transcatheterangio- Definitive hemostasis Bleeding recurrence: Results of initial failure and Moderate quality
[284] graphic embolization Complications – TAE group 34.4 % rebleeding are mixed In patients with ulcer bleeding after
(TAE): n = 23 Mortality – Surgery group 12.5 % failed endoscopic hemostasis, TAE
Surgery: n = 56 P = 0.1 reduces the need for surgery without
More complications after surgery: increasing the overall mortality and is
67.9 % vs. 40.6 %, P = 0.1 associated with fewer complications.
No difference in mortality: 25 %
vs. 30.4 %
Kyaw, 2014 Meta-analysis TAE patients were Definitive hemostasis Risk of rebleeding was significantly higher in Retrospective studies High quality
[285] 6 retrospective older, mean age: Complications TAE vs. surgery: A higher rebleeding rate was observed
studies that involved – TAE: 75 years vs. Mortality RR 1.82, 95 %CI 1.23 – 2.67 after TAE, suggesting surgery more
423 patients – Surgery: 68 years After age exclusion, the high risk of rebleed- definitively secured hemostasis, with
ing remained in the TAE group: no significant differences in mortality
RR 2.64, 95 %CI 1.48 – 4.71 rate or requirement for additional
No difference in: interventions.

Gralnek Ian M et al. Nonvariceal upper gastrointestinal hemorrhage: ESGE Guideline … Endoscopy 2015; 47: a1–a46
– Mortality, or
– Requirement for additional
interventions
Beggs, 2014 Systematic review TAE: n = 347 Mortality Deaths: Moderate quality
[286] (with homogeneity) Surgery: n = 364 Rebleeding – TAE: 61 When compared with surgery, TAE had
of cohort studies Length of hospital stay – Surgery: 101 a significantly increased risk of rebleed-
Adverse events Rebleeding: ing. However, there were no differences
– TAE: 78 in mortality.
– Surgery: 45
Length of hospital stay:
– Mean difference between TAE and sur-
gery: 0.75 days
Complications:
– TAE: 92
– Surgery: 81

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 Appendix e9 (Continuation)

First author, Study type Patient group Key outcomes Key results Limitations Level of evidence, Conclusion
year [ref.]
Smith, 2014 European register Patients who other- Definitive hemostasis Definitive hemostasis: Small number of patients Low quality
[287] wise might have – n = 8 (100 %) Hemospray may be useful as a rescue
required either therapy.
surgery or TAE
n=8
Sulz, 2014 Prospective, case n = 16 Definitive hemostasis Initial hemostasis: 15/16 Small number of patients Low quality
[288] series Salvage therapy: 13/14 Hemospray may be useful as a salvage
Monotherapy: 2/2 therapy.
Rebleeding: 12.5 %
Skinner, 2014 Retrospective Over-the-scope clip n = 12 Primary hemostasis: 11/12 Retrospective Low quality
[289] after failure of con- Cause of bleed: Rebleeding n = 2 (day1, day7) Small number of patients Over-the-scope clip effective and safe
ventional endoscopic – Duodenal ulcer: 6 No complication Expertise needed for severe acute gastrointestinal bleed-
treatment – Gastric ulcer: 2 ing when conventional endoscopic
– Dieulafoy lesion: 2 therapy fails.
– Anastomotic ulceration: 1
– Mallory-Weiss: 1
– Prior endoscopies
– Mean of 2
– Shock present:
– n = 9 (75 %)
RBC:
– Mean 5.1 units (2 – 12)
Manta, 2013 Retrospective Over-the-scope clip- n = 23 Primary hemostasis: 22 (96 %) Retrospective Low quality
[290] ping after failure of – Duodenal ulcer: 12 – Duodenal ulcer: 11 (1 rebleeding) Small number of patients Over-the-scope clipping is effective and
conventional endo- Forrest Ia n = 5 Expertise needed safe for severe acute gastrointestinal
scopic treatment Forrest Ib n = 4 bleeding when conventional endo-
– Gastric ulcer 6 – Gastric ulcer: 6 (1 rebleeding) scopic therapy fails.
Forrest Ia: n = 2
Forrest Ib: n = 2

– Mallory-Weiss: n = 3 – Mallory-Weiss: 2 (no rebleeding)

– Dieulafoy: n = 2 – Dieulafoy: 2 (no rebleeding)

– Anastomosis: n = 1 – Anastomosis1: (no rebleeding)

CI, confidence interval; NA, not available; NVUGIB, nonvariceal upper gastrointestinal bleeding; OR, odds ratio; RUT, rapid urease test; UBT, urea breath test.
Guideline

Gralnek Ian M et al. Nonvariceal upper gastrointestinal hemorrhage: ESGE Guideline … Endoscopy 2015; 47: a1–a46
a39

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a40 Guideline

Appendix e10 Helicobacter pylori and nonvariceal upper gastrointestinal hemorrhage (NVUGIH).

First author, year Study design, Participants Outcomes Results Level of evidence,
[ref.] study objective conclusions
Sánchez-Delgado, Meta-regression NVUGIB patients H. pylori infection Delayed testing for H. pylori increases Moderate
2011 [291] analysis rate after the event the detection rate (OR 2.08, 95 %CI
1.10 – 3.93)
Gisbert, 2006 [292] Meta-analysis NVUGIB patients H. pylori infection Low sensitivity of histology, RUT, Moderate
rate after the event culture, UBT, and serology
Barkun, 2010 [240] International NVUGIB patients Re-bleeding H. pylori therapy and eradication High
consensus re- confirmation needed
commendations
Gisbert, 2012 [293] Prospective study NVUGIB patients Re-bleeding after Rebleeding was 0.15 % per patient- Moderate
on 1000 patients H. pylori eradication year of follow-up and it was associated
with either re-infection or NSAIDs use.
Gisbert, 2004 [294] Meta-analysis NVUGIB patients Re-bleeding after Rebleeding was significantly lower in High

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eradication the H. pylori eradication group than in
antisecretory therapy group (1.6 % vs.
5.6 %)
Dixon, 1996 [295] International Gastritis NA Presence of neutrophil histology Moderate
workshop strongly suggests H. pylori infection
CI, confidence interval; NA, not available; NVUGIB, nonvariceal upper gastrointestinal bleeding; OR, odds ratio; RUT, rapid urease test; UBT, urea breath test.

Gralnek Ian M et al. Nonvariceal upper gastrointestinal hemorrhage: ESGE Guideline … Endoscopy 2015; 47: a1–a46
 Appendix e11 Risk of thromboembolism, recurrent gastrointestinal (GI) bleeding and death after warfarin therapy interruption for GI bleeding.

First author, Study type Study population Key outcomes Key results Limitations Conclusion
year [ref.] Intervention
Witt, (2012) Retrospective, 442 patients with warfar- Thromboembolic events 90-day thromboembolic event rate: Retrospective study The decision to not resume war-
[296] cohort in-associated GI bleeding Recurrent GI bleeding – 0.4 % (1/260) in warfarin group Data from administrative farin therapy in the 90 days fol-
Intervention: Death – 5.5 % (10/182) in no-warfarin group databases lowing a GI bleeding event is asso-
Withhold warfarin HR (95 %CI): 0.05 (0.001 – 0.58) Selection bias (greater ciated with increased risk for
(no-warfarin group): 182 No thromboembolic events in patients who co-morbidity burdens in thrombosis and death.
(41.2 %) resumed therapy within 14 days no-warfarin group, which Resuming warfarin within 7 days is
Resumed warfarin (war- 90-day recurrent GI bleeding rate: may have contributed to associated with a twofold higher
farin group): 260 (58.8 %) – Warfarin group: 10 % (26/260) their worse outcomes) risk of rebleeding.
– No-warfarin group: 5.5 % (10/182) Detection and survivor-
HR (95 %CI): 1.32 (0.50 – 3.57) ship biases
Higher risk of recurrent GI bleeding in patients who
resumed warfarin within 7 days from index bleeding
as compared with those who resumed warfarin
later:
– 12.4 % vs. 6.2 %
P = 0.03
90-day mortality rate:
– Warfarin group: 5.8 % (15/260) in
– No-warfarin group: 20.3 % (37/182)
HR (95 %CI): 0.31 (0.15 – 0.62)
Qureshi, 2014 Retrospective, 1329 atrial fibrillation Thromboembolic events Warfarin group vs. no-warfarin group, adjusted HR Retrospective study. Data The decision to not resume war-
[297] cohort study patients with warfarin- Recurrent GI bleeding (95 %CI): from administrative farin therapy after a GI bleeding
associated major GI Death – Thromboembolism: 0.71 (054 – 0.93) database event is associated with increased
bleeding – Recurrent GI bleeding; 1.20 (0.78 – 1.86) Selection bias (greater risk for thrombosis and death.
Intervention: – Mortality: 0.72 (0.60 – 0.86) co-morbidity burdens in There is a trend toward reduced
676 (50.9 %) withhold Incidence of adverse outcomes per 100 person- no-warfarin group) incidence of thromboembolic
warfarin (no-warfarin years in the warfarin group, stratified by the Detection and survivor- events the earlier the warfarin is
group) duration of warfarin interruption: ship biases introduced; this trend is more evi-
653 (49.1 %) resumed – < 7 days (n = 62): dent within the first 15 days.
warfarin (warfarin group) Thromboembolism: 11.6 (8.3 – 16.2) Resuming warfarin within 7 days is
Time duration of inter- Recurrent GI bleeding: 19.3 (14.6 – 25.5) associated with a twofold higher
ruption: – 7 – 15 days (n = 51): risk of rebleeding.
– < 7 days: 62 patients Thromboembolism: 12.0 (8.2 – 17.5) Decision to restart warfarin after
– 7 – 30 days: 162 pa- Recurrent GI bleeding: 10.8 (7.2 – 16.3) 7 days of interruption is associated
tients – 15 – 21 days (n = 58): with improved survival and de-
– 30 days: 429 patients Thromboembolism: 18.1 (13.4 – 24.5) creased thromboembolism with-
Recurrent GI bleeding: 10.9 (7.2 – 16.4) out increased risk of recurrent GI
– 21 – 30 days (n = 53): bleeding.
Thromboembolism 20.7 (15.5 – 27.7)
Recurrent GI bleeding 9.9 (6.3 – 15.5)
– > 30 days (n = 429):
Thromboembolism 20.4 (17.8 – 23.5)
Recurrent GI bleeding 9.9 (8.0 – 12.3)
Guideline

Gralnek Ian M et al. Nonvariceal upper gastrointestinal hemorrhage: ESGE Guideline … Endoscopy 2015; 47: a1–a46
a41

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 a42

Appendix e11 (Continuation)

First author, Study type Study population Key outcomes Key results Limitations Conclusion
year [ref.] Intervention
Guideline

Lee, 2011 Retrospective, 58 patients with NVUGIB Recurrent GI bleeding Warfarin vs. no-warfarin group: Retrospective design Anticoagulation is recommended
[298] case-control study on warfarin for native Thromboembolic events – Rebleeding rate: 7 % vs.0 % Time of resuming antico- to be resumed within 20 days from
valvular heart disease Mean follow-up: 255 + – Thromboembolism rate: 0 % vs. 17 % (6 throm- agulation not specified the cessation to prevent throm-
Controls (aspirin group): 14 days (range 182 – 330) boembolic events occurred, at days 21, 27, 28, Individual thromboem- boembolic events.
41 age- and gender-mat- 31, 58, 75 from admission)Aspirin group: bolic risk not specified
ched patients with NVU- – Rebleeding rate: 0 %
GIB on aspirin for is- – Thromboembolic event rate: 2 % (1 myocardial
chemic heart disease infarction at day 95 from admission)
presenting
Intervention
Cases:
– Discontinued
warfarin (no-warfarin
group): 36/58
– Restarted warfarin
(warfarin group): 22/58
Controls:
– Discontinued aspirin:
41/41
CI, confidence interval; HR, hazard ratio; NVUGIB, nonvariceal upper gastrointestinal bleeding.

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Appendix e12 Observational studies assessing the effect of proton pump inhibitors (PPIs) on clinical cardiovascular outcomes in patients prescribed clopidogrel.
First author, year [ref.]
Studies with evidence of a clinically significant interaction
Goodman, 2012 [299]
Stockl, 2010 [300]
Kreutz, 2010[301]
Ho, 2009 [302]
Huang, 2010 [303]
Zou, 2014 [304]
Van Boxel, 2010 [305]
Munoz-Torrero, 2011
[306]
Studies without evidence of a clinically significant interaction
O’Donoghue, 2009
[307]
Hsiao, 2011 [308]
Banerjee, 2011 [309]
Harjai, 2011 [310]
Aihara, 2012 [311]
Tentzeris, 2010 [312]
Schmidt, 2012 [313]
Rassen, 2009 [314]
Ray,
2010 [315]
CI, confidence interval; HR, hazard ratio; PLATO, Platelet Inhibition and Patient Outcomes; RCT, randomized controlled trial.
Guideline a43
Design Population Patients, n End point Results
PPI No PPI
Retrospective cohort Acute coronary syn- 3 255 6 021 Cardiovascular death, myocar- Clopidogrel cohort:
within RCT (PLATO) drome (ACS) dial infarction, cerebrovascular HR 1.20 (95 %CI
accident 1.04 – 1.38)
Ticagrelor cohort:
HR 1.24 (95 %CI,
1.07 – 1.45)
Retrospective Post myocardial infarc- 1 033 1 033 Myocardial infarction HR 1.93 (95 %CI,
Propensity matching tion or post percuta- Myocardial infarction or 1.05 – 3.54)
neous coronary inter- revascularization HR 1.91 (95 %CI
vention 1.19 – 3.06)
Retrospective cohort Post percutaneous cor- 6 828 9 862 Cardiovascular deaths, acute HR 1.51 (95 %CI,
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onary intervention coronary syndrome, cerebro- 1.39 – 1.64)
vascular accident revasculari-
zation
Retrospective cohort Post myocardial infarc- 5 244 2 961 Deaths, acute coronary syn- HR 1.25(95 %CI,
tion drome 1.11 – 1.41)
Registry Post percutaneous cor- 572 2 706 Death HR 1.65(95 % CI,
onary intervention 1.35 – 2.01)
Retrospective cohort Post percutaneous cor- 61 288 1 465 Myocardial infarction, stent HR 1.33 (95 % CI
onary intervention thrombosis, cardiovascular 1.12 – 1.57)
deaths
Retrospective cohort Clopidogrel users 5 734 12 405 Deaths, acute coronary HR 1.75 (95 % CI,
syndrome, cerebrovascular 1.58 – 1.94)
accident
Registry Vascular disease 519 703 Deaths, myocardial infarction, HR 1.8 (95 % CI,
acute coronary syndrome, cer- 1.1 – 2.7)
ebrovascular accident, chronic
limb ischemia
Retrospective cohort Acute coronary 2 257 4 538 Cardiovascular death, myocar- No effect
within RCT syndrome and post dial infarction, cerebrovascular
(TRITON-TIMI 38) percutaneous coronary accident
intervention
Retrospective Post myocardial 622 9 131 Acute coronary syndrome No effect
Propensity matching infarction
Retrospective Post percutaneous 867 3 678 Death, myocardial infarction, No effect
Propensity matching coronary intervention revascularization
Registry Post percutaneous 751 1 900 Death, myocardial infarction, No effect
Propensity matching coronary intervention revascularization
Registry Post percutaneous 819 1 068 Death, myocardial infarction No effect
Propensity matching coronary intervention
Registry Post percutaneous 691 519 Death, acute coronary No effect
Propensity matching coronary intervention syndrome
Retrospective cohort Post percutaneous 2 742 10 259 Cardiovascular deaths, acute No effect
coronary intervention coronary syndrome, cerebro-
vascular accident, revasculari-
zation
Retrospective cohort Post percutaneous 3 996 14 569 Death, myocardial infarction, No effect
coronary intervention revascularization
or post acute coronary
syndrome
Retrospective cohort Post percutaneous 7 593 13 003 Death, myocardial infarction, No effect
coronary intervention revascularization
or post acute coronary
syndrome
Gralnek Ian M et al. Nonvariceal upper gastrointestinal hemorrhage: ESGE Guideline … Endoscopy 2015; 47: a1–a46
a44 Guideline

Appendix e13 Meta-analyses evaluating the effect of proton pump inhibitors (PPIs) on clinical outcomes in patients treated with clopidogrel.

First author, Included studies Patients, n End point Results

year [ref.]
Kwok, 2010 1 nested case-control 93 278 Myocardial infarction or acute RR 1.43 (95 %CI 1.15 – 1.77)
[316] 20 retrospective coronary syndrome (12 studies) RR 1.15 (0.89 – 1.48): analysis from
(3 studies used a propensity propensity matched or trial
scoring method for the analysis) participants
3 post.hoc analyses of RCT Overall mortality (13 studies) RR 1.09 (95 %CI 0.94 – 1.53)
1 prospective RCT RR 1.00 (0.66 – 1.48): analysis from
propensity matched or trial
participants
Major adverse cardiovascular event RR 1.25 (95 %CI 1.09 – 1.42)
(MACE) RR 1.07 (0.90 – 1.48): analysis from
(19 studies) propensity matched or trial
participants
RR 1.31 (95 %CI 1.12 – 1.53)

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Siller-Matula, 2 nested case-control 159 138 Myocardial infarction
2010 [317] 20 retrospective cohort (13 studies)
(3 studies used a propensity Death RR 1.04 (95 %CI 0.93 – 1.24)
scoring method for the analysis) (13 studies)
2 post.hoc analyses of RCT MACE RR 1.29 (95 %CI 1.15 – 1.44)
1 prospective RCT (19 studies)
CI, confidence interval; RCT, randomized controlled trial; RR, risk ratio

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 Annals of Internal Medicine
International Consensus Recommendations on the Management of
Patients With Nonvariceal Upper Gastrointestinal Bleeding
Alan N. Barkun, MD, MSc (Clinical Epidemiology); Marc Bardou, MD, PhD; Ernst J. Kuipers, MD; Joseph Sung, MD; Richard H. Hunt, MD;
Myriam Martel, BSc; and Paul Sinclair, MSc, for the International Consensus Upper Gastrointestinal Bleeding Conference Group*
Description: A multidisciplinary group of 34 experts from 15 coun-
tries developed this update and expansion of the recommendations
on the management of acute nonvariceal upper gastrointestinal
bleeding (UGIB) from 2003.
Methods: The Appraisal of Guidelines for Research and Evaluation
(AGREE) process and independent ethics protocols were used.
Sources of data included original and published systematic reviews;
randomized, controlled trials; and abstracts up to October 2008.
Quality of evidence and strength of recommendations have been
rated by using the Grading of Recommendations Assessment, De-
velopment, and Evaluation (GRADE) criteria.
Recommendations: Recommendations emphasize early risk strati-
fication, by using validated prognostic scales, and early endoscopy
(within 24 hours). Endoscopic hemostasis remains indicated for
high-risk lesions, whereas data support attempts to dislodge clots
with hemostatic, pharmacologic, or combination treatment of the
underlying stigmata. Clips or thermocoagulation, alone or with epi-
nephrine injection, are effective methods; epinephrine injection
U pper gastrointestinal bleeding (UGIB) represents a
substantial clinical and economic burden, with re-
ported incidence ranging from 48 to 160 cases per 100 000
adults per year (1–5), and mortality generally from 10% to
14% (5, 6). For patients with and without complications
of nonvariceal UGIB in the United States, mean lengths of
stay were 4.4 and 2.7 days and hospitalization costs were
$5632 and $3402 (2004 US dollars), respectively (7).
Some data (2, 4, 5) suggest a decreasing annual incidence
of UGIB amid an unchanging (3, 5) or decreasing (8) inci-
dence of peptic ulcer bleeding, which is increasingly related to
the use of nonsteroidal anti-inflammatory drugs (NSAIDs) or
low-dose acetylsalicylic acid (ASA). Mortality from UGIB has
decreased by 23% in the United States (1998 to 2006) (4)
and by 40% in the United Kingdom (1993 to 2007) (6), but
has remained unchanged in Canada (1993 to 2003) (2) and
the Netherlands (1993 to 2003) (5).
Recent national data suggest that previous recommenda-
tions, although still not optimally adhered to, may result in
improved patient outcomes (9 –13). Furthermore, new data
have become available since the 2002 British Society of
Gastroenterology guidelines (14) and the 2003 consensus
guidelines (15) that warrant an update of the previous rec-
ommendations. A multidisciplinary group developed inter-
national guidelines to help clinicians make informed deci-
sions regarding the management of patients who present
with nonvariceal UGIB, which reflect the 2009 state of
the art.
Downloaded From: http://annals.org/ on 10/31/2016
Clinical Guidelines
alone is not recommended. Second-look endoscopy may be useful
in selected high-risk patients but is not routinely recommended.
Preendoscopy proton-pump inhibitor (PPI) therapy may downstage
the lesion; intravenous high-dose PPI therapy after successful en-
doscopic hemostasis decreases both rebleeding and mortality in
patients with high-risk stigmata. Although selected patients can be
discharged promptly after endoscopy, high-risk patients should be
hospitalized for at least 72 hours after endoscopic hemostasis. For
patients with UGIB who require a nonsteroidal anti-inflammatory
drug, a PPI with a cyclooxygenase-2 inhibitor is preferred to reduce
rebleeding. Patients with UGIB who require secondary cardiovascu-
lar prophylaxis should start receiving acetylsalicylic acid (ASA) again
as soon as cardiovascular risks outweigh gastrointestinal risks (usu-
ally within 7 days); ASA plus PPI therapy is preferred over clopi-
dogrel alone to reduce rebleeding.
Ann Intern Med. 2010;152:101-113. www.annals.org
For author affiliations, see end of text.
* For a list of voting participants, see Appendix 1, available at www.annals.org.
METHODS
The participants developed these recommendations
according to the Appraisal of Guidelines for Research and
Evaluation (AGREE) process for the development of clin-
ical practice guidelines (16, 17).
Scope and Purpose
These guidelines provide an international update to
the 2003 consensus recommendations for the management
of patients with nonvariceal UGIB. The participants deter-
mined issues to be covered by consensus, on the basis of a
review of the 2003 guidelines (15) and subsequent pub-
lished literature.
Stakeholder Involvement
A national survey of needs and barriers to the imple-
mentation of guidelines on UGIB identified target users
See also:
Print
Summary for Patients. . . . . . . . . . . . . . . . . . . . . . . I-48
Web-Only
Appendixes
Appendix Tables
References
CME quiz
Conversion of graphics into slides
© 2010 American College of Physicians 101
 Clinical Guidelines International Consensus on Nonvariceal Upper Gastrointestinal Bleeding
(18). As a result, an organizing committee (Drs. Bardou,
Kuipers, Sung, and Barkun [Chair]) selected an interna-
tional, multidisciplinary group of 34 voting participants
from 15 countries for their expertise in the areas of acute
nonvariceal UGIB, evidence-based medicine, and continu-
ing medical education (Appendix 1, available at www
.annals.org). The group included community-based and
academic family physicians, emergency department physi-
cians, intensive care physicians, pharmacologists, hospital
pharmacists, gastroenterologists, surgeons, radiologists, ep-
idemiologists, and ethicists. The committee initially also
consulted nurses and hospital administrators (18).
Sources and Searches
Literature searches included MEDLINE, Embase,
the Cochrane Central Register of Controlled Trials, and
ISI Web of Knowledge, with manual searches of bibli-
ographies of key articles and proceedings of abstracts of
major gastroenterology meetings held in the last 5 years
(from the American College of Gastroenterology, Diges-
tive Disease Week, and United European Gastroenter-
ology Week). Researchers retrieved data up to October
2008 by searching for updated topics from 2002 and
new topics from 1966. Researchers prioritized data from
randomized, clinical trials, when available, and per-
formed meta-analyses (when applicable) before the
meeting. They derived search terms from previous Co-
chrane meta-analyses on nonvariceal UGIB and through
discussions with the methodologists in the group, and
the terms were then approved by the entire group. An
independent research assistant performed the searches
and summarized them by using standardized report
forms. These were in turn reviewed by both method-
ological and content experts and approved by the entire
group. Search strings and Quality of Reporting of Meta-
analyses (QUOROM) diagrams for each of the state-
ments are available on request.
Review and Grading of Evidence
Initially, 3 members of the group (Drs. Rostom,
Malfertheiner, and Barkun) rated the level of evidence
available and the strength of each recommendation by
using the Grading of Recommendations Assessment,
Development, and Evaluation (GRADE) process (19,
20) (Appendix Table 1, available at www.annals.org).
The entire group subsequently revised and approved the
ratings after further review. The group considered
health benefits, side effects, and risks, as well as cost
data (when available). Seven new or updated meta-
analyses were performed for the meeting, relating to
statements A6, A8, B3, B11, C3, D6, and E4 (Appendix
Tables 2 and 3, available at www.annals.org), by using a
similar process as that for obtaining search string results.
Most of these (for statements A6 [21], A8 [22], B11
[23], C3 [24], and D6 [25]) were presented at Digestive
Disease Week 2009. All are available on request.
102 19 January 2010 Annals of Internal Medicine Volume 152 • Number 2
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Group Processes
All participants identified statements to be modified,
gaps in the previous recommendations, and the need for
any new statements. Using a modified Delphi process, an
organizing committee (chaired by Dr. Barkun) generated a
list of new and old statements and circulated it electroni-
cally to all participants through 2 iterations before the
meeting (26, 27). Participants anonymously voted on
which statements they felt warranted discussion at the
meeting, and provided comments on the wording of the
statements, which were progressively finalized through 2
separate iterations and ultimately at the consensus meeting.
All participants reviewed evidence packages before the
meeting, which included both summary analyses, individ-
ual trial descriptions, and an electronic copy of the indi-
vidual studies selected. The group analyzed further sum-
mary data and discussed individual studies at participants’
request.
The group held a 2-day consensus conference in Oc-
tober 2008, chaired by a nonvoting member (Dr. Hunt),
where data were presented and the grade attributed to the
evidence was modified as needed and voted on by each
participant. A statement was accepted if more than 75% of
participants voted a, b, or c (agree strongly, agree moder-
ately, or just agree) on a 6-point scale (with d, e, and f,
being just disagree, disagree moderately, and disagree
strongly, respectively). A working group drafted the manu-
script, which was then reviewed and approved by all
participants.
Applicability
The participants discussed cost implications and inter-
national availability and feasibility, as well as population-
based ethnic variations, where applicable (such as for
proton-pump inhibitor [PPI] pharmacokinetics). Initia-
tives on dissemination and economics are ongoing, includ-
ing an analysis of needs and barriers identified by nurses,
pharmacists, and physicians in applying guidelines and a
systematic review of health economic aspects of UGIB.
Separate papers will describe the criteria for monitoring
and audit purposes (quality indicators).
Ethics
The conference was guided by existing ethics stan-
dards of medical institutions (28 –30) and supplemented
by additional procedures. An unconflicted ethics consul-
tant (Dr. Jones) and an ad hoc advisory committee (Drs.
Jones, Enns, and Barkun) developed and implemented a
framework to manage declared conflicts of interest be-
fore the consensus meeting. Mandatory written disclo-
sures of financial declared conflicts of interest within the
24 months before the meeting were obtained a priori
from all voting participants and included in conference
materials. The ad hoc advisory committee identified one
third of the statements (7 of 21) as having the potential
for conflict of interest. Before discussion of the identi-
fied statements, participants were asked openly to vol-
www.annals.org
 International Consensus on Nonvariceal Upper Gastrointestinal Bleeding
untarily recuse themselves from the discussion if they
had a conflict of interest. The participants voted anon-
ymously by using touchpad technology after completing
scientific discussions for each statement (Appendix 2,
available at www.annals.org). Substantial numbers of
participants with declared conflicts of interests (ⱖ24%)
recused themselves from the discussions for 6 statements
(A8, C3, C4, E1, E2, E3, and E4) (Appendix 2). How-
ever, vote tallies with and without those of participants
with declared conflicts of interest revealed no differences
in the final outcomes of the “agree” decisions.
Additional Domains Addressed by the Consensus
Meeting
Knowledge gaps requiring further research were iden-
tified, and dissemination of the guidelines was discussed.
A large, Canadian, randomized, controlled trial (RCT)
(ClinicalTrials.gov registration number: NCT00840008)
is assessing whether adherence to existing consensus recom-
mendations on UGIB is improved with a multifaceted,
tailored implementation strategy. In addition, subcommit-
tees are developing manuscripts on methodology of RCTs
in UGIB, quality indicators, the effect of the adopted eth-
ical process, and endoscopic classification of ulcer bleeding
stigmata.
Role of the Funding Source
The conference was underwritten by unrestricted,
pooled funds contributed to the supporting societies.
Funding or in-kind support was provided by the Canadian
Association of Gastroenterology (CAG); European Associ-
ation for Gastroenterology and Endoscopy; Asian Pacific
Society of Digestive Endoscopy; and Institute of Diabetes,
Metabolism, and Nutrition (of the Canadian Institutes of
Health Research) and from at-arms-length contributions
from AstraZeneca Mölndal (Sweden), Abbott Canada, and
Olympus Canada provided to the CAG. The CAG ad-
ministered all aspects of the meeting. The funding
sources had no role in identifying statements, abstract-
ing data, synthesizing results, grading evidence, or pre-
paring the manuscript or in the decision to submit the
manuscript for publication.
RECOMMENDATION STATEMENTS
Each statement is followed by the grade of supporting
evidence, the result of the vote, and a discussion of the
evidence.
The Table summarizes the recommendations that are
new from this consensus and those that are revised from
the 2003 guidelines (15), as well as those that are un-
changed because the majority of the group felt that they
did not require revision at this time. (These are not dis-
cussed within the text [15].)
www.annals.org
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Clinical Guidelines
Section A: Resuscitation, Risk Assessment, and
Preendoscopy Management
Statement A2
Prognostic scales are recommended for early stratification
of patients into low- and high-risk categories for rebleeding
and mortality.
(Agree, 97% [Vote: a, 56%; b, 35%; c, 6%; d, 3%].
Grade: Low, 1c, “do it”)
As stated in the 2003 guidelines (15), patients should
be stratified into low and high risk by using prognostic
scales, on the basis of clinical, laboratory, and endoscopic
criteria. Early identification of high-risk patients allows ap-
propriate intervention, which minimizes morbidity and
mortality.
Clinical predictors of increased risk for rebleeding or
mortality include age greater than 65 years; shock; poor
overall health status; comorbid illnesses; low initial hemo-
globin levels; melena; transfusion requirement; fresh red
blood on rectal examination, in the emesis, or in the naso-
gastric aspirate; sepsis; and elevated urea, creatinine, or se-
rum aminotransferase levels (15). Other factors predictive
of outcomes include chronic alcoholism, active cancer, or
unsuitable sociofamily conditions (31), and an Acute Phys-
iology and Chronic Health Evaluation (APACHE) II score
of 11 or greater (32).
The Blatchford and preendoscopic Rockall scores (33)
use only clinical and laboratory data (before endoscopy) to
identify patients who require intervention, whereas the
complete Rockall score (34) also use endoscopic variables
to predict rebleeding or mortality.
The Blatchford score includes hemoglobin level, blood
urea level, pulse, systolic blood pressure, the presence of
syncope or melena, and evidence of hepatic disease or car-
diac failure and accurately identifies patients at low risk for
clinical intervention (35–37), even without inclusion of
urea level or syncope (38). Selected patients can be safely
managed as outpatients without early endoscopy by using
the Blatchford score (36, 37). This scale also compares
favorably with the preendoscopic and complete Rockall
scores (37–39).
Endoscopic predictors of increased risk for rebleeding
and mortality include active bleeding (especially arterial
bleeding rather than oozing), nonbleeding visible vessel
(NBVV) or adherent clot, ulcer size (generally ⬎2 cm)
(40 – 43), ulcer location (posterior lesser gastric curvature
or posterior duodenal wall), and lesion type (for example,
ulcer, varices, or cancer) (15). A comparison of the Baylor
College, Rockall, and Cedars–Sinai Medical Center predic-
tive indexes found that the Rockall score best identified
patients at low risk (44). This score has been validated in
multiple countries (44 – 47) but has better discriminative
ability for mortality than for rebleeding (38, 44, 46, 47).
Use of the Rockall score has been shown to yield a more
accurate diagnosis (significantly fewer undefined causes and
increased identification of peptic ulcer) and shorter dura-
tion of hospitalization (48).
19 January 2010 Annals of Internal Medicine Volume 152 • Number 2 103
 Clinical Guidelines International Consensus on Nonvariceal Upper Gastrointestinal Bleeding

Table. Summary of Consensus Recommendations for the Management of Patients With Nonvariceal Upper Gastrointestinal
Bleeding

A. Resuscitation, risk assessment, and preendoscopy management

A1. Immediately evaluate and initiate appropriate resuscitation.*
A2. Prognostic scales are recommended for early stratification of patients into low- and high-risk categories for rebleeding and mortality.†
A3. Consider placement of a nasogastric tube in selected patients because the findings may have prognostic value.*
A4. Blood transfusions should be administered to a patient with a hemoglobin level ⱕ70 g/L.
A5. In patients receiving anticoagulants, correction of coagulopathy is recommended but should not delay endoscopy.
A6. Promotility agents should not be used routinely before endoscopy to increase the diagnostic yield.
A7. Selected patients with acute ulcer bleeding who are at low risk for rebleeding on the basis of clinical and endoscopic criteria may be discharged promptly
after endoscopy.†
A8. Preendoscopic PPI therapy may be considered to downstage the endoscopic lesion and decrease the need for endoscopic intervention but should not delay
endoscopy.†

B. Endoscopic management
B1. Develop institution-specific protocols for multidisciplinary management.* Include access to an endoscopist trained in endoscopic hemostasis.*
B2. Have available on an urgent basis support staff trained to assist in endoscopy.*
B3. Early endoscopy (within 24 hours of presentation) is recommended for most patients with acute upper gastrointestinal bleeding.†
B4. Endoscopic hemostatic therapy is not indicated for patients with low-risk stigmata (a clean-based ulcer or a nonprotuberant pigmented dot in an ulcer bed).*
B5. A finding of a clot in an ulcer bed warrants targeted irrigation in an attempt at dislodgement, with appropriate treatment of the underlying lesion.†
B6. The role of endoscopic therapy for ulcers with adherent clots is controversial. Endoscopic therapy may be considered, although intensive PPI therapy alone
may be sufficient.†
B7. Endoscopic hemostatic therapy is indicated for patients with high-risk stigmata (active bleeding or a visible vessel in an ulcer bed).*
B8. Epinephrine injection alone provides suboptimal efficacy and should be used in combination with another method.†
B9. No single method of endoscopic thermal coaptive therapy is superior to another.*
B10. Clips, thermocoagulation, or sclerosant injection should be used in patients with high-risk lesions, alone or in combination with epinephrine injection.†
B11. Routine second-look endoscopy is not recommended.†
B12. A second attempt at endoscopic therapy is generally recommended in cases of rebleeding.*

C. Pharmacologic management
C1. Histamine-2 receptor antagonists are not recommended for patients with acute ulcer bleeding.*
C2. Somatostatin and octreotide are not routinely recommended for patients with acute ulcer bleeding.*
C3. An intravenous bolus followed by continuous-infusion PPI therapy should be used to decrease rebleeding and mortality in patients with high-risk stigmata
who have undergone successful endoscopic therapy.†
C4. Patients should be discharged with a prescription for a single daily-dose oral PPI for a duration as dictated by the underlying etiology.

D. Nonendoscopic and nonpharmacologic in-hospital management

D1. Patients at low risk after endoscopy can be fed within 24 hours.*
D2. Most patients who have undergone endoscopic hemostasis for high-risk stigmata should be hospitalized for at least 72 hours thereafter.
D3. Seek surgical consultation for patients for whom endoscopic therapy has failed.*
D4. Where available, percutaneous embolization can be considered as an alternative to surgery for patients for whom endoscopic therapy has failed.
D5. Patients with bleeding peptic ulcers should be tested for H. pylori and receive eradication therapy if it is present, with confirmation of eradication.†
D6. Negative H. pylori diagnostic tests obtained in the acute setting should be repeated.

E. Postdischarge, ASA, and NSAIDs

E1. In patients with previous ulcer bleeding who require an NSAID, it should be recognized that treatment with a traditional NSAID plus PPI or a COX-2
inhibitor alone is still associated with a clinically important risk for recurrent ulcer bleeding.
E2. In patients with previous ulcer bleeding who require an NSAID, the combination of a PPI and a COX-2 inhibitor is recommended to reduce the risk for
recurrent bleeding from that of COX-2 inhibitors alone.
E3. In patients who receive low-dose ASA and develop acute ulcer bleeding, ASA therapy should be restarted as soon as the risk for cardiovascular complication
is thought to outweigh the risk for bleeding.
E4. In patients with previous ulcer bleeding who require cardiovascular prophylaxis, it should be recognized that clopidogrel alone has a higher risk for
rebleeding than ASA combined with a PPI.

ASA ⫽ acetylsalicylic acid; COX-2 ⫽ cyclooxygenase-2; H. pylori ⫽ Helicobacter pylori; NSAID ⫽ nonsteroidal anti-inflammatory drug; PPI ⫽ proton-pump inhibitor.
* Recommendation unchanged from 2003 guidelines. See reference 15 for supporting evidence and discussions.
† Recommendation revised from 2003 guidelines.

Statement A4 cell transfusion is rarely indicated when hemoglobin level is

Blood transfusions should be administered to a patient
with a hemoglobin level of 70 g/L or less.
(Agree, 100% [Vote: a, 59%; b, 35%; c, 6%]. Grade:
Low, 1c, “do it”)
The threshold for transfusion for each patient should
be based on his or her underlying condition, hemodynamic
status, and markers of tissue hypoxia in acute situations.
The American Society of Anesthesiologists concluded (49)
that preoperative blood transfusion should be based on the
patient’s risk for complications from inadequate oxygen-
ation rather than by a fixed hemoglobin level. Red blood
104 19 January 2010 Annals of Internal Medicine Volume 152 • Number 2
greater than 100 g/L and is almost always indicated when
the level is less than 60 g/L.
The risk for adverse outcomes associated with anemia
must be weighed individually against the potential side
effects of blood transfusions. A meta-analysis of observa-
tional studies, including studies in trauma, surgery, and
intensive care (50), found that transfusion was associated
with a higher risk for death, nosocomial infection, multi-
organ dysfunction, and acute respiratory distress syn-
dromes than no exposure in multivariate analyses, although
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 International Consensus on Nonvariceal Upper Gastrointestinal Bleeding
confounding by need for transfusion could not be
excluded.
International guidelines (51) recommend initiating
red blood cell transfusions for most critically ill patients
when hemoglobin levels decrease to less than 70 g/L, with
a target level of 70 to 90 g/L, in the absence of tissue
hypoperfusion, coronary artery disease, or acute hemor-
rhage. The Transfusion Requirements in Critical Care trial
(52) in 838 critically ill patients suggested lower mortality
with hemoglobin levels of 70 to 90 g/L than with levels of
100 to 120 g/L (52). Unfortunately, these data excluded
patients with UGIB. The actual transfusion requirement
and threshold hemoglobin for transfusion in patients with
acute UGIB (assuming a value after equilibration) may be
higher because of hemodynamic instability, inaccurate he-
moglobin measures, or the presence of continued or recur-
rent bleeding that leads to a rapid decrease to dangerously
low hemoglobin levels. In a prospective cohort study (53),
hemoglobin levels less than 82 g/L in patients with UGIB
predicted elevated cardiac troponin I levels.
Because patients with UGIB are often elderly or have
comorbid cardiovascular conditions, they may have poor
tolerance for anemia. Threshold hemoglobin levels of 60 to
100 g/L may warrant transfusion in patients with underly-
ing cardiac disease (ischemic heart disease, peripheral vas-
cular surgery, or heart failure) (49). However, a prospective
study (54) found no difference in postoperative morbidity
and mortality between transfusion threshold levels less than
80 g/L and less than 90 g/L in patients undergoing coro-
nary artery bypass graft surgery.
Statement A5
In patients receiving anticoagulants, correction of coagu-
lopathy is recommended but should not delay endoscopy.
(Agree, 97% [Vote: a, 38%; b, 44%; c, 15%; d, 3%].
Grade: Low, 2c, “probably do it”)
Data on correction of coagulopathy are few and con-
flicting, as identified by a systematic review done for the
conference (55). A retrospective cohort study (56) that in-
cluded 233 patients with nonvariceal UGIB found that
95% of the patients who received anticoagulants had an
international normalized ratio (INR) between 1.3 and 2.7
(56). A baseline INR less than 1.3 versus 1.3 or greater did
not predict rebleeding, transfusion requirement, surgery,
length of stay, or mortality. Therefore, data suggest that it
may not be necessary to delay endoscopic therapy in pa-
tients with mild to moderate coagulation defects. Further-
more, an exploratory analysis of 1869 patients in the
RUGBE (Registry on Non-variceal Upper Gastrointestinal
Bleeding and Endoscopy) Canadian cohort study (9)
found that neither INR nor platelet count predicted re-
bleeding. Although platelet count did not significantly pre-
dict mortality, a presentation INR of 1.5 or greater was a
significant predictor of mortality in patients with UGIB
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Clinical Guidelines
(55), which may reflect its greater importance as a comor-
bid index.
Another study in patients with any UGIB (57) found
that intensive measures to correct INR can reduce mortal-
ity. Baradarian and colleagues (57), who used a historical
cohort comparison, suggested that correcting an INR to
less than 1.8 as part of intensive resuscitation led to lower
mortality and fewer myocardial infarctions in the interven-
tion group. The groups did not differ in length of stay,
units of blood transfused, or time to endoscopy. Other
data suggest that endoscopic treatment with injection or
heater probe may be safely performed in patients with an
INR less than 2.5 (58). A cohort study in patients who
underwent endoscopic treatment (58) found no differences
in rebleeding, surgery, mortality, or complication rates be-
tween patients receiving warfarin (baseline INR, 1.5 to
6.0), whose INRs were corrected to 1.5 to 2.5 by using
fresh frozen plasma, and a control group who did not re-
ceive anticoagulants.
Considering the paucity of data on INR correction
and the recognized benefits of early endoscopy (see state-
ment B3), the participants felt that treating coagulopathy
was necessary in patients who received anticoagulants but
that endoscopy should not be delayed while doing so un-
less the INR (or prothrombin time where INR is unavail-
able) is supratherapeutic, because correction in these pa-
tients may facilitate endoscopic treatment. This approach
should not be generalized to patients with cirrhosis because
the prothrombin time does not seem to predict bleeding
risk in this setting (59). Correction of coagulopathy from
other causes may be necessary on a case-by-case basis.
Statement A6
Promotility agents should not be used routinely before
endoscopy to increase the diagnostic yield.
(Agree, 82% [Vote: a, 35%; b, 35%; c, 12%; d, 6%;
e, 3%; f, 9%]. Grade: Moderate, 2b, “probably don’t
do it”)
Although the use of preendoscopy promotility agents
may improve diagnostic yield in selected patients with sus-
pected blood in the stomach, they are not warranted for
routine use in all patients who present with UGIB.
A meta-analysis (21) of 3 trials that evaluated erythro-
mycin (60 – 62), comprising 316 patients, and 2 abstracts
that evaluated metoclopramide (63, 64) found that use of a
prokinetic agent significantly reduced the need for repeated
endoscopy (odds ratio [OR], 0.51 [95% CI, 0.30 to 0.88])
in patients suspected of having blood in their stomach,
compared with placebo or no treatment (Appendix Table
2). The groups did not differ in length of stay, units of
blood transfused, or need for surgery. An analysis of data
from the 3 erythromycin trials (65) found that preendo-
scopic erythromycin resulted in a cost-effective outcome in
most of the trials.
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 Clinical Guidelines International Consensus on Nonvariceal Upper Gastrointestinal Bleeding
Because adequate visualization allows proper treatment
in most patients and on the basis of the characteristics of
patients selected for inclusion in the aforementioned trials,
participants felt that promotility agents were not warranted
for routine use but may be useful in patients who are sus-
pected to have substantial amounts of blood or clot in their
upper gastrointestinal tract or those who have recently
eaten.
Statement A7
Selected patients with acute ulcer bleeding who are at low
risk for rebleeding on the basis of clinical and endoscopic cri-
teria may be discharged promptly after endoscopy.
(Agree, 97% [Vote: a, 53%; b, 35%; c, 9%; d, 3%].
Grade: High, 1a, “do it”)
Although some highly selected patients may be dis-
charged before undergoing endoscopy (see statement A2),
most patients will require risk stratification by endoscopic
as well as clinical criteria. Those classified as being at low
risk for rebleeding can be discharged promptly after endos-
copy (15).
An RCT in 95 low-risk patients (66) prospectively
assessed the role of early discharge and found no differ-
ences in rates of recurrent bleeding but that early discharge
significantly reduced costs compared with admission (me-
dian costs, $340 and $3940, respectively; P ⫽ 0.001). Cri-
teria for early discharge included a clean ulcer base or flat
pigmented spot, hemodynamic stability, no serious concur-
rent medical illness, easy accessibility to hospital, and ade-
quate sociofamily support at home. No patient who was
discharged early had any serious adverse event, underwent
surgery, or died during the 30-day follow-up.
Substantial observational data (67–71) also support
early discharge of low-risk patients after endoscopy. Pa-
tients stratified as low risk who were discharged early did
not differ in complications (for example, rebleeding, sur-
gery, mortality), health status, or satisfaction from those
who were admitted (72–74). Unfortunately, recommenda-
tions for early discharge based on endoscopic findings are
often not followed (75).
Patients are not suitable for early discharge if they have
serious comorbid conditions (heart failure, recent cardio-
vascular or cerebrovascular event, chronic alcoholism, or
active cancer), are hemodynamically unstable, have an en-
doscopic finding of high-risk stigmata (active bleeding,
NBVV, or adherent clot), or have unsuitable sociofamily
conditions (31, 76). Patient location (distance to nearest
emergency care center), local legal regulations, and social
support should also be considered (76).
Statement A8
Preendoscopic PPI therapy may be considered to down-
stage the endoscopic lesion and decrease the need for endoscopic
intervention but should not delay endoscopy.
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(Agree, 94% [Vote: a, 32%; b, 38%; c, 24%; d, 3%; e,
3%]. Grade: Moderate, 1b, “do it”)
Although preendoscopic PPI therapy has not been
shown to affect rebleeding, surgery, or mortality, the ben-
eficial effects on the need for intervention, supportive cost-
effectiveness analyses, and excellent safety profile suggest
that these agents may be useful, particularly in those sus-
pected of having high-risk stigmata.
A Cochrane meta-analysis through February 2006 that
included 5 RCTs (77) was updated with an additional trial
(78) and the full publication (79) of an abstract (22) (Ap-
pendix Table 2). The updated meta-analysis in 2223 pa-
tients included 1 study that assessed oral PPI strategies and
5 studies that assessed intravenous strategies, only 1 of
which used a high-dose regimen (79). The investigators
found no statistically significant differences in rates of mor-
tality, rebleeding, or surgery between the PPI therapy and
control groups. However, preendoscopic PPI treatment
significantly reduced the proportion of patients with high-
risk stigmata (OR, 0.67 [CI, 0.54 to 0.84]) and the need
for endoscopic therapy (OR, 0.68 [CI, 0.50 to 0.93]) com-
pared with patients in the control group who received pla-
cebo or a histamine-2 receptor antagonist (22).
A North American analysis found that preendoscopic
PPI therapy was more effective and more costly in the
United States, whereas in Canada it became more effective
and less costly as the duration of hospitalization for high-
risk patients increased or that of low-risk patients decreased
(80). Identifying patients with a greater likelihood of hav-
ing a high-risk lesion, such as those who present with red
blood in the emesis or nasogastric aspirate, may optimize
the cost-effectiveness of this approach (81). Other cost-
effectiveness analyses have suggested either the economic
dominance of preendoscopic high-dose intravenous PPI
therapy (82) or the cost-effectiveness of oral PPI in this
setting (83), but certain model assumptions limit these
conclusions.
The observed lesion downstaging attributable to PPI
therapy before endoscopy may be even more beneficial in
situations in which early endoscopy may be delayed or
when available endoscopic expertise may be suboptimal.
Section B: Endoscopic Management
Statement B3
Early endoscopy (within 24 hours of presentation) is rec-
ommended for most patients with acute upper gastrointestinal
bleeding.
(Agree, 100% [Vote: a, 85%; b, 12%; c, 3%]. Grade:
Moderate, 1b, “do it”)
The definition of early endoscopy ranges from 2 to 24
hours after initial presentation (71, 75, 84, 85). Among the
1869 patients of the RUGBE cohort, 76% received their
first endoscopy within 24 hours of presentation (mean, 23
hours [SD, 38]) (9). In contrast, in a United Kingdom
survey of 6750 patients (13), only 50% received endoscopy
within 24 hours. Early endoscopy (within the first 24
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 International Consensus on Nonvariceal Upper Gastrointestinal Bleeding
hours), with risk classification by clinical and endoscopic
criteria, allows for safe and prompt discharge of patients
classified as low risk, improves patient outcomes for pa-
tients classified as high risk, and reduces use of resources
for patients classified as either low or high risk (15).
Although early endoscopy is encouraged for most pa-
tients, endoscopy may need to be delayed or deferred in
selected high-risk patients, such as those with active acute
coronary syndrome or suspected perforation. Also, a very
low Blatchford score can identify very low-risk patients
who are unlikely to have high-risk stigmata or benefit from
endoscopic therapy (38) or who can be safely managed as
outpatients (36, 37) without the need for early endoscopy;
however, this remains controversial (see statement A2).
Data suggest that early endoscopy is safe and effective
for all risk groups. A systematic review (71) found no ma-
jor complications in patients triaged to outpatient care af-
ter early endoscopy. Early endoscopy is associated with sig-
nificant reductions in length of hospital stay in patients at
low risk (66, 72, 85), high risk (84), and combined patient
groups (71, 86, 87), compared with delayed endoscopy.
Recent administrative data found that the performance of
early endoscopy was associated with a decreased need for
surgery in elderly patients (88) and that patients with non-
variceal UGIB who were admitted on weekends had higher
adjusted in-hospital mortality and were less likely to un-
dergo early endoscopy within 1 day of hospitalization (87).
A large United Kingdom cohort analysis (13) has also
shown a strong trend in risk-adjusted mortality ratio that
just failed to show a statistically significant link between
decreased mortality and the practice of after-hours
endoscopy.
Further analysis found no additional benefit from very
early or urgent (⬍12 hours) endoscopy over early (⬎12
hours) endoscopy. A meta-analysis of 3 trials (75, 84, 85),
comprising 528 patients, found no significant reduction in
rebleeding (OR, 0.71 [CI, 0.28 to 1.81]), surgery (OR,
1.16 [CI, 0.39 to 3.51]), or mortality (OR, 0.70 [CI, 0.14
to 3.57]) with urgent (1 to 12 hours) endoscopy compared
with later (⬎12 hours) endoscopy (Appendix Table 2).
One study (85) reported significantly shorter hospital stays
and lower costs with very early (1 to 2 hours) versus elec-
tive (1 to 2 days) endoscopy. In a subgroup of patients
with a bloody gastric aspirate, blood transfusions and hos-
pital stay were significantly reduced with urgent (⬍12
hours vs. ⬎12 hours) endoscopy (84). Retrospective anal-
yses that assessed urgent (0 to 8 hours) versus early (6 or 8
to 24 hours) endoscopy (89 –91) reported no between-
group differences in clinical outcomes; however, these
studies did not control for other endoscopist-related fac-
tors, type of therapeutic interventions, or co-interventions.
A study identified 4 independent predictors (P ⬍ 0.050) of
active bleeding and the need for very early endoscopy (⬍12
hours): fresh blood in the nasogastric tube, hemodynamic
instability, a hemoglobin level less than 80 g/L, and a leu-
kocyte count greater than 12 ⫻ 109 cells/L (92). Of note,
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Clinical Guidelines
indirect findings from recent administrative data (87) sug-
gest that early endoscopy may be associated with lower
mortality.
On the basis of available data, the participants recom-
mended a target time to endoscopy of within 24 hours of
presentation.
Statement B5
A finding of a clot in an ulcer bed warrants targeted
irrigation in an attempt at dislodgement, with appropriate
treatment of the underlying lesion.
(Agree, 97% [Vote: a, 59%; b, 29%; c, 9%; d, 0%; f,
3%]. Grade: Moderate, 2b, “probably do it”)
Statement B6
The role of endoscopic therapy for ulcers with adherent
clots is controversial. Endoscopic therapy may be considered,
although intensive PPI therapy alone may be sufficient.
(Agree, 86% [Vote: a, 24%; b, 50%; c, 12%; d, 9%; e,
3%; f, 3%]. Grade: Moderate, 2b, “probably do it”)
Vigorous irrigation (for example, water pump) of a
clot in an ulcer bed has successfully exposed the underlying
stigmata in 26% to 43% of cases (93, 94), and the revealed
stigmata were high risk in 70% of those cases (94). The
endoscopic findings present after clot removal should be
appropriately managed.
The risk for rebleeding with clots that remain adherent
after washing without endoscopic therapy (with or without
PPI therapy) has been reported to be as low as 0% to 8%
(94, 95) but also as high as 25% to 35% (93, 96 –98) in
clinically high-risk patients. The disparity of these data has
led to controversy as to the optimal management of adher-
ent clots (99).
For the most part, endoscopic therapy for adherent
clots refers to preinjecting them with epinephrine before
shaving them down with a cold guillotining snare tech-
nique—without disrupting the pedicle of the clot—and
then applying combination treatment to the residual stig-
mata of hemorrhage (97, 98).
One meta-analysis of 5 RCTs (99), comprising 189
patients with adherent clots, found no significant benefits
for endoscopic versus no endoscopic therapy (relative risk
[RR], 0.31 [CI, 0.06 to 1.77]). Similarly, another meta-
analysis that included 6 RCTs (100), comprising 240 pa-
tients, also found that endoscopic therapy did not signifi-
cantly reduce rebleeding (RR, 0.48 [CI, 0.18 to 1.30])
compared with medical therapy. A patient-level analysis of
data from 4 fully published trials (100) did find a signifi-
cant benefit for rebleeding (RR, 0.30 [CI, 0.10 to 0.77]).
These discrepant results fuel the controversy and may be
attributed to both varying patient populations and statisti-
cal heterogeneity not fully accounted for in the meta-
analytic methods (101). No data suggest excess risk; a
systematic review (102) found a low incidence of compli-
cations resulting from endoscopic therapy.
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 Clinical Guidelines International Consensus on Nonvariceal Upper Gastrointestinal Bleeding
The 1 RCT that compared endoscopic therapy plus
high-dose intravenous PPI therapy with high-dose intra-
venous PPI therapy alone found no rebleeding among 24
Asian patients with clots resistant to vigorous irrigation
(95). Therefore, among patients with adherent clots resis-
tant to vigorous irrigation, endoscopic therapy may be ben-
eficial in patients at high risk for rebleeding (such as those
with serious concurrent illness), whereas intensive PPI
therapy without endoscopic treatment may be sufficient in
patients at low risk (particularly those who are Asian or
Helicobacter pylori–positive) (99).
Statement B8
Epinephrine injection alone provides suboptimal efficacy
and should be used in combination with another method.
(Agree, 100% [Vote: a, 71%; b, 24%; c, 6%]. Grade:
Moderate, 1b, “don’t do it”)
Statement B10
Clips, thermocoagulation, or sclerosant injection should
be used in patients with high-risk lesions, alone or in combi-
nation with epinephrine injection.
(Agree, 97% [Vote: a, 50%; b, 35%; c, 12%; d, 3%].
Grade: High, 1a, “do it”)
Several recent meta-analyses have better quantified the
efficacy of endoscopic therapies (99, 102–107). Although
monotherapy with epinephrine injection is more effective
than medical therapy in patients with high-risk stigmata, it
is inferior to other monotherapies or to combination ther-
apy that uses 2 or more methods (99, 102–107). Numer-
ous meta-analyses indicate that adding a second procedure,
such as a second injectate (for example, alcohol, thrombin,
or fibrin glue), thermal contact, or clips, is superior to
epinephrine injection alone (99, 102, 103, 105, 107). Epi-
nephrine plus a second method for treating high-risk stig-
mata significantly reduced rebleeding (OR, 0.51 [CI, 0.39
to 0.66]), surgery (OR, 0.63 [CI, 0.45 to 0.89]), and mor-
tality compared with epinephrine monotherapy (OR, 0.50
[CI, 0.30 to 0.82]) (105).
Monotherapy with thermal devices, sclerosants, clips,
thrombin, or fibrin glue provides more effective endo-
scopic hemostasis than epinephrine alone (99) or pharma-
cotherapy alone (106). Clips were superior to injection
monotherapy in 4 (99, 102, 103, 106) of 5 meta-analyses
(99, 102–104, 106). Clips with injection were superior to
injection alone but not to clips alone (103, 106). Combi-
nation therapy (injection plus second injectate, thermal, or
clips) was superior to injection therapy alone, but not to
clips or thermal therapy alone (102, 106). The participants
felt that the data were insufficient to show superiority or
equivalence of the recommended treatments but that the
data were strongest for the use of thermal devices, clips, or
combination treatments.
Complications with dual versus single endoscopic
therapy included induction of bleeding (1.7% in each
108 19 January 2010 Annals of Internal Medicine Volume 152 • Number 2
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group) and perforation (0.6% vs. 0%; P ⫽ 0.003) (102);
however, perforation has also been reported with mono-
therapy in some RCTs (108, 109).
Statement B11
Routine second-look endoscopy is not recommended.
(Agree, 91% [Vote: a, 50%; b, 21%; c, 21%; d, 3%; e,
3%; f, 3%]. Grade: Moderate, 2b, “probably don’t do it”)
A routine second-look endoscopy is generally defined
as a preplanned systematic second endoscopy performed 16
to 24 hours after the initial endoscopy, with appropriate
therapy in patients with evidence of active bleeding or
NBVV.
Although data support some benefits associated with
second-look endoscopy, they are generally older data and
do not include the use of PPI therapy or optimal hemo-
static strategies. The findings are therefore not generaliz-
able to current clinical practice. In addition, cost-
effectiveness data do not seem to support the routine use of
second-look endoscopy.
Five published studies (110 –114) and 4 abstracts of
randomized trials (115–118) have assessed a second-look
approach, with only 1 in each group demonstrating statis-
tically significant benefits. The conclusions of 2 previous
meta-analyses of these trials (119, 120), which suggest ben-
efits in rebleeding, are hampered by methodological limi-
tations. In 1 case (119), the investigators noted analytical
shortcomings in data abstraction from 2 trials (111, 113),
whereas selection bias may have resulted in the other case
(120) from the inclusion of a decade-old abstract of a pos-
itive study (117), not yet fully published, but not of an-
other abstract from the same era (118) that failed to
show efficacy.
A more recent meta-analysis of 6 trials (121) found
that routine second-look endoscopy, with heater probe
therapy when appropriate, significantly reduced the risk for
rebleeding (RR, 0.29 [CI, 0.11 to 0.73]) compared with
single endoscopy; however, performing second-look endos-
copy with injection monotherapy conferred no advantage.
A meta-analysis performed for the meeting (23) included 6
trials comprising 750 patients. It excluded 2 older abstracts
(117, 118), which have not been fully published, and Rut-
geerts and colleagues’ study (114), which included second-
look endoscopy in both study groups. In the meta-analysis,
routine second-look endoscopy significantly decreased re-
bleeding (OR, 0.59 [CI, 0.38 to 0.91]) and surgery (OR,
0.43 [CI, 0.19 to 0.96]) but not mortality (OR, 0.65 [CI,
0.26 to 1.62]) (Appendix Table 2). These findings must be
interpreted in light of differences across trials with regard
to patient selection, adopted methodologies, and both in-
tervention and control treatments, as well as sensitivity
analyses that show poor robustness of the results. The most
favorable results were from studies with the greatest pro-
portions of high-risk patients (110, 113). Indeed, Chiu
and colleagues (110) included 47% of patients who pre-
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 International Consensus on Nonvariceal Upper Gastrointestinal Bleeding
sented with shock and more than 40% with active bleed-
ing. Similarly, Saeed and colleagues (113) assessed patients
with a very high risk for rebleeding (on the basis of Forrest
high-risk stigmata, as well as additional clinical and endo-
scopic criteria), of whom 70% had active bleeding. Al-
though the investigators reported the noted decrease in
rebleeding (OR, 0.08 [CI, 0.00 to 1.50]) as statistically
significant in the final results of the latter trial, it did not
remain so when conventional 2-sided inferential testing,
adapted to the small sample size, was applied.
Of note, the most recently published trial—and the
only one with a control group that received high-dose in-
travenous PPI therapy (115)—found no benefit with
second-look endoscopy. High-dose intravenous PPI ther-
apy is the current standard in many health care systems,
which suggests that second-look endoscopy may not pro-
vide additional benefits when PPI therapy is available.
A U.S. cost-effectiveness analysis (122) found that a
strategy of selective (not routine) second-look endoscopy at
24 hours only in patients at high risk for rebleeding was
more effective and less expensive than repeated endoscopy
in patients with rebleeding (with or without intravenous
PPIs) or routine repeated endoscopy in all patients, al-
though extrapolations were made from trials that did not
actually use high-dose intravenous PPI therapy. Intra-
venous PPI therapy became the dominant strategy if the
rebleeding rate was 9% (closer to real-life outcomes) or if
the cost of PPI dropped below $10 per day. When consid-
ering baseline assumptions in the model and how they
relate to current practice, PPI therapy seemed to be the
most cost-effective alternative.
In the only study that fully reported risks (110), no
complications directly attributable to the second-look en-
doscopy were reported.
In conclusion, although older data supported a
second-look approach, these trials did not use contempo-
rary management strategies associated with decreased re-
bleeding, such as initial endoscopic hemostasis with hemo-
clips or combination therapy (123), or post– endoscopic
hemostasis high-dose PPI therapy (24). Furthermore, the
few existing contemporary data do not favor the use of
routine second-look endoscopy at this time. A subgroup of
patients with particularly high-risk presentations may ben-
efit, but this requires further study. In light of these con-
siderations, the participants did not recommend the rou-
tine use of second-look endoscopy.
Section C: Pharmacologic Management
Statement C3
An intravenous bolus followed by continuous-infusion
PPI therapy should be used to decrease rebleeding and mortal-
ity in patients with high-risk stigmata who have undergone
successful endoscopic therapy.
(Agree, 94% [Vote: a, 65%; b, 24%; c, 6%; d, 3%; e,
0%; f, 3%]. Grade: High, 1a, “do it”)
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Clinical Guidelines
A 2006 Cochrane meta-analysis of data as of Novem-
ber 2004 (124) included 24 RCTs and was updated (24)
with 7 additional trials (125–131) (Appendix Table 2).
The updated meta-analysis included 5792 patients. Over-
all, PPI therapy with or without endoscopic therapy re-
duced rebleeding (OR, 0.45 [CI, 0.36 to 0.57]) and sur-
gery (OR, 0.56 [CI, 0.45 to 0.70]) but not mortality (OR,
0.90 [CI, 0.67 to 1.19]) compared with placebo or
histamine-2 receptor agonist. Proton-pump inhibitor ther-
apy reduced mortality among patients with active bleeding
or NBVV and in trials conducted in Asia. Further analysis
showed that in patients with active bleeding or NBVV who
received endoscopic hemostatic therapy, high-dose intra-
venous PPI therapy (80 mg bolus plus 8 mg/h continuous
infusion) reduced rebleeding (OR, 0.43 [CI, 0.27 to
0.67]), surgery (OR, 0.60 [CI, 0.37 to 0.96]), and mortal-
ity (OR, 0.57 [CI, 0.34 to 0.96]). Lower doses of PPI
(either intravenous or oral) reduced rebleeding but no ev-
idence was found of an effect on mortality.
Similarly, the meta-analysis by Laine and McQuaid
(99) found significant benefit in rebleeding (RR, 0.40
[CI, 0.28 to 0.59]), surgery (RR, 0.43 [CI, 0.24 to
0.58]), and mortality (RR, 0.41 [CI, 0.20 to 0.84]) with
high-dose intravenous PPI therapy after endoscopic
therapy, whereas lower doses were associated with sig-
nificant benefits in rebleeding (RR, 0.53 [CI, 0.35 to
0.78]) but not surgery or mortality compared with pla-
cebo or no treatment.
Strong evidence demonstrates the efficacy of high-dose
intravenous PPI therapy after successful endoscopy, but it
is not possible to make conclusions regarding the efficacy
of either lower intravenous doses or high-dose oral therapy.
Indeed, head-to-head comparisons and subgroup analyses
of high versus lower intravenous doses are underpowered,
and no direct comparisons of high-dose intravenous ther-
apy and high-dose oral therapy have been made. However,
lower intravenous doses or high-dose oral PPI therapy (at
doses equivalent to at least 4 times the standard daily oral
dose) are also effective (especially in Asian populations)
and can be considered when high-dose intravenous therapy
is not available or feasible.
In patients with UGIB who have undergone successful
endoscopic hemostasis, administering high-dose intra-
venous PPI therapy for 3 days is both more effective and
less costly than not doing so, as demonstrated by cost anal-
yses (132–134)— or can become so, as demonstrated by
sensitivity analyses (83, 122). The intervention group usu-
ally receives high-dose intravenous PPI therapy, and the
comparator group usually receives placebo; few trials have
included low-dose intravenous or oral PPI as comparators.
High-dose intravenous PPI therapy is a dominant strategy
mainly because the cost of the medications is relatively
lower than the incremental expenses of 1 additional re-
bleeding episode. Comparisons of intravenous and oral PPI
use remain theoretical, because only a few underpowered
RCTs (135–137) have assessed this comparison.
19 January 2010 Annals of Internal Medicine Volume 152 • Number 2 109
 Clinical Guidelines International Consensus on Nonvariceal Upper Gastrointestinal Bleeding
Although recent data have linked PPI use to in-
hospital Clostridium difficile infection (138, 139), the par-
ticipants felt that the benefits outweighed the risks in pa-
tients who have acute UGIB that requires PPI therapy.
Statement C4
Patients should be discharged with a prescription for a
single daily-dose oral PPI for a duration as dictated by the
underlying etiology.
(Agree, 94% [Vote: a, 56%; b, 32%; c, 6%; d, 3%; e,
3%]. Grade: Low, 1c, “do it”)
Because rebleeding episodes may occur more than 3
days after endoscopy (125, 140, 141), most RCTs that
assess the role of postendoscopic PPI therapy have also
included a prescription for once-daily PPI therapy that
starts 72 hours after endoscopic hemostasis (125, 129,
140 –142). In the nonacute setting, once-daily PPI therapy
has demonstrated effective ulcer healing for patients with
peptic ulcer disease (143), and inadequate evidence sup-
ports the need for twice-daily therapy in the maintenance
setting. In the absence of direct comparative trial data of
single versus daily PPI administration, this recommenda-
tion is supported by observational results in studies that
used a standard once-daily dosage (125, 129, 140 –142).
However, the duration and dose of the PPI will be deter-
mined by the underlying etiology; for example, healing
rates for complicated or severe esophagitis are relatively low
in some studies, and twice-daily doses may be warranted in
the context of UGIB (144). In addition, patients who re-
quire ASA or NSAID therapy may require long-term sec-
ondary prophylaxis, as discussed in statements E1 to E4.
In community-based population studies, the use of
PPIs has been associated with potential side effects, includ-
ing C. difficile infection (145), pneumonia (146), and
osteoporosis-related fractures (147). These findings remain
controversial, and the benefits of PPI administration for
acute ulcer healing outweigh these potential risks in the
acute treatment setting; however, caution may be war-
ranted during long-term use.
Section D: Nonendoscopic and Nonpharmacologic
In-Hospital Management
Statement D2
Most patients who have undergone endoscopic hemostasis
for high-risk stigmata should be hospitalized for at least 72
hours thereafter.
(Agree, 100% [Vote: a, 68%; b, 24%; c, 9%]. Grade:
Low, 1c, “do it”)
Studies of the natural history of ulcer lesions show that
it takes 72 hours for most high-risk lesions to become
low-risk lesions after endoscopic therapy (96, 148). In
many contemporary trials (125, 140, 141), 60% to 76% of
patients who had rebleeding within 30 days after endo-
scopic hemostasis plus high-dose PPI therapy did so within
the first 72 hours. Thus, patients identified as being at high
risk for rebleeding, such as those with high-risk endoscopic
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stigmata, should be admitted to a hospital for at least 72
hours.
However, 1 RCT showed that selected patients at
higher risk might be safely managed as outpatients after
endoscopic therapy without an increased risk for compli-
cations (149). The study in 82 patients with NBVV, ulcer
size less than 1.5 cm, no hypovolemia, no associated severe
disease, and appropriate family support found no differ-
ences in rebleeding, morbidity, or mortality at the 30-day
follow-up among patients randomly assigned to outpatient
or hospital care (149). Mean cost of care per patient was
significantly lower for the outpatient group than for the
hospital group ($970 vs. $1595; P ⬍ 0.001). However, the
study was underpowered to be able to confidently recom-
mend early discharge of patients at higher risk at this time.
The consensus participants felt that further research was
needed, especially in light of recent data that suggest some
patients may be discharged too early (150).
Patients should be admitted to a monitored setting for
at least the first 24 hours on the basis of risk (hemody-
namic instability, increasing age, severe comorbidity, active
bleeding at endoscopy, or large ulcer size [for example, ⬎2
cm]) (5, 32, 40, 151, 152) or clinical condition.
One study (153) showed that use of a checklist with
specific recommendations on diet, PPI therapy, H. pylori
eradication therapy, NSAID use, discharge, and follow-up
can significantly reduce the length of hospital stay for pa-
tients with UGIB.
Statement D4
Where available, percutaneous embolization can be con-
sidered as an alternative to surgery for patients for whom
endoscopic therapy has failed.
(Agree, 100% [Vote: a, 62%; b, 32%; c, 6%]. Grade:
Low, 2c, “probably do it”)
Percutaneous or transcatheter arterial embolization has
been investigated as an alternative to surgery in patients for
whom endoscopic therapy has failed, especially those who
are high-risk candidates for surgery. Gelatin sponges, poly-
vinyl alcohol, cyanoacrylic glues, and coils have been used
to embolize the vessels feeding bleeding lesions (154).
In uncontrolled trials, primary rates of technical suc-
cess range from 52% to 98%, with recurrent bleeding oc-
curring in about 10% to 20% of patients (155–159). A
retrospective, single-center study (160) showed no signifi-
cant differences between embolization therapy and surgery
for rates of rebleeding, surgery, or mortality, despite pa-
tients in the embolization group being older and having a
higher prevalence of heart disease.
Although uncommon with modern, highly selective
techniques, complications include bowel ischemia; second-
ary duodenal stenosis; and gastric, hepatic, and splenic in-
farction (154, 155, 159, 161). The high periprocedural
mortality of 25% to 30% is largely attributed to patients
being selected for this procedure because they are at high
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 International Consensus on Nonvariceal Upper Gastrointestinal Bleeding
surgical risk because of advanced age and underlying con-
ditions (156, 158 –160).
For patients who had rebleeding after initial successful,
endoscopic hemostasis, a second attempt at endoscopic
therapy remains the preferred strategy (15, 162). When
persistent or recurrent bleeding cannot be controlled by
endoscopic therapy, percutaneous embolization can be
considered as an alternative to surgery, if such expertise is
available.
Statement D5
Patients with bleeding peptic ulcers should be tested for
H. pylori and receive eradication therapy if it is present, with
confirmation of eradication.
(Agree, 94% [Vote: a, 82%; b, 12%; c, 0%; d, 3%; e,
3%]. Grade: High, 1a, “do it”)
Statement D6
Negative H. pylori diagnostic tests obtained in the acute
setting should be repeated.
(Agree, 94% [Vote: a, 68%; b, 21%; c, 6%; d, 3%; e,
3%]. Grade: Moderate, 1b, “do it”)
As recommended in the previous consensus (15), pa-
tients with UGIB should be tested for H. pylori and receive
eradication therapy if infection is present. A meta-analysis
(163) demonstrated that eradication of H. pylori was sig-
nificantly more effective than PPI therapy alone in prevent-
ing rebleeding from peptic ulcer disease. The rebleeding
rate was even lower among the subgroup of patients with
successful eradication, which emphasizes the importance of
confirming eradication.
Tests for H. pylori may show increased false-negative
rates in the context of acute bleeding, although the data
vary. Although the biological mechanisms involved are
poorly understood—and may indeed vary depending on
the test— one suggestion is the pH buffering effect of the
blood, because more alkaline settings are known to be as-
sociated with more false-negative results (164). A system-
atic review of 23 studies (165–187), done for the consensus
meeting, found that diagnostic tests for H. pylori infection
(including serology, histology, urea breath test, rapid ure-
ase test, stool antigen, and culture) demonstrate high pos-
itive predictive value (0.85 to 0.99) but low negative pre-
dictive value (0.45 to 0.75) in the setting of acute UGIB,
with 25% to 55% of H. pylori–infected patients yielding
false-negative results (Appendix Table 3) (25). This sug-
gests caution in the interpretation of initially negative re-
sults and the need for repeated testing at follow-up.
Section E: Postdischarge, ASA, and NSAIDs
The following statements are similar to those included
in the NSAID guidelines developed by a Canadian consen-
sus group, which included 8 of the participants present at
this consensus (188). Statements E1 and E2 were included
in the NSAID guidelines and are here in condensed for-
mat. We also refer the reader to consensus publications
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Clinical Guidelines
from U.S. and international groups on the reduction of
gastrointestinal risks associated with NSAID and antiplate-
let therapy (189, 190).
Statement E1
In patients with previous ulcer bleeding who require an
NSAID, it should be recognized that treatment with a tradi-
tional NSAID plus PPI or a cyclooxygenase-2 (COX-2) inhib-
itor alone is still associated with a clinically important risk for
recurrent ulcer bleeding.
(Agree, 97% [Vote: a, 73%; b, 21%; c, 3%; d, 3%].
Grade: Moderate, 1b)
Statement E2
In patients with previous ulcer bleeding who require an
NSAID, the combination of a PPI and a COX-2 inhibitor is
recommended to reduce the risk for recurrent bleeding from
that of COX-2 inhibitors alone.
(Agree, 94% [Vote: a, 52%; b, 33%; c, 9%; d, 0%; e,
6%]. Grade: Moderate, 1b, “do it”)
Two small RCTs conducted in Asia (191–193) found
no significant difference in the rate of recurrent bleeding or
ulcer complications (about 4% to 6%) at 6 months with
COX-2 inhibitor therapy alone versus therapy with a tra-
ditional NSAID plus PPI. The relatively small numbers of
patients in these studies do not exclude a benefit of one
strategy over the other. These studies did not assess tradi-
tional NSAID therapy alone or complete withdrawal of
NSAID therapy, and although a strategy of COX-2 inhib-
itor therapy alone or therapy with a traditional NSAID plus
PPI may have lowered the rates of recurrent bleeding com-
pared with historical rates from therapy with traditional
NSAIDs alone, the risk was not eliminated (191–193).
Population-based studies (194, 195) also support add-
ing a PPI to traditional NSAID therapy or administering a
COX-2 inhibitor to reduce the risk for upper gastrointes-
tinal complications; however, the combination of a COX-2
inhibitor with a PPI was associated with the greatest risk
reduction.
One RCT (196) demonstrated a significantly lower
rate of recurrent UGIB with a COX-2 inhibitor plus a PPI
(0%) compared with a COX-2 inhibitor alone (8.9%) over
1 year (difference, 8.9 percentage points [CI, 4.1 to 13.7
percentage points). A subgroup analysis (197) of pooled
data from 3 RCTs with similar study designs, comprising
34 701 patients, suggested a lower incidence of clinical gas-
trointestinal events with a COX-2 inhibitor plus a PPI
compared with a COX-2 inhibitor alone; however, no sta-
tistical analysis was performed. Several studies (198, 199)
have also shown lower risks for endoscopic ulcers in pa-
tients who receive a COX-2 inhibitor plus a PPI compared
with those who receive a COX-2 inhibitor alone.
Two meta-analyses (200, 201) have demonstrated an
excess risk for serious cardiovascular events associated with
COX-2 inhibitors compared with placebo. Optimal man-
19 January 2010 Annals of Internal Medicine Volume 152 • Number 2 111
 Clinical Guidelines International Consensus on Nonvariceal Upper Gastrointestinal Bleeding
agement of patients who require long-term NSAID ther-
apy should consider both gastrointestinal and cardiovascu-
lar risks (188). No evidence has been found of a further
increased risk for renal, cardiovascular, or dermatologic ad-
verse events with COX-2 inhibitor plus PPI therapy com-
pared with COX-2 inhibitor therapy alone (196).
Several cost-effectiveness analyses (202–204) in pa-
tients at high risk for gastrointestinal events found that a
COX-2 inhibitor was more cost-effective than a traditional
NSAID plus PPI, and a traditional NSAID plus PPI was
more cost-effective than a traditional NSAID alone; how-
ever, these analyses did not include a strategy of therapy
with a COX-2 inhibitor plus PPI.
In summary, patients with previous ulcer bleeding re-
quire more careful follow-up and alternative strategies, in-
cluding discontinuation of NSAID therapy when possible
or therapy with a COX-2 inhibitor plus PPI. Statement C4
discusses the potential side effects associated with long-
term PPI use.
Statement E3
In patients who receive low-dose ASA and develop acute
ulcer bleeding, ASA therapy should be restarted as soon as the
risk for cardiovascular complication is thought to outweigh the
risk for bleeding.
(Agree, 100% [Vote: a, 70%; b, 30%]. Grade: Mod-
erate, 1b, “do it”)
Patients receiving low-dose ASA who develop UGIB
are often advised to discontinue ASA therapy until the
ulcers have healed. However, prolonged discontinuation of
ASA therapy increases thrombotic risk in patients who re-
quire cardioprotective ASA therapy (205, 206). In a meta-
analysis (206), ASA nonadherence or withdrawal was asso-
ciated with a 3-fold higher risk for major adverse cardiac
events. The delay to a thrombotic event is generally re-
ported as between 7 and 30 days, and usually between 7
and 10 days (205, 207, 208). This temporal pattern has
biological plausibility because the inhibited platelets circu-
late in the blood for about 10 days (205). The American
Heart Association recommends (189) that the decision to
discontinue ASA therapy in the setting of acute ulcer
bleeding be made on an individual basis, on the basis of
cardiac and gastrointestinal risks.
Data from RCTs (209, 210) suggest that the cardio-
vascular benefits of early reintroduction of ASA or clopi-
dogrel may outweigh the gastrointestinal risks. An RCT in
156 patients with ASA-induced ulcer bleeding who under-
went endoscopic therapy (209) found that immediate re-
introduction of ASA in the presence of intravenous and
oral PPI therapy was associated with a 2-fold (but statisti-
cally insignificant) increase in the risk for recurrent bleed-
ing from peptic ulcers, but discontinuation of ASA therapy
was associated with a significantly increased 8-week mor-
tality rate. Another RCT (210) found no cases of rebleed-
ing in patients with ASA-associated endoscopic ulcers who
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were treated with a PPI and randomly assigned to restart
antiplatelet therapy with ASA or clopidogrel within 1
day of endoscopy. Therefore, the participants agreed
that no ASA-free period should be mandated; instead,
patients who require ASA for cardiovascular protection
should restart ASA therapy as soon as the risks for car-
diovascular complication are thought to outweigh the risks
for bleeding.
Statement E4
In patients with previous ulcer bleeding who require car-
diovascular prophylaxis, it should be recognized that clopi-
dogrel alone has a higher risk for rebleeding than ASA com-
bined with a PPI.
(Agree, 100% [Vote: a, 70%; b, 24%; c, 6%]. Grade:
Moderate, 1b, “do it” [adding PPI to ASA])
Clopidogrel is often perceived as relatively safe in
terms of gastrointestinal adverse events, but data show that
even as monotherapy, clopidogrel is associated with a high
risk for rebleeding (9% to 14%) (211, 212).
Pooled results of 2 RCTs (211, 212) showed a signif-
icant reduction in rebleeding with ASA plus a PPI com-
pared with clopidogrel therapy alone (OR, 0.06 [CI, 0.01
to 0.32]) but no significant effect on mortality (OR, 0.63
[CI, 0.24 to 1.64]) (Appendix Table 2). The 2 groups did
not differ in the development or relapse of cardiovascular
or cerebrovascular events.
Physicians should be aware that PPIs may decrease the
platelet inhibitory effect of clopidogrel (213–215). The
PPI and clopidogrel may compete for the cytochrome
P450 isoenzyme CYP2C19, which is required to convert
the prodrug clopidogrel to its active metabolite (216 –218).
Some observational studies in clopidogrel recipients (218 –
220) show a small but significant association between PPI
use and cardiovascular events, whereas others (215, 221,
222) do not. No randomized trials addressing this issue are
available.
The American College of Cardiology, American Heart
Association, and American College of Gastroenterology
currently recommend that patients receiving these medica-
tions not change their treatment regimen unless advised by
their health care provider (223). The U.S. Food and Drug
Administration found sufficient evidence of an interaction
to require the inclusion of a statement on the clopidogrel
product label that concomitant administration of drugs
that inhibit CYP2C19 (such as omeprazole) should be dis-
couraged (224). On the basis of pharmacologic profiles,
some experts suggest a staggered schedule of intake for
clopidogrel and the PPI (216, 225), but further research in
this area is needed.
With regard to the potential side effects associated
with long-term PPI use, we refer the reader to statement
C4.
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 International Consensus on Nonvariceal Upper Gastrointestinal Bleeding
FUTURE DIRECTIONS
Although considerable advances have been made in
both endoscopic and pharmacologic therapies for UGIB,
more data are needed in many areas (Appendix Table 4,
available at www.annals.org).
We plan to facilitate the application of these guidelines
by disseminating them to all participating societies and
regions through such venues as symposia sessions or work-
shops at society meetings. Other scheduled application
initiatives include preparation of an algorithm, a standard-
ized slide presentation, and additional relevant peer-
reviewed publications (including ethics; dissemination of
guidelines; methodology of randomized, controlled trials in
UGIB; quality indicators; endoscopic classification of ulcer
bleeding stigmata; and health economics of UGIB); post-
ing of major recommendations on society and government
health Web sites; and translation of the guidelines in society
or regional journals. Finally, we anticipate that these guide-
lines will be updated periodically as new data become avail-
able, as was the case for this update of the 2003 guidelines.
From McGill University, Montreal, Quebec, Canada; INSERM CIC-P
803 and Service de Pharmacologie, Centre Hospitalier Universitaire de
Dijon, Dijon, France; Erasmus MC University Medical Center, Rotter-
dam, the Netherlands; Chinese University of Hong Kong, Sha Tin,
Hong Kong, China; McMaster University Health Science Centre, Ham-
ilton, Ontario, Canada; and Canadian Association of Gastroenterology,
Oakville, Ontario, Canada.
Note: This consensus conference, organized by the Canadian Association
of Gastroenterology, was held in Vienna, Austria, on 23–24 October
2008. These consensus recommendations are endorsed by the Canadian
Association of Gastroenterology, the Asian Pacific Society of Digestive
Endoscopy, and the European Association for Gastroenterology and En-
doscopy. Since the consensus conference, the following professional so-
cieties have reviewed and also endorsed the recommendations: European
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Clinical Guidelines
Society of Gastrointestinal Endoscopy, Hong Kong Society of Digestive
Endoscopy, Italian Society of Digestive Endoscopy, Asociación Española
de Gastroenterologı́a, Centro de Investigación Biomédica en Red en el
Área temática de Enfermedades Hepáticas y Digestivas, and Sociedad de
Gastroenterologia del Uruguay.
Acknowledgment: The authors thank Pauline Lavigne for editorial as-
sistance; Anoush Rhazzagi, Alexandra Shingina, and Aurélie Fichet for
research assistance; and Sandra Daniels and Andres Gardeazabal for or-
ganization of the consensus conference.
Grant Support: By the Canadian Association of Gastroenterology; Eu-
ropean Association for Gastroenterology and Endoscopy; Asian Pacific
Society of Digestive Endoscopy; and Institute of Diabetes, Metabolism,
and Nutrition (of the Canadian Institutes of Health Research), and at-
arms-length contributions to these societies from AstraZeneca Mölndal,
Abbott Canada, and Olympus Canada.
Potential Conflicts of Interest: Consultancies: A.N. Barkun (Astra
Zeneca), R.H. Hunt (Schering-Plough), P. Sinclair (AstraZeneca).
Honoraria: M. Bardou (AstraZeneca), E.J. Kuipers (AstraZeneca), J.
Sung (Nycomed), R.H. Hunt (Nycomed). Grants pending: A.N.
Barkun (AstraZeneca, Olympus), E.J. Kuipers (AstraZeneca), J. Sung
(AstraZeneca). Patents pending: A.N. Barkun (Abbott). Other: E.J.
Kuipers (AstraZeneca).
Requests for Single Reprints: Alan Barkun, MD, MSc (Clinical Epi-
demiology), Division of Gastroenterology, Montreal General Hospital
Site, The McGill University Health Centre, 1650 Cedar Avenue, Room
D7.148, Montreal, Quebec H3G 1A4, Canada.
Current author addresses and author contributions are available at www
.annals.org.
References
References are available at www.annals.org.
19 January 2010 Annals of Internal Medicine Volume 152 • Number 2 113
 Annals of Internal Medicine
Current Author Addresses: Dr. Barkun: Division of Gastroenterology,
Montreal General Hospital Site, The McGill University Health Centre,
1650 Cedar Avenue, Room D7.148, Montreal, Quebec H3G 1A4,
Canada.
Dr. Bardou: INSERM CIC-P 803, CHU de Dijon, 2 boulevard de
Lattre de Tassigny, 21000 Dijon, France.
Dr. Kuipers: Erasmus University Medical Centre, Room Ba-391, Box
2040, 3000 CA Rotterdam, the Netherlands.
Dr. Sung: Department of Medicine and Therapeutics, 9/F Clinical Sci-
ence Building, Prince of Wales Hospital, Chinese University of Hong
Kong, Sha Tin NT, Hong Kong.
Dr. Hunt: Division of Gastroenterology, McMaster University Health
Science Centre, 1200 Main Street West, Hamilton, Ontario L8N 3Z5,
Canada.
Ms. Martel: 1299 Rue Prospect, Sherbrooke, Quebec J1J 1J4, Canada.
Mr. Sinclair: Canadian Association of Gastroenterology, #224, 1540
Cornwall Road, Oakville, Ontario L6J 7W5, Canada.
Author Contributions: Conception and design: A.N. Barkun, E.J.
Kuipers, J. Sung, P. Sinclair.
Analysis and interpretation of the data: A.N. Barkun, M. Bardou, E.J.
Kuipers, J. Sung, R.H. Hunt, M. Martel, P. Sinclair.
Drafting of the article: A.N. Barkun, E.J. Kuipers, J. Sung, R.H. Hunt,
P. Sinclair.
Critical revision of the article for important intellectual content: A.N.
Barkun, M. Bardou, J. Sung, P. Sinclair.
Final approval of the article: A.N. Barkun, M. Bardou, E.J. Kuipers, J.
Sung, R.H. Hunt, P. Sinclair.
Provision of study materials or patients: J. Sung.
Statistical expertise: A.N. Barkun, M. Martel.
Obtaining of funding: E.J. Kuipers, P. Sinclair.
Administrative, technical, or logistic support: A.N. Barkun, E.J. Kuipers,
P. Sinclair.
Collection and assembly of data: M. Bardou, E.J. Kuipers, M. Martel, P.
Sinclair.
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19106083]
223. American College of Cardiology (ACC), American College of Gastroen-
terology (ACG), American Heart Association (AHA). Joint comment on studies
regarding possible interaction of clopidogrel and proton pump inhibitors [News
release]. Dallas: American Heart Assoc; 11 November 2008. Accessed at http:
//americanheart.mediaroom.com/index.php?s⫽43&item⫽611 on 17 November
2009.
224. U.S. Food and Drug Administration. Plavix (clopidogrel bisulfate) 75 mg
tablets. Detailed view: safety labeling changes approved by FDA Center for Drug
Evaluation and Research (CDER)—May 2009. Silver Spring, MD: U.S. Food
and Drug Administration; 2009. Accessed at www.fda.gov/Safety/MedWatch
/SafetyInformation/ucm165166.htm on 17 November 2009.
225. Shi S, Klotz U. Proton pump inhibitors: an update of their clinical use and
pharmacokinetics. Eur J Clin Pharmacol. 2008;64:935-51. [PMID: 18679668]
APPENDIX 1: LIST OF ATTENDEES, INTERNATIONAL
CONSENSUS UPPER GASTROINTESTINAL BLEEDING
CONFERENCE GROUP
Nonvoting chair: Richard Hunt, Canada.
Voting steering committee: Alan N. Barkun, Canada; Marc
Bardou, France; Ernst J. Kuipers, the Netherlands; Joseph Sung,
Hong Kong.
Voting participants: Lars Agreus, Sweden; David Armstrong,
Canada; Xavier Calvet, Spain; Naoki Chiba, Canada; Livio Ci-
polletta, Italy; Henry Cohen, Uruguay; Robert Enns, Canada;
Lars-Gunnar Ericsson, Sweden; Ian Gralnek, Israel; Dennis
Jensen, United States; Michio Kaminishi, Japan; Fasiha Kanwal,
United States; Loren Laine, United States; Angel Lanas, Spain;
James Lau, Hong Kong; Grigoris Leontiadis, Greece; Lars Lun-
dell, Sweden; Peter Malfertheiner, Germany; John Marshall,
Canada; Janet Martin, Canada; David Metz, United States; Paul
Moayyedi, Canada; Jean-Pierre Quenot, France; Erik Rauws, the
Netherlands; Joseph Romagnuolo, United States; Alaa Rostom,
Canada; Brennan Spiegel, United States; Frances Tse, Canada;
Monique Van Leerdam, the Netherlands; and Christo Van Rens-
burg, South Africa.
Nonvoting ethics expert: Derek J. Jones, Canada.
Represented societies: Canadian Association of Gastroen-
terology, American Society for Gastrointestinal Endoscopy,
Asian Pacific Society of Digestive Endoscopy, European Asso-
ciation for Gastroenterology and Endoscopy, European Soci-
ety of Gastrointestinal Endoscopy, and Asociación Interameri-
cana de Gastroenterologı́a.
Nonvoting observers: Andres Gardeazabal, Canada; István
Rácz, Hungary; Pauline Lavigne, United States; and Paul Sin-
clair, Canada.
APPENDIX 2
Statements Identified as Having Potential for Conflict of
Interest and Participants Who Were Recused From the
Discussions
Statement A8: David Armstrong, Lars Agreus, Angel Lanas,
Xavier Calvet, Joseph Romagnuolo, Alan Barkun, Ernst Kuipers,
Joseph Sung, Loren Laine, Rob Enns, Henry Cohen, Paul
Moayyedi, and David Metz.
Statement B10: None.
www.annals.org
Downloaded From: http://annals.org/ on 10/31/2016
Statement C3: David Armstrong, Lars Agreus, Angel Lanas,
Xavier Calvet, Joseph Romagnuolo, Alan Barkun, Ernst Kuipers,
Joseph Sung, Loren Laine, Rob Enns, Henry Cohen, Paul
Moayyedi, and David Metz.
Statement C4: David Armstrong, Lars Agreus, Peter Malfer-
theiner, Michio Kaminishi, Dennis Jensen, Angel Lanas, Joseph
Romagnuolo, Alan Barkun, Ernst Kuipers, Joseph Sung, Loren
Laine, Rob Enns, Henry Cohen, Paul Moayyedi, and David
Metz.
Statement E1: Lars Agreus, Angel Lanas, Alan Barkun, Loren
Laine, Rob Enns, Brennan Spiegel, Paul Moayyedi, David Metz.
Statement E2: David Armstrong, Lars Agreus, Angel Lanas,
Joseph Romagnuolo, Alan Barkun, Ernst Kuipers, Loren Laine,
Rob Enns, Brennan Spiegel, Paul Moayyedi, and David Metz.
Statement E3: None.
Statement E4: David Armstrong, Lars Agreus, Angel Lanas,
Joseph Romagnuolo, Alan Barkun, Ernst Kuipers, Loren Laine,
Rob Enns, Brennan Spiegel, and Paul Moayyedi.
Declaration of Personal Interests
Marc Bardou, Naoki Chiba, Livio Cipolletta, Lars-Gunnar
Ericsson, Ian Gralnek, Fasiha Kanwal, Lars Lundell, Myriam
Martel, Janet Martin, Jean-Pierre Quenot, Erik Rauws, Frances
Tse, Monique Van Leerdam, and Christo Van Rensburg have no
personal interests to declare.
Lars Agreus has served as a speaker for AstraZeneca and a
consultant for Orexo AB and has received research support from
AstraZeneca.
David Armstrong has served as both a speaker and a consul-
tant for AstraZeneca and Abbott and as a speaker for Nycomed
and has received research support and funding for educational
programs from AstraZeneca and Abbott.
Alan Barkun has served as both a speaker and a consultant
and has received research support from AstraZeneca and Abbott.
Xavier Calvet has served as a speaker for AstraZeneca and
Almirall-Prodesfarma and has received research support from
AstraZeneca and Janssen-Cilag.
Henry Cohen has served as both a speaker and a consultant
for AstraZeneca and Roemmers.
Rob Enns has served as both a speaker and a consultant for
Abbot, AstraZeneca, Given Imaging, Nycomed, Olympus, Proc-
tor & Gamble, Schering-Plough, and UCB Pharma.
Richard Hunt has served as a consultant for Alevium Phar-
maceuticals, AstraZeneca, Nycomed, Santarus, Schering-Plough,
Steba Biotech, and TAP Pharmaceuticals; has received research
support from Steba Biotech; and is CEO of Strategic Consultants
International.
Dennis Jensen has served as both a speaker and a consultant
for AstraZeneca and Boston Scientific and has received research
support from AstraZeneca, Boston Scientific, Ethicon Endosur-
gery, and Olympus.
Michio Kaminishi has served as a speaker for Taiho and
Otsuka and has received research support from Esai, Otsuka,
Taiho, Takeda, and Zeria.
19 January 2010 Annals of Internal Medicine Volume 152 • Number 2 W-27
 Ernst Kuipers has served as both a speaker and a consultant
for AstraZeneca and has received research support from Astra-
Zeneca, Janssen-Cilag, and Nycomed.
Loren Laine has served as a consultant for AstraZeneca,
Bayer, Bristol-Myers Squibb, Eisai, Horizon, Merck, Novartis,
Nicox, Pfizer, Pozen, and Santarus and has received research
funding from GlaxoSmithKline and TAP Pharmaceuticals.
Angel Lanas has served as both a speaker and a consultant
for AstraZeneca and Pfizer and has received research funding
from AstraZeneca, Bayer, Cogentus, and Pfizer.
James Lau has served as a consultant for AstraZeneca.
Grigoris Leontiadis has served as a speaker for AstraZeneca
and sanofi-aventis and a consultant for GlaxoSmithKline and
Given Imaging.
Peter Malfertheiner has served as a speaker for Abbott,
AstraZeneca, and Nycomed.
John Marshall has served as both a speaker and a consultant
for Abbott, Axcan, Proctor & Gamble, Schering-Plough, Shire,
Solvay Pharma, and UCB Pharma and has served as a consultant
for Ferring Pharmaceuticals.
W-28 19 January 2010 Annals of Internal Medicine Volume 152 • Number 2
Downloaded From: http://annals.org/ on 10/31/2016
David Metz has served as a consultant for AstraZeneca, Ny-
comed, Wyeth, and TAP Pharmaceuticals and has served as a
speaker for Santarus and TAP Pharmaceuticals.
Paul Moayyedi has served as both a speaker and a con-
sultant for AstraZeneca and Janssen Ortho and as a speaker
for Nycomed and Esai and has received research support from
AstraZeneca.
Joseph Romagnuolo has served as a consultant for Astra-
Zeneca and Olympus and has received research support from
Lantheus Imaging and Ethicon Endosurgery.
Alaa Rostom has served as a speaker for AstraZeneca.
Paul Sinclair has served as a consultant for AstraZeneca.
Brennan Spiegel has served as a speaker for AstraZeneca,
Prometheus Laboratories, and Sucampo Pharmaceuticals and a
consultant for AstraZeneca, Johnson & Johnson, Novartis, and
Phynova.
Joseph Sung has served as speaker for Nycomed and a con-
sultant for AstraZeneca.
www.annals.org
Acute upper gastrointestinal
bleeding in over 16s:
management

Clinical guideline
Published: 13 June 2012
www.nice.org.uk/guidance/cg141

© NICE 2020. All rights reserved. Subject to Notice of rights (https://www.nice.org.uk/terms-and-conditions#notice-of-

rights). Last updated 25 August 2016
Acute upper gastrointestinal bleeding in over 16s: management (CG141)

Your responsibility
The recommendations in this guideline represent the view of NICE, arrived at after careful
consideration of the evidence available. When exercising their judgement, professionals and
practitioners are expected to take this guideline fully into account, alongside the individual needs,
preferences and values of their patients or the people using their service. It is not mandatory to
apply the recommendations, and the guideline does not override the responsibility to make
decisions appropriate to the circumstances of the individual, in consultation with them and their
families and carers or guardian.

Local commissioners and providers of healthcare have a responsibility to enable the guideline to be
applied when individual professionals and people using services wish to use it. They should do so in
the context of local and national priorities for funding and developing services, and in light of their
duties to have due regard to the need to eliminate unlawful discrimination, to advance equality of
opportunity and to reduce health inequalities. Nothing in this guideline should be interpreted in a
way that would be inconsistent with complying with those duties.

Commissioners and providers have a responsibility to promote an environmentally sustainable

health and care system and should assess and reduce the environmental impact of implementing
NICE recommendations wherever possible.

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Acute upper gastrointestinal bleeding in over 16s: management (CG141)

Contents
Introduction ......................................................................................................................................................................... 4

Patient-centred care ......................................................................................................................................................... 5

Key priorities for implementation ............................................................................................................................... 6

1 Guidance ............................................................................................................................................................................ 8

1.1 Risk assessment ........................................................................................................................................................................ 8

1.2 Resuscitation and initial management ............................................................................................................................. 8

1.3 Timing of endoscopy................................................................................................................................................................ 9

1.4 Management of non-variceal bleeding ............................................................................................................................ 9

1.5 Management of variceal bleeding ...................................................................................................................................... 10

1.6 Control of bleeding and prevention of re-bleeding in patients on NSAIDs, aspirin or clopidogrel ......... 11

1.7 Primary prophylaxis for acutely ill patients in critical care...................................................................................... 11

1.8 Information and support for patients and carers ........................................................................................................ 11

More information ............................................................................................................................................................................. 12

Update information ........................................................................................................................................................... 13

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conditions#notice-of-rights). Last updated 25 August 2016 of 13
Acute upper gastrointestinal bleeding in over 16s: management (CG141)

This guideline is the basis of QS38.

Introduction
Acute upper gastrointestinal bleeding is a common medical emergency that has a 10% hospital
mortality rate. Despite changes in management, mortality has not significantly improved over the
past 50 years.

Elderly patients and people with chronic medical diseases withstand acute upper gastrointestinal
bleeding less well than younger, fitter patients, and have a higher risk of death. Almost all people
who develop acute upper gastrointestinal bleeding are treated in hospital and the guideline
therefore focuses on hospital care. The most common causes are peptic ulcer and oesophago-
gastric varices.

Endoscopy is the primary diagnostic investigation in patients with acute upper gastrointestinal
bleeding but it has not always been clear whether urgent endoscopy is cost effective as well as
clinically valuable. Endoscopy aids diagnosis, yields information that helps predict outcome and
most importantly allows treatments to be delivered that can stop bleeding and reduce the risk of
re-bleeding.

Drugs may have a complementary role in reducing gastric acid secretion and portal vein pressure.
Not every patient responds to endoscopic and drug treatments; emergency surgery and a range of
radiological procedures may be needed to control bleeding.

This guideline aims to identify which diagnostic and therapeutic steps are useful in managing acute
upper gastrointestinal bleeding. This should enable hospitals to develop a structure in which
clinical teams can deliver an optimum service for people who develop this condition.

The guideline will assume that prescribers will use a drug's summary of product characteristics to
inform decisions made with individual patients.

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conditions#notice-of-rights). Last updated 25 August 2016 of 13
Acute upper gastrointestinal bleeding in over 16s: management (CG141)

Patient-centred care
This guideline offers best practice advice on the care of adults and young people aged 16 years and
older with acute variceal and non-variceal upper gastrointestinal bleeding.

Treatment and care should take into account patients' needs, preferences and religious beliefs.
People with acute upper gastrointestinal bleeding should have the opportunity to make informed
decisions about their care and treatment, in partnership with their healthcare professionals. If
patients do not have the capacity to make decisions, healthcare professionals should follow the
Department of Health's advice on consent and the code of practice that accompanies the Mental
Capacity Act. In Wales, healthcare professionals should follow advice on consent from the Welsh
Government. In taking account of patients' religious beliefs in the context of blood transfusion,
healthcare professionals should follow the advice from UK Blood Transfusion and Tissue
Transplantation Services.

Good communication between healthcare professionals and patients is essential. It should be

supported by evidence-based written information tailored to the patient's needs. Treatment and
care, and the information patients are given about it, should be culturally appropriate. It should also
be accessible to people with additional needs such as physical, sensory or learning disabilities, and
to people who do not speak or read English.

If the patient agrees, families and carers should have the opportunity to be involved in decisions
about treatment and care.

Families and carers should also be given the information and support they need.

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Acute upper gastrointestinal bleeding in over 16s: management (CG141)

Key priorities for implementation

The following recommendations have been identified as priorities for implementation.

Risk assessment

• Use the following formal risk assessment scores for all patients with acute upper
gastrointestinal bleeding:

－ the Blatchford score at first assessment, and

－ the full Rockall score after endoscopy.

Timing of endoscopy

• Offer endoscopy to unstable patients with severe acute upper gastrointestinal bleeding
immediately after resuscitation.

• Offer endoscopy within 24 hours of admission to all other patients with upper gastrointestinal
bleeding.

• Units seeing more than 330 cases a year should offer daily endoscopy lists. Units seeing fewer
than 330 cases a year should arrange their service according to local circumstances.

Management of non-variceal bleeding

• Do not use adrenaline as monotherapy for the endoscopic treatment of non-variceal upper
gastrointestinal bleeding.

• For the endoscopic treatment of non-variceal upper gastrointestinal bleeding, use one of the
following:

－ a mechanical method (for example, clips) with or without adrenaline

－ thermal coagulation with adrenaline

－ fibrin or thrombin with adrenaline.

• Offer interventional radiology to unstable patients who re-bleed after endoscopic treatment.
Refer urgently for surgery if interventional radiology is not promptly available.

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Acute upper gastrointestinal bleeding in over 16s: management (CG141)

Management of variceal bleeding

• Offer prophylactic antibiotic therapy at presentation to patients with suspected or confirmed

variceal bleeding.

• Consider transjugular intrahepatic portosystemic shunts (TIPS) if bleeding from oesophageal

varices is not controlled by band ligation.

Control of bleeding and prevention of re-bleeding in patients on NSAIDs, aspirin or clopidogrel

• Continue low-dose aspirin for secondary prevention of vascular events in patients with upper
gastrointestinal bleeding in whom haemostasis has been achieved.

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conditions#notice-of-rights). Last updated 25 August 2016 of 13
Acute upper gastrointestinal bleeding in over 16s: management (CG141)

1 Guidance
The following guidance is based on the best available evidence. The full guideline gives details of
the methods and the evidence used to develop the guidance.

1.1 Risk assessment

1.1.1 Use the following formal risk assessment scores for all patients with acute
upper gastrointestinal bleeding:

• the Blatchford score at first assessment, and

• the full Rockall score after endoscopy.

1.1.2 Consider early discharge for patients with a pre-endoscopy Blatchford

score of 0.

1.2 Resuscitation and initial management

1.2.1 Transfuse patients with massive bleeding with blood, platelets and clotting
factors in line with local protocols for managing massive bleeding.

1.2.2 Base decisions on blood transfusion on the full clinical picture, recognising that
over-transfusion may be as damaging as under-transfusion.

1.2.3 Do not offer platelet transfusion to patients who are not actively bleeding and
are haemodynamically stable.

1.2.4 Offer platelet transfusion to patients who are actively bleeding and have a
platelet count of less than 50 x 109/litre.

• Offer fresh frozen plasma to patients who are actively bleeding and have a
prothrombin time (or international normalised ratio) or activated partial
thromboplastin time greater than 1.5 times normal. If a patient's fibrinogen level
remains less than 1.5 g/litre despite fresh frozen plasma use, offer cryoprecipitate as
well.

1.2.5 Offer prothrombin complex concentrate to patients who are taking warfarin

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conditions#notice-of-rights). Last updated 25 August 2016 of 13
Acute upper gastrointestinal bleeding in over 16s: management (CG141)

and actively bleeding.

1.2.6 Treat patients who are taking warfarin and whose upper gastrointestinal
bleeding has stopped in line with local warfarin protocols.

1.2.7 Do not use recombinant factor Vlla except when all other methods have failed.

1.3 Timing of endoscopy

1.3.1 Offer endoscopy to unstable patients with severe acute upper gastrointestinal
bleeding immediately after resuscitation.

1.3.2 Offer endoscopy within 24 hours of admission to all other patients with upper
gastrointestinal bleeding.

1.3.3 Units seeing more than 330 cases a year should offer daily endoscopy lists. Units
seeing fewer than 330 cases a year should arrange their service according to
local circumstances.

1.4 Management of non-variceal bleeding

Endoscopic treatment
1.4.1 Do not use adrenaline as monotherapy for the endoscopic treatment of non-
variceal upper gastrointestinal bleeding.

1.4.2 For the endoscopic treatment of non-variceal upper gastrointestinal bleeding,

use one of the following:

• a mechanical method (for example, clips) with or without adrenaline

• thermal coagulation with adrenaline

• fibrin or thrombin with adrenaline.

Proton pump inhibitors

1.4.3 Do not offer acid-suppression drugs (proton pump inhibitors or H2-receptor
antagonists) before endoscopy to patients with suspected non-variceal upper
gastrointestinal bleeding.

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conditions#notice-of-rights). Last updated 25 August 2016 of 13
Acute upper gastrointestinal bleeding in over 16s: management (CG141)

1.4.4 Offer proton pump inhibitors to patients with non-variceal upper

gastrointestinal bleeding and stigmata of recent haemorrhage shown at
endoscopy.

Treatment after first or failed endoscopic treatment

1.4.5 Consider a repeat endoscopy, with treatment as appropriate, for all patients at
high risk of re-bleeding, particularly if there is doubt about adequate
haemostasis at the first endoscopy.

1.4.6 Offer a repeat endoscopy to patients who re-bleed with a view to further
endoscopic treatment or emergency surgery.

1.4.7 Offer interventional radiology to unstable patients who re-bleed after

endoscopic treatment. Refer urgently for surgery if interventional radiology is
not promptly available.

1.5 Management of variceal bleeding

1.5.1 Offer terlipressin to patients with suspected variceal bleeding at presentation.
Stop treatment after definitive haemostasis has been achieved, or after 5 days,
unless there is another indication for its use[ ]. 1

1.5.2 Offer prophylactic antibiotic therapy at presentation to patients with suspected

or confirmed variceal bleeding.

Oesophageal varices
1.5.3 Use band ligation in patients with upper gastrointestinal bleeding from
oesophageal varices.

1.5.4 Consider transjugular intrahepatic portosystemic shunts (TIPS) if bleeding from

oesophageal varices is not controlled by band ligation.

Gastric varices
1.5.5 Offer endoscopic injection of N-butyl-2-cyanoacrylate to patients with upper
gastrointestinal bleeding from gastric varices.

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conditions#notice-of-rights). Last updated 25 August 2016 of 13
Acute upper gastrointestinal bleeding in over 16s: management (CG141)

1.5.6 Offer TIPS if bleeding from gastric varices is not controlled by endoscopic
injection of N-butyl-2-cyanoacrylate.

1.6 Control of bleeding and prevention of re-bleeding in

patients on NSAIDs, aspirin or clopidogrel
1.6.1 Continue low-dose aspirin for secondary prevention of vascular events in
patients with upper gastrointestinal bleeding in whom haemostasis has been
achieved.

1.6.2 Stop other non-steroidal anti-inflammatory drugs (including cyclooxygenase-2

[COX-2] inhibitors) during the acute phase in patients presenting with upper
gastrointestinal bleeding.

1.6.3 Discuss the risks and benefits of continuing clopidogrel (or any other
thienopyridine antiplatelet agents) in patients with upper gastrointestinal
bleeding with the appropriate specialist (for example, a cardiologist or a stroke
specialist) and with the patient.

1.7 Primary prophylaxis for acutely ill patients in critical

care
1.7.1 Offer acid-suppression therapy (H2-receptor antagonists or proton pump
inhibitors) for primary prevention of upper gastrointestinal bleeding in acutely
ill patients admitted to critical care. If possible, use the oral form of the drug.[ ] 2

1.7.2 Review the ongoing need for acid-suppression drugs for primary prevention of
upper gastrointestinal bleeding in acutely ill patients when they recover or are
discharged from critical care.

1.8 Information and support for patients and carers

1.8.1 Establish good communication between clinical staff and patients and their
family and carers at the time of presentation, throughout their time in hospital
and following discharge. This should include:

• giving verbal information that is recorded in medical records

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conditions#notice-of-rights). Last updated 25 August 2016 of 13
Acute upper gastrointestinal bleeding in over 16s: management (CG141)

• different members of clinical teams providing consistent information

• providing written information where appropriate

• ensuring patients and their families and carers receive consistent information.

More information
You can also see this guideline in the NICE pathway on Acute upper gastrointestinal bleeding.
To find out what NICE has said on topics related to this guideline, see our web page on Digestive
tract conditions.
See also the guideline committee's discussion and the evidence reviews (in the full guideline),
and information about how the guideline was developed, including details of the committee.

[1]
At the time of publication (June 2012), terlipressin was indicated for the treatment of bleeding
from oesophageal varices, with a maximum duration of treatment of 72 hours (3 days). Prescribers
should consult the relevant summary of product characteristics. Informed consent for off-label use
of terlipressin should be obtained and documented.

[2]
As of August 2016, only the H2-receptor antagonists ranitidine and cimetidine are licensed for
prophylaxis of gastrointestinal bleeding in acutely ill patients. The proton pump inhibitors
omeprazole, esomeprazole, lansoprazole, pantoprazole and rabeprazole are not licensed for
prophylaxis of gastrointestinal bleeding in acutely ill patients. The use of proton pump inhibitors or
H2-receptor antagonists other than ranitidine and cimetidine for this indication would be off label.

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conditions#notice-of-rights). Last updated 25 August 2016 of 13
Acute upper gastrointestinal bleeding in over 16s: management (CG141)

Update information
August 2016
2016: A footnote was added to recommendation 1.7.1 about which proton pump inhibitors
and H2-receptor antagonists are licensed for use and which are classed as off-label.

April 2015
2015: Recommendation 1.2.5 has been amended to add the use of cryoprecipitate as further
treatment.

ISBN: 978-1-4731-2041-9

Accreditation

© NICE 2020. All rights reserved. Subject to Notice of rights (https://www.nice.org.uk/terms-and- Page 13
conditions#notice-of-rights). Last updated 25 August 2016 of 13
 GUIDELINE
The role of endoscopy in the management of acute non-variceal upper
GI bleeding
This is one of a series of statements discussing the use of
GI endoscopy in common clinical situations. The Stan-
dards of Practice Committee of the American Society for
Gastrointestinal Endoscopy (ASGE) prepared this text. In
preparing this guideline, a search of the medical literature
was performed by using PubMed. Additional references
were obtained from the bibliographies of the identified
articles and from recommendations of expert consultants.
When few or no data exist from well-designed prospective
trials, emphasis is given to results from large series and
reports from recognized experts. Guidelines for appropri-
ate use of endoscopy are based on a critical review of the
available data and expert consensus at the time that the
guidelines are drafted. Further controlled clinical studies
may be needed to clarify aspects of this guideline. This guide-
line may be revised as necessary to account for changes in
technology, new data, or other aspects of clinical practice.
The recommendations are based on reviewed studies and are
graded on the strength of the supporting evidence1 (Table 1).
The strength of individual recommendations is based on
both the aggregate evidence quality and an assessment of the
anticipated benefits and harms. Weaker recommendations
are indicated by phrases such as “We suggest . . . ,” whereas
stronger recommendations are typically stated as “We rec-
ommend . . . .”
This guideline is intended to be an educational device
to provide information that may assist endoscopists in
providing care to patients. This guideline is not a rule and
should not be construed as establishing a legal standard of
care or as encouraging, advocating, requiring, or discour-
aging any particular treatment. Clinical decisions in any
particular case involve a complex analysis of the patient’s
condition and available courses of action. Therefore, clin-
ical considerations may lead an endoscopist to take a
course of action that varies from these guidelines.
INTRODUCTION
Upper GI bleeding (UGIB) results in over 300,000 hos-
pital admissions annually in the United States, with a
mortality of 3.5% to 10%.2-3 Appropriate management of
Copyright © 2012 by the American Society for Gastrointestinal Endoscopy
0016-5107/$36.00
doi:10.1016/j.gie.2012.02.033
1132 GASTROINTESTINAL ENDOSCOPY Volume 75, No. 6 : 2012
patients with non-variceal UGIB has been demonstrated to
improve patient outcomes.4 This updated ASGE guideline
focuses on the role of GI endoscopy in patients with acute
non-variceal UGIB. This guideline will not address ob-
scure GI bleeding or the role of endoscopy in the man-
agement of variceal bleeding, both of which are addressed
in existing ASGE practice guidelines.5-6 UGIB refers to GI
blood loss having an origin proximal to the ligament of
Treitz. Acute UGIB can manifest as hematemesis, “coffee
ground’’ emesis, the return of red blood via a nasogastric
tube, and/or melena with or without hemodynamic com-
promise. Hematochezia may occur in patients with ex-
tremely brisk UGIB.7-8
INITIAL ASSESSMENT AND MANAGEMENT
Initial assessment
A primary goal of the initial assessment is to determine
whether the patient requires urgent intervention (eg, en-
doscopic, surgical, transfusion) or can undergo delayed
endoscopy or even be discharged to outpatient manage-
ment. Although numerous factors from the patient history,
physical examination, and initial tests have been exam-
ined for an association with a need for intervention, no
single factor is sufficiently predictive of UGIB severity to
be used for triage. The most predictive individual factors
are a history of malignancy or cirrhosis,9 presentation with
hematemesis,9-10 and signs of hypovolemia including hy-
potension,9,11 tachycardia and shock, and a hemoglobin
⬍8 g/dL.9-10 Some factors, such as a history of aspirin or
nonsteroidal anti-inflammatory drug (NSAID) use, may not
be useful for immediate disposition but are still important
to assess for future management (eg, if peptic ulcer disease
[PUD] were the etiology of UGIB, then NSAID use should
be discontinued).11 Patients who have significant comor-
bidities may require admission regardless of the severity of
the UGIB.
Because individual clinical factors are generally not
diagnostic of UGIB severity, there have been attempts to
create prediction rules. In 3 studies comparing clinical
prediction rule scores in the same study population, the
Blatchford score performed better than the Clinical Rockall
score for predicting patients at high risk for clinical
intervention.12-14 The Blatchford score15 and the Clinical
Rockall score16 have been examined in several studies and
may determine the need for urgent endoscopy. The
www.giejournal.org
 Endoscopy in acute non-variceal upper GI bleeding

TABLE 1. GRADE system for rating the quality of TABLE 2. Blatchford scoring: Admission risk markers
evidence for guidelines and associated score component values

Quality of Admission risk marker Score component value

evidence Definition Symbol
Blood urea, mmol/L
High Further research is very unlikely QQQQ
to change our confidence in 6.5-⬍8.0 2
the estimate of the effect 8.0-⬍10.0 3
Moderate Further research is likely to QQQŒ 10.0-⬍25.0 4
have an important impact on
our confidence in the estimate ⱖ25 6
of the effect and may change
the estimate Hemoglobin for men, g/dL

Low Further research is very likely to QQŒŒ 12.0-⬍13.0 1

have an important impact on 10.0-⬍12.0 3
our confidence in the estimate
of the effect and is likely to ⬍10.0 6
change the estimate
Hemoglobin for women, g/dL
Very low Any estimate of effect is very QŒŒŒ
10.0-⬍12.0 1
uncertain
Adapted from Guyatt GH, Oxman AD, Vist GE, et al; GRADE Working 10.0 6
Group. GRADE: an emerging consensus on rating quality of evidence
Systolic blood pressure, mm Hg
and strength of recommendations. BMJ 2008;336:924-6.1
100-109 1

90-99 2
Blatchford score uses data on blood urea and hemoglobin ⬍90 3
levels, systolic blood pressure, pulse, presentation with
Other markers
melena, presentation with syncope, history of hepatic dis-
ease, and history of heart failure (Table 2).15 A Blatchford Pulse ⱖ100/min 1
score ⬎0 was 99% to 100% sensitive for identifying a Presentation with melena 1
severe bleed in 5 studies.12-15,17 The specificity of the
Blatchford scoring system is low (4%-44%), but clinically it Presentation with syncope 2
is more important to be comfortable identifying all severe Hepatic disease 2
UGIB at the expense of admitting some patients with
Cardiac failure 2
minor bleeding episodes. Patients found to have minor
Adapted with permission from Blatchford O, Murray WR, Blatchford
bleeding episodes typically may be discharged soon after
M. A risk score to predict need for treatment for upper-
endoscopy. Use of the Blatchford score may allow early gastrointestinal haemorrhage. Lancet 2000;356:1318-21.15
discharge of 16% to 25% of all patients presenting with
UGIB.12-15

Resuscitation be useful in identifying patients with high-risk lesions, but

Initially, crystalloid fluids should be infused to maintain
adequate blood pressure. Patients with evidence of severe
hypovolemia, shock, or evidence of ongoing blood loss
should be admitted to an intensive care setting. Blood
products, such as packed red blood cells, should be trans-
fused in patients with evidence of ongoing active blood
loss or in patients who have experienced significant blood
loss or cardiac ischemia. Other blood products, such as
coagulation factors and platelets, also may be necessary to
help control bleeding in the appropriate clinical setting.18
Nasogastric tube
The placement of a nasogastric tube should be consid-
ered in select patients who have suspected active UGIB.
The presence of bright red blood in a gastric aspirate can
is not as useful if coffee ground material or other findings
are present without red blood.9-10,19 It should be noted that
the absence of blood in a gastric aspirate does not exclude
the presence of active UGIB, because approximately 15%
of patients with active bleeding can have a negative result
for nasogastric lavage.19 Because of these limitations, and
the potential patient discomfort, use of a nasogastric tube
remains controversial.20-21
Before-procedure proton pump inhibitor
therapy
The role of proton pump inhibitor (PPI) therapy in pa-
tients with suspected acute UGIB was systematically re-
viewed in a Cochrane meta-analysis that included 6 random-
ized controlled trials (RCT) published between 1992 and

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Endoscopy in acute non-variceal upper GI bleeding
2007.22 The analysis found that patients with nonvariceal
UGIB administered intravenous PPI therapy prior to endos-
copy did not experience any statistically significant differ-
ences in the outcomes of mortality, rebleeding, or progres-
sion to surgery compared with patients in the control group.
However, the analysis did show that before-procedure PPI
therapy resulted in significantly reduced rates of high-risk
stigmata identified on endoscopy (odds ratio [OR] 0.67; 95%
confidence interval [CI], 0.54-0.84) and need for endoscopic
therapy (OR 0.68; 95% CI, 0.50-0.93). Therefore, intravenous
PPI therapy is recommended for patients who are suspected
of having acute UGIB.
Prokinetic agents
A recent meta-analysis of randomized trials evaluated
the effectiveness of using prokinetic agents before endos-
copy in acute UGIB.23 The analysis demonstrated that
intravenous erythromycin or metoclopramide adminis-
tered 20 to 120 minutes before endoscopy in patients with
acute UGIB decreased the need for a repeat endoscopy to
determine the site and cause of bleeding (OR 0.55; 95% CI,
0.32-0.94). However, there was no improvement in other
clinical outcomes, such as duration of hospitalization,
transfusion requirements, or surgery. Although the routine
use of prokinetic agents is not recommended, use in pa-
tients with a high probability of having fresh blood or a
clot in the stomach when undergoing endoscopy may
result in a higher diagnostic yield.24-27
ENDOSCOPY IN THE MANAGEMENT OF UGIB
Endoscopy in patients with UGIB is effective in diagnos-
ing and treating most causes of UGIB and is associated with
a reduction in blood transfusion requirements and length of
intensive care unit/total hospital stay.28 Early endoscopy
(within 24 hours of hospital admission) has a greater impact
than delayed endoscopy on length of hospital stay and re-
quirements for blood transfusion.29 In appropriate settings,
endoscopy can be used to assess the need for inpatient
admission. Several studies have demonstrated that he-
modynamically stable patients who are evaluated for
UGIB with upper endoscopy and subsequently found to
have low-risk stigmata for recurrent bleeding can be
safely discharged and followed as outpatients.30-33
ENDOSCOPIC TREATMENT MODALITIES FOR
UGIB
There are a variety of endoscopic treatment modalities
available for the management of UGIB, including injection
methods, cautery, and mechanical therapy.34 These are
reviewed briefly here. A full discussion of these tech-
niques and their risks can be found in other ASGE
documents.34-35
1134 GASTROINTESTINAL ENDOSCOPY Volume 75, No. 6 : 2012
Injection
The primary mechanism of action of injection therapy is
tamponade resulting from volume effect.34 Some agents
also have a secondary pharmacologic effect. Agents avail-
able for injection to produce tamponade include normal
saline solution and dilute epinephrine. Sclerosants such as
ethanol, ethanolamine, and polidocanol are not used to
produce tamponade, but instead cause direct tissue injury
and thrombosis. Agents also can be used in combination,
such as epinephrine followed by ethanolamine. Limited
data suggest that higher volumes of epinephrine injected
at endoscopy are superior to saline solution for achieving
hemostasis.36 A separate class of injectable agents includes
thrombin, fibrin, and cyanoacrylate glues, which are used
to create a primary tissue seal at a bleeding site.37 With the
exception of dilute epinephrine, injectable agents are not
commonly used in the treatment of non-variceal UGIB.
Cautery
Cautery devices include heater probes, neodymium-
yttrium aluminum garnet lasers, argon plasma coagulation,
and electrocautery probes. Laser therapy is not widely used
in many centers because of cost, training, and support issues.
Electrocautery refers to the use of monopolar electrocautery
or bipolar/multipolar electrocautery. Heater probes and elec-
trocautery probes also use local tamponade (mechanical
pressure of the probe tip on the bleeding site) combined with
heat or electrical current to coagulate blood vessels, a pro-
cess known as coaptation. Argon plasma coagulation uses
a stream of ionized gas to conduct electricity, without
mechanical contact, resulting in coagulation of superfi-
cial tissues. Argon plasma coagulation is primarily used
for the treatment of superficial lesions, such as vascular
abnormalities.38
Mechanical therapy
Mechanical therapy refers to the use of a device that
causes physical tamponade of a bleeding site. Currently,
the only endoscopic mechanical therapies widely avail-
able are clips and band ligation devices. Endoscopic clips
are deployed over a bleeding site (eg, visible vessel) and
typically slough off within days to weeks after place-
ment.39 Endoscopic band ligation devices, commonly used
in variceal bleeding, also have been used to treat non-
variceal UGIB and involve the placement of elastic bands
over tissue to produce mechanical compression and
tamponade.40
OVERVIEW OF ENDOSCOPIC APPROACHES
TO COMMON CAUSES OF ACUTE UGIB
In patients with UGIB, the most common etiologies are:
PUD (20%-50%), gastroduodenal erosions (8%-15%),
esophagitis (5%-15%), varices (5%-20%), Mallory-Weiss
tears (8%-15%), and vascular malformations (about 5%),
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TABLE 3. Stigmata of ulcer hemorrhage and risk of
recurrent bleeding without endoscopic therapy47-51
Risk of recurrent
bleeding
Stigmata without therapy
Active arterial bleeding (spurting) Approaches 100%
Non-bleeding visible vessel Up to 50%
Non-bleeding adherent clot 8%-35%
Ulcer oozing (without other stigmata) 10%-27%
Flat spots ⬍8%
Clean-based ulcers ⬍3%
with other conditions (eg, malignancy) making up the
remaining cases.41-42
Peptic ulcer bleeding
The most common causes of PUD are NSAID therapy
and Helicobacter pylori infection, although a variety of
other clinical scenarios can predispose patients to PUD. A
2009 meta-analysis of 75 studies evaluating endoscopic
therapy for bleeding peptic ulcers demonstrated that ther-
mal devices, injectable agents other than epinephrine (ie,
sclerosants and thrombin/fibrin glue), and clips were all
effective methods for achieving hemostasis in PUD, with
no single modality being superior.43 Multiple meta-
analyses have demonstrated that combination therapy
with epinephrine injection in conjunction with a second
endoscopic treatment modality, such as cautery or clips, is
superior to epinephrine alone for treating lesions with
high-risk stigmata, significantly reducing the risk of re-
bleeding, surgery, and mortality.43-46 Therefore, it is rec-
ommended that if epinephrine is used to treat peptic ulcer
bleeding with high-risk stigmata, a second endoscopic
treatment modality (ie, coaptive thermal device, sclero-
sants, thrombin/fibrin glue, or clips) should also be used.
Endoscopic prognostic features in PUD
Several endoscopic findings portend a higher risk for
recurrent bleeding and thus, potential benefit from endo-
scopic therapy (Table 3).47-51 Endoscopic therapy is indi-
cated for patients found to have actively bleeding or spurt-
ing arterial vessels and for those with a non-bleeding
visible vessel (ie, pigmented protuberance) in an ulcer.47
Ulcers with an overlying clot should be irrigated to eval-
uate and potentially treat the underlying lesion.24 How-
ever, the management of peptic ulcers with overlying
adherent clots that are resistant to removal by irrigation is
controversial. A meta-analysis of 6 RCT including 240 pa-
tients with adherent clots suggested that endoscopic ther-
apy is superior to medical therapy for preventing recurrent
bleeding (pooled relative risk, 0.43; 95% CI, 0.19-0.98).
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Endoscopy in acute non-variceal upper GI bleeding
This analysis, however, failed to demonstrate any signifi-
cant differences in the need for surgery, length of hospital
stay, transfusion requirements, or mortality between en-
doscopic approaches. Another meta-analysis of 5 RCT that
included 189 patients with adherent clots showed no sig-
nificant differences in the risks of rebleeding, need for
surgery, or mortality with endoscopic therapy versus no
endoscopic therapy.43 Therefore, in the absence of con-
vincing evidence, the practice of clot removal followed by
endoscopic therapy should be individualized. Similarly,
flat, pigmented spots or lesions with slow oozing of blood
without other stigmata have not been definitively shown
to benefit from endoscopic therapy. Clean-based ulcers
have an extremely low recurrent bleeding rate and do not
require endoscopic treatment.47-48 Additional information
regarding the management of patients with PUD is de-
tailed in a 2009 ASGE guideline.52
After-procedure PPI therapy
The administration of a continuous infusion, high-dose,
intravenous PPI for a period of 72 hours has been dem-
onstrated to be effective in reducing rebleeding rates and
mortality after endoscopic therapy of ulcers with high-risk
stigmata.53-56
Esophageal lesions
Esophagitis, a common cause of UGIB, can be caused
by gastroesophageal reflux, infection, medications, caustic
ingestion, or radiation.57 In the majority of patients, no
endoscopic therapy is required. A Mallory-Weiss tear is a
laceration of the mucosa at the gastroesophageal junction,
gastric cardia, or distal esophagus. Bleeding is usually
self-limited.58 Patients with ongoing or severe bleeding
require endoscopic therapy. Multipolar electrocautery ap-
pears to be the most effective therapy, but epinephrine
injection, clips, or band ligation also appear to be
effective.59-63 There are no prospective trials comparing
treatment methods for Mallory-Weiss tears. Uncontrolled
bleeding may require angiographic therapy or surgery.
Vascular abnormalities
Vascular malformations typically cause chronic occult
blood loss and occasionally acute GI hemorrhage. These
lesions can occur sporadically or in association with other
disorders, such as cirrhosis, renal failure, radiation injury,
various collagen vascular diseases, and hereditary hemor-
rhagic telangiectasia. Endoscopic ligation, laser, argon
plasma coagulation, coaptive cautery methods, and scle-
rotherapy can be effective therapies for UGIB due to
vascular abnormalities.64-65 There are no prospective trials
comparing treatment methods for acute UGIB caused by
vascular malformations.
Dieulafoy lesions typically present with intermittent,
recurrent, hemodynamically significant UGIB. The lesion
occurs when an abnormally large-caliber submucosal ar-
tery becomes exposed at the surface of the mucosa and
Volume 75, No. 6 : 2012 GASTROINTESTINAL ENDOSCOPY 1135
Endoscopy in acute non-variceal upper GI bleeding
then ruptures. These lesions are usually in the stomach but
may occur throughout the GI tract.66 Endoscopic methods
to treat Dieulafoy lesions include banding, clipping, elec-
trocautery, cyanoacrylate glue, sclerosant injection, epi-
nephrine injection, heater probe, and laser therapy. Large,
single-center experiences have not identified one modality
as being superior to others; however, epinephrine injec-
tion monotherapy is associated with a higher rate of re-
current bleeding.67-69 Given the difficulty in identifying
these lesions absent active hemorrhage, tattooing of the
lesion should be considered to facilitate identification and
treatment in the event of recurrent bleeding. If endoscopic
therapy fails, interventional radiology or surgical ap-
proaches may be required. Placement of a clip can help
identify the lesion should recurrent bleeding cease before
these non-endoscopic interventions.
Aortoenteric fistulas
Aortoenteric fistulas may be primary (caused by arte-
riosclerosis, aortic aneurysms, aortic infections),68 or sec-
ondary (aortic repair with a synthetic graft).69 This condi-
tion is a medical emergency that may present with what
appears to be self-limited bleeding (“herald” bleed). The
clinical suspicion of an aortoenteric fistula should prompt
emergency CT imaging. CT scans and angiography can
demonstrate the fistula if contrast extravasation into the
bowel is visualized.70-72 There is no endoscopic therapy
for a bleeding aortoenteric fistula, although endoscopy
may be required to confirm the diagnosis or exclude other
causes of UGIB. Most aortoenteric fistulas occur at the
level of the distal duodenum or the jejunum and may be
beyond the reach of a standard upper endoscope. In
some cases, aortic graft material may be seen protruding
into the bowel lumen. Emergency surgical consultation
should be obtained.
GI tumors
Benign or malignant GI tumors, whether primary or
metastatic, cause approximately 5% of cases of UGIB.73
Case series of endoscopic therapy have reported initial
hemostasis rates similar to, or lower than, those seen in
PUD and high recurrent bleeding rates, between 16% and
80%.74-76 Procedure-related complications also appear to
be more common.75-76 The optimal treatment modality has
not been defined and depends on the goals of therapy.
Surgery or angiography may be better approaches to en-
suring long-term hemostasis. Any lesion appearing malig-
nant when seen in the context of an episode of UGIB
should be biopsied.
RECURRENT BLEEDING AFTER ENDOSCOPIC
THERAPY
Despite adequate initial endoscopic therapy, recurrent
UGIB can occur in up to 24% of high-risk patients. The use
of PPI therapy in addition to combination endoscopic
1136 GASTROINTESTINAL ENDOSCOPY Volume 75, No. 6 : 2012
therapy reduces the rate of recurrent bleeding to approx-
imately 10%.54,56 Patients with recurrent bleeding generally
respond favorably to repeat endoscopic therapy.77-78 Rou-
tine second-look endoscopy, defined as a planned endos-
copy performed within 24 hours of the initial endoscopy,
is not recommended.79 In cases where the initial endos-
copy failed to identify the source (eg, because of a large
clot in the stomach) or if there are concerns that inade-
quate therapy was delivered, repeat endoscopy may be
appropriate.
RECOMMENDATIONS
● We recommend that patients with UGIB be adequately
resuscitated before endoscopy. QŒŒŒ
● We recommend antisecretory therapy with PPIs for
patients with bleeding caused by peptic ulcers or in
those with suspected peptic ulcer bleeding awaiting
endoscopy. QQQQ
● We suggest prokinetic agents in patients with a high
probability of having fresh blood or a clot in the stom-
ach when undergoing endoscopy. QQŒŒ
● We recommend endoscopy to diagnose the etiology of
acute UGIB. QQQŒ
The timing of endoscopy should depend on clinical
factors. Urgent endoscopy (within 24 hours of presen-
tation) is recommended for patients with a history of
malignancy or cirrhosis, presentation with hematem-
esis, and signs of hypovolemia including hypotension,
tachycardia and shock, and a hemoglobin ⬍8 g/dL.
● We recommend endoscopic therapy for peptic ulcers
with high-risk stigmata (active spurting, visible vessel).
QQQQ
The management of PUD with an adherent clot is con-
troversial. Recommended endoscopic treatment modal-
ities include injection (sclerosants, thrombin, fibrin, or
cyanoacrylate glue), cautery, and mechanical therapies.
● We recommend against epinephrine injection alone for
peptic ulcer bleeding. If epinephrine injection is per-
formed, it should be combined with a second endo-
scopic treatment modality (eg, cautery or clips). QQQQ
● We recommend that patients with low-risk lesions be
considered for outpatient management. QQQŒ
● We recommend against routine second-look endos-
copy in patients who have received adequate endo-
scopic therapy. QŒŒŒ
● We recommend repeat endoscopy for patients with
evidence of recurrent bleeding. QQQŒ
DISCLOSURES
T. Ben-Menachem is a consultant for Boston Scientific.
D. Fisher is a consultant for Epigenomics, Inc. K. Chathadi
is a speaker for Boston Scientific. Rajeev Jain is a consul-
tant for Boston Scientific and does research for Barxx. J.
Saltzman is a consultant for Hemoclip Development and
www.giejournal.org

has a relationship with Cook Endoscopy. No other finan-
cial relationships relevant to this publication were
disclosed.
Abbreviations: NSAID, nonsteroidal anti-inflammatory drug; PPI, proton
pump inhibitor; PUD, peptic ulcer disease; UGIB, upper GI bleeding.
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Joo Ha Hwang, MD, PhD
Deborah A. Fisher, MD, MHS
Tamir Ben-Menachem, MD
Vinay Chandrasekhara, MD
Krishnavel Chathadi, MD
G. Anton Decker, MD
Dayna S. Early, MD
John A. Evans, MD
Robert D. Fanelli, MD, SAGES Representative
Kimberly Foley, RN, BSN, CGRN, SGNA Representative
Norio Fukami, MD
Rajeev Jain, MD
Terry L. Jue, MD
Kahlid M. Khan, MD
Jenifer Lightdale, MD, MPH
Phyllis M. Malpas, RN, SGNA Representative
John T. Maple, DO
Shabana Pasha, MD
John Saltzman, MD
Ravi Sharaf, MD
Amandeep K. Shergill, MD
Jason A. Dominitz, MD, MHS, Prior Chair
Brooks D. Cash, MD, Chair
www.giejournal.org
 Guidelines
1
Liver Unit, University Hospitals
Birmingham NHS Foundation
Trust, Birmingham, UK
2
GI Unit, Glasgow Royal
Infirmary, Glasgow, UK
3
Liver Unit, Royal Infirmary of
Edinburgh, Edinburgh, UK
4
The Royal Free Sheila Sherlock
Liver Centre, Royal Free
Hospital and University College
London, London, UK
5
Gastrointestinal and Liver
Services, York Teaching
Hospitals NHS Foundation
Trust, York, UK
6
Department of Interventional
Radiology, University Hospitals
Birmingham NHS Foundation
Trust, Birmingham, UK
7 The nature of variceal haemorrhage in cirrhotic
Department of
Gastroenterology, Derby
Hospitals NHS Foundation
Trust, Derby, UK
8
Liver Unit, Freeman Hospital,
Newcastle upon Tyne, UK
9
Department of
Gastroenterology, Royal Devon
and Exeter Hospital, Devon,
UK
Correspondence to
Dr Dhiraj Tripathi, Liver Unit,
Queen Elizabeth Hospital,
Edgbaston, Birmingham B15
2TH, UK; Dhiraj.Tripathi@uhb.
nhs.uk, d.tripathi@bham.ac.uk
Received 28 January 2015
Revised 11 March 2015
Accepted 17 March 2015
Published Online First
17 April 2015
Open Access
Scan to access more
free content
To cite: Tripathi D,
Stanley AJ, Hayes PC, et al.
Gut 2015;64:1680–1704.
1680
UK guidelines on the management of variceal
haemorrhage in cirrhotic patients
Dhiraj Tripathi,1 Adrian J Stanley,2 Peter C Hayes,3 David Patch,4 Charles Millson,5
Homoyon Mehrzad,6 Andrew Austin,7 James W Ferguson,1 Simon P Olliff,6
Mark Hudson,8 John M Christie9
ABSTRACT
These updated guidelines on the management of
variceal haemorrhage have been commissioned by the
Clinical Services and Standards Committee (CSSC) of the
British Society of Gastroenterology (BSG) under the
auspices of the liver section of the BSG. The original
guidelines which this document supersedes were written
in 2000 and have undergone extensive revision by 13
members of the Guidelines Development Group (GDG).
The GDG comprises elected members of the BSG liver
section, representation from British Association for the
Study of the Liver (BASL) and Liver QuEST, a nursing
representative and a patient representative. The quality
of evidence and grading of recommendations was
appraised using the AGREE II tool.
patients with its complex range of complications makes
rigid guidelines inappropriate. These guidelines deal
specifically with the management of varices in patients
with cirrhosis under the following subheadings:
(1) primary prophylaxis; (2) acute variceal haemorrhage;
(3) secondary prophylaxis of variceal haemorrhage; and
(4) gastric varices. They are not designed to deal with
(1) the management of the underlying liver disease;
(2) the management of variceal haemorrhage in children;
or (3) variceal haemorrhage from other aetiological
conditions.
Summary of all recommendations
Recommendations: primary prophylaxis of variceal
haemorrhage in cirrhosis (Figure 2)
1. What is the best method for primary prophylaxis?
1.1. We recommend non-cardioselective β
blockers (NSBB) or variceal band ligation
(VBL). We suggest pharmacological treat-
ment with propranolol as first line. VBL is
offered if there are contraindications to
NSBB. The choice of VBL or NSBB should
also take into account patient choice (level
1a, grade A).
1.2. We suggest carvedilol or nadolol as alterna-
tives to propranolol (level 1b, grade A).
1.3. Dose:
1.3.1. Propranolol: 40 mg twice daily. Dose
titrated to maximum tolerated or once
heart rate (HR) of 50–55 bpm is
reached to a maximum dose of
320 mg (level 1a, grade A).
1.3.2. Nadolol: 40 mg daily dose. Dose
titrated to maximum tolerated or
once HR of 50–55 bpm is reached a
Tripathi D, et al. Gut 2015;64:1680–1704. doi:10.1136/gutjnl-2015-309262
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maximum dose of 240 mg (level 1a,
grade A).
1.3.3. Carvedilol: 6.25 mg once daily to
increase to maintenance of 12.5 mg
after a week if tolerated or once HR
of <50–55 bpm is reached (level 1a,
grade A).
1.3.4. It is suggested that NSBB are discon-
tinued at the time of spontaneous
bacterial peritonitis, renal impair-
ment and hypotension (level 2b,
grade B).
1.4. In cases of contraindications or intolerance
to NSBB, we recommend variceal band
ligation (level 1a, grade A).
2. Who should have surveillance for variceal
bleeding?
2.1. We recommend all patients with cirrhosis
should be endoscoped at the time of diag-
nosis (level 1a, grade A). There is no indica-
tion to repeat endoscopy in patients
receiving NSBB.
3. How often should cirrhotic patients be
endoscoped?
3.1. If at the time of first endoscopy no varices
are seen, we suggest that patients
with cirrhosis should be endoscoped at
2–3-year intervals (level 2a, grade B).
3.2. If grade I varices are diagnosed, we suggest
that patients should be endoscoped at yearly
intervals (level 2a, grade B).
3.3. If there is clear evidence of disease progres-
sion we suggest that the intervals can be
modified by the clinician. Endoscopy should
also be offered at time of decompensation
(level 2a, grade B).
4. Which patients with cirrhosis should have
primary prophylaxis?
4.1. If grade I varices and red signs or grade 2–
3 varices are diagnosed, we recommend
that patients have primary prophylaxis irre-
spective of the severity of the liver disease
(level 1a, grade A).
5. Treatments not recommended:
5.1. Proton pump inhibitors are not recom-
mended unless otherwise required for
peptic ulcer disease (level 1b, grade B).
5.2. Isosorbide mononitrate monotherapy is not
recommended as primary prophylaxis (level
1b, grade A). There is insufficient evidence
to recommend isosorbide mononitrate in
combination with NSBB (level 1b, grade A).

5.3. Shunt surgery or transjugular intrahepatic portosystemic
stent shunt (TIPSS) is not recommended as primary
prophylaxis (level 1a, grade A).
5.4. Sclerotherapy is not recommended as primary prophy-
laxis (level 1a, grade A).
6. Areas requiring further study:
6.1. Role of NSBB in patients without varices, with focus on
carvedilol.
6.2. Role of NSBB in patients with small varices, with focus
on carvedilol.
6.3. Comparison of carvedilol versus propranolol in primary
prophylaxis.
6.4. Identification of, and trials assessing, new drugs for
primary prophylaxis such as statins.
7. Quality indicator:
7.1. Percentage of patients at diagnosis of cirrhosis who have
had an endoscopy to screen for varices (level 1a,
grade A).
Numerator; patients diagnosed with cirrhosis who have
had an endoscopy either before or after diagnosis within
6 months.
Denominator; patients newly diagnosed with cirrhosis.
7.2. Percentage of patients receiving primary prophylaxis
among those newly diagnosed with grade I varices and
red signs or grade 2–3 varices.
Numerator; patients who have grade 1 varices with red
signs or grade 2–3 varices receiving primary prophylaxis.
Denominator; patients diagnosed with cirrhosis who
have grade I varices with red signs or grade 2–3 varices.
Recommendations: control of active variceal haemorrhage in
cirrhosis (Figure 3)
1. Suggestions for resuscitation and initial management
1.1. Units offering an emergency acute upper gastrointestinal
bleeding service should have expertise in VBL, balloon
tamponade and management of gastric variceal bleeding
(level 5, grade D).
1.2. Transfuse patients with massive bleeding with blood, pla-
telets and clotting factors in line with local protocols for
managing massive bleeding (level 5, grade D).
1.3. Base decisions on blood transfusion on the full clinical
picture, recognising that overtransfusion may be as dam-
aging as undertransfusion. A restrictive transfusion policy
aiming for a haemoglobin of 70–80 g/L is suggested in
haemodynamically stable patients (level 1b, grade B).
1.4. Do not offer platelet transfusion to patients who are not
actively bleeding and are haemodynamically stable (level
5, grade D).
1.5. Offer platelet transfusion to patients who are actively
bleeding and have a platelet count of <50×109/L (level
5, grade D).
1.6. Offer fresh frozen plasma to patients who have either:
▸ a fibrinogen level of <1 g/L (level 5, grade D), or
▸ a prothrombin time (international normalised ratio)
or activated partial thromboplastin time >1.5 times
normal (level 5, grade D).
1.7. Offer prothrombin complex concentrate to patients who
are taking warfarin and actively bleeding (level 5, grade D).
1.8. Treat patients who are taking warfarin and whose upper
gastrointestinal bleeding has stopped in line with local
warfarin protocols (level 5, grade D).
1.9. There is insufficient evidence for the use of recombinant
factor VIIa in acute variceal haemorrhage (level 1b,
grade B).
Tripathi D, et al. Gut 2015;64:1680–1704. doi:10.1136/gutjnl-2015-309262
Guidelines
2. Suggestions for timing of upper gastrointestinal endoscopy:
2.1. Offer endoscopy to unstable patients with severe acute
upper gastrointestinal bleeding immediately after resusci-
tation (level 5, grade A).
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2.2. Offer endoscopy within 24 h of admission to all other
patients with upper gastrointestinal bleeding (level 2b,
grade A).
2.3. Units seeing more than 330 cases a year should offer
daily endoscopy lists. Units seeing fewer than 330 cases
a year should arrange their service according to local cir-
cumstances (level 5, grade D).
3. Control of bleeding:
3.1. Antibiotics are recommended for all patients with sus-
pected or confirmed variceal bleeding (level 1a,
grade A).
3.2. In all patients, vasoconstrictors such as terlipressin or
somatostatin are recommended and should be started as
soon variceal bleeding is suspected and continued until
haemostasis is achieved or for up to 5 days. Octreotide
(unlicensed) is suggested if terlipressin or somatostatin
are unavailable (level 1a, grade A).
3.3. Variceal band ligation is recommended as the preferred
endoscopic method (level 1a, grade A).
3.4. After satisfactory haemostasis with the methods above,
and depending on local resources, early covered TIPSS
(<72 h after index variceal bleed) can be considered in
selected patients with Child’s B cirrhosis and active
bleeding or Child’s C cirrhosis with Child’s score <14
(level 1b, grade B).
3.5. Proton pump inhibitors are not recommended unless
otherwise required for peptic ulcer disease (level 1b,
grade B).
4. Failure to control active bleeding:
4.1. If bleeding is difficult to control, a Sengstaken–
Blakemore tube should be inserted until further
endoscopic treatment, TIPSS or surgery is performed
depending on local resources and expertise (level 1b,
grade B).
4.2. Specialist help should be sought at this time and transfer
to a specialist centre should be considered. Units that do
not offer a TIPSS service should identify a specialist
centre which offers a 24 h emergency TIPSS service and
have appropriate arrangements for safe transfer of
patients in place (level 2a, grade B).
5. Areas requiring further study:
5.1. The efficacy of restrictive blood transfusion in variceal
haemorrhage.
5.2. The role of blood products in variceal haemorrhage.
5.3. The utility of early TIPSS (<72 h) in acute variceal
haemorrhage.
5.4. The role of removable oesophageal stents in acute vari-
ceal haemorrhage.
5.5. The role of haemostatic powders in acute variceal
haemorrhage.
5.6. The role of proton pump inhibitors in variceal
haemorrhage.
6. Quality indicators
6.1. Antibiotic administration in acute variceal bleeding
within 1 day either before or after the procedure
(level 1a, grade A).
Numerator; patients with an acute variceal bleed who
have received antibiotics within 1 day either before or
after the procedure.
Denominator; patients with an acute variceal bleed.
1681
 Guidelines
6.2. Endoscopy performed within 24 h of presentation of an
acute variceal bleed (level 2b, grade A).
Numerator; patients with an acute variceal bleed who
have received endoscopy within 24 h of presentation.
Denominator; patients with an acute variceal bleed.
Recommendations: secondary prophylaxis of variceal haemor-
rhage in cirrhosis (figure 3)
1. Should VBL be used in combination with NSBB?
1.1. NSBB ( propranolol or nadolol)+VBL combination
therapy are recommended as secondary prophylaxis
(level 1a, grade A).
1.2. NSBB or VBL monotherapy are suggested as alternative
options taking into account patient preference and clin-
ical judgement (level 1a, grade B).
1.3. Carvedilol is suggested as an alternative to propranolol
and nadolol (level 1b, grade B).
1.4. If NSBB alone are used, there is no need to undertake
further endoscopy unless clinically indicated (level 1a,
grade A).
1.5. We recommend that VBL alone is used to eradicate
varices if there are contraindications or intolerance to
combined use with NSBB (level 1a, grade A).
2. What is the optimal protocol for VBL?
2.1. It is suggested that varices are banded at 2–4-weekly
intervals until eradication (level 1b, grade B).
2.2. After successful eradication of the varices, patients
should be endoscoped at 3 months, then 6 monthly
thereafter. Any recurrent varices should be treated with
further VBL until eradication (level 1b, grade B).
2.3. Proton pump inhibitors are not recommended unless
otherwise required for peptic disease (level 1b, grade B).
3. When is TIPSS indicated?
3.1. We suggest that TIPSS is used for patients who rebleed
despite combined VBL and NSBB therapy (or when
monotherapy with VBL or NSBB is used owing to
intolerance or contraindications to combination therapy),
and in selected cases owing to patient choice. PTFE-
covered stents are recommended (level 1a, grade A).
3.2. Where TIPSS is not feasible in Child’s A and B patients,
we suggest shunt surgery can be used where local
expertise and resources allow (level 1b, grade B).
4. Areas requiring further study:
4.1. Combination of VBL and carvedilol (or other NSBB)
versus carvedilol as monotherapy.
4.2. Comparison of carvedilol with propranolol in secondary
prophylaxis.
4.3. Optimum time interval between VBL sessions.
4.4. Strategy of VBL or NSBB discontinuation after variceal
eradication during combination therapy with VBL
+NSBB.
4.5. Strategy of VBL add-on therapy to failure of NSBB
monotherapy.
4.6. Strategy of NSBB add-on therapy to failure of VBL
monotherapy.
4.7. Role of early TIPSS in secondary prophylaxis.
4.8. Role of statins in secondary prophylaxis.
5. Quality indicator:
5.1. Institution of secondary prophylaxis after acute variceal
bleeding (level 1a, grade A)
Numerator; patients with an acute variceal bleed who
have received either NSBB or banding or both within
4 weeks of the index bleed.
Denominator; patients with an acute variceal bleed.
1682
Recommendations: management of active haemorrhage from
gastric varices (Figure 3)
1. What is the optimal management of bleeding gastro-
oesophageal varices?
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1.1. Gastro-oesophageal varices (GOV)-1: treat as for
oesophageal varices (level 2b, grade B).
1.2. GOV-2 and isolated gastric varices (IGV):
1.2.1. We recommend initial endoscopic therapy with
cyanoacrylate injection (level 1a, grade A).
1.2.2. Thrombin may also be considered (level 4, grade C).
1.3. TIPSS can be considered, depending on local resources
and clinical judgement (level 3a, grade B).
2. If control of bleeding fails:
2.1. Balloon tamponade is suggested for GOV and IGV-1
until definitive treatment is undertaken (level 2b, grade B).
2.2. Salvage TIPSS is suggested as the first-line definite treat-
ment, where feasible (level 3a, grade B).
2.3. Balloon-occluded retrograde transvenous obliteration
(B-RTO) or surgical shunting can be considered if TIPSS
is not possible (eg, portal vein thrombosis present) and
depending on local resources (level 3a, grade B).
3. What are the therapeutic options for prevention of rebleed-
ing from gastric varices?
3.1. We recommend that patients with GOV-1 are entered into
a VBL surveillance programme (level 2b, grade B).
3.2. We recommend endoscopic surveillance with cyano-
acrylate injection as needed for GOV-2 and IGV (level
2b, grade B). Note the optimum endoscopic follow-up
strategy remains unclear. Thrombin can also be consid-
ered (level 4, grade C).
3.3. NSBB can be considered in certain circumstances after
taking into account the patient’s preferences and clinical
judgement (level 1b, grade B).
3.4. We suggest TIPSS if patients rebleed despite cyanoacryl-
ate injection. TIPSS can also be considered in other
selected patients (eg, those with large or multiple gastric
varices) (level 1b, grade B).
3.5. Shunt surgery may be used in selected patients with
well-compensated cirrhosis and depending on local
resources (level 3c, grade B).
3.6. Splenectomy or splenic artery embolisation should be
considered in all patients where there is splenic vein
thrombosis or left-sided portal hypertension (level 4,
grade C).
4. Is there a role for primary prophylaxis of gastric variceal
bleeding?
4.1. NSBB (level 2a, grade B) can be considered in selected
high-risk patients with large GOV-2 after taking into
account the patient’s preferences and clinical judgement.
4.2. Cyanoacrylate injection is not recommended outside
clinical trials (level 2a, grade A).
5. Areas requiring further study:
5.1. Role of thrombin in gastric varices, comparing this with
tissue adhesives in both acute gastric variceal bleeding
and secondary prophylaxis.
5.2. Role of TIPSS in acute gastric variceal bleeding and sec-
ondary prophylaxis.
5.3. Role of haemostatic powders in controlling refractory
active gastric variceal bleeding.
5.4. Role of NSBB in the prevention of rebleeding from
gastric varices.
5.5. Role of B-RTO as monotherapy or in combination with
endoscopic injection of tissue adhesives in prevention of
bleeding from gastric varices.
Tripathi D, et al. Gut 2015;64:1680–1704. doi:10.1136/gutjnl-2015-309262

5.6. Role of endoscopic ultrasound-guided injection of tissue
adhesives or thrombin.
5.7. Primary prevention of gastric variceal bleeding with
tissues adhesives and NSBB.
INTRODUCTION
The guidelines refer closely to the Baveno V consensus state-
ment published in 20101 and the 2012 NICE Guidelines on
Acute Upper GI bleeding (CG141).2 These documents are
widely used and offer useful evidence-based guidance. However,
we feel that owing to significant recent advances, further addi-
tions and refinements to the published guidance, with particular
focus on resource implications, service development and the
patient pathway, are necessary. The previously mentioned docu-
ments1 2 do not cover all the recent advances—in particular, in
the field of acute variceal bleeding and the role of transjugular
intrahepatic portosystemic stent shunt (TIPSS). There have also
been developments and better insights into drug treatment for
prevention of varices and variceal bleeding—in particular, the
role of non-cardioselective β blockers (NSBB).
Guideline development
These guidelines were drafted after discussions within the liver
section of the British Society of Gastroenterology (BSG) and
acceptance of the proposal by the Clinical Services and
Standards Committee (CSSC). There followed division of sec-
tions to be researched by designated authors and an exhaustive
literature review. The Baveno V consensus and NICE guidelines
were closely followed and guideline quality was assessed using
the AGREE tool3 (section ‘Assessing the quality of guidelines:
the AGREE II instrument’).
A preliminary guideline document was drafted by the authors
following discussion and, where necessary, voting by members
of the Guidelines Development Group (GDG). The draft guide-
lines were submitted for review by CSSG, then BSG council
members. Finally, full peer review was undertaken by reviewers
selected by the editor of Gut.
Attempts were made to preserve the format of the original
guidelines, with additional sections relating to service develop-
ment, the patient pathway and pre-primary prophylaxis. The
section on the management of acute variceal bleeding has been
extensively rewritten to take into account recent important
developments in interventional radiology, drug treatment and
resuscitation.
Assessing the quality of guidelines: the AGREE II instrument
The AGREE II instrument is an accepted method for appraising
clinical guidelines.3 Six domains are listed:
Scope and purpose
The guidelines are intended for use by clinicians and other
healthcare professionals managing patients with cirrhosis and
gastro-oesophageal varices in light of recent guidance published
by NICE2 and the Baveno V Consensus.1 Important subsequent
developments are covered in depth due to the potential impact
on clinical practice. The guidelines are primarily aimed at man-
agement of adult patients
Guideline development group membership and stakeholder
involvement
Membership of the group includes gastroenterologists, hepatolo-
gists and interventional radiologists with nursing and patient
representation.
Tripathi D, et al. Gut 2015;64:1680–1704. doi:10.1136/gutjnl-2015-309262
Guidelines
Rigour of development
The published literature was searched using Pubmed, Medline,
Web of Knowledge and the Cochrane database between October
2013 and February 2015. The GDG met through a series of tel-
Gut: first published as 10.1136/gutjnl-2015-309262 on 17 April 2015. Downloaded from http://gut.bmj.com/ on June 3, 2020 by guest. Protected by copyright.
econferences during that time. The guidelines rely considerably
on consensus statements published by the Baveno V Consensus
and NICE.1 2 The style of graded recommendations is deter-
mined by the level of supporting evidence (graded level 1 to 5)
as described by the Oxford Centre For Evidence Based
Medicine4 (table 1) and is as follows:
A: consistent level 1 studies;
B: consistent level 2 or 3 studies or extrapolations from level 1
studies;
C: level 4 studies or extrapolations from level 2 or 3 studies;
D: level 5 evidence or troublingly inconsistent or inconclusive
studies of any level.
Areas of disagreement about the recommendation grade were
subjected to discussion and, if necessary, voting by members of
the guidelines group. Where possible, the health benefits, side
effects and risks of recommendations have been discussed. The
guidelines were subject to peer review after submission for con-
sideration of publication in Gut.
Clarity and presentation
Recommendations are intended to be specific to particular situa-
tions and patient groups; where necessary, different options are
listed. Key recommendations are linked to discussion threads on
a discussion forum hosted on the BSG website.
Applicability
Where necessary, we have discussed organisational changes that
may be needed in order to apply recommendations. We have
attempted to identify key criteria for monitoring and audit
purposes.
Editorial independence and conflict of interest
Guideline group members have declared any conflicts of
interest.
Scheduled review of guidelines
The proposed time for review of the guidelines is 5 years to
take into account new developments. To ensure that there is a
facility for feedback after publication, links to the BSG discus-
sion forums corresponding to the particular section of these
guidelines are included with this document. This facility to
provide new evidence is provided to all BSG members. In
accordance with the AGREE II tool the BSG forum will provide
feedback.
SERVICE DELIVERY AND DEVELOPMENT
Despite improvements in outcomes following variceal bleeding,
the need to optimise the management of acute variceal bleed-
ing is highlighted in recent publications and national reports.
In a national audit,5 variceal bleeding accounted for just over
10% of all admissions with acute GI bleeding in the UK, with
two-thirds having a previous history of variceal bleeding and
over 50% presenting during normal working hours. Endoscopy
within 24 h of presentation was achieved in only 66% of all
patients and in 70% of patients with documented cirrhosis.
Most procedures were performed in the endoscopy depart-
ment, with just 14% performed under general anaesthetic
despite high-risk stigmata and endoscopic therapy being
required in two-thirds of cases. Notably, antibiotics were
1683
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Table 1 Levels of evidence

Therapy/prevention, aetiology/
Level harm Prognosis Diagnosis DDX/symptom prevalence study

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1a SR (with homogeneity*) of SR (with homogeneity*) of inception SR (with homogeneity*) of level 1 SR (with homogeneity*) of
randomised controlled trial (RCT) cohort studies; CDR† validated in diagnostic studies; CDR† with 1b studies prospective cohort studies
different populations from different clinical centres
1b Individual RCT (with narrow CI) Individual inception cohort study with Validating‡ cohort study with good§ Prospective cohort study with good
≥80% follow-up; CDR† validated in a reference standards; or CDR† tested follow-up¶
single population within one clinical centre
1c All or none** All or none case series Absolute SpPins and SnNouts†† All or none case series
2a SR (with homogeneity*) of cohort SR (with homogeneity*) of either SR (with homogeneity*) of level >2 SR (with homogeneity*) of 2b and
studies retrospective cohort studies or untreated diagnostic studies better studies
control groups in RCTs
2b Individual cohort study (including Retrospective cohort study or follow-up Exploratory‡ cohort study with good§ Retrospective cohort study, or poor
low-quality RCT; eg, <80% of untreated control patients in an RCT; reference standards; CDR† after follow-up
follow-up) derivation of CDR† or validated on split derivation, or validated only on split
sample‡‡ only sample‡‡ or databases
2c ‘Outcomes’ research; ecological ‘Outcomes’ research Ecological studies
studies
3a SR (with homogeneity*) of case– SR (with homogeneity*) of 3b and better SR (with homogeneity*) of 3b and
control studies studies better studies
3b Individual case–control study Non-consecutive study; or without Non-consecutive cohort study or
consistently applied reference standards very limited population
4 Case series (and poor quality Case series (and poor quality prognostic Case–control study, poor or Case series or superseded reference
cohort and case-control studies§§) cohort studies¶¶) non-independent reference standard standards
5 Expert opinion without explicit Expert opinion without explicit critical Expert opinion without explicit critical Expert opinion without explicit
critical appraisal or based on appraisal or based on physiology, bench appraisal or based on physiology, bench critical appraisal or based on
physiology, bench research or ‘first research or ‘first principles’ research or ‘first principles’ physiology, bench research or ‘first
principles’ principles’
*Homogeneity means a systematic review (SR) that is free of worrisome variations (heterogeneity) in the directions and degrees of results between individual studies. Not all SRs with
statistically significant heterogeneity need be worrisome, and not all worrisome heterogeneity need be statistically significant.
†CDR, Clinical Decision Rule (algorithms or scoring systems which lead to a prognostic estimation or a diagnostic category).
‡Validating studies test the quality of a specific diagnostic test based on prior evidence. An exploratory study collects information and trawls the data (eg, using a regression analysis) to
find which factors are ‘significant’.
§Good reference standards are independent of the test, and applied blindly or objectively to all patients. Poor reference standards are haphazardly applied, but still independent of the
test. Use of a non-independent reference standard (where the ‘test’ is included in the ‘reference’, or where the ‘testing’ affects the ‘reference’) implies a level 4 study.
¶Good follow-up in a differential diagnosis study is >80%, with adequate time for alternative diagnoses to emerge (eg, 1–6 months acute, 1–5 years chronic).
**Met when all patients died before the treatment became available but some now survive while receiving it; or when some patients died before the treatment became available but
none now die while receiving it.
††An ‘absolute SpPin’: a diagnostic finding whose Specificity is so high that a Positive result rules in the diagnosis. An ‘Absolute SnNout’: a diagnostic finding whose Sensitivity is so
high that a Negative result rules out the diagnosis.
‡‡Split-sample validation is achieved by collecting all the information in a single tranche, then artificially dividing this into ‘derivation’ and ‘validation’ samples.
§§Poor quality cohort study: one that failed to clearly define comparison groups and/or failed to measure exposures and outcomes in the same (preferably blinded) objective way in
both exposed and non-exposed individuals and/or failed to identify or appropriately control known confounders and/or failed to carry out a sufficiently long and complete follow-up of
patients. Poor quality case–control study: one that failed to clearly define comparison groups and/or failed to measure exposures and outcomes in the same (preferably blinded)
objective way in both cases and controls and/or failed to identify or appropriately control known confounders.
¶¶Poor quality prognostic cohort study: one in which sampling was biased in favour of patients who already had the target outcome, or the measurement of outcomes was
accomplished in <80% of study patients, or outcomes were determined in an unblinded non-objective way, or there was no correction for confounding factors.

administered in only 27% of patients before endoscopy, and
administration of vasoactive drugs before endoscopy was only
slightly higher at 44%. Furthermore, only four patients (<1%)
were referred for TIPSS, which may reflect the lack of access
to interventional radiology, and that the audit was conducted
before the trial of early TIPSS.6 The National Confidential
Enquiry into Patient Outcome and Death (NCEPOD) report
‘Measuring the units’ assessed clinical management before
death of 594 patients with alcoholic liver disease over a
6-month period in the UK.7 Gastrointestinal bleeding was
noted in 35% of cases, with approximately 50% having vari-
ceal bleeding. Delays in endoscopy were noted in 10% of
cases, and several aspects of clinical and/or organisational care
were judged to be poor or unacceptable in 18% of patients
presenting with GI bleeding. There were deficiencies noted in
the out-of-hours rotas for GI bleeding, with 27% of hospitals
not having a dedicated-out-of hours GI bleeding service.
Studies from other countries have also reported deficiencies,
with delays in admission to hospital and administration of anti-
biotics. Two observational studies showed that access to
emergency endoscopy and use of prophylactic antibiotics and
vasoactive drugs was better in tertiary centres, although this
did not appear to affect survival.8 9
Acute variceal haemorrhage refractory to endoscopic and
pharmacological treatments, where TIPSS is usually indicated,
must be managed with appropriate resources. TIPSS is an estab-
lished interventional treatment for refractory or recurrent vari-
ceal haemorrhage. It remains a highly specialised procedure,
requiring adequate training and experience. Knowledge of the
relevant equipment, anatomy and how to deal with any compli-
cations is essential. It should therefore be performed in centres
with adequate personnel, multidisciplinary support and equip-
ment required to optimise management and minimise risks.10
Regional centres with easily accessible interventional radiology
services are generally best equipped to perform this procedure.
Setting up regional agreements and pathways to allow transfer of
appropriate patients to hospitals that undertake TIPSS proce-
dures is an important step. These pathways could also be used to
provide emergency endoscopic management if necessary due to
problems with out-of-hours endoscopic cover in smaller

1684 Tripathi D, et al. Gut 2015;64:1680–1704. doi:10.1136/gutjnl-2015-309262


hospitals. This model referred to as “spoke and wheel” or
network model, is well established for other complex procedures
and helps to expedite and streamline the process. In the
NCEPOD report ‘Measuring the units’ just 15% of hospitals had
on-site access to TIPSS, while 72% had access to TIPSS in other
centres.7
There have been significant efforts to address the need to
improve the upper GI bleeding (UGIB) service. A toolkit was
produced in collaboration with BSG; Association of Upper
Gastrointestinal Surgeons (AUGIS); Royal Colleges of
Physicians, Radiology and Nursing; and Academy of Medical
Royal Colleges.11 The key nine service standards recommended
by the document are detailed below:
1. There will be a nominated individual with the authority to
ensure implementation by the contracted provider.
2. Contracted providers will ensure the minimum service is
adequately resourced.
3. All patients with suspected UGIB should be properly
assessed and their risk scored on presentation.
4. All patients should be resuscitated before therapeutic
intervention.
5. All high-risk patients with UGIB should be endoscoped
within 24 h, preferably on a planned list in the first instance.
6. For patients who require more urgent intervention either for
endoscopy, interventional radiology or surgery formal 24/7
arrangements must be available.
7. The necessary team, meeting an agreed competency level,
should be available throughout the complete patient pathway.
8. Each stage of the patient pathway should be carried out in
an area with ‘appropriate’ facilities, equipment and support
including staff experienced in the management of UGIB.
9. All hospitals must collect a minimum dataset in order to
measure service provision against auditable outcomes
(case-mix adjusted as appropriate).
NICE recommendations for endoscopy provision are detailed
in the section ‘Management of active variceal haemorrhage’
recommendations.2 The BSG has also produced a care bundle
for patients admitted with decompensated cirrhosis in light of
the NCEPOD report with a check list method which includes
gastrointestinal bleeding.12
Since the 2008 Darzi report, quality has become a priority
for the NHS.13 With these guidelines there is real opportunity
to introduce quality outcomes based on good clinical evidence.
Furthermore by incorporating them into the liver accreditation
scheme, Liver Quest, one can improve and assure quality in
liver services across the UK.14 Therefore a small number of
quality outcomes measures have been chosen and form part of
the key recommendations.15
DEFINITIONS
It is important to define the terms that should be used in the
context of a variceal bleed. These are the Baveno V consensus
definitions.1
Variceal haemorrhage
Variceal haemorrhage is defined as bleeding from an oesopha-
geal or gastric varix at the time of endoscopy or the presence of
large oesophageal varices with blood in the stomach and no
other recognisable cause of bleeding. An episode of bleeding is
clinically significant when there is a transfusion requirement for
2 units of blood or more within 24 h of the time zero, together
with a systolic blood pressure of <100 mm Hg or a postural
change of >20 mm Hg and/or pulse rate >100 bpm at time
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Guidelines
zero (time zero is the time of admission to the first hospital to
which the patient is taken).
Time frame of acute bleeding
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The acute bleeding episode is represented by an interval of
120 h (5 days) from time zero. Evidence of any bleeding after
120 h is the first rebleeding episode.
Failure to control active bleeding
Failure to control active bleeding is defined as death or need to
change treatment defined by one of the following criteria:16 17
1. Fresh haematemesis or nasogastric aspiration of ≥100 mL of
fresh blood ≥2 h after the start of a specific drug treatment
or therapeutic endoscopy.
2. Development of hypovolaemic shock.
3. 30 g/L drop in haemoglobin (9% drop of haematocrit)
within any 24 h period if no transfusion is given. This time
frame needs to be further validated.
Variceal rebleeding
Variceal rebleeding is defined as the occurrence of a single
episode of clinically significant rebleeding from portal hyperten-
sive sources from day 5. Clinically significant rebleeding is
defined as recurrent melaena or haematemesis in any of the fol-
lowing settings:
1. hospital admission;
2. blood transfusion;
3. 30 g/L drop in haemoglobin;
4. death within 6 weeks.
Early mortality
Death within 6 weeks of the initial episode of bleeding.
NATURAL HISTORY OF VARICES IN CIRRHOSIS
Development of varices
The rise in portal pressure is associated with the development
of collateral circulation, which allows the portal blood to be
diverted into the systemic circulation. These spontaneous shunts
occur (a) at the cardia through the intrinsic and extrinsic gastro-
oesophageal veins; (b) in the anal canal where the superior
haemorrhoidal vein belonging to the portal system anastomoses
with the middle and inferior haemorrhoidal veins which belong
to the caval system; (c) in the falciform ligament of the liver
through the para-umbilical veins, which are the remains of the
umbilical circulation of the fetus; (d) in the abdominal wall and
the retroperitoneal tissues, from the liver to the diaphragm,
veins in the lienorenal ligament, in the omentum and lumbar
veins; and (e) blood diversion from the diaphragm, gastric, pan-
creatic, splenic, and adrenal veins, which may drain into the left
renal vein.
Numerous lines of evidence suggest that varices develop and
enlarge with time. Christensen et al18 followed up a cohort of
532 patients with cirrhosis and showed that the cumulative inci-
dence of patients with varices increased from 12% to 90% over
12 years. In a study involving 80 patients followed up for
16 months, Cales and Pascal19 showed that 20% of patients
who did not have varices developed new varices and 42% of
patients with small varices showed definite enlargement. Czaja
et al20 also showed that the prevalence of varices increased from
8% to 13% over 5 years in a cohort of patients with chronic
active hepatitis even though they were treated with prednisol-
one. Merli et al,21 in a study of 213 patients with cirrhosis with
no or small varices, demonstrated that the annual progression of
varices was 12%. A recent database analysis by D’Amico et al22
1685
 Guidelines
using a competing risk model showed that the cumulative inci-
dence of varices at 10 and 20 years was 44% and 53%, respect-
ively, suggesting an overestimation in previous studies not using
a competing risk model.
The main factors that appear to determine the development
of varices are continued hepatic injury, the degree of portosyste-
mic shunting, endoscopic appearances and portal pressure.
Evidence for the role of hepatic injury is derived from studies in
which varices were shown to regress with time. Baker et al23 fol-
lowed up a cohort of 115 patients with oesophageal varices and
showed that varices had disappeared in nine patients, regressed
in seven and remained unchanged in six. They concluded that
the disappearance and regression of varices might be related to
abstinence from alcohol. This observation was confirmed in a
study by Dagradi24 who followed up a cohort of patients with
alcoholic cirrhosis over 3 years and showed a reduction in vari-
ceal size in 12 of the 15 patients with alcoholic cirrhosis who
stopped drinking and an enlargement in variceal size in 17
patients who continued to drink. On the other hand, Cales and
Pascal19 showed that regression of varices occurred in 16% of
patients with alcoholic cirrhosis who continued to imbibe
alcohol. This might be related to the development of large por-
tosystemic collaterals, which decompress the portal system and
reduce the risk of the development of large oesophageal varices.
The degree of portosystemic shunting can be quantified by
measuring the diameter of portal veins and collaterals, and can
be significant in those with gastrorenal or splenorenal shunt-
ing.25 26 Others have shown that the presence of alcoholic cir-
rhosis, Child’s B or C cirrhosis and red whale signs on index
endoscopy predicted progression of varices.21 Groszmann
et al27 in a placebo-controlled randomised trial of timolol in
213 cirrhotic patients without varices showed that a baseline
hepatic venous pressure gradient (HVPG) of >10 mm Hg or a
≥10% increase in HVPG during follow-up were both predictive
of the development of varices.
Diagnosis of gastro-oesophageal varices
Until recently, endoscopy has been used exclusively to diagnose
varices. Non-invasive methods of screening for varices include
capsule endoscopy, transient elastography and use of laboratory
and radiological findings.
Endoscopy
There is universal acceptance that endoscopy is the ‘gold stand-
ard’ for diagnosing gastro-oesophageal varices. The main limita-
tions are intraobserver variability in the diagnosis of small or
grade I oesophageal varices (figure 1A–C). Recently, unsedated
nasal gastroscopy has been found to have similar accuracy to
conventional endoscopy and has the advantage of tolerability
and potential cost saving since it can be performed in the clinic
setting in some institutions.28 29 However, there are no con-
trolled studies and banding of varices is not possible.
Figure 1 (A) Grade I oesophageal
varices. These collapse to inflation of
the oesophagus with air. (B) Grade II
oesophageal varices. These are varices
between grades 1 and 3. (C) Grade III
oesophageal varices. These are large
enough to occlude the lumen.
1686
Capsule endoscopy
Capsule endoscopy uses a 26 mm pill-shaped device which
transmits video footage which is stored and later analysed.
Patients are not sedated, but patient cooperation is essential.
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In a large study by de Franchis et al,30 capsule endoscopy was
compared with standard gastroscopy. The primary end point of
90% or greater concordance was not achieved. Lapalus et al,31
in a prospective study of 120 patients, demonstrated similar
results with capsule endoscopy. Therefore, capsule endoscopy
cannot be considered an alternative to standard endoscopy,
although may have a role in patient who refuse gastroscopy.
Transient elastography
Transient elastography ((FibroScan, Echosens, Paris, France) uses
the principles of ultrasound to derive tissue stiffness by measur-
ing the speed of propagation of a low-frequency wave, which
then correlates with liver fibrosis. Vizzutti et al32 in a study of
61 patients with hepatitis C showed a sensitivity for prediction
of oesophageal varices of 90% using a threshold 17.6 kPa.
However, specificity was poor at 43%. A study of 298 patients
found the optimal cut-off point for the prediction of oesopha-
geal varices was 21.5 kPa (sensitivity 76% and specificity
78%).33 In one uncontrolled study the use of transient elasto-
graphy was found to be as effective as HVPG at predicting
portal hypertension-related complications.34 Therefore, the role
of transient elastography in predicting varices is controversial
due to the lack of consistent results and controlled studies. This
modality may be more useful for predicting decompensation in
patients with cirrhosis.
Radiological and serum parameters.
A prospective study of 311 patients with chronic hepatitis C
showed that a platelet-to-spleen size ratio with a threshold of
909 had positive and negative predictive values of 100% and
94%, respectively.35 These good results have not been repro-
duced by others as demonstrated in a meta-analysis.36
Risk factors for first variceal bleeding
The factors that predispose to, and precipitate, variceal haemor-
rhage are still not clear. The suggestion that oesophagitis may
precipitate variceal haemorrhage has been discarded.37
Presently, the most important factors that have been held
responsible include (i) pressure within the varix, (ii) variceal
size, (iii) tension on the variceal wall and (iv) severity of the
liver disease.
Portal pressure
In most cases, portal pressure reflects intravariceal pressure38
and a HVPG >10 mm Hg is necessary for the development of
oesophageal varices.27 There is no linear relationship between
the severity of portal hypertension and the risk of variceal
haemorrhage, although HVPG >12 mm Hg is an accepted
Tripathi D, et al. Gut 2015;64:1680–1704. doi:10.1136/gutjnl-2015-309262

threshold for variceal bleeding.39 40 However, the HVPG tends
to be higher in bleeders as well as in patients with larger varices.
In a prospective study comparing propranolol with placebo for
the prevention of first variceal haemorrhage, Groszmann et al41
showed that bleeding from varices did not occur if the portal
pressure gradient (PPG) could be reduced to <12 mm Hg.
Others have shown that a 20% reduction in portal pressure pro-
tects against further bleeding.42 These haemodynamic goals
have been accepted as the aim of pharmacological treatment of
portal hypertension. It is important to appreciate that gastric
varices can bleed at pressures <12 mm Hg, and the influence of
wall tension of the varix plays a greater role in the risk of bleed-
ing.43 A greater pressure reduction may be necessary to protect
against bleeding. This is further discussed in the section ‘Gastric
varices’. At present, measurement of portal pressure in guiding
pharmacological treatments is limited to clinical trials in the UK.
Variceal size
Variceal size is best assessed endoscopically (figure 1A–C).
Published results are variable owing to the lack of a definition dis-
tinguishing between large and small varices. Small (grade I)
varices tend to be narrow and flatten easily with air, whereas
larger (grade 2 and 3) varices are usually broader and flatten with
difficulty, if at all. Numerous studies40 44 have shown that the
risk of variceal haemorrhage increases with the size of varices.45
Variceal wall and tension
Polio and Groszmann46 using an in vitro model showed that
rupture of varices was related to the tension on the variceal
wall. The tension depends on the radius of the varix. In this
model, increasing the size of the varix and decreasing the thick-
ness of the variceal wall caused variceal rupture. Recently, endo-
scopic ultrasound and manometry have been used to estimate
wall tension of varices.47
Endoscopic features such as ‘red spots’ and ‘whale’ markings
were first described by Dagradi.24 They have been described as
being important in the prediction of variceal haemorrhage.
These features represent changes in variceal wall structure and
tension associated with the development of microtelangiectasias
and reduced wall thickness. In a retrospective study by the
Japanese Research Society for Portal Hypertension, Beppu
et al48 showed that 80% of patients who had blue varices or
cherry red spots bled from varices, suggesting that this was an
important predictor of variceal haemorrhage in cirrhosis.
Severity of liver disease and bleeding indices
Two independent groups prospectively assessed factors predict-
ing first variceal haemorrhage in cirrhosis (table 2). The North
Italian Endoscopic Club (NIEC)49 reported their findings in
1988, followed in 1990 by data from the Japanese.50 Both these
studies showed that the risk of bleeding was based on three
factors: severity of liver disease as measured by Child class, vari-
ceal size and red wale markings. The NIEC study showed a
wide range for the risk of bleeding of 6–76%, depending on the
presence or absence of the different factors. Using the same vari-
ables the NIEC index was simplified by de Franchis et al51 and
shown to correlate with the original index. Further studies
showed that the HVPG and intravariceal pressure were also
independent predictors of first variceal haemorrhage when ana-
lysed in conjunction with the NIEC index.52 53
In summary, the most important factors that determine the risk of
variceal haemorrhage are the severity of liver disease, size of varices,
and presence of red signs. Measurement of HVPG is a useful guide
for selection of patients for treatment and their response to
Tripathi D, et al. Gut 2015;64:1680–1704. doi:10.1136/gutjnl-2015-309262
Guidelines
Table 2 Scoring systems for quantifying the severity of cirrhosis
Severity of liver disease can be described using the Child–Pugh
score or MELD score.
Gut: first published as 10.1136/gutjnl-2015-309262 on 17 April 2015. Downloaded from http://gut.bmj.com/ on June 3, 2020 by guest. Protected by copyright.
The Child–Pugh score is the sum of severity scores for Child class,
variceal size and red wale markings the variables shown below.
Category 1 2 3
Encephalopathy 0 I/II III/IV
Ascites Absent Mild-moderate Severe
Bilirubin (μmol/L) <34 34–51 >51
Albumin (g/L) >35 28–35 <28
INR <1.3 1.3–1.5 >1.5
Child–Pugh class A represents a score of ≤6, class B a score of 7–9, and class C, ≥10.
The MELD score is a formula that includes three laboratory-based variables reflecting
the severity of liver disease. It was originally used to predict the short-term mortality
after placement of a transjugular intrahepatic portosystemic stent-shunt for variceal
bleeding. Subsequently, it has been used in selecting candidates for liver
transplantation.
MELD score: please use the online calculator https://www.esot.org/Elita/meldCalculator.
aspx.
INR, international normalised ratio.
treatment, although the predictive value does not appear to
improve on the NIEC index and presence of red whale marking.54
Risk and mortality of first variceal bleed
Data describing the overall risk of bleeding from varices must be
viewed with caution and have some pitfalls in interpretation.
The natural history of patients who have varices that are diag-
nosed as part of their baseline investiations is different from
that of patients who have complications of liver disease such as
ascites and encephalopathy. Most studies do not comment on
either the severity of liver disease or whether patients with alco-
holic cirrhosis are continuing to drink. Both these factors have a
significant effect on the risk of variceal haemorrhage.
Most studies report bleeding from varices in about 20–50%
of patients with cirrhosis during the period of follow-up. Baker
et al23 reported variceal bleeding in 33 of 115 patients that they
followed up for a mean of 3.3 years, with a mortality of 48%
from the first variceal haemorrhage. These data were confirmed
by Christensen et al.18 About 70% of the episodes of bleeding
occur within 2 years of diagnosis. Recent studies demonstrate a
dramatic reduction in mortality following variceal bleeding of
20% 6-week mortality55 and 15% in-hospital mortality,5 with
contributions from improved endoscopic, pharmacological and
radiological therapies, notably TIPSS. Intensive care treatment
has also improved, with outcomes being particularly good for
those requiring minimal organ support.
Analysis of the non-active treatment arms in the primary
prophylaxis trials comparing propranolol with placebo show
results similar to those of the primary prophylaxis shunt trials,
with most episodes of bleeding occurring within the first 2 years
of follow-up. In these studies the rate of first variceal haemor-
rhage ranged from 22% to 61%.56–60 This large difference in
the rate of first bleed relates almost certainly to the number of
patients with severe liver disease included in the study (Pascal,
Child C—46%, bleeding—61%; Italian Multicenter Project for
Propranolol in Prevention of Bleeding (IMPP), Child C—6%,
bleeding—32%; Conn, Child C—6%, bleeding—22%).
Mortality varied from 24% to 49% over 2 years (Pascal, mortal-
ity—49%; IMPP, mortality—24%; Conn, mortality—24%).
Primary prophylaxis
Since 30–50% of patients with portal hypertension will bleed
from varices and about 20% will die from the effects of the first
1687
 Guidelines
bleed, it seems rational to develop prophylactic regimens to
prevent the development of, and bleeding from, these varices.
However, most of the published trials do not have sufficient
power to identify favourable treatment effects. Based on the
expected bleeding and death rates in the control group, the
minimum number of patients needed to detect a 50% reduction
in bleeding would be 270, and 850 patients in each arm to
detect the same reduction in mortality. A proposed algorithm
for surveillance and prophylaxis of varices is shown in figure 2.
At this time there is insufficient evidence to support treating
patients without varices or ‘pre-primary prophylaxis’. A large
randomised placebo-controlled trial of timolol in patients
without varices and portal hypertension defined as HVPG
>6 mm Hg did not show any effect on the development of
varices or variceal bleeding.27 The role of drug treatment in pre-
venting bleeding in patients with small varices is unclear. Three
randomised placebo-controlled trials have studied this. Cales
et al61 showed that propranolol in patients with small, or no,
varices resulted in greater development of varices. However,
patients without varices were included and there was significant
loss of patients to follow-up. The second trial showed that
nadolol reduced variceal bleeding without survival benefit and
increased adverse events.62 Sarin et al63 did not show any effect
with propranolol, despite a significant effect on portal pressure.
Surgery
Portacaval shunts
Four trials of portacaval shunts have been published, which ran-
domised a total of 302 patients64–67 either to prophylactic shunt
surgery or to non-active treatment. A meta-analysis of these
studies showed a significant benefit in the reduction of variceal
bleeding (OR=0.31, 95% CI 0.17 to 0.56) but also a signifi-
cantly greater risk of hepatic encephalopathy (OR=2, 95% CI
1.2 to 3.1) and mortality (OR=1.6, 95% CI 1.02 to 2.57) in
patients treated with shunt surgery.68 At this time, there is no
evidence for the use of TIPSS for primary prophylaxis.1
Figure 2 Algorithm for surveillance of varices and primary prophylaxis in cirrhosis.
*– If there is clear evidence of disease progression this interval can be modified by clinician. Endoscopy should also be offered at time of
decompensation.
1688
Devascularisation procedures
Inokuchi50 showed that there was a significant reduction in vari-
ceal bleeding and in mortality in patients treated with a variety
of devascularisation procedures. There are, however, numerous
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problems with the interpretation of this study because of the
use of different procedures in each of the 22 centres. These
results require confirmation.
Pharmacological treatment
Non-cardioselective β blockers
The mainstay of the pharmacological approach to the primary
prophylaxis of variceal haemorrhage has been NSBB.
Propranolol which has been shown to reduce the PPG, reduce
azygos blood flow, and also variceal pressure. It achieves this by
causing splanchnic vasoconstriction and reducing cardiac
output. There is no clear dose-related reduction in HVPG or
correlation of HPVG reduction with reduction in heart rate.69
Observational studies have shown that a 10–12% reduction in
HVPG after acute administration of propranolol was associated
with reduced bleeding and hepatic decompensation.54 70
However, HVPG monitoring is not routinely available in most
centres outside of larger institutions. A meta-analysis of nine
placebo-controlled randomised trials (964 patients) showed that
the pooled risk difference for bleeding was −11% (95% CI
−21% to −1%), and for death was −9% (95% CI −18% to
−1%) in favour of propranolol.71
Nadolol exerts similar effects on portal haemodynamics,
although the effect on blood pressure may not be as pro-
nounced. Two placebo-controlled trials58 59 have shown
reduced bleeding, although in one study this was only seen on
per protocol analysis.59 There was no effect on overall survival.
Carvedilol is a NSBB like propranolol, and a vasodilator due
to α1 receptor blockade. The latter reduces portocollateral
resistance, and by actions on hepatic stellate cells leads to a
reduction in intrahepatic resistance. Haemodynamic studies
demonstrate a greater reduction in portal pressure with
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carvedilol than with propranolol, although blood pressure is
reduced.72 73 The optimum dose is 6.25–12.5 mg/day.74 Higher
doses are not more effective and are associated with more
adverse events—in particular, hypotension. Carvedilol at a dose
of 12.5 mg/day at current UK prices is considerably cheaper
than propranolol 40 mg twice a day and nadolol 80 mg/day
(monthly cost, £1.20, £5.62 and £5, respectively). Two RCTs of
carvedilol versus variceal band ligation (VBL) in primary
prophylaxis have been published.75 76 The first study75 showed
significantly reduced bleeding in the carvedilol arm (10% vs
23%, relative hazard 0.41; 95% CI 0.19 to 0.96), with no effect
on survival. The second trial by Shah et al76 did not show any
differences in bleeding or mortality. Compliance with VBL was
better in the latter trial, and unlike the first trial, there were sig-
nificantly more patients with viral hepatitis than alcoholic cir-
rhosis. A further study74 assessed the effect of carvedilol in
patients who were haemodynamic non-responders to propran-
olol, where haemodynamic response was defined as HVPG
reduction to ≤12 mm Hg or by >20% of baseline after 4 weeks
of treatment. Patients who were haemodynamic non-responders
or intolerant to carvedilol were treated with VBL. Carvedilol
resulted in significantly lower variceal bleeding compared with
VBL, and haemodynamic responders to carvedilol or propran-
olol had significantly lower mortality than those treated with
VBL. It is worth noting that the study was not randomised.
There have been recent suggestions based on low-level evi-
dence that NSBB may result in a poorer outcome in patients
with cirrhosis and refractory ascites.77 The ‘window hypothesis’
for β blockers in cirrhosis has also recently been described, sug-
gesting that NSBB are helpful in the compensated and early
decompensated cirrhotic period, but may not be helpful in very
early cirrhosis, such as in a patient with no varices, and may be
harmful in patients with end-stage cirrhosis with refractory
ascites.78 However, recent large observational studies question
the last hypothesis, with improved survival seen in patients with
refractory ascites treated with NSBB,79 unless patients have an
episode of spontaneous bacterial peritonitis.80 Therefore, until
there are further prospective controlled studies, NSBB should be
continued in patients with refractory ascites. The clinician must
carefully monitor haemodynamic parameters such as blood pres-
sure, and discontinue NSBB in patients with hypotension and
renal impairment as can occur after an episode of spontaneous
bacterial peritonitis. Other potentially severe adverse events
with NSBB include symptomatic bradycardia, asthma and
cardiac failure. Less severe side effects such as fatigue, insomnia
and sexual dysfunction may also result.
Isosorbide mononitrate
Interest in the use of vasodilators such as isosorbide mononitrate
(ISMN) developed after the demonstration that it reduces portal
pressure as effectively as propranolol,81 but has subsequently
waned. A trial comparing ISMN with propranolol showed no
significant difference between these agents.82 Another rando-
mised trial of ISMN versus placebo did show any difference in
the two arms.83 Therefore, ISMN is not recommended as
monotherapy in primary prophylaxis.
β Blocker and ISMN
The combination of nadolol and ISMN has been compared with
nadolol in a RCT. The combination therapy reduced the fre-
quency of bleeding significantly but no significant differences
were detected in mortality.84 However, Garcia-Pagan et al85 in a
double-blind RCT of propranolol plus ISMN versus propranolol
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Guidelines
plus placebo failed to show any differences between the two
arms. Combination therapy is associated with more side effects.
Proton pump inhibitors
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A placebo-controlled randomised trial reported reduced bleed-
ing and mortality with rabeprazole after eradication of varices.86
However, the study had a heterogeneous population with VBL
performed for both primary and secondary prophylaxis and
small numbers (n=43), limiting the validity of the conclusions.
Furthermore, there was no arm comparing proton pump inhibi-
tors with NSBB. The use of proton pump inhibitors in patients
with cirrhosis and ascites was associated with increased risk of
spontaneous bacterial peritonitis in a large retrospective study.87
This was not confirmed in a larger prospective non-randomised
study.88 However, a recent prospective observational study has
shown proton pump use to be associated with increased mortal-
ity in cirrhosis.89 Proton pump inhibitors are also associated
with increased risk of Clostridium difficile infection.90 There
remains continuing concern about proton pump inhibitors in
patients with cirrhosis, therefore caution should be used.
Endoscopic therapy
Variceal band ligation
VBL has been compared with NSBB in 19 trials in a recent
Cochrane meta-analysis of 1504 patients.91 Despite reduced
bleeding (RR=0.67, 95% CI 0.46 to 0.98) with VBL, there was
no difference in overall mortality and bleeding-related mortality.
The difference in bleeding was not seen when only trials with
low selection or attrition bias were included. Banding can have
serious complications. The risk of fatal banding-induced bleed-
ing was highlighted in a meta-analysis showing reduced fatal
adverse events with NSBB (OR=0.14, 95% 0.02 to 0.99).92
The optimal timing of banding intervals is discussed in the
section ‘Secondary prophylaxis of variceal haemorrhage’. A ran-
domised trial of 96 patients who underwent endoscopic surveil-
lance at 6 or 3 months after eradication of varices with VBL did
not demonstrate a difference in bleeding on mortality.93
However, the trial had a heterogeneous study group of patients
who underwent VBL both for primary (65%) and secondary
prevention (35%).
Sclerotherapy
Nineteen trials have compared endoscopic variceal sclerotherapy
with no treatment.68 Owing to the marked heterogeneity
between these studies a meta-analysis is clinically inappropri-
ate.68 Sclerotherapy does not offer any benefit in combination
with NSBB or VBL compared with VBL or NSBB alone, and
increases iatrogenic complications such as strictures.94–96 At this
time sclerotherapy cannot be recommended for prophylaxis of
variceal haemorrhage in patients with cirrhosis.
Recommendations: primary prophylaxis of variceal haemor-
rhage in cirrhosis (figure 2)
1. What is the best method for primary prophylaxis?
1.1. We recommend NSBB or variceal band ligation (VBL).
We suggest pharmacological treatment with propranolol
as first line. VBL is offered if there are contraindications
to NSBB. The choice of VBL or NSBB should also take
into account patient choice (level 1a, grade A).
1.2. We suggest carvedilol or nadolol as alternatives to pro-
pranolol (level 1b, grade A).
1.3. Dose:
1.3.1. Propranolol: 40 mg twice daily. Dose titrated to
maximum tolerated or once heart rate (HR) of
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 Guidelines
50–55 bpm is reached to a maximum dose of
320 mg (level 1a, grade A).
1.3.2. Nadolol: 40 mg daily dose. Dose titrated to
maximum tolerated or once HR of 50–55 bpm is
reached a maximum dose of 240 mg (level 1a,
grade A).
1.3.3. Carvedilol: 6.25 mg once daily to increase to
maintenance of 12.5 mg after a week if tolerated
or once HR of <50–55 bpm is reached (level 1a,
grade A).
1.3.4. It is suggested that NSBB are discontinued at the
time of spontaneous bacterial peritonitis, renal
impairment and hypotension (level 2b, grade B).
1.4. In cases of contraindications or intolerance to NSBB, we
recommend variceal band ligation (level 1a, grade A).
2. Who should have surveillance for variceal bleeding?
2.1. We recommend all patients with cirrhosis should be
endoscoped at the time of diagnosis (level 1a, grade A).
There is no indication to repeat endoscopy in patients
receiving NSBB.
3. How often should cirrhotic patients be endoscoped?
3.1. If at the time of first endoscopy no varices are seen, we
suggest that patients with cirrhosis should be endos-
coped at 2–3-year intervals (level 2a, grade B).
3.2. If grade I varices are diagnosed, we suggest that patients
should be endoscoped at yearly intervals (level 2a,
grade B).
3.3. If there is clear evidence of disease progression we
suggest that the intervals can be modified by a clinician.
Endoscopy should also be offered at time of decompen-
sation (level 2a, grade B).
4. Which patients with cirrhosis should have primary
prophylaxis?
4.1. If grade I varices and red signs or grade 2–3 varices are
diagnosed, we recommend that patients have primary
prophylaxis irrespective of the severity of the liver
disease (level 1a, grade A).
5. Treatments not recommended:
5.1. Proton pump inhibitors are not recommended unless
otherwise required for peptic ulcer disease (level 1b,
grade B).
5.2. Isosorbide mononitrate monotherapy is not recommended
as primary prophylaxis (level 1b, grade A). There is insuffi-
cient evidence to recommend isosorbide mononitrate in
combination with NSBB (level 1b, grade A).
5.3. Shunt surgery or TIPSS is not recommended as primary
prophylaxis (level 1a, grade A).
5.4. Sclerotherapy is not recommended as primary prophy-
laxis (level 1a, grade A).
6. Areas requiring further study:
6.1. Role of NSBB in patients without varices, with focus on
carvedilol.
6.2. Role of NSBB in patients with small varices, with focus
on carvedilol.
6.3. Comparison of carvedilol versus propranolol in primary
prophylaxis.
6.4. Identification of, and trials assessing, new drugs for
primary prophylaxis such as statins.
7. Quality indicator:
7.1. Percentage of patients at diagnosis of cirrhosis who have
had an endoscopy to screen for varices (level 1a,
grade A).
Numerator; patients diagnosed with cirrhosis who have
had an endoscopy either before or after diagnosis within
1690
6 months.
Denominator; patients newly diagnosed with cirrhosis.
7.2. Percentage of patients receiving primary prophylaxis
among those newly diagnosed with grade I varices and
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red signs or grade 2–3 varices.
Numerator; patients who have grade 1 varices with red
signs or grade 2–3 varices receiving primary prophy-
laxis.
Denominator; patients diagnosed with cirrhosis who
have grade I varices with red signs or grade 2–3 varices.
MANAGEMENT OF ACTIVE VARICEAL HAEMORRHAGE
The average 6-week mortality of the first episode of variceal
bleeding in most studies is reported to be up to 20%. There has
been considerable improvement in survival since the early 1980s
when the in-hospital mortality was 40–50%,97 compared with
15% from a recent UK audit.5 Such is the improvement in out-
comes, that a patient with Child’s A cirrhosis is very unlikely to
succumb to an index variceal bleed. Studies have shown the
Child–Pugh score, MELD score, and HVPG to be strong predic-
tors of outcomes.98–103 The MELD score has been shown to
outperform Child’s score in a recent study, with a score >19
associated with 20% 6 week mortality.103 Furthermore, the
MELD score has been shown to perform as well as the trad-
itional intensive care unit scores in predicting mortality in
patients admitted to intensive care in the UK.104 MELD >18,
active bleeding, transfusing >4 units of packed red blood cells
have been shown to be predictors of mortality and early
rebleeding.99 101 102 HVPG has also been shown to predict
outcome when measured at 2 weeks after a bleed,44 and a value
of ≥20 mm Hg when measured acutely within 48 h has been
shown to provide significant prognostic information.100
However, this technique is not used routinely in the manage-
ment of patients around the world, and substitution of clinical
data in the latter study was shown to provide the same clinical
predictive value.100 These scoring systems are not purely aca-
demic; they allow the referring clinician to predict those
patients with a high chance of rebleeding to be transferred to a
specialist centre offering, for instance, TIPSS before the patient
rebleeds.
Nonetheless, probably the most important step in the man-
agement of acute variceal haemorrhage is the initial resuscitation
assessed according to standard ‘ABC’ practice, together with
protection of the airway to prevent aspiration. Although early
endoscopy allows for accurate diagnosis of the bleeding site and
decisions about management (figure 3), therapeutic intervention
in acute variceal bleeding can be initiated, safely in most cases,
before diagnostic endoscopy. As similar efficacy is demonstrated
with pharmacological treatment as with sclerotherapy, the
former should be first-line therapy.99 β Blockade should not be
started in the acute setting, and those already taking β blockers
as prophylaxis should probably stop taking them for 48–72 h in
order that the patient’s physiological response to blood loss can
be allowed to manifest.
General considerations
Patient evaluation
The majority of patients with a variceal bleed will be sufficiently
stable to enable a full history and examination to take place.
History of alcohol excess and or intravenous drug use should be
sought and may become particularly relevant if the patient has
withdrawal symptoms after admission. Comorbidity is important
when estimating risk and deciding on use of vasopressors. The
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Figure 3 Algorithm for the
management of acute variceal
bleeding. TIPSS, transjugular
intrahepatic portosystemic stent shunt.
following risk factors doubled mortality after an acute variceal
bleed in one US study: older age, comorbidities, male gender and
not undergoing a gastroscopy within 24 h.105
A full examination is helpful for the important negatives as
much as the positives. Baseline observations should include the
temperature, as infection is a serious complication with signifi-
cant mortality. Confusion may be present because of encephal-
opathy, intoxication with alcohol or drugs or withdrawal from
alcohol or drugs. The patient should be on continuous BP and
pulse monitor and their haemodynamic status recorded.
An oxygen saturation monitor is helpful. Stigmata of chronic
liver disease and concurrent jaundice provide insight into the
current status of a patient’s liver, and also give warning of
potential further decompensation if significant bleeding persists
(see scoring systems above). Pneumonia must be actively
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excluded. Evidence of ascites requires a diagnostic tap to search
for infection.
Investigations including full blood count, coagulation
profile, liver and renal function and blood group and save and
cross-match. Blood and urine should also be cultured. An ultra-
sound scan later in the admission is helpful to identify subclin-
ical ascites, flow in portal vein and any obvious emergence of an
hepatocellular carcinoma (HCC).
Location of patient
A decision must be made as to where the patient is best managed.
Variceal bleeding is unpredictable, generally occurs in patients
with significant liver disease and is associated with significant mor-
tality. Hence, a high-dependency unit is usually the most appropri-
ate initial location, although a properly staffed ‘gastrointestinal
1691
 Guidelines
bleeding bed’ may be appropriate. If a patient is vomiting blood,
or there is a perceived risk of a haemodynamically unstable patient
having blood in the stomach, then the patient must be intubated
before endoscopy, and return to an intensive care or high-
dependency unit will be necessary until extubation.
Volume resuscitation and blood products
Intravenous access (two 16–18G cannulae) should have been
secured on admission with a reported GI bleed. Further intra-
venous access may be necessary. In patients with poor venous
access, advanced liver disease, or renal failure associated with
their liver disease, central venous access may be helpful with
guiding fluid infusions. However, the drawbacks include the risk
of the procedure and a potential source of infection. Therefore,
there is no absolute requirement for a central line, and no evi-
dence of unequivocal benefit. Intravenous fluid resuscitation
should be initiated with plasma expanders aiming to maintain a
systolic blood pressure of 100 mm Hg. Care with monitoring is
paramount in this group of patients.
Overtransfusion has been shown to have a deleterious effect
on outcome. In a recent single-centre RCT, a restrictive transfu-
sion policy of maintaining haemoglobin between 70 and 80 g/L
improved the control of variceal bleeding (11% vs 22%,
p=0.05), and lowered HVPG compared with a liberal transfu-
sion policy without effect on 45-day survival.106 However, it
should be noted that these results were from a single Spanish
centre, which was a tertiary unit for variceal bleeding, where all
patients underwent endoscopy within 6 h. Nonetheless, a
restrictive transfusion policy has been recommended for some
time1 and there is now good evidence to support not transfusing
a stable patient with a haemoglobin of ≥80 g/L. However, under-
resuscitation should also be avoided and while goal-oriented
fluid replacement has generally not been useful in an intensive
therapy unit setting, a venous saturation >70% remains an easily
measurable target with some evidence to support it.107
Interpretation and management of clotting profile is challen-
ging in liver disease, where there is usually a balanced deficiency
of both procoagulant and anticoagulant factors.108 The NICE
guidelines recommend activation of a hospital’s massive transfu-
sion policy when there is major haemorrhage, and platelet
support when the value is <50, and clotting factor support
when the international normalised ratio (INR) is >1.5 times
normal.2 There is no evidence for the use of ‘prophylactic’ clot-
ting or platelet support to reduce the risk of rebleeding. There
is insufficient evidence to support the routine use of transexamic
acid, or recombinant factor VIIa.109
Pharmacological treatment
The two major classes of drugs that have been used in the
control of acute variceal bleeding are vasopressin or its analo-
gues (either alone or in combination with nitroglycerine) and
somatostatin or its analogues. Terlipressin is the only agent that
has been shown to reduce mortality in placebo-controlled trials.
However, in trials comparing terlipressin, somatostatin and
octreotide, no difference in efficacy was identified in a system-
atic review110 and in a recent large RCT.111 Prophylactic anti-
biotics can result in a similar survival benefit following acute
variceal bleeding.
Vasopressin
Vasopressin reduces portal blood flow, portal systemic collateral
blood flow and variceal pressure. It does, however, have signifi-
cant systemic side effects such as an increase in peripheral resist-
ance, and reduction in cardiac output, heart rate and coronary
1692
blood flow. In comparison with no active treatment, the pooled
results of four randomised trials showed that it reduced failure
to control variceal bleeding (OR=0.22, 95% CI 0.12 to 0.43),
although survival was unaffected.68 Meta-analysis of five trials
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comparing sclerotherapy with vasopressin has shown a signifi-
cant effect on reduction in failure to control bleeding
(OR=0.51, 95% CI 0.27 to 0.97), with no effect on survival.68
Vasopressin with nitroglycerine
The addition of nitroglycerine enhances the effect of vasopres-
sin on portal pressure and reduces cardiovascular side effects.112
Meta-analysis of three randomised trials comparing vasopressin
alone with vasopressin and nitroglycerine showed that the com-
bination was associated with a significant reduction in failure to
control bleeding (OR=0.39, 95% CI 0.22 to 0.72), although no
survival benefit was shown.68
Terlipressin
Terlipressin is a synthetic analogue of vasopressin, which has an
immediate systemic vasoconstrictor action followed by portal
haemodynamic effects due to slow conversion to vasopressin. In
a Cochrane meta-analysis of seven placebo-controlled trials, ter-
lipressin was shown to reduce failure to control bleeding
(RR=0.66, 95% CI 0.55 to 0.93) and also to improve survival
(RR=0.66, 95% CI 0.49 to 0.88).113 In the same meta-analysis,
there was no difference between terlipressin versus vasopressin,
balloon tamponade or endoscopic therapy in failure to control
bleeding or survival.113 The role of terlipressin in combination
with VBL is explored in the section ‘Endoscopic therapy in
combination with pharmacological therapy’.
The recommended dose of terlipressin is 2 mg IV every 4 h,
although many units reduce the dose to 6 hourly as it may cause
peripheral vasoconstriction which manifests as painful hands
and feet. While 5 days of IV treatment has been advocated in
the Baveno V guidelines,1 this prolonged treatment has not
been shown to have a survival benefit, and for pragmatic
reasons many units will stop treatment shortly after satisfactory
haemostasis. In a randomised trial terlipressin given for 24 h
after satisfactory haemostasis with VBL after oesophageal vari-
ceal bleeding was as effective as 72 h of treatment.114
In patients intolerant of terlipressin or in countries where ter-
lipressin is not available, alternatives should be considered.
Somatostatin and octreotide
Somatostatin causes selective splanchnic vasoconstriction and
reduces portal pressure and portal blood flow.115 Octreotide is a
somatostatin analogue. The mechanism of action of these two
agents is not clear. Inhibition of glucagon increases vasodilatation
rather than a direct vasoconstrictive effect and post-prandial gut
hyperaemia is also reduced. The actions of octreotide on hepatic
and systemic hemodynamics are transient, making continuous
infusion necessary. Octreotide is given as a 50 μg bolus followed
by an infusion of 25–50 μg/h. Somatostatin is given as a 250 mg
intravenous bolus followed by an infusion of 250 mg/h.
Somatostatin and octreotide have been shown to be as
effective as terlipressin in acute variceal bleeding in a
meta-analysis.110 Seo et al111 in a large RCT of 780 patients com-
paring these three agents failed to show a difference in treatment
success (range 83.8–86.2%), rebleeding (range 3.4–4.4%) and
mortality (range 8–8.8%). A low systolic blood pressure at pres-
entation, high serum creatinine level, active bleeding in the emer-
gency endoscopy, gastric variceal bleeding and Child–Pugh grade
C were independent factors predicting 5-day treatment
failure.111
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Antibiotics
Antibiotics that provide Gram-negative cover are one of the inter-
ventions which positively influence survival in variceal haemor-
rhage as shown in a Cochrane meta-analysis of 12
placebo-controlled trials (RR=0.79, 95% CI 0.63 to 0.98).116
Antibiotics were also shown to reduce bacterial infections
(RR=0.43, 95% CI 0.19 to 0.97) and early rebleeding (RR=0.53,
95% CI 0.38 to 0.74).116 Therefore, short-term antibiotics should
be considered standard practice in all cirrhotic patients who have a
variceal bleed, irrespective of the presence of confirmed infection.
Third-generation cephalosporins, such as ceftriaxone (1 g IV,
daily), have been shown to be more effective at reducing
Gram-negative sepsis than oral norfloxacin,117 but choice of anti-
biotics must be dictated by local resistance patterns and availability.
Proton pump inhibitors
One RCT compared a short course of proton pump inhibitors
with vasoconstrictor therapies after haemostasis in acute variceal
bleeding.118 Despite larger ulcers noted in the vasoconstrictor
arm, there were no differences in bleeding or survival. Nearly
50% of patients had ascites, which might have implications in
light of the reports of increased incidence of spontaneous bac-
terial peritonitis as mentioned earlier.
Endoscopic therapy
Endoscopy should take place within 24 h of admission and
earlier if there is excessive bleeding, based on low-level evi-
dence.105 While many guidelines and reviews suggest that
endoscopy should be carried out within 12 h the only study that
examined the influence of timing on outcome failed to demon-
strate any advantage of endoscopy before 12 h.119 The optimal
time is after sufficient resuscitation, and pharmacological treat-
ment, with the endoscopy performed by a skilled endoscopy
team, in a suitably equipped theatre environment and with
airway protection. Airway protection is essential where risk of
aspiration is high, and affords the endoscopist time for thorough
evaluation, including complete clot aspiration and controlled
application of treatment, including tamponade if required. The
endoscopy team must comprise an experienced endoscopy
nurse acquainted with the equipment necessary for endoscopy
therapy of varices, and a skilled endoscopist, competent in using
banding devices and deployment of balloon tamponade.
Variceal band ligation
This technique is a modification of that used for the elastic band
ligation of internal haemorrhoids. Its use in humans was first
described in 1988.120 A meta-analysis of seven trials comparing
VBL with sclerotherapy in acute bleeding showed that VBL
reduced rebleeding from varices (OR=0.47, 95% CI 0.29 to
0.78), reduced mortality (OR=0.67, 95% CI 0.46 to 0.98) and
resulted in fewer oesophageal strictures (OR=0.10, 95% CI
0.03 to 0.29).121 The number of sessions required to obliterate
varices was lower with VBL (2.2 fewer sessions (95% CI 0.9
to 3.5)).
Sclerotherapy
Sclerotherapy has been replaced by VBL and should no longer
be offered as standard of care in acute variceal haemorrhage.
Other endoscopic measures
In an RCT, cyanoacrylate offered no benefit over VBL, with the
additional risk of embolisation and trend towards increased
rebleeding with cyanoacrylate.122
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Guidelines
Haemostatic powder (TC-325; Hemospray; Cook Medical,
USA) has been described in a small study of nine patients who
received endoscopic spray treatment for acute variceal bleeding.
The study reported no rebleeding within 24 h and no mortality
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at 15 days.123
Endoscopic therapy in combination with pharmacological therapy
The role of combining vasoactive drugs with endoscopic
therapy (VBL or sclerotherapy) was reported in a meta-analysis
of eight trials.124 Combination therapy resulted in better initial
control of bleeding (RR=1.12, 95% CI 1.02 to 1.23), and
5-day haemostasis (RR=1.28, 95% CI 1.18 to 1.39), without
any difference in survival. Adverse events were similar in both
groups. Two RCTs have compared VBL with sclerotherapy in
combination with vasoactive agents in acute variceal bleed-
ing.125 126 Lo et al125 used vasopressin and found that VBL
resulted in better 72 h haemostasis (97% vs 76%, p=0.009),
with fewer complications (5% vs 29%, p=0.007). Villanueva
et al used somatostatin, and reported lower failure to control
acute bleeding with VBL (4% vs 15%, p=0.02), with fewer
serious complications (4% vs 13%, p=0.04). Overall survival
was similar in both trials.125 126
Balloon tamponade
Balloon tamponade is highly effective and controls acute bleed-
ing in up to 90% of patients although about 50% rebleed when
the balloon is deflated.127 128 It is, however, associated with
serious complications such as oesophageal ulceration and aspir-
ation pneumonia in up to 15–20% of patients. Despite this, it
may be a life-saving treatment in cases of massive uncontrolled
variceal haemorrhage pending other forms of treatment. An
appropriately placed Sengstaken–Blakemore tube allows for
resuscitation, safe transportation and either repeat endoscopy or
radiological shunting in a patient with a stable cardiovascular
system. The oesophageal balloon is rarely required, must never
be used on its own and should be used only if there is continu-
ing bleeding despite an adequately inflated gastric balloon cor-
rectly placed and with appropriate tension. Placement of the
tube endoscopically or over a guide wire might reduce the risk
of complications, especially oesophageal rupture.
Removable oesophageal stents
The SX-Ella Danis stent (ELLA-CS, Hradec Kralove, Czech
Republic) is a removable covered metal mesh stent placed endo-
scopically in the lower oesophagus without radiological screen-
ing. It has no role in the management of gastric variceal
bleeding. These stents can be left in situ for up to 2 weeks
unlike the Sengstaken–Blakemore tube which should be
removed after a maximum of 24–48 h.129 130 No published con-
trolled trials have compared this modality with balloon
tamponade.
Transjugular intrahepatic portosystemic stent-shunt
Several uncontrolled studies have examined the role of salvage
bare TIPSS in acute variceal bleeding. In a review of 15 studies,
control of bleeding was achieved in 90–100%, with rebleeding
in 6–16%.131 Mortality varied between 75% (in hospital) and
15% (30 day). It is important to appreciate that sclerotherapy
was used as first-line endoscopic therapy in most of these
studies. Long-term follow-up of a study that compared TIPSS
with H-graft portacaval shunts in patients for whom non-
operative management had failed suggested that H-grafts were a
useful method of reducing portal pressure and had a signifi-
cantly lower failure rate ( p=0.04), but had no significant
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improvement in overall survival despite a benefit seen in Child’s
A and B disease.132 A recent RCT compared emergency porto-
caval surgery with bare TIPSS within 24 h of presenting with
acute oesophageal variceal bleeding in unselected cirrhotic
patients. Emergency portocaval surgery resulted in better out-
comes for long-term bleeding control, encephalopathy and sur-
vival ( p<0.001).133 Before wider application of surgery for
acute variceal bleeding, more data are needed in light of the
recent adoption of covered stents.
There has also been a generalised established change in prac-
tice in using covered TIPSS stents ( polytetrafluoroethylene
(PTFE)) rather than a bare metal stent, with evidence to support
this change. In randomised controlled studies, these stents were
shown to have higher primary patency rates than bare stents,
without significant differences in survival, and the potential for
reduced incidence of hepatic encephalopathy.134 135
There is, however, growing evidence from two RCTs for the
earlier use of TIPSS in selected patients stratified by HVPG,
Child–Pugh class and active bleeding, and not just use as a
salvage option.6 136 Monescillo et al136 randomised patients
presenting with acute oesophageal variceal haemorrhage to bare
TIPSS or standard of care if the HVPG was ≥20 mm Hg within
24 h of admission. Significantly reduced treatment failure, as
defined by failure to control acute bleeding and/or early rebleed-
ing (12% vs 50%), was seen and improved survival (62% vs
35%) in the patients randomised to undergo a TIPSS procedure.
However, the standard of care was sclerotherapy and not com-
bination endoscopic and pharmacological treatment. This limita-
tion and the lack of availability of HVPG measurement in most
centres meant this trial did not have a significant impact on clin-
ical practice.
Garcia-Pagan et al6 selected patients with active bleeding and
Child’s B cirrhosis or patients with Child’s C cirrhosis (Child’s
score <14) for randomisation to early PTFE-covered TIPSS
within 72 h or standard of care with VBL and pharmacological
treatment. This has shown encouraging results with reduced risk
of treatment failure (3% vs 50%), improved survival (86% vs
61% at 1 year), yet without increased risk of hepatic encephal-
opathy. The results were supported by an observational study
from the same group, although a survival benefit was not
seen.137 Furthermore, a recent well-conducted observational
study did not demonstrate such high survival rates with early
TIPSS, with 11-year survival of 67%, which was similar to that
of patients given endoscopic and pharmacological treatments
only.138 Therefore, larger multicentred RCTs need to be under-
taken to further evaluate the role of early TIPSS. It is important
to make the distinction between salvage TIPSS and early TIPSS
to prevent rebleeding.
Liver transplantation
This is probably appropriate only for patients who bleed while
awaiting liver transplantation, although studies comparing VBL
or TIPSS placement with urgent liver transplantation in this
situation need to be done. Liver transplantation is an exceed-
ingly rare option for the vast majority of patients, both because
it is not commonly available and because of shortages and
delays in organ procurement. No controlled trials of liver trans-
plantation in uncontrolled/active bleeding are available.
Recommendations for the control of variceal bleeding in cir-
rhosis are given below and in figure 3.
Recommendations: control of active variceal haemorrhage in
cirrhosis (figure 3)
1. Suggestions for resuscitation and initial management
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1.1. Units offering an emergency acute upper gastrointestinal
bleeding service should have expertise in VBL, balloon
tamponade and management of gastric variceal bleeding
(level 5, grade D).
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1.2. Transfuse patients with massive bleeding with blood,
platelets and clotting factors in line with local protocols
for managing massive bleeding (level 5, grade D).
1.3. Base decisions on blood transfusion on the full clinical
picture, recognising that overtransfusion may be as dam-
aging as undertransfusion. A restrictive transfusion
policy aiming for a haemoglobin of 70–80 g/L is sug-
gested in haemodynamically stable patients (level 1b,
grade B).
1.4. Do not offer platelet transfusion to patients who are not
actively bleeding and are haemodynamically stable
(level 5, grade D).
1.5. Offer platelet transfusion to patients who are actively
bleeding and have a platelet count of <50×109/L
(level 5, grade D).
1.6. Offer fresh frozen plasma to patients who have either:
▸ a fibrinogen level of <1 g/L (level 5, grade D), or
▸ a prothrombin time (international normalised ratio)
or activated partial thromboplastin time >1.5 times
normal (level 5, grade D).
1.7. Offer prothrombin complex concentrate to patients who
are taking warfarin and actively bleeding (level 5, grade D).
1.8. Treat patients who are taking warfarin and whose upper
gastrointestinal bleeding has stopped in line with local
warfarin protocols (level 5, grade D).
1.9. There is insufficient evidence for the use of recombinant
factor VIIa in acute variceal haemorrhage (level 1b,
grade B).
2. Suggestions for timing of upper gastrointestinal endoscopy:
2.1. Offer endoscopy to unstable patients with severe acute
upper gastrointestinal bleeding immediately after resusci-
tation (level 5, grade A).
2.2. Offer endoscopy within 24 h of admission to all other
patients with upper gastrointestinal bleeding (level 2b,
grade A).
2.3. Units seeing more than 330 cases a year should offer
daily endoscopy lists. Units seeing fewer than 330 cases
a year should arrange their service according to local
circumstances (level 5, grade D).
3. Control of bleeding:
3.1. Antibiotics are recommended for all patients with suspected
or confirmed variceal bleeding (level 1a, grade A).
3.2. In all patients, vasoconstrictors such as terlipressin or
somatostatin are recommended and should be started as
soon variceal bleeding is suspected and continued until
haemostasis is achieved or for up to 5 days. Octreotide
(unlicensed) is suggested if terlipressin or somatostatin
are unavailable (level 1a, grade A).
3.3. Variceal band ligation is recommended as the preferred
endoscopic method (level 1a, grade A).
3.4. After satisfactory haemostasis with the methods above,
and depending on local resources, early covered TIPSS
(<72 h after index variceal bleed) can be considered in
selected patients with Child’s B cirrhosis and active
bleeding or Child’s C cirrhosis with Child’s score <14
(level 1b, grade B).
3.5. Proton pump inhibitors are not recommended unless
otherwise required for peptic ulcer disease (level 1b,
grade B).
4. Failure to control active bleeding:
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4.1. If bleeding is difficult to control, a Sengstaken–
Blakemore tube should be inserted until further endo-
scopic treatment, TIPSS or surgery is performed depend-
ing on local resources and expertise (level 1b, grade B).
4.2. Specialist help should be sought at this time and transfer
to a specialist centre should be considered. Units that do
not offer a TIPSS service should identify a specialist
centre which offers a 24 h emergency TIPSS service and
have appropriate arrangements for safe transfer of
patients in place (level 2a, grade B).
5. Areas requiring further study:
5.1. The efficacy of restrictive blood transfusion in variceal
haemorrhage.
5.2. The role of blood products in variceal haemorrhage.
5.3. The utility of early TIPSS (<72 h) in acute variceal
haemorrhage.
5.4. The role of removable oesophageal stents in acute vari-
ceal haemorrhage.
5.5. The role of haemostatic powders in acute variceal
haemorrhage.
5.6. The role of proton pump inhibitors in variceal
haemorrhage.
6. Quality indicators:
6.1. Antibiotic administration in acute variceal bleeding
within 1 day either before or after the procedure (level
1a, grade A).
Numerator; patients with an acute variceal bleed who
have received antibiotics within 1 day either before or
after the procedure.
Denominator; patients with an acute variceal bleed.
6.2. Endoscopy performed within 24 h of presentation of an
acute variceal bleed (level 2b, grade A).
Numerator; patients with an acute variceal bleed who
have received endoscopy within 24 h of presentation.
Denominator; patients with an acute variceal bleed.
SECONDARY PROPHYLAXIS OF VARICEAL HAEMORRHAGE
β Blockers
A meta-analysis of 12 trials comparing propranolol or nadolol139
with no active treatment showed a significant reduction in
rebleeding but no significant reduction in mortality.140 The
greater reduction in portal pressure with carvedilol compared
with propranolol has been described in the section ‘Primary
prophylaxis’ of this guideline.
Nitrates
The addition of ISMN to NSBB has been shown to reduce vari-
ceal rebleeding compared with NSBB alone, although no sur-
vival benefit was seen.141 In addition, adverse events leading to
drug withdrawal were more common in the group receiving
combined drug treatment. A meta-analysis of ISMN alone or
with either NSBB or endoscopic therapy reported that there was
no mortality benefit from combining nitrates and NSBB com-
pared with NSBB alone.142
Side effects of ISMN include dizziness and headache. Owing
to the side effects and relative lack of data, ISMN is not com-
monly used in clinical practice.
A recent RCT of 121 patients reported carvedilol to be
similar to combined ISMN and NSBB therapy in the prevention
of variceal rebleeding and mortality, although severe adverse
events were less common with carvedilol.143
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Guidelines
Simvastatin
A recent abstract of a multicentre RCT of 158 patients reported
a survival benefit (91% vs 78%, p=0.03) from adding simvasta-
tin to VBL and NSBB compared with placebo, VBL and NSBB,
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as treatment for the prevention of variceal rebleeding.144 There
was no difference in rebleeding and the survival benefit was
restricted to Child A and B patients. Serious adverse events were
similar in both groups. More data are required to investigate
this interesting observation of a survival benefit from simvastatin
in this situation, which may relate to its effects on hepatocellular
function, fibrosis and portal pressure.
Proton pump inhibitors
A double-blind randomised placebo-controlled trial showed that
pantoprazole reduced the size of ulcers in patients who under-
went VBL. However, the total number of ulcers and other out-
comes were similar in the two groups.145
Endoscopic therapy
VBL has been accepted as the preferred endoscopic treatment
for the prevention of variceal rebleeding, with a lower rate of
rebleeding, mortality and complications than sclerother-
apy.146 147 The time interval between VBL sessions to achieve
eradication of varices is debateable. However, a recent RCT
comparing monthly with biweekly VBL after initial haemostasis
with VBL in 70 patients suggested that there were fewer
post-VBL ulcers in the monthly group (11% vs 57%;
p<0.001).148 Variceal recurrence, rebleeding and mortality were
similar in both groups.
Two meta-analyses showed there is no evidence that the add-
ition of sclerotherapy to VBL improves clinically relevant out-
comes, including variceal rebleeding and death, and the
combination led to higher stricture rates.149 150
Endoscopic therapy versus drug therapy
VBL has been reported to be more effective than combined
NSBB and ISMN drug therapy.151 However, an 8-year
follow-up study of this RCT found that although VBL was
superior in reducing variceal rebleeding, survival rates were sig-
nificantly higher in the group treated with combined drug treat-
ment.152 Other studies have found no superiority of VBL over
combined drug therapy for prevention of variceal rebleeding or
mortality.153 154 A recent small multicentre RCT reported carve-
dilol to be similar to VBL in the prevention of variceal rebleed-
ing, with a trend in favour of survival with carvedilol (73% vs
48%, p=0.110).155
Several meta-analyses have compared drug therapy with VBL
in the prevention of variceal rebleeding. One meta-analysis of
six RCTs showed no significant difference in variceal rebleeding
rates when comparing VBL alone with combined NSBB and
ISMN therapy. However, all-cause mortality was significantly
higher in patients treated with the VBL (RR=1.25, 95% CI
1.01 to 1.55).156 Three meta-analyses comparing drug therapy
(NSBB alone or with ISMN) with endoscopic therapy alone
reported no difference in variceal rebleeding or mortality.157–159
Endoscopic+drug therapy versus either alone
Numerous studies and several meta-analyses have compared
combined endoscopic and drug therapy with monotherapy
(endoscopic or drugs alone) in the prevention of variceal
rebleeding. A meta-analysis of 23 trials assessing sclerotherapy
or VBL combined with NSBB reported that combination
therapy reduced rebleeding more than either endoscopic
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 Guidelines
therapy or NSBB alone ( pooled RR=0.68, 95% CI 0.52 to
0.89), although no difference in mortality was detected.160
A meta-analysis of fewer studies suggested no significant dif-
ference in rebleeding between combined drug and VBL therapy
and either alone.157 A further meta-analysis reported reduced
variceal rebleeding (RR=0.601, 95% CI 0.440 to 0.820) but
similar mortality with combined drug and endoscopic therapy
versus endoscopic therapy alone.159 Another meta-analysis of
17 trials (14 using sclerotherapy and three using VBL) reported
that combined endoscopic and NSBB therapy reduced rebleed-
ing (OR=2.20, 95% CI 1.69 to 2.85) and overall mortality
(OR=1.43, 95% CI 1.03 to 1.98) compared with endoscopic
therapy alone.161
A further meta-analysis of 10 RCTs suggested that combin-
ation therapy reduces the risk of rebleeding from oesophageal
varices compared with VBL (RR=0.68, 95% CI 0.45 to 0.93)
or medical treatment (RR=0.60, 95% CI 0.43 to 0.84).162 This
meta-analysis included seven trials comparing combination
therapy with VBL and three trials comparing combination
therapy with drug treatment. Combined VBL and drug therapy
gave a survival benefit when compared with VBL alone
(RR=0.52, 95% CI 0.27 to 0.99), but not when compared with
medical treatment alone.
Another recent meta-analysis assessed five studies comparing
VBL alone with combination VBL and drug therapy, and four
studies comparing drugs alone or combined with VBL.163 This
found that adding drugs to VBL reduced rebleeding (RR=0.44,
95% CI 0.28 to 0.69) with a trend towards reduced mortality,
but adding VBL to drug treatment did not significantly affect
either rebleeding or mortality.
The meta-analyses are not entirely consistent, although it
would appear that combined VBL and drug treatment might
improve survival, but is likely to increase adverse effects com-
pared with VBL alone. There appears to be less clear benefit
from combined VBL and drug treatment compared with drug
treatment alone.
Transjugular intrahepatic portosystemic stent-shunt
Three meta-analyses comparing TIPSS with endoscopic treat-
ment (sclerotherapy or VBL) have been published.164–166 The
results are similar, with the largest meta-analysis of 12 RCTs
showing that (bare) TIPSS reduces variceal rebleeding
(OR=0.32, 95% CI 0.24 to 0.43), but is associated with an
increased risk of encephalopathy (OR=2.21, 95% CI 1.61 to
3.03).166 No differences in survival were seen.164–166 Despite
the problem of shunt insufficiency and the cost of shunt surveil-
lance, TIPSS has been shown to be more cost-effective than
endoscopic therapy.167
A meta-analysis of six studies comparing TIPSS (both bare
and covered) with or without variceal embolisation showed that
adjuvant embolisation during TIPSS reduced rebleeding
(OR=2.02, 95% CI 1.29 to 3.17) with similar shunt dysfunc-
tion, encephalopathy and mortality rates.168 However, owing to
heterogeneity of the study methodology, the authors recom-
mended larger randomised studies using covered stents to
confirm the findings. Generally, TIPSS placement using
PTFE-covered stents134 is recommended for patients for whom
endoscopic and pharmacological treatment for the prevention
of variceal rebleeding fails.1
The evidence for undertaking an ‘early’ TIPSS procedure6 in
patients shortly after a first variceal bleed has been discussed in
the “Management of acute variceal bleeding” section of this
guideline.
1696
Surgery
A meta-analysis demonstrated that non-selective shunts reduced
rebleeding compared with no active treatment or sclerotherapy,
at the expense of increased encephalopathy, with no survival
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benefit.68 Non-selective shunts resulted in similar outcomes
compared with distal splenorenal shunts.68 Extended follow-up
of a randomised study comparing portocaval shunt surgery with
sclerotherapy following acute variceal bleeding, reported better
long-term bleeding control (100% vs 20%, p<0.001) and
improved survival (5-year survival 71% vs 21%, p<0.001) in
the portocaval shunt arm.169 Distal splenorenal shunt surgery
was compared with TIPSS in a multicentre RCT including 140
patients with Child’s A and B cirrhosis.170 Results showed
similar rebleeding and survival, but higher rates of shunt dys-
function and re-intervention in the TIPSS group, although
covered stents were not used. A follow-up study suggested that
TIPSS was more cost-effective.171
Portosystemic shunts (total surgical, distal splenorenal or bare
TIPSS) were compared with endoscopic therapy for variceal
rebleeding in a Cochrane database systematic review.172
Twenty-two trials incorporating 1409 patients were included. All
shunt therapies reduced rebleeding (OR=0.24, 95% CI 0.18 to
0.30) at the expense of higher rates of encephalopathy
(OR=2.09, 95% CI 1.20 to 3.62), with no survival advantage.
TIPSS was complicated by a high incidence of shunt dysfunction.
Laparoscopic splenectomy plus VBL was also compared with
TIPSS for variceal rebleeding in a recent non-randomised trial
of 83 patients.173 This reported surgery plus VBL to be better
than TIPSS in preventing variceal rebleeding, with low rates of
encephalopathy.
Liver transplantation should be considered in eligible patients
following a variceal bleed determined by the selection criteria of
the country.174 There is no clear evidence that prior shunt
surgery has a significant impact on transplant outcome.169
Recommendations for the secondary prophylaxis of variceal
bleeding in cirrhosis are given below and in figure 3.
Recommendations: secondary prophylaxis of variceal haemor-
rhage in cirrhosis (figure 3)
1. Should VBL be used in combination with NSBB?
1.1. NSBB ( propranolol or nadolol)+VBL combination
therapy are recommended as secondary prophylaxis
(level 1a, grade A).
1.2. NSBB or VBL monotherapy are suggested as alternative
options taking into account patient preference and clin-
ical judgement (level 1a, grade B).
1.3. Carvedilol is suggested as an alternative to propranolol
and nadolol (level 1b, grade B).
1.4. If NSBB alone are used, there is no need to undertake
further endoscopy unless clinically indicated (level 1a,
grade A).
1.5. We recommend that VBL alone is used to eradicate
varices if there are contraindications or intolerance to
combined use with NSBB (level 1a, grade A).
2. What is the optimal protocol for VBL?
2.1. It is suggested that varices are banded at 2–4-weekly
intervals until eradication (level 1b, grade B).
2.2. After successful eradication of the varices, patients
should be endoscoped at 3 months, then 6 monthly
thereafter. Any recurrent varices should be treated with
further VBL until eradication (level 1b, grade B).
2.3. Proton pump inhibitors are not recommended unless
otherwise required for peptic disease (level 1b, grade B).
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3. When is TIPSS indicated?
3.1. We suggest that TIPSS is used for patients who rebleed
despite combined VBL and NSBB therapy (or when mono-
therapy with VBL or NSBB is used owing to intolerance or
contraindications to combination therapy), and in selected
cases owing to patient choice. PTFE-covered stents are
recommended (level 1a, grade A).
3.2. Where TIPSS is not feasible in Child’s A and B patients,
we suggest shunt surgery can be used where local
expertise and resources allow (level 1b, grade B).
4. Areas requiring further study:
4.1. Combination of VBL and carvedilol (or other NSBB)
versus carvedilol as monotherapy.
4.2. Comparison of carvedilol with propranolol in secondary
prophylaxis.
4.3. Optimum time interval between VBL sessions.
4.4. Strategy of VBL or NSBB discontinuation after variceal
eradication during combination therapy with VBL
+NSBB.
4.5. Strategy of VBL add-on therapy to failure of NSBB
monotherapy.
4.6. Strategy of NSBB add-on therapy to failure of VBL
monotherapy.
4.7. Role of early TIPSS in secondary prophylaxis.
4.8. Role of statins in secondary prophylaxis.
5. Quality indicator:
5.1. Institution of secondary prophylaxis after acute variceal
bleeding (level 1a, grade A)
Numerator; patients with an acute variceal bleed who
have received either NSBB or banding or both within
4 weeks of the index bleed.
Denominator; patients with an acute variceal bleed.
GASTRIC VARICES
Natural history
At first endoscopy in patients with portal hypertension, 20% are
shown to have gastric varices.175 They are commonly seen in
patients with portal hypertension due to portal or splenic vein
obstruction.175 Only 10–20% of all variceal bleeding occurs
from gastric varices, but outcome is worse than with bleeding
from oesophageal varices.175 176
Gastric varices can be classified on the basis of their location
in the stomach and relationship with oesophageal varices. This
classification has implications for management. The commonly
used Sarin classification divides them into (a) gastro-oesophageal
varices (GOV), which are associated with oesophageal varices;
and (b) isolated gastric varices (IGV), which occur independ-
ently of oesophageal varices.175 Both GOV and IGV are subdi-
vided into two groups. Type 1 GOV are continuous with
oesophageal varices and extend for 2–5 cm below the gastro-
oesophageal junction along the lesser curvature of the stomach.
Type 2 GOV extend beyond the gastro-oesophageal junction
into the fundus of the stomach. Type 1 IGV refers to varices
that occur in the fundus of the stomach and type 2 IGV
describes varices anywhere else in the stomach, including the
body, antrum and pylorus. The most common type of varices
seen in cirrhosis is GOV type 1. Patients who bleed from IGV
are at a significantly higher risk of dying from an episode of
variceal bleeding than patients bleeding from GOV.177
Management of acute gastric variceal bleeding
Although no studies have reported the use of vasopressors and
antibiotics specifically for the initial management of gastric vari-
ceal haemorrhage, any patient with suspected variceal bleeding
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Guidelines
should be managed as described above (see section
‘Management of active variceal haemorrhage’). Once endoscopy
has identified the source of bleeding as gastric varices, thera-
peutic options include endoscopic methods, TIPSS, other radio-
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logical procedures, surgery and long-term NSBB. Splenic vein
thrombosis should be considered and appropriate investigations
undertaken in patients presenting with gastric variceal bleeding.
Endoscopic therapy
Endoscopic sclerotherapy
Sclerotherapy has been largely replaced by VBL and tissue adhe-
sives or thrombin when appropriate for gastric varices, owing to
the lower complication and rebleeding rates.
Endoscopic VBL
Standard VBL or the use of detachable snares has been shown
to control active bleeding from gastric varices, but rebleeding
and recurrence rates are high.178 179 As GOV-1 are generally
considered extensions of oesophageal varices, VBL is often used
to treat bleeding from here. However, given the larger diameter
and the anatomy of other types of gastric varices, and the
limited data on use of VBL in this situation, this technique is
generally not recommended for these.
Endoscopic injection therapy with tissue adhesives
Numerous studies have reported the use of tissue adhesives,
most commonly histoacryl (N-butyl-cyanoacrylate), in the treat-
ment of gastric varices.180–194 Variations in technique, dilution
with lipiodol and follow-up strategy have been described. These
studies have reported an initial haemostasis success rate with
tissue glue of 86–100%, with rebleeding rates of 7–28%.
Uncommon, but severe complications, including emboli to the
pulmonary and cerebral circulations, have been described.181
A randomised study compared cyanoacrylate injection with
VBL in 60 patients with gastric variceal bleeding.186 Patients
treated with cyanoacrylate had a higher haemostasis rate (87%
vs 45%), lower rebleeding (31% vs 54%) and lower mortality
(29% vs 48%) than those treated with VBL. Another rando-
mised study comparing cyanoacrylate with VBL in 97 patients
with gastric variceal bleeding, reported equal haemostasis rates
at 93%, but significantly higher rebleeding with VBL (72% vs
27%).193 This study reported no difference in survival or com-
plications between groups.
A non-randomised study comparing cyanoacrylate with VBL
for gastric variceal bleeding reported similar haemostasis rates,
but lower rebleeding with cyanoacrylate (32% vs 72%).194
Survival and complication rates were similar in both groups. In
a controlled but non-randomised study comparing cyanoacrylate
with sclerotherapy for gastric variceal bleeding, Oho et al188
showed that the haemostasis rate was significantly higher in the
cyanoacrylate group. Survival was also significantly greater in
patients treated with cyanoacrylate.
Mishra et al187 reported a randomised study comparing
cyanoacrylate injection with β blockers in the prevention of
rebleeding in 67 patients with bleeding GOV-2 or IGV-1.
During a median 26-month follow-up, patients in the cyano-
acrylate group had significantly lower rates of both variceal
rebleeding (15% vs 55%) and mortality (3% vs 25%).
Treatment modality, presence of portal hypertensive gastropathy
and gastric variceal size >20 mm correlated with mortality.
Another recent RCT compared repeated gastric variceal obtura-
tion with or without NSBB in patients with bleeding GOV-2 or
IGV-1.182 Mortality and rebleeding rates were similar in the two
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 Guidelines
groups, although adverse effects were more common in the
combination group.
In a non-randomised study, Lee et al185 suggested that endo-
scopic ultrasound (EUS)-guided biweekly cyanoacrylate injection
versus ‘on demand’ injection after recurrent bleeding led to sig-
nificantly lower rebleeding (19% vs 45%) from gastric varices,
although survival was similar. However, others have not con-
firmed this approach.189 EUS-guided coil therapy has recently
been described as having similar efficacy, but fewer adverse
events, compared with cyanoacrylate injection in a small non-
randomised study.191
Binmoeller et al180 described a new method for the manage-
ment of fundal gastric varices in 30 patients, using EUS and a
combination of 2-octyl-cyanoacrylate and coils. Haemostasis
was achieved in 100% of patients with no procedure-related
complications. Use of coils appeared to reduce the volume of
cyanoacrylate required to obliterate varices.
Endoscopic injection of thrombin
Injection of bovine thrombin to successfully control gastric vari-
ceal bleeding was initially described in a small cohort in
1994.195 Varices were eradicated in all patients after a mean of
two injections. Przemioslo et al196 reported 94% haemostasis
and 18% rebleeding in 52 patients with gastric variceal bleeding
treated with bovine thrombin. Ramesh et al197 also studied
bovine thrombin for bleeding gastric varices. They reported
92% haemostasis, with no rebleeding during follow-up. No
adverse events or technical problems were noted. More recent
studies have used human rather than bovine thrombin because
of safety concerns with the latter. McAvoy et al198 reported on
the largest series of patients treated with human thrombin injec-
tion for gastric or ectopic variceal bleeding. They reported 11%
rebleeding in the 33 patients who had gastric variceal haemor-
rhage, with no significant adverse events. A recent series by
Smith et al199 reported a high rate of initial haemostasis in acute
bleeding. However, failure to control bleeding or rebleeding was
reported in >50%, suggesting that thrombin has a role in bridg-
ing to definitive treatment in acute bleeding. Where thrombin
was used as prophylaxis, rebleeding occurred in 20%. To date,
no randomised studies assessing thrombin injection for gastric
variceal bleeding have been reported.
New endoscopic therapies
Two recent reports have described the successful use of
Hemospray (Cook Medical, USA) in the management of active
gastric variceal bleeding refractory to cyanoacrylate injection
therapy.200 201 In the latter case this was used as a bridge to a
TIPSS procedure,201 but in the former case TIPSS was not
undertaken owing to pre-existing cardiomyopathy.200 No
rebleeding was reported in either case at a 30-day follow-up.
Further data on the use of haemostatic powders in gastric vari-
ceal bleeding are required.
Balloon tamponade
Insertion of a Sengstaken–Blakemore or Linton–Nachlas tube
may sometimes help to temporarily stabilise the patient with
severe gastric variceal bleeding, which is uncontrolled by stand-
ard endoscopic methods as described above.127 The Linton–
Nachlas tube has been reported to have greater efficacy in
gastric varices haemorrhage in a controlled trial.128 However,
rebleeding is almost universal if another treatment modality is
not instituted.
1698
Transjugular intrahepatic portosystemic stent-shunt
An initial TIPSS series using bare stents reported control of
active bleeding from gastric varices in almost all patients in
whom the shunt was performed successfully.202–206 Tripathi
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et al43 described 272 patients who had a TIPSS procedure for
either gastric or oesophageal variceal bleeding. They reported
similar rebleeding rates after TIPSS for either gastric or
oesophageal varices. Initial PPG was lower in patients with
bleeding from gastric varices. In addition, mortality was lower
in those patients with initial PPG >12 mm Hg, who had TIPSS
for gastric compared with oesophageal variceal bleeding. Shunt
insufficiency and encephalopathy rates were similar in both
groups. The authors suggested aiming to reduce HVPG to
<7 mm Hg in gastric variceal bleeding.
Lo et al207 undertook a randomised trial in 72 patients com-
paring TIPSS with cyanoacrylate injection in the prevention of
gastric variceal rebleeding. Control of active bleeding had
been achieved with cyanoacrylate in all patients before random-
isation. They reported a significantly lower rate of gastric vari-
ceal rebleeding with TIPSS (11% vs 38%), although overall
upper gastrointestinal rebleeding was similar in both groups.
Encephalopathy was more common in those patients treated
with TIPSS (26% vs 3%), but overall complications and survival
were similar in both groups.
A non-randomised study compared TIPSS with cyanoacrylate
injection for gastric variceal bleeding.208 No differences were found
in haemostasis, rebleeding or survival, but the group treated with
TIPSS had increased encephalopathy. Another comparative study
described lower rebleeding with TIPSS, but reduced in-patient
length of stay with cyanoacrylate, and similar mortality.209 This
study also reported cyanoacrylate to be more cost-effective.
Other radiological procedures
The use of balloon-occluded retrograde transvenous obliteration
(B-RTO) for the treatment of bleeding gastric varices was pio-
neered by the Japanese.184 210 This procedure involves insertion
of a balloon catheter into an outflow shunt (gastrorenal or
gastric-inferior vena caval) via the femoral or internal jugular
vein. Blood flow is blocked by balloon inflation, then the veins
draining gastric varices are embolised with microcoils and a
sclerosant injected to obliterate the varices.
In a small randomised study, B-RTO was compared with
TIPSS in the management of 14 patients with active gastric vari-
ceal bleeding and gastrorenal shunts.211 Immediate haemostasis,
rebleeding and encephalopathy were similar in both groups. In a
non-randomised study of 27 high-risk patients, Hong et al212
compared B-RTO with cyanoacrylate injection in acute gastric
variceal bleeding. Active bleeding at baseline was more common
in the cyanoacrylate group. Haemostasis rates after B-RTO and
cyanoacrylate were similar at 77% and 100%. Rebleeding was
higher in the cyanoacrylate group (71% vs 15%), with compli-
cations and mortality similar in both groups. This rebleeding
rate after cyanoacrylate is much higher than figures reported
from other studies.
A large Korean retrospective study evaluated B-RTO for the
management of gastric variceal haemorrhage.213 Technical
success of B-RTO was 97% with procedure-related complica-
tions seen in 4% and rebleeding in 22%. Another retrospective
study of B-RTO for bleeding gastric varices described 95% tech-
nical success and 50% 5-year survival.214 Cho et al215 assessed
B-RTO in 49 patients who had gastric varices with spontaneous
gastro-systemic shunts. Procedural success rate was 84% but two
procedure-related deaths occurred. No variceal recurrence or
Tripathi D, et al. Gut 2015;64:1680–1704. doi:10.1136/gutjnl-2015-309262

rebleeding was noted. It has been reported that B-RTO can
increase PPG and may aggravate pre-existing oesophageal
varices and ascites.215 216 Although B-RTO appears to be an
effective alternative to TIPSS in patients with gastric variceal
bleeding who have appropriate shunts,217 it is rarely performed
outside Asian centres.218
Percutaneous transhepatic variceal embolisation with cyano-
acrylate and standard endoscopic cyanoacrylate injection have also
been compared in a non-randomised study of 77 patients.219 The
authors reported lower rebleeding with the percutaneous
approach, although mortality was similar in both groups.
Surgery
Surgery for portal hypertension should be performed by experi-
enced surgeons in lower-risk patients, ideally in specialist
units.220 Because of the increasing use of simpler endoscopic
and radiological procedures as described above, the need for
such an intervention has reduced dramatically, and is mainly
confined to splenectomy or splenic artery embolisation in
patients with splenic vein thrombosis.221 222
Under-running of gastric varices has been shown to control
active bleeding but is followed by recurrence of bleeding in
50% of patients and is associated with a perioperative mortality
of >40%.223 Complete devascularisation of the cardia, stomach
and distal oesophagus for bleeding from gastric varices is asso-
ciated with good control of bleeding but is followed by rebleed-
ing in >40% of patients and early mortality in about 50%.224
The use of distal splenorenal shunting for bleeding from gastric
varices in patients with cirrhosis was reported in six patients
with Child class A or B cirrhosis.225 Although good control of
bleeding was attained, two patients died in the postoperative
period. Orloff et al169 reported that a portal-systemic shunt can
be an effective treatment for bleeding varices in patients with
portal vein thrombosis and preserved liver function.
Primary prophylaxis of gastric variceal bleeding
A randomised study of 89 patients compared β blockers, cyano-
acrylate injection and no active treatment in the primary preven-
tion of bleeding from larger (>10 mm) GOV-2 and IGV-1.226
Over a 26-month follow-up period, bleeding occurred in 38%,
10% and 53% of patients in the β blocker, cyanoacrylate and
no-treatment groups, respectively. The cyanoacrylate group had
significantly lower bleeding rates than the other groups for
GOV-2, but not for IGV-1 patients. Mortality was lower in the
group treated with cyanoacrylate (7%) than in those given no
treatment (26%) but was similar to that in the β blocker group
(17%). However, this was a small, single-centre study with an
unusually high failure rate for NSBB. Many clinicians have sig-
nificant concerns about the safety of cyanoacrylate injection in
the context of primary prophylaxis.
In a retrospective study, Kang et al suggested that cyanoacryl-
ate injection may be an effective prophylactic treatment for
higher-risk gastric varices.227
A retrospective study evaluated the clinical outcomes of
B-RTO for gastric varices, in which the procedure was per-
formed as a primary prophylactic treatment in 40 patients.228
The procedure was successful in 79% of patients, although pro-
cedural complications were reported in 9%. Survival at 1 and 5
years was 92% and 73%, respectively.
Recommendations: management of active haemorrhage from
gastric varices (figure 3)
1. What is the optimal management of bleeding gastro-
oesophageal varices?
Tripathi D, et al. Gut 2015;64:1680–1704. doi:10.1136/gutjnl-2015-309262
Guidelines
1.1. GOV-1: treat as for oesophageal varices (level 2b,
grade B).
1.2. GOV-2 and IGV:
1.2.1. We recommend initial endoscopic therapy with
Gut: first published as 10.1136/gutjnl-2015-309262 on 17 April 2015. Downloaded from http://gut.bmj.com/ on June 3, 2020 by guest. Protected by copyright.
cyanoacrylate injection (level 1a, grade A).
1.2.2. Thrombin may also be considered (level 4, grade C).
1.3. TIPSS can be considered, depending on local resources
and clinical judgement (level 3a, grade B).
2. In control of bleeding fails:
2.1. Balloon tamponade is suggested for GOV, IGV-1 until
definitive treatment is undertaken (level 2b, grade B).
2.2. Salvage TIPSS is suggested as the first-line definite treat-
ment, where feasible (level 3a, grade B).
2.3. B-RTO or surgical shunting can be considered if TIPSS
is not possible (eg, portal vein thrombosis present) and
depending on local resources (level 3a, grade B).
3. What are the therapeutic options for prevention of rebleed-
ing from gastric varices?
3.1. We recommend that patients with GOV-1 are entered
into a VBL surveillance programme (level 2b, grade B).
3.2. We recommend endoscopic surveillance with cyano-
acrylate injection as needed for GOV-2 and IGV (note
the optimum endoscopic follow-up strategy remains
unclear)(level 2b, grade B). Thrombin can also be con-
sidered (level 4, grade C).
3.3. NSBB can be considered in certain circumstances after
taking into account the patient’s preferences and clinical
judgement (level 1b, grade B).
3.4. We suggest TIPSS if patients rebleed despite cyanoacryl-
ate injection. TIPSS can also be considered in other
selected patients (eg, those with large or multiple gastric
varices) (level 1b, grade B).
3.5. Shunt surgery may be used in selected patients with
well-compensated cirrhosis and depending on local
resources (level 3c, grade B).
3.6. Splenectomy or splenic artery embolisation should be
considered in all patients where there is splenic vein
thrombosis or left-sided portal hypertension (level 4,
grade C).
4. Is there a role for primary prophylaxis of gastric variceal
bleeding?
4.1. NSBB (level 2a, grade B) can be considered in selected
high-risk patients with large GOV-2 after taking into
account the patient’s preferences and clinical judgement.
4.2. Cyanoacrylate injection is not recommended outside
clinical trials (level 2a, grade A).
5. Areas requiring further study:
5.1. Role of thrombin in gastric varices, comparing this with
tissue adhesives in both acute gastric variceal bleeding
and secondary prophylaxis.
5.2. Role of TIPSS in acute gastric variceal bleeding and sec-
ondary prophylaxis.
5.3. Role of haemostatic powders in controlling refractory
active gastric variceal bleeding.
5.4. Role of NSBB in the prevention of rebleeding from
gastric varices.
5.5. Role of B-RTO as monotherapy or in combination with
endoscopic injection of tissue adhesives in prevention of
bleeding from gastric varices.
5.6. Role of EUS-guided injection of tissue adhesives or
thrombin.
5.7. Primary prevention of gastric variceal bleeding with
tissues adhesives and NSBB.
1699
 Guidelines
Correction notice This article has been corrected since it published Online First.
The article now has an Open Access licence.
Acknowledgements BSG Liver Section 2013–2015—in particular, Dr Grace
Dolman, trainee member of the BSG liver section for review of the guideline on
behalf of BSG liver section and Dr Stuart McPherson, member of the BSG liver
section for review of the guideline on behalf of the BSG liver section.
Collaborators Mr Benedict Lowsley-Williams, UK. Patient representative. Member
of guidelines development group. Sister Kathy Guo, research nurse, University
Hospitals Birmingham, Birmingham, UK. Member of guidelines development group.
Contributors DT: consultant hepatologist, University Hospitals Birmingham.
Member of BSG liver section. Chair of GDG and lead author. AJS: consultant
gastroenterologist, Glasgow Royal Infirmary. Coauthor of sections ‘Secondary
prophylaxis of variceal haemorrhage’ and ‘Gastric varices’. Review of entire
guideline. PCH: consultant hepatologist, Royal Infirmary of Edinburgh. Coauthor of
sections ‘Natural history of varices in cirrhosis’ and ‘Management of active variceal
haemorrhage’. Review of entire guideline. DP: consultant hepatologist, Royal Free
Hospital, London. Coauthor of section ‘Management of active variceal
haemorrhage’. Review of entire guideline. CM: consultant hepatologist, The York
Hospital. Member of BSG liver section. Coauthor of section ‘Management of active
variceal haemorrhage’. Review of entire guideline. HM: consultant interventional
radiologist, University Hospitals Birmingham. Coauthor of sections ‘Service delivery
and development’ and ‘Management of active variceal haemorrhage’ in relation to
TIPSS. AA: consultant hepatologist, Royal Derby Hospital. Derby. Chair of BSG liver
section. Contribution to sections ‘Secondary prophylaxis of variceal haemorrhage’
and ‘Gastric varices’. Review of entire guideline. JWF: consultant hepatologist,
University Hospitals Birmingham. Clinical lead of Liver QuEST. Development of
quality indicators and implementation through Liver QuEST. SPO: consultant
interventional radiologist, University Hospitals Birmingham. Review of entire
guideline with focus on radiological aspects. MH: consultant hepatologist, The
Freeman Hospital, Newcastle. Member of BSG liver section and BASL. Review of
entire guideline. JMC: consultant gastroenterologist, Royal Devon and Exeter
Hospital. Member of BSG liver section. Review of entire guideline. Benedict
Lowsley-Williams: patient representative. Advice given relating to patient aspects.
Sister Kathy Guo, RGN: research nurse, University Hospitals Birmingham. Nursing
representative. Advice given relating to nursing aspects.
Funding This guideline was commissioned by Clinical Services and Standards
Committee (CSSC) of the British Society of Gastroenterology (BSG) under the
auspices of the liver section of the BSG.
Competing interests DT: speaker fees for Gore Medical. AA: educational grant
from Ferring Pharmaceuticals. PCH: speaker fees for Gore Medical. SPO: speaker
fees for Gore Medical. DP: involvement in NICE guidelines on Acute GI Bleeding.
Provenance and peer review Not commissioned; externally peer reviewed.
Open Access This is an Open Access article distributed in accordance with the
Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which
permits others to distribute, remix, adapt, build upon this work non-commercially,
and license their derivative works on different terms, provided the original work is
properly cited and the use is non-commercial. See: http://creativecommons.org/
licenses/by-nc/4.0/
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