Digestive Endoscopy 2021; : –
14144
Review
Management of acute upper gastrointestinal bleeding:
Urgent versus early endoscopy
James Yun Wong Lau
Department of Surgery, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China
For decades, timing of endoscopy has been a controversy in
the management of patients who present with upper gas-
trointestinal bleeding (GIB). The advent of endoscopic hemo-
static therapy led to reduced further bleeding, surgery and
mortality. Observational studies suggest that in patients at low
risk of further bleeding, early endoscopy establishes diagnosis
and allows their prompt hospital discharge. In the high-risk
patients, early endoscopy with hemostatic treatment can stop
bleeding and improve outcomes. Sample size in early
randomized controlled trials (RCTs) was small. They included
low-risk patients or patients with poorly defined risks. We
designed a RCT to test the hypothesis that in high-risk
patients (defined by those with an admission Glasgow
Blatchford Score of 12 or greater), endoscopy within 6 h of
Timing of endoscopy in the management of acute upper
gastrointestinal bleeding (AUGIB) has been a subject of
perennial debate. In a book titled Controversies in
Gastroenterology published in 1984 and edited by Dr Gary
Gitnick,1 two eminent gastroenterologists debated on the
subject. Dr Joel Panish represented the affirmative side
arguing for emergency endoscopy to be utilized in such
patients. Without endoscopy, he argued that doctors and
patients would be “ignorant of the correct diagnosis,
unaware of their prognosis, have no idea of whether any
future preventive measures are indicated, nor have any idea
of any chances of a repeat bleeding episode might be”. Dr
Panish also suggested that stigmata of bleeding are
observed more often in the first 12 h of admissions and
these stigmata of bleeding are prognostic. In an era of
therapeutic endoscopy, hemostatic treatment would impact
upon patients’ outcomes. Dr David Graham from Texas
defended the premise that endoscopy should not be
performed within the first 24 h following admissions. He
Corresponding: James Yun Wong Lau, Department of Surgery,
Faculty of Medicine, The Chinese University of Hong Kong, 4/F
Lui Che Woo Clinical Sciences Building, Prince of Wales Hospital,
Shatin, Hong Kong SAR, China. Email: laujyw@surgery.
cuhk.edu.hk
Received 12 July 2021; accepted 20 September 2021.
© 2021 Japan Gastroenterological Endoscopy Society
doi: 10.1111/den.
gastrointestinal consultation, when compared to the standard
of care i.e. endoscopy within 24 h, would improve out-
comes. The primary outcomes, all-cause mortality at 30 days
did not differ between groups; 23 of 258 (8.9%) in the urgent-
endoscopy group and 17 of 258 (6.6%) in the early-endoscopy
group died (difference 2.3%, 95% confidence interval 2.3 to
6.9%). Further bleeding was similar (10.9% vs. 7.8%) between
groups. A higher rate in endoscopic hemostatic treatment was
observed in the urgent-endoscopy group (60.1% vs. 48.4%). In
patients with peptic ulcers, active bleeding or visible vessels
were found on initial endoscopy in 105 of the 158 patients
(66.4%) and in 76 of 159 (47.8%) in the respective group. In the
majority of patients with GIB, endoscopy earlier than 24 h is
not indicated.
argued that the true mortality rate following upper GIB is
unknown. Most deaths are not caused by exsanguination
but are related to the severity of comorbid illnesses. An
improvement in mortality rate reflects an improvement in
overall standard of care, perhaps the establishment of a
dedicated GIB team and a careful selection of patients for
endoscopy. He concurred that if endoscopy is to have an
immediate and measurable value, the results must somehow
be tied to a therapeutic intervention. In the 1980s,
endoscopy was firmly established only as a diagnostic tool.
The correct diagnosis made at endoscopy, however, does
not benefit the patient. This was supported by a widely cited
study by Peterson et al.2 in which patients were randomized
to routine (n = 100) or no routine endoscopy (n = 106).
The study showed no difference in hospital deaths (11 vs. 8)
and rebleeding (33 vs. 32).
A decade later, two meta-analyses3,4 of randomized
controlled trials (RCTs) on endoscopic therapy provided
evidence that endoscopic therapy would reduce further
bleeds, surgery and mortality. In the meta-analysis of 30
RCTs by Sacks et al. a pooled rate difference of 30% in
mortality was shown with endoscopic therapy. With this
effective treatment firmly established, many argued for early
endoscopy with the belief that early endoscopy would stop
bleeding, prevent recurrent bleeding and thereby improve
overall outcomes.
1
2 J. Y. W. Lau
OBSERVATIONAL STUDIES ON THE OPTIMAL
TIMING OF ENDOSCOPY
T HERE HAVE BEEN many published observational
studies to suggest benefits with early endoscopy. A
notable example was a retrospective study5 by Cooper et al.
In which case records of 909 patients from 13 metropolitan
hospitals around Cleveland, USA, were reviewed. Early
endoscopy (endoscopy within 24 h) were carried out in 64%
among a cohort of 909 patients. Those with ulcer disease
with active bleeding, visible vessels or varices were catego-
rized as high risk. In this subgroup, endoscopy <24 h was
associated with a reduction in further bleeds or surgery (60–
37.5%). In all risk groups, endoscopy <24 h led to reduction
in hospitalization. In a meta-analysis of mostly observational
studies and a handful of controlled trials by Brennan
Spiegel,6 the same author concluded that clinical benefits
of early endoscopy, however, need to be confirmed in a well
designed large RCT. In an editorial,7 the same author argued
for endoscopy to be performed within 24 h as a standard of
care. He went on to assert that it was the time for 24-h
endoscopy to become universal and compared this to 1-h
“door-to-needle” times for acute myocardial infarction.
More recently, a nationwide cohort study of 12,601
patients from Denmark8 studied the relationship between
timing of endoscopy and mortality. The authors performed
scatterplots of the association between timing of endoscopy
(0–48 h after admission) and in-hospital mortality. Patients
were stratified according to the presence of hemodynamic
instability and comorbidities categorized by the American
Society of Anesthesiologists score. In those with hemody-
namic instability, endoscopy 6–24 h after admission was
associated with lower in-hospital mortality, compared with
endoscopy outside this time frame. The authors suggested
that a short period of resuscitation before endoscopy may
improve outcomes. Another cohort study from Korea9 that
studied 961 patients with GIB and a Glasgow Blatchford
Score (GBS) of 7 provided conflicting evidence. Mortality
was significantly lower in those who underwent endoscopy
within 6 h when compared to those scoped between 6 to 48 h
(1.6 vs. 3.8%). In this series, the overall 28 days mortality
was only 2.5%. This low mortality contrasts sharply with
reported mortality in most studies. It is likely that observa-
tional studies have inherent bias and confounding. Patients
who underwent endoscopy within 6 h were likely to be very
different from those who received endoscopy later.
EARLY RCTS
T HERE HAD BEEN three RCTs on timing of endoscopy
in AUGIB. Lin et al.10 from Taiwan randomized 325
© 2021 Japan Gastroenterological Endoscopy Society
Digestive Endoscopy 2021; : –
consecutive patients with peptic ulcer bleeding (PUB) to
endoscopy within or after 12 h of presentation. Nasogas-
tric aspirates were routinely obtained in patients. The
study showed that in the subgroup of 30 patients with
bloody nasogastric aspirate, endoscopy within 12 h
reduced blood transfusions and shortened hospital stay.
In another RCT by Lee et al.,11 patients with PUB, but
without comorbid illnesses requiring intensive care, under-
went either early endoscopy within 1–2 h in the emer-
gency department or elective endoscopy within 1–2 days.
Early endoscopy was again associated with shorter
hospital stay and therefore lower hospitalization costs.
Finally, Bjorkman et al.12 performed a multicenter study
comparing endoscopy within 6 h versus within 48 h in
low-risk patients with AUGIB (Rockall score 5). This
study’s sample size and power calculations were based on
differences in length of hospitalization between the two
groups. The study was prematurely terminated because of
small observed difference between groups in an interim
analysis. None of these studies showed any differences in
rebleeding or mortality (Table 1). These studies were
limited by their sample size, lack of patient risk stratifi-
cation or inclusion of only low-risk patients, heteroge-
neous temporal definitions of early vs. later endoscopy,
and non-contemporary clinical practice.
A “DEFINITIVE” TRIAL
E DESIGNED A RCT13 to evaluate whether urgent
W endoscopy i.e. within 6 h of access to GI care, when
compared to the recommended 24-h time frame, would
improve outcome in patients predicted to be at high risk for
further bleeds and death. We included patients with overt
signs of upper GI bleeds (those with melena, hematemesis or
both) and with an admission GBS 12 or higher. We
previously validated several admission scores including the
GBS in a cohort study of 1087 patients14 who presented
with AUGIB; 297 (27.3%) required endoscopic therapy.
Area under the receiver operating characteristic (AUROC)
curve with GBS was 0.72. Those with a score of 12 or more
constituted to about 20% of patients in this cohort. The need
for endoscopic therapy in this subgroup was 48%. The
mortality was around 16%. In this trial, we excluded patients
who remained hypotensive despite initial resuscitation.
These patients required urgent intervention. The primary
endpoint to this RCT was mortality from all causes within
30 days. Our sample size was determined to detect a 50%
reduction (16% to 8%) in the primary endpoint with a type
one error of 5% and a power of 80%. Of 598 patients with
GBS ≥12, 561 patients were enrolled (n = 258 to each
group). The mean time from GI consult to endoscopy was
Digestive Endoscopy 2021; : – Timing of endoscopy 3

Table 1 Early randomized trials that compared urgent to early endoscopy in patients with acute gastrointestinal bleeding (GIB)

Author, Inclusion criteria 30 days outcomes

year
Rebleeding (n/N) Bleeding related Death from all causes (n/
death (n/N) N)

EGD ≤12 h EGD >12 h Urgent Elective EGD <6 h EGD <48 h

Lin 1996 Patients who had hematemesis and/or 6/162 8/163 1/162 1/163 2/162 1/163
melena. Risk stratified by nasogastric
aspirate (clear, coffee grounds, or bloody)
Lee 1999 Stable hospitalized patients with upper GIB 2/56 3/54 Not Not 0/56 2/54
reported reported
Bjorkman Patients with acute upper GIB who were Not Not 0/47 0/46 0/47 0/46
2004 hemodynamically stable and without severe reported reported
comorbid illnesses (Rockall score of 5 or
less)
EGD, esophagogastroduodenoscopy

2.5 and 16.8 h respectively. About 61% in either group were

bleeding peptic ulcers. Esophago-gastric varices accounted
for 9.7% and 7.4% of cases in respective group.
All-cause mortality at 30 days after randomization did not
differ between groups. A total of 23 patients (8.9%) in the
urgent-endoscopy group and 17 (6.6%) in the early-
endoscopy group died (difference 2.3%, 95% confidence
interval 2.3% to 6.9%). Deaths from GIB accounted for
two of 17 and five of 23 in the two groups.
Further bleeding within 30 days occurred in 28 patients
(10.9%) in the urgent-endoscopy group and in 20 (7.8%) in
the early-endoscopy group (difference 3.1%, 95% con-
fidence interval 1.9 to 8.1).
Peptic ulcers with active bleeding or visible vessels were
found on initial endoscopy in 105 of the 158 patients (66.4%)
with peptic ulcers in the urgent-endoscopy group and in 76 of
159 (47.8%) in the early-endoscopy group. Therefore,
endoscopic hemostatic treatment was administered at initial
endoscopy for 155 patients (60.1%) in the urgent-endoscopy
group and for 125 (48.4%) in the early-endoscopy group.
To understand if there was a quality issue to after-hours
endoscopy, we performed a post hoc analysis to investigate
the association between the time of the day during which
patients underwent endoscopy (6 a.m. to 5:59 p.m. vs.
6 p.m. to 5:59 a.m.) and the endpoints of further bleeding
and death. The percentage of patients with further bleeding
and the death did not differ significantly according to the
time of day of endoscopy (further bleeding, 10.7% [17 of
159] for endoscopy performed during office hours and
10.4% [10 of 96] for endoscopy performed after hours;
death, 7.5% [12 of 159] and 10.4% [10 of 96], respectively).
LESSONS FROM THE TRIAL
A CUTE UPPER GASTROINTESTINAL bleeding, in
the majority of patients, is self-limiting. In this trial, we
used a high dose intravenous infusion of proton pump
inhibitor (PPI). In the group of patients assigned to
endoscopy within 24 h, only 20 of 258 (7.8%) of them
required immediate endoscopy because of persistent or
recurrent bleeding. Maximal acid suppression can stabilize
clots and accelerate ulcer healing. In a placebo-controlled
trial that evaluated pre-endoscopy use of a high dose
intravenous PPI,15 we found that early use of PPI reduced
the need for endoscopic hemostatic intervention (19.1% vs.
28.4%, P = 0.007). During index endoscopy, there were
fewer ulcers with active bleeding (12 of 187 vs. 28 of 190,
P = 0.01), a downstaging of stigmata of bleeding and more
clean based ulcers (120 of 187, 90 of 190, P = 0.001) in
those who received intravenous PPI. After initial resuscita-
tion, it is logical to initiate medical therapy and plan
endoscopy the next morning and allow time to optimize
patients’ medical conditions. Even in the context of variceal
bleeding, early administration of a vascoactive drug can
reduce active bleeding seen during endoscopy and make
treatment easier.16 In a Cochrane Review of 17 RCTs17 that
compared endoscopic treatment to vasoactive drugs in the
acute variceal bleeding, outcomes in terms of bleeding
control, further bleeding and mortality were similar between
the two groups. Under the provision that these patients are
monitored closely and emergency endoscopy is readily
available, outcomes following endoscopy within 24 h are
similar to those following urgent or earlier endoscopy.

© 2021 Japan Gastroenterological Endoscopy Society

4 J. Y. W. Lau
LIMITATIONS TO THE TRIAL
T HERE ARE SEVERAL limitations to the trial. By
virtue of its design, it evaluates interventions under
ideal conditions in a highly selected population. In the real-
world settings, the trial findings may not be applicable. And
in particular, the study was performed in a single university
hospital. This limits generalizability to other hospitals
especially community-based hospitals.
We did not stipulate a resuscitation protocol. An optimal
resuscitation protocol has not been defined in the acute
management of upper GIB. An International Consensus
Group stated that there was insufficient evidence to make a
recommendation regarding restrictive versus liberal fluid
management, types of fluid to be used and the role of goal-
directed therapy.18
The observed 30 days mortality in the trial was much
lower than the rate of 16% used to calculate our sample size.
The included patients probably belonged to a lower risk
group. Of 598 patients screened, 32 underwent emergency
endoscopy because of failure to stabilize after volume
resuscitation and did not enter into the trial.
We choose arbitrarily to include only patients with a GBS of
12 or more. In an international multicenter validation study,19
GBS was shown to have the highest discriminative ability at
predicting need or intervention or death (AUROC 0.86). A
threshold score of 7 or more was best at predicting endoscopic
treatment with a sensitivity of 80% and a specificity of 57%. In
an observational study from Singapore, a delay in endoscopy
(>13 h from presentation to endoscopy) in those with GBS
≥12 was associated with high mortality of 44%.20 If we were
to include patients with intermediate GBS, a much larger
sample size would be required to detect a small difference in
mortality. We could also be criticized for choosing the GBS to
risk stratify patients as the score selects patients also with
significant comorbidities including heart and hepatic failure.
Earlier endoscopy would not impact upon their survival. A
risk score with high accurary to predict the need for urgent
endoscopy (earlier than 24 h) is required. Such a score will
likely include hypotension and other signs of ongoing
hemorrhage.
It has also been suggested that we should compare
endoscopy <12 h to endoscopy <24 h. The rationale is to
allow sufficient time for resuscitation and stabilization of
medical conditions in patients at high risk of further bleeds
and deaths. The optimal time may be endoscopy between 6
and 12 h.
In summary, patients with AUGIB and at high predicted
risks of further bleed and deaths will benefit from initial
resuscitation, medical therapy and optimization to their
comorbid illnesses. They should then be carefully
© 2021 Japan Gastroenterological Endoscopy Society
Digestive Endoscopy 2021; : –
monitored. We should offer urgent endoscopy only in those
with signs of ongoing bleeding.
CONFLICT OF INTEREST
A UTHOR DECLARES NO conflict of interest for this
article.
FUNDING INFORMATION
N ONE.
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