PRIMER

Non-variceal upper gastrointestinal

bleeding
Angel Lanas1,2, Jean-Marc Dumonceau3, Richard H. Hunt4, Mitsuhiro Fujishiro5,
James M. Scheiman6, Ian M. Gralnek7, Helen E. Campbell8, Alaa Rostom9,
Càndid Villanueva2,10 and Joseph J. Y. Sung11
Abstract | Non-variceal upper gastrointestinal bleeding (NVUGIB) is bleeding that develops in the
oesophagus, stomach or proximal duodenum. Peptic ulcers, caused by Helicobacter pylori infection
or use of NSAIDs and low-dose aspirin (LDA), are the most common cause. Although the incidence
and mortality associated with NVUGIB have been decreasing owing to considerable advances in the
prevention and management of NVUGIB over the past 20 years, it remains a common clinical problem
with an annual incidence of ~67 per 100,000 individuals in the United States in 2012. NVUGIB is a
medical emergency, and mortality is in the range ~1–5%. After resuscitation and initial assessment,
early (within 24 hours) diagnostic and therapeutic endoscopy together with intragastric pH control
with proton pump inhibitors (PPIs) form the basis of treatment. With a growing ageing population
treated with antiplatelet and/or anticoagulant medications, the clinical management of NVUGIB is
complex as the risk between gastrointestinal bleeding events and adverse cardiovascular events needs
to be balanced. The best clinical approach includes identification of risk factors and prevention of
bleeding; available strategies include continuous treatment with PPIs or H. pylori eradication in those
at increased risk of developing NVUGIB. Treatment with PPIs and/or use of cyclooxygenase‑2‑selective
NSAIDs should be implemented in those patients at risk of NVUGIB who need NSAIDs and/or LDA.

Correspondence to A.L.
Service of Digestive Diseases,
University Clinic Hospital
Lozano Blesa, University
of Zaragoza, IIS Aragón,
Zaragoza, Spain.
alanas@unizar.es
Article number: 18020
doi:10.1038/nrdp.2018.20
Published online 19 Apr 2018
Gastrointestinal bleeding is a medical emergency and
represents the most common cause of hospitalizations
associated with digestive diseases in most countries1,2.
Upper gastrointestinal bleeding (UGIB) is defined by
any gastrointestinal bleeding above the ligament of Treitz,
which includes the oesophagus, stomach and proximal
duodenum. By contrast, middle and lower gastrointesti-
nal bleeding originate in the small bowel below the liga-
ment of Treitz or in the colorectum3. UGIB events can be
classified as non-variceal UGIB (NVUGIB) and variceal
UGIB (VUGIB). NVUGIB is most often caused by peptic
ulcers (a break of the mucosal barrier that exposes the
submucosa to the damaging effects of acid and pepsin
present in the gastroduodenal lumen), which are com-
monly associated with Helicobacter pylori infection and
the use of NSAIDs (including aspirin doses of ≥500 mg)
or low-dose aspirin (LDA; which is a dose of ≤325 mg but
is typically 75–100 mg). By contrast, VUGIB is caused by
oesophageal or gastric varices (dilated sub­mucosal veins),
which are usually associated with chronic liver diseases
and/or portal hypertension. The incidence of NVUGIB
in most countries is fivefold higher than that of VUGIB
(BOX  1), and NVUGIB represents a serious clinical
­challenge with considerable mortality 4.
In this Primer, we focus on NVUGIB in the com-
munity setting, which is more common and less severe
than NVUGIB in inpatient hospital settings, which
occurs in association with hospitalizations due to other
serious conditions (such as neurological, renal, cardiac,
pulmonary, metabolic, traumatic or septic conditions).
Although both conditions are life threatening, the
mortality associated with NVUGIB is fourfold higher
in patients who develop bleeding in the hospital than in
those who develop bleeding in the community setting 4,5.
Epidemiology
The most common cause of NVUGIB is gastroduo­
denal peptic ulcers followed by gastroduodenal ero-
sions, p­ eptic oesophageal lesions (oesophagitis or
oesophageal ulcers), vascular lesions (such as Dieulafoy
lesions; a medical condition associated with an abnormal
tortuous arteriole that penetrates into the gastrointesti­
nal mucosa) and vascular ectasias such as angio­dys­
plasia (a small vascular malformation in the gut)),
Mallory–Weiss tears (lacerations in the mucosa at the
gastro-­oesophageal junction that occur associated with
recurrent vomiting often after excessive alcohol intake
or a heavy meal) and, less often, neoplastic lesions6,7.

NATURE REVIEWS | DISEASE PRIMERS VOLUME 4 | ARTICLE NUMBER 18020 | 1

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PRIMER

Author addresses Although differences in incidence might be evident

1
Service of Digestive Diseases, University Clinic Hospital Lozano Blesa, University of
Zaragoza, IIS Aragón, Zaragoza, Spain.
2
Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas,
Madrid, Spain.
3
Gedyt Endoscopy Center, Buenos Aires, Argentina.
4
Division of Gastroenterology and Farncombe Family Digestive Health Research Institute,
McMaster University, Hamilton, Ontario, Canada.
5
Department of Endoscopy and Endoscopic Surgery, Graduate School of Medicine,
The University of Tokyo, Tokyo, Japan.
6
Division of Gastroenterology, University of Virginia, Charlottesville, VA, USA.
7
Ellen and Pinchas Mamber Institute of Gastroenterology, Emek Medical Center, Afula,
Israel.
8
National Perinatal Epidemiology Unit, Nuffield Department of Population Health,
University of Oxford, Oxford, UK.
9
Division of Gastroenterology, University of Ottawa, Ottawa, Ontario, Canada.
10
Hospital de la Santa Creu i Sant Pau, Universitat Autónoma de Barcelona, Barcelona,
Spain.
11
Division of Gastroenterology, The Chinese University of Hong Kong, Hong Kong, China.
Important developments in medicine in the past 20 years
have affected the incidence and outcomes of NVUGIB.
On the one hand, the introduction of potent medications
to suppress acid secretion, the recognition of H. pylori
as an important aetiological factor of peptic ulcers with
subsequent eradication therapy, the progress in diag-
nostic and therapeutic endoscopy, the introduction of
restrictive blood transfusion policies and improvements
in the management of critically ill patients are key fac-
tors that have reduced the risk of developing NVUGIB
and have improved the management and outcomes8–11.
On the other hand, some risk factors are becoming
more common, including an ageing population (which
results in increasing prevalence of cardiovascular dis-
eases and other comorbidities that increase the risk of
mortality associated with NVUGIB) and the increas-
ing use of LDA, NSAIDs and other antiplatelet and
anticoagulant agents8–11.
Incidence
The overall incidence of NVUGIB, particularly bleeding
events associated with peptic ulcers (that is, peptic ulcer
bleeding (PUB)), has decreased during the past 20 years
and has now stabilized globally 9,12,13. In the United States,
the incidence of NVUGIB associated with any cause has
decreased from 78.4 per 100,000 individuals in 2001 to
60.6 per 100,000 individuals in 2009 (P = 0.004), and the
incidence of PUB has decreased from 48.7 per 100,000
individuals in 2001 to 32.1 per 100,000 individuals in
2009 (P <0.001) on the basis of hospital discharge data9,14.
More recent data also show a 21% decrease in the inci-
dence of NVUGIB from 2002 to 2012, from 81 to 67
cases per 100,000 individuals15. Similar trends have
been reported in Europe (FIG. 1), with an incidence of
NVUGIB of ~55–60 per 100,000 people in the 1990s
to ~25–35 per 100,000 people in the early 2000s16–19.
However, data are difficult to compare between stud-
ies owing to variability in the methodology used. Time
trends of NVUGIB are less well documented outside
Europe and the United States, but a few studies show a
similar decline in incidence20.
between ethnicities, studies are limited21. For example,
in New Zealand, age-adjusted incidence seems higher
among people of Maori descent than in those of European
descent (91.3 versus 37.0 per 100,000 i­ndividuals, rate
ratio of 2.47, P <0.001)22.
Causes of NVUGIB
The causes of NVUGIB have changed over time. Erosive
gastritis as a cause of NVUGIB declined by 55% in the
United States between 2001 and 2009 and peptic ulcers
as a cause declined by 30%. By contrast, NVUGIB due
to neoplasm increased by 50%, as did Dieulafoy lesions
(33%), angiodysplasia (32%) and oesophagitis (20%)15.
The decreased incidence of PUB in developed countries
is linked to a decreased prevalence of H. pylori and an
increased use of gastric-acid-suppressing drugs, which
protects against peptic ulcer diseases3. Globally, the life-
time prevalence of peptic ulcer disease in the general
population has been estimated at ~5–10% and the inci-
dence at 0.1–0.3% per year 3,11–13. However, despite the
decrease in PUB in the general population in developed
countries, the incidence of PUB in elderly individuals
is increasing (on the basis of hospital admissions for
ulcer complications), which can probably be attributed
to the ageing population3,18,23. Overall, compared with
decades ago, fewer individuals with PUB are positive
for H. pylori, whereas PUB associated with NSAID
use or not related to either NSAIDs or H. pylori has
increased24,25. In a multicentre study in France, 40% of
PUB events were related to H. pylori infection, 18.7% to
gastrotoxic drug use, 19.8% to both factors and 21.6%
were unrelated to either H. pylori infection or gastrotoxic
drug use26.
Similar trends can be observed in some Asian popu­
lations. In 2001, one study conducted in Hong Kong
reported that only 4.1% of PUB cases were unrelated
to NSAID use, LDA use or H. pylori infection, whereas
the remaining 51.9% of cases were related to H. pylori
infection and 44% to NSAID or LDA use27. However,
other studies conducted more recently have reported
rates of idiopathic peptic ulcers of 23.5% in Korea28
and 13.8–18.8% in Hong Kong29,30. In a 2014 review, the
prevalence of idiopathic ulcers in Asia was reported as
10–30% since the year 2000 (REF. 31).
Mortality
Overall global mortality associated with NVUGIB
has decreased over time6,13. A large case–control study
including >500,000 individuals with NVUGIB in
England showed that mortality within 28 days of hos-
pital admission significantly decreased from 14.7% in
1999 to 13.1% in 2007, even after adjusting for age, sex
and comorbidities32. Large observational studies docu-
mented an improvement in survival in the United States
across various age groups along a similar time range9,33,34.
Mortality associated with gastric and duo­denal ulcers
also declined in Argentina, Australia, Chile, Hong
Kong, Japan, Mexico, Singapore and Taiwan between
1971 and 2004 (REF. 20). Interestingly, mortality associ-
ated with gastric ulcers compared with duodenal ulcers

2 | ARTICLE NUMBER 18020 | VOLUME 4 www.nature.com/nrdp

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 PRIMER

was threefold higher in Mexico, twofold higher in
Argentina and Chile and only slightly higher in Taiwan
and Singapore, whereas no difference was observed in
Hong Kong.
Despite these improvements, mortality associ­
ated with NVUGIB remains high, with values varying
between different studies and stable, non-­decreasing
­v alues over time in some countries (for example,
Spain)17. A systematic review of 18 studies showed
mortality of NVUGIB ranging from 1.1% in Japan to
11% in Denmark, although most studies included in
the review placed that figure closer to 5%35. These dis-
crepancies in the reported mortality of NVUGIB are
attributable to differences in study methodologies and
populations studied.
Improvement in NVUGIB outcomes is likely due
to factors such as advances in endoscopic and med-
ical manage­ment and improvements in emergency
and critical care or geriatric medicine8,10,11. Risk factors
for mortality linked to NVUGIB include increased
age, comorbidities (such as respiratory or cardiac
insufficiency, renal failure and sepsis), severe haemo­
dynamic instability or develop­ment of further bleed-
ing 36. However, at present, most deaths associated with
NVUGIB are not due to uncontrolled bleeding but are
the consequence of complications induced by bleeding
(for example, organ ­failure), comorbidities or older age4.
Mechanisms/pathophysiology
The mechanisms involved in the development of
NVUGIB are not well understood. The mucosal ­barrier
and submucosal blood vessels must be damaged for
the bleeding event to occur. Disruption of the mucosal
­barrier is commonly associated with H. pylori infection
and/or NSAID or LDA use, but exposure of the blood
vessels to the luminal content can also be the conse-
quence of causes such as Mallory–Weis syndrome,
vascular lesions and neoplastic lesions. Whatever the
cause, exposure of the underlying blood vessels to
the action of acid and pepsin further erodes the vessel
wall and interferes with blood coagulation3 (FIG. 2).
Mucosal damage
H. pylori infection. Mucosal damage and ulcer forma-
tion are considered to be consequences of the inter­
action between H. pylori and the host immune response.
H. pylori strains show genetic diversity, but those that
exhibit a cag pathogenic island encoding virulence fac-
tors such as cytotoxicity-associated immunodominant
antigen (CagA), vacuolating cytotoxin autotransporter
(VacA), blood group antigen-binding adhesin (BabA)
or outer inflammatory protein adhesin (OipA) strongly
induce the host immune response3,37,38. This immune
response is initiated in the gastric epithelium, where
these bacterial virulence factors elicit an intracellu-
lar cascade of events that activate kinases involved in
the regulation of cell growth and differentiation and the
nuclear factor-κB (NF-κB) signalling pathway. Cytokines
that have a key role in the immune and inflammatory
response to H. pylori infection include IL‑1β, IL‑1 recep-
tor antagonist protein (IL1RN), tumour necrosis factor
(TNF), IL‑6, IL‑8 and IL‑10 (REFS 3,38).
H. pylori induces different types of lesions in the
­lining of the stomach and duodenum, most commonly
mild asymptomatic gastritis. Pan-gastritis is associ-
ated with hyposecretion of gastric acid and is linked
to the development of gastric ulcers. However, some
patients develop an antrum-predominant gastritis that
is associ­ated with duodenal ulcers and increased ­gastric
acid secretion due to hypersecretion of gastrin and
hypo­secretion of somatostatin3,39. Gastric acid hyper­
secretion in antrum-­predominant gastritis is associated
with the development of gastric metaplasia in the duo-
denal bulb, which may be colonized by H. pylori and
favour ulcer formation3,40.

Box 1 | Variceal upper gastrointestinal bleeding
Variceal upper gastrointestinal bleeding (VUGIB) is due to portal hypertension and/or
chronic liver diseases and in most cases is associated with liver cirrhosis. Presentation
often involves vomiting large amounts of ‘fresh’ red blood. The first-line therapy
combines vasoactive drugs and variceal ligation. Drugs with vasoactive properties,
such as terlipressin, somatostatin or octreotide, should be given as soon as acute VUGIB
is suspected. Upper gastrointestinal endoscopy should be performed within the first
12 hours after admission once haemodynamic stability has been achieved to ascertain
the cause of haemorrhage; when VUGIB is confirmed, ligation should be performed
within the same procedure. Early pre-emptive insertion of a covered (that is, with fabric
or graft material over the metal structure) transjugular intrahepatic portosystemic
shunt to treat portal hypertension should be considered in patients with high risk of
failure of endoscopic ligation or when failure develops. Balloon tamponade (in which an
inflated balloon applies pressure to compress bleeding varices) in the oesophagus or
stomach should be used in cases of uncontrolled bleeding as a temporary measure
(<24 hours) until definitive treatment can be instituted. Removable, covered and
self-expanding oesophageal stents are a promising alternative to balloon tamponade.
Eventually, liver transplantation should be considered when bleeding is not controlled
after transjugular intrahepatic portosystemic shunt insertion and when liver function
has deteriorated. Peptic ulcer bleeding (that is, non-variceal bleeding) in patients with
cirrhosis has a mortality similar to that of VUGIB with a similar incidence of
complications and decompensation of liver disease, which account for a great
proportion of fatalities201,202.
NSAID and LDA use. Studies have shown that NSAIDs
and LDA induce damage to the gastroduodenal mucosa
by both systemic and local effects41. Locally, NSAIDs
and LDA can decrease the hydrophobicity of the
mucous layer owing to their amphiphilic properties,
thereby exposing the underlying epithelium to luminal
acid and pepsin. NSAIDs also uncouple mitochondrial
oxid­ative phosphorylation in the epithelial cells, lead-
ing to cellular dysfunction with decreased levels of ATP
and glutathione, mitochondrial swelling, generation
of free radicals, calcium release into the cytosol and,
eventually, loss of integrity of tight junctions, apop­tosis
and cell death, all contributing to increased mucosal
­permeability and disruption.
The local effects of NSAIDs depend on their acid
dissociation constant; acidic NSAIDs are not ionized
at the low pH of the gastric lumen and can, therefore,
be absorbed by epithelial cells, where they become
‘trapped’ because of the neutral intracellular pH. The
ability of an NSAID to uncouple mitochondrial oxid­
ative phosphoryl­ation (that is, its uncoupling potency)
is also directly proportional to its acid dissociation

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 PRIMER

constant, with acidic NSAIDs being the most potent.
Consequently, use of acidic NSAIDs (including aspirin)
may need to be combined with proton pump inhibitors
(PPIs) in some high-risk patients (see below); non-acidic
NSAIDs (such as paracetamol) are ­considered safer for
the gastrointestinal tract 41.
Systemically, NSAIDs contribute to mucosal dam-
age by inhibiting the prostaglandin secretion associated
with cyclooxygenase 1 (COX1; also known as PTGS1)
and COX2. The reduction in prostaglandin levels dis-
rupts the mucosal barrier as prostaglandins stimulate
mucous and bicarbonate secretion by epithelial cells,
inhibit acid secretion and promote cell proliferation
and mucosal blood flow. The ischaemic effect of NSAIDs
leads to increased leukocyte adherence, damaging blood
­vessels. The gastric mucosa is especially sensitive to the
reduced COX1‑derived prostaglandin levels compared
with other segments of the gastrointestinal tract 42 for
reasons that are not yet clear. COX2 is not expressed in
the absence of a pre-existing lesion or H. pylori infec-
tion. However, given that H. pylori infections are fre-
quent, many patients who take NSAIDs or LDA may
be infected, which seems to exacerbate the potential
­damaging effects of these drugs41,43.
Bleeding
Role of pH. The coagulation system is extremely sen-
sitive to minor pH changes. In vitro studies show that
coagulation becomes abnormal at pH 6.8, platelet
aggregation reduces by >50% at pH 6.4 and platelet
aggregation and plasma coagulation are abolished and
previously aggregated platelets disaggregate at a pH <5.9
(REF. 44). In addition, an increase in pH to 6.8 (or even
slightly higher) induces platelet aggregation, calcium
release and serotonin release from the platelets as well
as normaliza­tion of the blood clotting time (meas-
ured using ­prothrombin and partial ­thromboplastin
times)44 (FIG. 3).
Pepsin, a proteolytic enzyme that becomes activated
at pH <6, further enhances platelet disaggregation and
clot disintegration44. Acid, pepsin and other proteolytic
0 LDA can damage the gastrointestinal mucosa42.
Change in the incidence of NVUGIB (%)
enzymes are present in abundance in the gastric lumen;
these circumstances make the stomach and proximal
duodenum a hostile environment that facilitates contin-
ued bleeding once the blood vessel is breached. Thus, the
medical treatment of bleeding lesions aims at attempt-
ing to keep the gastric pH above the proteolytic range
for pepsin (that is, pH >6). Current medical treatment
with a high-dose PPI is able to achieve this pH target45–47.
As PPIs suppress acid secretion by covalent binding of
the protonated drug to activated proton pumps, which
are at rest in the cytoplasm in the fasting patient, the
use of PPI therapy provides highly effective pH control
following endoscopic treatment.
Some studies have shown clinical benefits of main-
taining an intragastric pH >6 during the bleeding epi-
sode. A meta-analysis48 showed a significant decrease in
further bleeding, need for surgery and mortality among
patients with high-risk bleeding ulcers after endoscopic
therapy and high-dose continuous infusion with PPIs
when compared with placebo.
Inhibition of platelets. In addition to mucosal damage,
NSAIDs and LDA might also contribute to bleeding by
inhibiting the formation of thromboxane A2 in platelets.
Platelet COX1‑derived thromboxane A2 is activated to
control bleeding following damage to blood vessels
(FIG. 2). A similar mechanism has been proposed for
non-aspirin antiplatelet agents49.
Some have questioned the mucosal-damaging
­capacity of LDA and have suggested that the role of LDA
in NVUGIB is mainly due to its antiplatelet effect. In this
context, the antiplatelet effect would be similar to that
of anticoagulants such as vitamin K antagonists, which
do not produce mucosal damage but may induce severe
bleeding of gastrointestinal lesions caused by other
agents (such as NSAIDs and H. pylori). If so, LDA and
non-aspirin antiplatelet agents would induce bleeding
only in patients with pre-existing lesions. This hypoth­
esis is supported by one study involving individuals with
osteoarthritis, in whom the rate of peptic ulcers did
not differ between those taking LDA and those t­ aking
­placebo50. However, this finding must be interpreted
with caution because other studies have shown that even

Another intriguing question is why NSAIDs and LDA

–10 have a universal effect on platelet and COX inhib­ition,
but only 1 in 1,000 individuals51 receiving these agents
–20 eventually develop NVUGIB, prompting an examin­
ation of susceptibility factors. One study found that some
–30
patients who developed a bleeding event after LDA use
were hyper-responsive to the drug, as demonstrated by an
–40
abnormal prolonged bleeding time due to an u ­ nexplained
intrinsic defect, subclin­ical von Willebrand disease
–50
(in which the clotting protein von Willebrand factor
(vWF) is missing or defective) or abnormalities in aspi-
–60
United States Sweden Netherlands Spain Italy New Zealand
rin metabolism52. Polymorphisms in genes encoding
1994–2009 1987–2005 1993–2000 1996–2005 2001–2010 2001–2010 proteins involved in drug metabolism, mucosal defence
Figure 1 | The decline in incidence of NVUGIB over time. Percentage
Nature Reviews decrements
| Disease Primers or coagulation have been proposed to increase the risk
in the incidence of non-variceal upper gastrointestinal bleeding (NVUGIB) in different of PUB in NSAID or LDA users, but more studies are
countries over different time periods as indicated. Graph based on data presented needed before these factors can be taken into account for
in REFS 9,11–14,16–20,22,23,218,219. clinical purposes3,53.

4 | ARTICLE NUMBER 18020 | VOLUME 4 www.nature.com/nrdp

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 PRIMER

Gastric lumen
Systemic effects NSAIDs Acid
LDA Pepsin H. pylori
↓ COX1

↓ Prostaglandins
Fundus
Oesophagus ↓ Cell proliferation Local Inflammatory response
↓ HCO3– secretion effects
Cardia ↓ Mucus H. pylori Mucous
Lesser
curvature Body Mucosal
damage

Antrum Necrotic cell

Submucosal
Mucosal break Bleeding artery
Greater
curvature
Ligament
Duodenum of Treitz Platelets Aspirin Activated platelets

↓ pH Inhibition of thrombosis
Blood clot

Figure 2 | Mechanisms of upper gastrointestinal bleeding induced by NSAIDs, LDA orNature H. pylori infection.
Reviews NSAIDs
| Disease Primers
(including aspirin doses of ≥500 mg) or low-dose aspirin (LDA; which is a dose of ≤325 mg but is typically 75–100 mg)
induce a break in the mucosa by acting both locally and systemically, whereas Helicobacter pylori damages the epithelial
barrier by inducing a cytokine-mediated host immune response. Once the mucosal barrier is disrupted, the underlying
blood vessels are exposed to gastric acid and pepsin, which affect blood vessel integrity and can induce bleeding.
Platelets and the coagulation system, which should be activated to stop the bleeding, are inhibited by the low pH and
pepsin. In addition, platelet cyclooxygenase 1 (COX1) activity suppression by LDA inhibits thromboxane formation
and, therefore, platelet aggregation and clot formation. HCO3−, bicarbonate.

Mallory–Weiss syndrome. In Mallory–Weiss syn- be induced by local thrombosis or by ischaemia in the

drome, mucosal disruption and laceration result from
several factors, including a rapid increase of pressure
in the upper part of the stomach (the cardia)54,55. The
consequent hyperextension of the stomach limits the
mobility between the mucosa and submucosa, resulting
in insuffi­cient closure of the cardia. Furthermore, dis-
coordinated muscle contractions of the different layers
in the lower part of the oesophagus and cardia, together
with the longitudinal disposition of gastric mucosal folds
at the gastro-oesophageal junction, lead to deep linear
lacerations of the mucosa that expose submucosal vessels
that are also damaged in this process. Age-related loss
of collagen in the submucosal layers may contribute to
loss of mucosal–submucosal mobility 55. The common
location of the most severe lacerations is the right lateral
wall of the stomach, where the oesophagus is aligned
with the lesser curvature of the stomach54 owing to dif-
ferent thicknesses and ligament arrangements of the
gastric tissues55.
Vascular lesions. Vascular lesions such as those that
occur in Dieulafoy syndrome and vascular ectasias
are associated with NVUGIB15. The Dieulafoy lesion
involves an artery with an abnormally large diameter
(1–3 mm) that penetrates the submucosa, runs a tor-
tuous course and protrudes into the mucosa, where a
small defect with fibrinoid necrosis initiates a subse-
quent severe bleeding event. The bleeding lesion may
artery due to pulsation of the vessel, which damages
the overlying epithelium and exposes the vessel to the
gastrointestinal lumen. Dieulafoy and vascular lesions
often occur in elderly individuals and are associated with
severe comorbidities56.
Bleeding from vascular ectasias such as angiodys­
plasia of the stomach may have a similar pathogenetic
profile as Dieulafoy lesions. Intermittent submucosal
venous obstruction, intermittent arterial blood flow
and local vascular degeneration with local hypox­aemia
and vascular endothelial growth factor-dependent
proliferation have been proposed as being involved in
these bleeding events. Association with cardiac, renal
and other comorbidities is also common. Vascular
­ectasias, often multiple or diffuse, predominantly occur
in the gastric antrum, which may be linked with the
more vigor­ous muscular contraction of the antrum,
­predisposing to venous obstruction57,58 (FIG. 4).
Other comorbidities. Several non-gastrointestinal
comorbidities are independent risk factors for developing
NVUGIB59; the mechanisms involved depend on the type
of comorbidity. Reduced mucosal microperfusion and
hypoxia can be important in patients with heart failure60;
furthermore, chronic hypoxia and increased concentra-
tion of mucosal free radicals, corresponding to systemic
inflammation, have been identified as important fac-
tors in patients with chronic pulmonary obstruction61,

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PRIMER

100 bleeding complications, whereas individuals with one or

90 more risk factors have increased risk. A history of previ-
ous ulcers puts any patient r­ eceiving NSAIDs or LDA at
80
pH 7.4 high risk of NVUGIB67.
70
Preventive strategies. The role of preventive treat-

Aggregation (%)
60
50
40
30
20
ADP
10 A
0 tive in reducing acid secretion, but at the expense of
0 1 2 3
Time (minutes)
Figure 3 | Effects of an acidic environment on platelet
Nature Reviews | Disease Primers
aggregation. At pH 7.4, platelet aggregation induced by
ADP is normal and occurs rapidly. Arrow A denotes the
time point at which the pH of plasma is decreased by the
addition of hydrochloric acid in an experimental setting.
At pH 6.8, platelet aggregation is negatively affected,
and at pH 5.9, it is completely abolished. Adapted with
permission from REF. 44.
whereas platelet and clotting dysfunction, platelet–­vessel
interaction and haemodynamic instability are mech-
anisms involved in end-stage renal disease-­associated
gastrointestinal bleeding 62. Most of these conditions
are also associated with poor nutritional s­ tatus, which,
together with the common use of LDA, antiplatelet thera­
pies, anticoagulants and NSAIDs in these conditions,
may contribute to gastrointestinal mucosa ­damage.
Most of these mechanisms, especially those related to
altered microperfusion, hypoxia, free radical concen-
tration and pH, are also involved in diffuse mucosal
damage or stress ulcers in patients needing ­respiratory
assistance in the intensive care setting 60,61 (FIG. 4).
Diagnosis, screening and prevention
Prevention
Risk stratification. Prevention of bleeding events is the
best clinical approach in NVUGIB. A careful medical
history, physical examination and laboratory investi­
gations provide the basis to identify risk factors and
comorbid conditions (BOX 2) and to select a sound pre-
vention strategy, which should balance the benefits
and risks of preventive measures. In NSAID and LDA
users, balancing risks is especially important when
cardio­vascular and gastrointestinal risk factors are both
present. Some risk factors can be easily identified and
prevented or discontinued63,64, whereas others are not
(such as advanced age or the presence of comorbidi-
ties)59 (FIG. 4). The risk of developing bleeding increases
with the presence and number of risk factors, in addi-
tion to NSAID and LDA use, and appreciation of these
factors offers the opportunity to stratify patients into
risk categor­ies65,66. Those taking NSAIDs or LDA with
no other identified risk factors are at low risk of ulcer
ment has not been systematically evaluated but should
be considered in patients with one or more risk factor
when using NSAIDs or LDA67; however, prevention is
rarely required for low-risk patients. Acid suppression
with antisecretory drugs is recommended in the pres-
pH 6.8
ence of risk factors; PPIs are preferred and are superior
to histamine H2 receptor antagonists67. Prostaglandins
(such as misoprostol) are cytoprotective and effec-
pH 5.9
adverse events that reduce their tolerability 67. In those
4 5 who have a history of peptic ulcers, the risk associ-
ated with NSAID use can be modified first by treating
H. pylori infection if present and then by switching to a
COX2‑selective NSAID. Eradication of H. pylori infec-
tion in those taking NSAIDs or LDA can considerably
reduce, although not abolish, the risk of ulcers, bleeding
or re‑bleeding events68,69.
Concomitant NSAID treatment with several other
drugs increases the risk of developing gastrointestinal
bleeding 64,66,70 (BOX 2; FIG. 5), but the risk might be modi­
fied by co‑treatment with antisecretory drugs. Indeed,
use of omeprazole (a PPI) while continuing clopidogrel
treatment decreases the number of gastrointestinal
bleeding events without an increase in cardiovascular
adverse events71. Monitoring international normal-
ized ratio (INR; a parameter used to standardize pro­
thrombin time) is indicated when a PPI is started or
stopped in patients on vitamin K antagonists. Indeed,
the metabolism of PPIs involves the hepatic cytochrome
P450 (CYP) enzyme system, which might affect metabo­
lism or activation of drugs taken concomitantly. How
different PPIs interact with different CYPs might inform
PPI choice. For example, the selection of pantoprazole
and rabeprazole rather than other PPIs has been recom-
mended in patients taking vitamin K antagonists, but the
real clinical impact of this recommendation remains to
be shown72. The identification of polymorphisms lead-
ing to poor metabolism of PPIs in the CYP2C19 gene
in a Japanese population could be predictive of adverse
events73. These findings could also be extended to other
populations, but additional studies are needed. To date,
no interaction has been reported with novel direct oral
anticoagulants (DOACs) and CYP enzymes. When using
corticosteroids, PPI treatment should be considered if an
individual has a history of peptic ulcers or in the case
of combined corticosteroid and NSAID or LDA use67.
Identification of a history of uncomplicated or com-
plicated ulcers should prompt a test-and-treat strategy
for H. pylori infection to prevent a first-bleeding or
re‑­bleeding event 74,75. Identification of H. pylori infec-
tion during a bleeding event represents a clin­ical chal-
lenge, as an invasive test such as urease testing during
the endoscopic procedure may provide false-­negative
results owing to the presence of blood in the gastric
lumen, ­inadequate sampling or the previous use of PPIs.

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 PRIMER

Histological analysis and/or culture of biopsy speci-
mens may also provide false-negative results76. In this
clinical scenario, the presence of H. pylori infection
should be tested or retested if negative after ulcer healing
(4–8 weeks after the bleeding event) with patients being
off PPI for at least 7 days and no antibiotic therapy the
month before. A positive test should prompt eradication
therapy with a confirmatory negative test performed
at least 1 month after therapy 3,75,76.
Diagnosis
In clinical practice, the diagnosis and management of
NVUGIB are intermingled. Following resuscitation and
initial assessment, pre-endoscopic management is per-
formed followed by endoscopic diagnosis and endoscopic
management. For example, medical treatment with, for
example, PPIs, is often started before endoscopic diag­
nosis and treatment. In this Primer, we d ­ iscuss the
­diagnosis and management options separately.
Initial, pre-endoscopic assessment. The presentation of
overt NVUGIB varies considerably from asymptomatic
outpatients with melena (black faeces due to the pres-
ence of blood) to those presenting with large-volume
haematemesis (vomiting of blood), passage of ‘fresh’ red
blood, severe hypotension and a compromised airway.
The presence of haematemesis indicates that the source
of the bleeding is the upper gastrointestinal tract (above
the ligament of Treitz), whereas the source of bleeding
in most individuals with melena is also the upper gastro­
intestinal tract (90%), but the small bowel and ascending
colon cannot be excluded. Caution should be taken to
exclude oral or nasopharyngeal sources of bleeding as
patients who swallow fresh blood might present with
haematemesis or melena. The probability that a patient
has NVUGIB is higher when melena is observed on
rectal examination than with patient-reported history
of melena or the presence of blood clots in the stool77.
The initial assessment and management of these
patients is focused on emergency assessment and
stabiliza­tion protocols aimed at restoring and protect-
ing the airway and maintaining the circulation followed
by NVUGIB-specific pre-endoscopic assessment and
interventions. In a minority of patients who present with
large-volume haematemesis and/or diminished level of
consciousness, orotracheal intubation should be consid-
ered to protect the airway and to facilitate initial resusci­
tation and subsequent endoscopy in the emergency
setting. Blood should be drawn during catheter insertion
to analyse complete blood count, INR, electrolytes, urea,
albumin, creatinine and liver enzymes. Additional blood
tests or investigations can be performed depending on
the underlying comorbidities5,78.
During initial resuscitation, a directed history and
physical exam is conducted and aimed at ascertaining
the potential aetiology for the gastrointestinal bleeding
and identifying important risk factors and comorbidi­
ties that modify survival and warrant lowered thresh-
olds for transfusion or early endoscopy. A digital
rectal examination enables verification of the presence
of either melena or blood and may avoid unnecessary
­confirmatory tests79.

Risk factors • Angiodysplasia Genetic

• Vascular lesions predisposition
Comorbidities • Renal
Dysregulated processes insufficiency
• Chronic hypoxia • Cardiovascular
Gastrointestinal pathology • Ischaemia
• Free radicals disease
• Fibrinoid necrosis
• Clotting • Pulmonary
• Degeneration
dysfunction insufficiency
• Vitamin K Inhibition of • Altered • Coagulopathy
antagonists coagulating factors microperfusion • Organ failure
• DOACs • Systemic • Age
NVUGIB
• P2Y12 antagonists Inhibition of inflammatory • Other
• SSRIs platelet activation status comorbidities
• LDA
• NSAIDs Mallory–Weiss Mucosal damage Gastric cancer Genetic
Syndrome predisposition
Inflammation
• COX inhibition Smoking
• Excessive Vomiting • Vascular damage
alcohol intake
Steroids Virulence Immune response
• Heavy meals factors cytokines
• Other conditions • Non-selective NSAIDs
• LDA H. pylori Previous inflammatory
• COX2 inhibitors infection conditions

Figure 4 | Complex pathophysiology of NVUGIB. Many factors contribute to the development NatureofReviews
non-variceal upper
| Disease Primers
gastrointestinal bleeding (NVUGIB). Bleeding is usually the result of mucosal damage induced by drugs such as NSAIDs
or low-dose aspirin (LDA; typically 75–100 mg) or is often associated with Helicobacter pylori infection. Additional risk
factors or comorbidities might make the gastrointestinal mucosa more susceptible to bleeding. NVUGIB can also be the
consequence of vascular lesions, which are also often associated with ageing or comorbidities. Bleeding from these lesions
may be precipitated by antiplatelet or anticoagulation agents, which can also act on pre-existing mucosal damage induced
by other factors, or other pathogenetic mechanisms, such as Mallory–Weiss syndrome or gastric carcinoma59. COX,
cyclooxygenase; DOAC, direct oral anticoagulant; P2Y12, P2Y purinoceptor 12; SSRI, selective serotonin reuptake inhibitor.

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PRIMER

Each patient presenting with NVUGIB should have
pre-endoscopic risk stratification. Among the different
risk-scoring systems (BOX 3), the Glasgow–Blatchford
Score (GBS) performs well80 and is used globally. The
GBS performs better at predicting intervention, compli-
cations or death than the full (preadmission and post-­
endoscopy) Rockall score, the admission Rockall score,
the AIMS65 score and the Progetto Nazionale Emorragia
Digestiva (PNED) score80. The PNED and AIMS65 scores
perform best at predicting mortality 80. In general, high-
risk patients are those who present with hypotension,
vomiting of bright red (fresh) blood, passage of red blood
per rectum (in the setting of NVUGIB) and/or have con-
siderable comorbidities and are of advanced age. These
patients have an increased risk of mortality and require
careful assessment and early management.
In individuals who develop NVUGIB when on anti-
platelet or anticoagulation therapy to prevent cardio­
vascular events, this treatment should generally be
stopped and/or reversed. However, endoscopy should
Box 2 | Risk factors for increased bleeding risk
Drugs
• Compared with non-use, NSAID use increases the risk of developing non-variceal
upper gastrointestinal bleeding (NVUGIB) fourfold, and low-dose aspirin (LDA) use
increases the risk twofold3,66,203. The risk progressively increases with increasing drug
dose; dangers of ‘dose creep’ or surreptitious addition of over-the-counter NSAIDs
should be considered66. The risk associated with different NSAIDs is not the same in
clinical practice and seems to be higher in drugs with longer half-lives, slow-release
formulations or cyclooxygenase 1 (COX1) selectivity; COX2‑selective antagonists
have been associated with lower NVUGIB risk67.
• Anticoagulants and non-aspirin antiplatelet agentsa (such as clopidogrel) increase the
risk of NVUGIB twofold204.
• Other drugsa (such as serotonin reuptake inhibitors70, metamizole, calcium channel
blockers and aldosterone antagonists) have also been associated with NVUGIB, but
less consistently.
• Combined use of NSAIDs (both unselective COX inhibitors and COX2‑selective
inhibitors) with LDA, thienopyridine antiplatelet agents (for example, clopidogrel),
warfarin, novel antiplatelet drugs (for example, prasugrel and ticagrelor), direct oral
anticoagulants, corticosteroids67 or serotonin reuptake inhibitors70 increases the risk
of NVUGIB. Combining NSAIDs and aldosterone antagonists might increase the risk of
developing NVUGIB more than the risk associated with individual drug use64,66,70.
Gastrointestinal comorbidities
• Eradication of Helicobacter pylori infection before NSAID use reduces ulcer risk by
2.8‑fold and ulcer bleeding risk by 6.4‑fold205.
• The single most important risk factor for bleeding is a history of ulcer complications,
especially in patients treated with NSAIDs or LDA67.
• A history of uncomplicated ulcers increases the risk of complications; eradication of
H. pylori may not reduce the risk completely in patients treated with NSAIDs or LDA67.
• History of dyspepsia, which may be a marker of underlying peptic ulcer disease,
increases the risk of NVUGIB.
Other comorbidities
• Bleeding risk increases with age; >75 years of age is considered high risk67.
• Concomitant disability; for example, the prevalence of gastrointestinal bleeding
events is higher in those with rheumatoid arthritis than in those with
osteoarthritis65,206.
• The risk of NVUGIB increases with an increasing number of comorbidities65,66.
a
These drugs do not induce damage to the gastrointestinal tract; patients must have lesions
caused by other aetiology.
usually not be delayed until the action of the anticoagu-
lant is completely reversed. An INR <2.5 is adequate and
enables successful endoscopic management if needed5,81.
The decision to stop and when to resume antiplatelet
anticoagulant agents at the time of NVUGIB is difficult
and should be guided by post-endoscopy risk assess-
ment and ­consultation with a cardiologist (discussed in
detail below).
Endoscopy. Endoscopy is essential to reveal the cause of
NVUGIB, and early upper gastrointestinal endoscopy
within 24 hours of presentation improves patient out-
comes82–84. Several studies have found no differences in
outcomes between patients who undergo early endoscopy
and those undergoing very early endoscopy (<12 hours of
patient presentation)85–87. Nevertheless, controversy per-
sists because very early endoscopy reveals active bleed-
ing stigmata and need of endoscopic treatment of lesions
without evidence of reduction of the risk of re-bleeding
or improved survival88,89.
Endoscopy should be used to diagnose the cause of
the bleeding and evaluate stigmata of recent haemorrhage
(such as active bleeding, a visible blood vessel, presence of
clots or red or black spots covering the ulcer lesion) and to
classify them according the Forrest classification, which
enables patient selection for endoscopic treatment and
stratification of the risks of re-bleeding, surgery and mor-
tality 90–92 (TABLE 1). Of note, the interobserver agreement
for the Forrest classification is low to moderate93. Vigorous
water irrigation on the ulcer base is r­ ecommended to
improve the accuracy of Forrest classification.
Endoscopic treatment should be provided to patients
with bleeding of Forrest types Ia, Ib and IIa. A meta-­
analysis of randomized clinical trials (RCTs) confirmed
that endoscopic therapy was effective in preventing per-
sistent or recurrent bleeding in Forrest types Ia and Ib
(relative risk (RR) 0.29, 95% CI 0.20–0.43; n ­ umber
needed to treat (NNT) 2, 95% CI 2–2) and Forrest
type IIa (RR 0.49, 95% CI 0.40–0.59; NNT 5, 95% CI 4–6)
compared with no endoscopic therapy 94. The necessity
for endoscopic treatment in patients with Forrest type IIb
bleeding, which is defined as a lesion with a clot that is
red, maroon or black in colour and amorphous in ­texture
and that cannot be dislodged by suction or forceful water
irrigation, remains controversial. The above-mentioned
meta-analysis showed no benefit for endoscopic ther-
apy in Forrest type IIb bleeding 94; however, the studies
included showed significant hetero­geneity, with two
concluding that there was a bene­ficial effect of com-
bining therapeutic endoscopy with intra­venous PPI
therapy compared with PPI alone95,96. Thus, at present,
the approach to managing patients with Forrest type IIb
bleeding should be determined on a case‑by‑case
basis, considering, among others, medical resources,
­endoscopist experience and patient status.
Stigmata of recent haemorrhage, which are visible
on endoscopy, have been used for decades to make risk
stratification and treatment decisions in NVUGIB, but
Doppler assessments of arterial blood flow in the gastro-
intestinal wall, which can be measured using endoscopy,
could revolutionize the field. Detection rates of arterial

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Reference However, current evidence-based guidelines do not

No drug use recommend a routine second-look endoscopy 5,8,10,11,78,
nsNSAIDs
which is defined as scheduled endoscopic assess-
COX2 inhibitors
LDA
ment within 24 hours of the initial diagnosis. A meta-­
Corticosteroids analysis reported a significant reduction in re-bleeding
Corticosteroids + nsNSAIDs (OR 0.55; 95% CI 0.37–0.81) and need for emergency
SSRIs surgery (OR 0.43; 95% CI 0.19–0.96), but not mortality
Treatments

SSRIs + nsNSAIDs
Calcium antagonists
Calcium antagonists + nsNSAIDs
Aldosterone antagonists
Aldosterone antagonists + nsNSAIDs
Anticoagulants
Anticoagulants + nsNSAIDs
Non-aspirin antiplatelet agents
Non-aspirin antiplatelet agents + nsNSAIDs
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14
Relative risk
Figure 5 | Risk of developing NVUGIB associated withNature certainReviews Diseaserisk
drugs. |Relative Primers
and 95% CIs of developing non-variceal upper gastrointestinal bleeding (NVUGIB)
associated with the use of various types of drugs alone or combined with non-selective
NSAIDs (nsNSAIDS) compared with no drug use. Based on data reported in European
databases64. The different colours refer to the different drug classes; the dashed line
highlights a relative risk= 1. COX2, cyclooxygenase 2; LDA, low-dose aspirin; SSRI,
selective serotonin reuptake inhibitor.
signals on ulcer bases using a Doppler probe in patients
with Forrest type Ia bleeding are high (100%) but are
lower in those with Forrest types Ib (46.7%), IIa (90.7%),
IIb (68.4%), IIc (40.5%) and III (8.3%) bleeding 97. These
data could explain the finding that patients with Forrest
type Ib bleeding had a very low re-bleeding rate after
success­ful endoscopic haemostasis in a recent RCT,
although both Forrest types Ia and Ib are often included
together as ‘active bleeding’ (REF. 98). Furthermore, the
use of the Doppler probe facilitates tracing of the under-
lying artery for effective endoscopic haemostasis, which
improves patient outcomes99.
Recently, iatrogenic ulcers following mucosal or sub-
mucosal endoscopic tumour resection have become a
substantial cause of NVUGIB, especially in east Asia,
where endoscopic tumour resection for upper gastro­
intestinal neoplasia is more frequent than in other parts
of the world100. Although evidence is limited, endoscopic
evaluation and management of bleeding from these
ulcers should be considered on a similar basis to those
with peptic ulcers100. Literature regarding endoscopic
evaluation and management methods for bleeding from
other causes such as Mallory–Weiss tear, oesophagitis,
erosive gastritis, duodenitis, vascular abnormalities,
anasto­motic wounds after surgery and upper gastro­
intestinal neoplasia are sparse. Spontaneous haemostasis
is usually achieved in these conditions, and endoscopic
treatment should be considered only in cases of active
bleeding­101. In cases of curative-intent treatment for neo-
plastic lesion, endoscopic or surgical removal of the entire
lesion should be prioritized over endoscopic h ­ aemostasis
to control bleeding.
Second-look endoscopy. Re-bleeding after endoscopic
treatment occurs in 10–15% of individuals with PUB
and results in a twofold to fivefold increase in mortality 5.
(OR 0.65; 95% CI 0.26–1.62), when routine second-look
endoscopy was performed compared with an as‑needed
endoscopy 102. Further analysis showed that any protec-
tive effect for second-look endoscopy was limited to
high-risk patients (that is, those with active bleeding at
index endoscopy). In addition, scheduled second-look
endoscopy is cost effective only in patients at high risk of
recurrent ulcer bleeding, defined as those with high-risk
endoscopic stigmata103.
Management
Initial, pre-endoscopic management
Peripheral intravenous access should be obtained soon
after or at the same time as initial assessment and be
of sufficient size to allow rapid blood transfusion if
required. Resuscitation with crystalloid fluid should be
guided by the haemodynamic status of the patient. The
decision to provide additional blood transfusion should
be individualized on the basis of the patient’s clinical
­status and should take ongoing bleeding, haemoglobin
level and presence of underlying comorbidities that
make the patient sensitive to reduced oxygen-­carrying
capacity into consideration. In general, a restrictive
blood transfusion strategy is recommended. Guidelines5
typically recommend blood transfusion for patients who
have a haemoglobin level <70 g per litre and recommend
targeting a haemoglobin value of 70–90 g per litre104.
These targets can be individualized for patients who are
sensitive to low oxygen-carrying capacity, but overtrans-
fusion should be avoided as it can be associated with
harm (such as congestive heart failure)5,78.
Guidelines recommend administration of intra­
venous high-dose PPI pre-endoscopy to stabilize clots,
downgrade endoscopic stigmata of recent ­haemorrhage
and reduce the need for endoscopic therapy 5,10,78.
However, the use of intravenous pre-endoscopy PPIs has
not shown reductions in the rates of re-bleeding, surgi-
cal intervention or mortality in meta-analyses, therefore,
its use should not delay endoscopy 5,78,105,106. The use of
pre-endoscopy PPIs is considered to be cost effective in
high-risk patients and in low-risk patients with expected
short hospitalizations or outpatient manage­ment 107. The
cost effectiveness of pre-endoscopic intravenous PPIs
is likely maximized in patients with the likelihood of
a high-risk lesion on initial assessment or in those in
whom a delay in endoscopic therapy is expected. By con-
trast, post-endoscopy intravenous PPI use reduces the
risk of re-bleeding and need for surgical intervention
(see below).
Guidelines do not support the routine use of
somato­statin or somatostatin analogues (aimed mainly
at splanchnic vasoconstriction) or tranexamic acid
(an antifibrinolytic agent) in NVUGIB. Although not
­routinely recommended, a single dose of the anti­biotic

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PRIMER

Box 3 | Risk-scoring systems for NVUGIB

Glasgow–Blatchford bleeding score
The Glasgow–Blatchford bleeding scoring system80,207 (0–23 points) aims to predict the need for hospital-based
interventions (such as endoscopic or surgical intervention and blood transfusion) or the risk of hospital-based
complications (such as in‑hospital re-bleeding and substantial decrease in haemoglobin concentration after admission)
or mortality. Although studies use different cut-off values, a score of ≤1 is usually considered low risk and discharge is
considered safe, whereas a score of >7 is usually considered high risk. Parameters included in the scoring system are
haemoglobin level, blood urea concentration, systolic blood pressure, heart rate, sex, presence of melena, recent
syncope, presence of liver disease and heart failure.
Admission Rockall score for NVUGIB (pre-endoscopy)
This scoring system (0–7 points) aims to predict the risk of re-bleeding and mortality80,208. Parameters included in the scoring
system are age, presence of hypovolaemic shock, pulse, systolic blood pressure, minor comorbidities (such as congestive
cardiac failure and ischaemic heart disease) and major comorbidities (such as renal failure, liver failure and cancer).
AIMS65
This scoring system (0–5 points) aims to predict the risk of re-bleeding and mortality80,209,210; a score of ≥2 is considered
high risk. Parameters included in the scoring system are albumin, international normalized ratio for prothrombin time,
mental status, systolic blood pressure and age, which are the basis of the name of the score.
PNED
The Progetto Nazoinale Emorragia Digestiva (PNED) scoring system (0–21 points) aims to predict mortality risk80,211.
A score of ≤4 is considered low risk, 5–8 is considered intermediate risk and ≥9 is considered high risk. Parameters
included in class 3 and 4 of the scoring system are the American Society of Anesthesiologists Physical Status score, time
since admission (<8 hours), haemoglobin level (<7 g per dl), renal failure, advanced age (>80 years), re-bleeding, cirrhosis,
advanced-stage cancer and failure of endoscopic treatment.
Full Rockall score for NVUGIB (post-endoscopy)
This scoring system (0–11 points) aims to predict the risk of re-bleeding and mortality80,212. A score of ≤2 is considered low
risk, 3–4 is considered intermediate risk and ≥5 is considered high risk. Parameters included in the scoring system are the
same as those of the preadmission score and those related endoscopic diagnosis and endoscopic stigmata. The presence
or absence of Mallory–Weiss tears, gastrointestinal malignancy or all other diagnoses are also included in the scoring
system alongside endoscopic stigmata (absence of stigmata or dark spots on ulcers, blood in the upper gastrointestinal
tract, adherent clots or visible or spurting vessels).
NVUGIB, non-variceal upper gastrointestinal bleeding.

erythromycin 30–120  minutes before endoscopy,
­especially in those with severe and ongoing bleeding,
can improve endoscopic visualization, reduce the need
for blood transfusion and second-look endoscopy and
reduce the length of hospitalization5,78,108.
Endoscopic management
Various modalities to achieve endoscopic haemostasis
aimed at stopping active bleeding in those with UGIB
associated with peptic ulcers or other causes exist and
are detailed in BOX 4.
PUB. Meta-analyses show that injection therapy with
solutions other than adrenaline, thermal therapy and
haemoclip therapy (BOX 4) are all effective methods for
achieving haemostasis in PUB with no single modality
being superior 109–114. For high-risk PUB, adrenaline plus
any second haemostasis modality (except spray ther-
apy) significantly reduced re-bleeding (OR 0.53; 95% CI
0.35 – 0.81) and need for emergency surgery (OR 0.68;
95% CI 0.50 – 0.93), but not mortality, as compared with
adrenaline injection monotherapy 113. Thus, if adrenaline
injection is used to treat PUB with high-risk stigmata,
it should be used only in combination with a second
endoscopic haemostasis modality. The use of soft coagu­
lation using haemostatic forceps (FIG. 6) has become
more frequent along with development of endoscopic
­submucosal dissection115.
Over-the-scope clip (OTSC system; OVESCO
Endo­s copy AG, Tübingen, Germany) and haemo-
static powders such as TC‑325 (Haemospray; Cook
Medical, Bloomington, IN, USA) and the EndoClot
polysacchar­ide haemostatic system (EndoClot Plus,
Santa Clara, CA, USA) are newly developed devices or
substances with promising outcomes, but they still lack
sufficient data to draw robust conclusions concerning
efficacy 116–118. Over-the-scope clips overcome the limita­
tions of haemoclips, such as smaller size and lower
capacity to include the whole lesion and induce pres-
sure, and are good options for salvage or rescue endo-
scopic haemo­stasis interventions after conventional
endoscopic therapies have failed before surgical or
radio­logical intervention. Haemostatic powders mainly
act as a tamponade and a physical barrier from factors
such as gastric acid and might be more effective than
conventional endoscopic therapies in cases in which
targeting the bleeding point is difficult. Notably, bleed-
ing duodenal ulcers at the posterior wall may require
subsequent vigilance after endoscopic therapy; if the
gastroduodenal artery is affected, radiological coiling
or surgery may be needed to stop the bleeding 1.
Non-PUB NVUGIB. For NVUGIB other than PUB,
endoscopic haemostasis should be selected according
to the nature of the disease, severity of bleeding and
preference of the endoscopist because of the low quality

10 | ARTICLE NUMBER 18020 | VOLUME 4 www.nature.com/nrdp

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of evidence and scarcity of comparative data. Bleeding
associated with Mallory–Weiss tears is u ­ sually self-­
limited, and endoscopic haemostasis would be applied
only when active bleeding is detected. Among various
endoscopic haemostatic modalities, haemoclip and
band ligation therapy are preferred as they achieve
haemostasis and closing of the mucosal tear without
thermal damage to the thinner lacerated tissue119,120.
Endoscopic haemostasis to control bleeding associated
with vascular abnormalities is usually carried out using
coagulation therapy such as argon plasma coagula-
tion, laser therapy or radiofrequency ablation. Argon
plasma coagulation is especially useful for lesions that
are spread (for example, gastric antral vascular ectasia
(longitudinal antral folds converging on the pylorus
that contain visible columns of tortuous red ectatic
vessels)) or for multiple lesions (arteriovenous malfor-
mations or telangiectases) as its coagulation depth is
uniform and the risk of perforation is lower than that
of laser therapy 121.
For patients with a few or localized lesions, haemo-
stasis using mechanical therapy or injection therapy are
also applicable. As a new approach for refractory gastric
antral vascular ectasia, radiofrequency ablation using
the HALO90 Ablation Catheter System (Covidien GI
Solutions, Sunnyvale, CA, USA) has been tested with
promising outcomes122–125. In Dieulafoy lesions, either
mechanical therapy (such as band ligation) or haemo-
clips are considered to be the first-line treatment
and over-the-scope clips are a rescue treatment for
refractory cases126.
Medical therapy after endoscopy
The goals of medical treatment are to reduce the risk
of re-bleeding while healing the ulcer and preventing
long-term recurrence. The rationale for raising intra-
gastric pH to >6 is based on studies that demonstrated
that acidity affects platelet aggregation and destabilizes
clot formation44,127,128. A meta-analysis of RCTs found a
significant reduction in re-bleeding (RR 0.40, 95% CI
0.28–0.59; NNT 12, 95% CI 10–18), surgery (RR 0.43,
95% CI 0.24–0.76; NNT 28, 95% CI 21–67) and mor-
tality (RR 0.41, 95% CI 0.20–0.84; NNT 45, 95% CI
33–167) with intravenous post-endoscopic PPI ther-
apy (bolus injection followed by continuous infusion
versus placebo or no treatment for 72 hours after endo-
scopic therapy)94. High-dose intravenous omeprazole
(a PPI) was superior to intravenous administration
of ranitidine (a histamine H 2 receptor antagonist)
in maintaining gastric pH >6 (percentage of time
gastric pH <6 in the study period was 15.3 ± 5.9%
(mean ± standard deviation) for omeprazole versus
61.8 ± 5.6% (mean ± standard deviation) for ranitidine,
P <0.0001)45.
Given the cost of continuous intravenous ther-
apy, less costly intermittent (including oral) therapy
is a ­logical consideration, although a recent study
has shown that the timing or dosing of PPI has little
impact on cost, much less than efficient triage and dis-
charge of patients129,130. Several meta-analyses found
that intermittent PPI use was non-inferior compared
with bolus plus continuous infusion of PPIs in terms
of re-bleeding (at 3, 7 and 30 days), the need for blood
transfusion and urgent intervention and mortality 131,132.
Intermittent oral PPI may be as effective in pH control
as equivalent doses of intravenous PPIs given intermit-
tently. Both oral and intravenous PPIs (lansoprazole)
given intermittently achieved similar pH control during
the study period (percentage time gastric pH <6 was
67.8 ± 4.5% (mean ± standard error) for intravenous PPI
versus 64.8 ± 4.2% (mean ± standard error) for oral PPI),
although intravenous PPI increased pH to >6 sooner
than oral PPI (by 1 hour)47, but the ranges are wide.
Thus, intermittent, high-dose PPIs given at least twice
daily are an option, using oral PPIs in patients able to
tolerate oral medications94.

Table 1 | Risk prediction using the Forrest classification

Endoscopic stigmata Forrest Risk of persistent Risk of Risk of needing Risk of
classification bleeding or re-bleeding surgery for mortality
re-bleeding after bleeding without without
without endoscopic endoscopic endoscopic endoscopic
treatment haemostasis treatment treatment
Acute bleeding
Spurting haemorrhage Type Ia Very high High High Low
Oozing haemorrhage Type Ib Very lowa
Signs of recent bleeding
Non-bleeding visible vessel Type IIa High High High Low
Adherent clot Type IIb High Very low Low Low
Flat pigmented spot Type IIc Low Not Very low Very low
applicableb
Lesion without active bleeding or signs of bleeding
Clean base (no vessel, Type III Very low Not Extremely low Very low
blood or clot on the base) applicableb
Table based on data in REF. 220. aA recent study demonstrates that Forrest type Ib has a very low re-bleeding rate within 72 hours
after successful endoscopic haemostasis98. bIn patients with Forrest type IIc and type III, the risk of re-bleeding is <10%; thus,
endoscopic haemostasis provides no advantage.

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Patients with PUB have an unacceptably high
rate of recurrent bleeding. In an RCT of patients with
H. pylori-associated PUB, the rate of recurrent bleed-
ing after 12‑month follow‑up was 27% in patients who
did not undergo H. pylori eradication therapy com-
pared with 0% in those who did133. H. pylori eradication
is more effective than long-term maintenance anti­
secretory therapy in reducing recurrence; a systematic
review of studies assessing re-bleeding in patients with
documented H. pylori eradication revealed a 1.1% inci-
dence of re-bleeding over mean follow‑up periods of
11–53 months. However, the re-bleeding rate in patients
who did not undergo H. pylori eradication therapy but
were maintained with long-term anti­secretory therapy
was 5.6%134. These findings set the current Cochrane rec-
ommendations to test all patients with PUB for H. pylori
and provide eradication therapy if needed134.
When patients have to use NSAIDs after PUB, RCTs
have shown that maintenance PPI therapy significantly
lowers the risk of recurrent ulcer bleeding at 6 months
compared with H. pylori eradication alone (4.4% ver-
sus 18.8%, P = 0.005; NNT = 7) 68,135. In a 12‑month
double-blind study, patients taking celecoxib (a COX2
inhibitor) plus twice-daily PPI had fewer recurrent
ulcer bleeding events than those taking celecoxib plus
­placebo (0% versus 8.9%, P = 0.0004; NNT = 12)69.
Another meta-analysis also found that the combination
of selective COX2 inhibitors plus PPIs provides the best
gastro­intestinal protection, followed by selective COX2
inhibitors alone and non-selective NSAIDs plus PPI136.
Thus, the current best practice for those patients with a
PUB who must remain on NSAIDs is that they should
receive a COX2‑selective NSAID at the lowest effective
dose plus PPI therapy 68,69.
Recurrent bleeding
In patients with clinical evidence of re-bleeding, repeat
upper endoscopy should be performed with haemo­stasis
of high-risk endoscopic stigmata of haemorrhage, if pres-
ent. A seminal RCT comparing endoscopic therapy with
surgery for recurrent PUB following successful initial
endoscopic control of PUB showed that 73% of patients
randomly assigned to endoscopic re-treatment had long-
term control of their bleeding and avoided ­surgery com-
pared with 93.1% of surgery-treated patients137. Patients
in the endoscopy group had a lower rate of complica-
tions than those in the surgery group (14.5% versus 36%;
P = 0.03)137. If further bleeding occurs following a second
endoscopic treatment, transcatheter angiographic embo-
lization or surgery should be considered5,10,11. In those
with PUB after failed endoscopic haemostasis, a higher
re-bleeding rate was observed following transcatheter

Box 4 | Examples of endoscopic therapy for NVUGIB

Injection therapy
• Endoscopic injection of small volumes of treatment solution close to the bleeding site
• Several types of treatment solutions can be used:
-- Absolute ethanol: aimed at inducing dehydration and fixation of the bleeding blood vessel, with subsequent
vasoconstriction and necrosis
-- Adrenaline in an isotonic or hypertonic saline solution: adrenaline induces vasoconstriction and vascular tamponade
and hypertonic saline solution induces tissue swelling, fibrinoid necrosis and thrombogenesis
-- Polidocanol: a sclerosant that irritates and induces endothelial cell damage and thrombogenesis
Mechanical therapy
• Haemoclip: mechanical compression of the bleeding vessel using a metallic clip
• Band ligation: mechanical compression of the bleeding vessel using a rubber band commonly used for oesophageal
variceal ligation
• Over-the-scope clip (OTSC system; OVESCO Endoscopy AG, Tübingen, Germany): a large superelastic nitinol clip
with a bear-trap shape that fits on the endoscope tip and is commonly used for closures of perforations and fistulas
Thermal therapy
• Soft coagulation using haemostatic forceps: monopolar or bipolar electrocautery or heat probe are contact devices
that use heat or electrical current to coagulate the bleeding vessel
• Argon plasma coagulation: a stream of ionized argon gas conducts electricity, without direct contact, resulting in
coagulation of superficial tissues
• Laser therapy: a stream of intense, small and nearly non-divergent beams of monochromatic radiation in the visible
region induces heat and coagulates or cuts tissues
• Radiofrequency ablation: a flexible strap that slides over the endoscope tip and generates radiofrequency energy,
commonly used for ablation of Barrett oesophagus
Spray therapy
• Thrombin or fibrin glue: acceleration of the blood coagulation cascade by thrombin or supply of fibrinogen and
thrombin (that is, fibrin) to create a primary tissue seal at a bleeding site
• TC‑325 (Haemospray; Cook Medical, Bloomington, IN, USA): a mineral blend powder that absorbs and acts both
cohesively and adhesively by forming a mechanical barrier over the bleeding site
• EndoClot polysaccharide haemostatic system (EndoClot Plus, Santa Clara, CA, USA): a polysaccharide powder modified
from plant starch that forms a gel in the presence of blood and adheres to and seals the bleeding tissue

12 | ARTICLE NUMBER 18020 | VOLUME 4 www.nature.com/nrdp

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 PRIMER

Indeed, the time interval from discontinuation of

a b
c d
LDA to an adverse cardiovascular event was ~8 days for
acute coronary syndrome, 14 days for cerebrovascular
syndromes and 25 days for acute peripheral arterial
syndromes147, whereas the risk of recurrent gastro­
intestinal bleeding is highest in the first 3 days after the
index event 135. As a consequence, antiplatelet therapy
is often stopped and resumed after 3–5 days in those
at high risk of recurrent NVUGIB to avoid the period
of high risk of recurrent bleeding while the antiplatelet
function of LDA to prevent cardiovascular events may
persist. On the basis of existing evidence, several guide-
lines have been formulated5,49 (FIG. 7). To our knowledge,
no study designed to investigate the withdrawal and/or
resumption of antiplatelet agents other than LDA has
been carried out.

Patients on anticoagulant therapy

Figure 6 | Management of using soft coagulation. a | Fresh blood flows from the ulcer
Nature Reviews | Disease Primers
to the greater curvature of the gastric body (arrow). b | Bleeding point under the clot
|
is near the upper rim of the ulcer (arrow). c   Slight removal of the clot shows spurting
bleeding (arrow). d | Soft coagulation by using haemostatic forceps successfully
stops the bleeding (arrow). Images courtesy of Prof. M. Fujishiro, The University of Tokyo
Hospital, Japan.
angiographic embolization than surgery, but no signifi­
cant difference in mortality or need for additional
interventions was observed138,139. Emerging data sug-
gest that haemostatic powders and over-the-scope clips
can be successfully employed as salvage haemostasis
­therapy 140,141, but more data are needed10,11,118,142,143.
Patients on antiplatelet therapy
The evidence to guide practice in those with NVUGIB
who are using antiplatelet agents is very limited and
mostly restricted to LDA monotherapy. The risk of
recurrent PUB, most of which occurred within the first
5 days after the index bleeding event, was increased in
those on continued LDA before endoscopy (HR 1.9)
compared with discontinuing LDA use for 8 weeks
after PUB144. However, none of these bleeding events
were fatal, whereas all-cause mortality in those who
discontinued receiving LDA was increased owing to
thrombo­embolic events. In a smaller retrospective study,
individuals with cardiovascular disease who stopped
LDA therapy had an increased risk of death or cardio­
vascular event (HR 6.8) in the first 6 months of follow-up
compared with those who continued LDA therapy.
Early resumption of LDA after the bleeding event was
not associated with a signifi­cant increase in mortality
related to PUB. These studies144–146, albeit small, provide
strong evidence to continue LDA in individ­uals who
develop a PUB ­during treatment or at least to resume
treatment early.
The management of patients on anticoagulant therapy
who develop an NVUGIB represents a clinical challenge,
and two clinical scenarios should be considered: treat-
ment before endoscopy and treatment after diagnosis
has been established and the bleeding event has been
controlled. Irrespective of whether patients are taking
vitamin K antagonists or DOACs, treatment should be
stopped immediately and pre-endoscopic management
should be initiated as usual. Endoscopy should not
be delayed in patients with an INR <2.5 as outcomes
(such as need for intervention or death) are similar in
those with normal versus elevated INR at admission if
INR is corrected to values <2.5 before endoscopy 5,81,148,149.
Conversely, a retrospective study in 134 patients with
bleeding events with INR ≥3.5 suggested that effec-
tive therapeutic endoscopic intervention becomes
less frequently possible as the INR increases150. Under
these circumstances, reversal of INR (see below) seems
­appropriate before endoscopy.
Vitamin K antagonists. For patients on vitamin K
antagonists (such as warfarin and dicumarinics), pro-
longed INR can be reversed with vitamin K, which acts
slowly (INR begins to decrease within 2–4 hours and
normalizes within 24 hours) but more dur­ably than pro-
thrombin complex concentrates (PCCs) or fresh frozen
plasma (FFP)151. Vitamin K should be injected slowly
to minimize severe (anaphylactic or anaphy­lactoid)
reactions152 and INR should be monitored as vitamin K
antagonists have a long half-life153. Haemostatic factors
(such as PCCs and FFP) can also be used to normal-
ize haemostasis when reversal of anticoagulation is
urgent. PCCs are preferred over FFP because they can
be administered more rapidly without blood group test-
ing or thawing in smaller volumes and are associated
with lower mortality, quicker INR normalization (dif-
ference of 6.5 hours) and a similarly low risk of throm-
boembolism154. Four-factor PCC provides more reliable
INR correction than three‑factor PCC155, but reported
differences in mortality are inconsistent 156,157. FFP is
still widely used because of perceived lower cost than
PCCs158; however, the difference in price for identical
INR correction is only 50%159. Recombinant factor VIIa

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PRIMER

is not recommended (high cost and 11% thromboembo-
lism risk)160. FIGURE 8 summarizes commonly accepted
recommendations for patients on vitamin K antagonists
who develop NVUGIB161–163.
DOACs. DOACs target single enzymes of the coagu-
lation process; apixaban, edoxaban and rivaroxaban
inhibit factor Xa whereas dabigatran directly inhibits
thrombin72. Plasma monitoring of coagulation factors
is not needed, which is a clinical advantage over vita-
min K antagonists. However, unlike vitamin K antago­
nists and dabigatran, anti-factor Xa agents currently
have no widely available reversal agents, are not yet
approved and normalization of clotting factor levels
takes 12–24 hours164.
Routine coagulation tests may be conducted, but
they are unreliable (BOX 5). Renal function should be
monitored as it is frequently compromised in those
with UGIB on DOACs, and aggressive fluid replace-
ment may be needed to maintain renal function165,166.
Creatinine clearance enables the estimation of the per-
sisting DOAC effect 167. Haemodialysis can be of help
for dabigatran clearance treatment only but requires
haemodynamic stability. Prolonged continuous haemo-
dialysis may help to prevent bleeding rebound effects168.
Finally, activated charcoal can also be used in the case
of a recent (≤3 hours) overdose and when no emergency
UGIB endoscopy is contemplated169–171.
Haemostatic agents such as PCCs or activated PCCs
have been shown to be effective at restoring coagula-
tion in patients with NVUGIB who are taking DOACs,
although evidence is limited172–174. By contrast, FFP is
not recommended as clotting factors are 25‑fold more
dilute than in PPCs, and very large volumes are required
to overwhelm the binding capacity of DOACs. The most
promising therapeutic options rely on the availability
of reversal agents, which could be used in the case of
life-threatening gastrointestinal bleeding, but reliable data
are needed because of the risk of thromboembolism175,176.
Dabigatran has a specific antidote (idarucizumab), which
works effectively in minutes with thromboembolism and
a rebound effect reported in 6.8% and 23% of patients,
respectively 171. In this cohort study 171, including patients
who had uncontrolled bleeding (45.5% of whom had
gastro­intestinal bleeding and 32.6% had intracranial
haemorrhage), the median maximum percentage reversal
of dabigatran was 100% on the basis of either the diluted
thrombin time or the ecarin clotting time; the median
time to cessation of bleeding was 2.5 hours. In those
undergoing emergency procedures, haemostasis was

NVUGIB in patients taking antiplatelet agents

High-risk stigmata on endoscopy Low-risk stigmata on endoscopy

(Forrest classification Ia, Ib, IIa or IIb) (Forrest classification IIc or III)

Successful endoscopic treatment

Antiplatelet agents Antiplatelet agents Antiplatelet agents Antiplatelet agents

for primary prevention for secondary prevention for primary prevention for secondary prevention

• Withhold antiplatelet agents Aspirin DAPT • Withhold antiplatelet agents

• Re-evaluate indication • Re-evaluate indication Continue
• Reintroduce after ulcer • Reintroduce before discharge aspirin
healing or earlier if needed if indicated or DAPT

Second-look endoscopy at • Continue LDA

Resume the discretion of endoscopist • Consult cardiologist before restarting
by day 3–5 or if re-bleeding is suspected additional antiplatelet agent

Figure 7 | Management of NVUGIB in those using antiplatelet agents. If the antiplatelet therapy
Nature is taken
Reviews for primary
| Disease Primers
prevention of cardiovascular events, it should be discontinued in patients with a history of peptic ulcer bleeding (PUB);
if an indication for continuing antiplatelet therapy exists, the risk of recurrent bleeding should be assessed by clinical
and endoscopic criteria. Antiplatelet agents should not be stopped or, if stopped, they should be resumed a few days after
endoscopy in those with non-variceal upper gastrointestinal bleeding (NVUGIB) who are on secondary cardiovascular
prevention (for example, those with a previous ischaemic vascular event). In patients with PUB at low risk of recurrent
bleeding, antiplatelet treatment should not be discontinued as the risk of a thromboembolic event outweighs the risk
of recurrent bleeding from the gastrointestinal tract. In patients at high risk of recurrent bleeding, antiplatelet treatment
should be stopped and can be resumed within 3–5 days. If the patient is receiving dual antiplatelet therapy (DAPT;
combination of low-dose aspirin (LDA) and a P2Y purinoceptor 12 inhibitor), then the least potent antiplatelet drug should
be restarted and a cardiologist’s opinion should be sought for resuming the second antiplatelet agent3. Algorithm based
on recommendation of the European Society of Cardiology Working Group on Thrombosis49 and the European Society of
Gastrointestinal Endoscopy guidelines5.

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 PRIMER

NVUGIB in patients taking vitamin K antagonists

Stop vitamin K antagonist

Determine INR

INR <2.5 INR >2.5

No haemodynamic compromise Haemodynamic compromise

Reverse vitamin K antagonistsa

Reverse vitamin K antagonists a
• Stop treatment with
vitamin K antagonists
• Administer vitamin K:
5–10 mg intravenous infusion
Endoscopy over 30 minutes
• Stop treatment with vitamin K antagonists
• Administer vitamin K: 5–10 mg intravenous infusion over 30 minutes)
• PCC according to baseline INR valueb
Check INR 20–30 minutes after PCC infusion
• INR <1.5: recheck in 6 hours, then daily
• INR >1.5: seek advice and consider PCC reinfusion

Figure 8 | Management of NVUGIB in those using vitamin K antagonists. Vitamin K antagonists such as
Nature Reviews warfarin
| Disease Primers
or coumadin should be stopped in patients who develop upper gastrointestinal bleeding and resumed soon after
the bleeding is controlled. The international normalized ratio (INR) should be determined, and if INR is <2.5, diagnostic
and therapeutic endoscopy can be performed safely. If INR is >2.5, endoscopy can be delayed until therapy to reverse
the effect of the vitamin K antagonist has been implemented. The haemodynamic compromise (that is, blood pressure
and volume that are not adequate to support normal organ function) will determine the type of therapy needed.
The INR can be tested at intervals of 4, 12, 24, 28 and 72 hours, but this is based on little evidence. aBalancing
with the risk of thrombosis, which is highest in patients who have atrial fibrillation, a CHA2DS2‑VASc score of ≥6,
a mechanical mitral valve or a cardiac assist device. bFresh frozen plasma can be given at 15 ml per kg if PCC is
unavailable. Algorithm based on expert consensus49,161–163. NVUGIB, non-variceal upper gastrointestinal bleeding;
PCC, prothrombin complex concentrate.

assessed as normal in 93.4% at the start of the intended
procedure (1.6 hours after idarucizumab administration).
At 90 days, thrombotic events had occurred in 6.3% and
7.4% of patients and the mortality was 18.8% and 18.9%
in those with uncontrolled bleeding and those under-
going emergency surgery, respectively. Rebound effects
may occur for up to 6 days and require repeat dosing 177.
The costs of these compounds may hamper the use in
clinical practice. Other investigational antidotes include
andexa­net alfa (for anti-factor Xa agents) and ciraparan-
tag (for many DOACs)178,179. FIGURE  9 summarizes
current recommendations167,176,180.
Continuing therapy following bleeding control. Once
the bleeding event has been controlled, the decision to
resume anticoagulation should involve a multi­disci­
plinary team and the patient; the need for anti­coagu­
lants should be reassessed using available risk scores (for
example, CHA2DS2‑VASc and HAS-BLED)181,182. The
implementation of alternative management (for example,
ablation therapy for atrial fibrillation or catheter-­based
atrial appendage occlusion), change of anti­coagulants
(for example, apixaban may have a lower risk of gastro-
intestinal bleeding than other DOACs in indirect com-
parison studies)72 and optimization of treatment (for
example, PPI, H. pylori eradication, stricter INR control
or DOAC dose adaptation) should also be considered.
Data, mostly involving vitamin K antago­nists72,183, show
that resuming oral anticoagulation is associated with a
lower mortality despite more frequent major bleeding 184.
A recent study involving 1,539 patients suggested that
dabigatran offers simi­lar protection against thrombo­
embolism with less re-­bleeding than warfarin after
major bleeding 185. With respect to timing, although it
is still a matter of debate, war­farin should be restarted
7–14 days following NVUGIB on the basis of a single
available study, whereas DOACs act more rapidly 186.
If early anticoagulation is indicated (for example, in
those with a high thrombo­e mbolic risk), a bridge
approach with heparin may be used. A recent joint con-
sensus document composed by several international
cardiology societies advocates an earlier resumption
of vitamin K antago­nists — within the first week for
patients with atrial f­ ibrillation ­associated with valvular
heart disease187.
Quality of life
At the time of an NVUGIB, symptoms can include
vomit­ing of blood and blood in stools, abdominal pain,
chest pain, cramping, burning, fatigue, dizziness, palpi­
tations and diarrhoea. Thus, the burden on patients
during a bleeding event and hospitalization is con-
siderable, and health-related quality of life (HRQOL)
is substantially impaired105,188,189. A negative associ­
ation exists between the number of symptoms experi-
enced by patients and self-reported levels of HRQOL189.
Impairment to physical health accounts for most of
the decrement in HRQOL experienced by individuals
at the time of a bleeding event. Issues with mobility,
performing daily activities, pain and discomfort have
all been more frequently cited by patients than issues
with a­ nxiety and depression, and following hospital

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PRIMER

Box 5 | Coagulation tests for DOACs
Results of routine coagulation tests in patients taking
direct oral anticoagulants (DOACs) are unreliable and
vary depending on the reagents used. Approximately
20% of patients who take dabigatran have a normal
activated partial thromboplastin time213,214. However,
the American Society of Hematology states in its
practice guide that dabigatran is unlikely to contribute
to bleeding if partial thromboplastin time is normal215.
Similar findings have been reported with prothrombin
time for rivaroxaban216. In some specialized laboratories,
activity assays calibrated to the specific drug can be
performed (that is, diluted thrombin time specific
for dabigatran and anti-factor Xa assays specific for
rivaroxaban, apixaban and edoxaban)217.
admission for NVUGIB, patients have reported levels
of general and physical fatigue to be considerably higher
than mental and motivational fatigue105,188,190.
With clinically effective endoscopic, surgical and
medical therapies to stop and prevent bleeding, many
physical symptoms can be resolved and improvements
in HRQOL following the bleeding event can be r­ ealized.
The few studies taking repeated HRQOL measures
from patients who have had an NVUGIB have shown
a signifi­cant reduction in symptoms and improvements
in the physical dimensions of health following discharge
compared with during the hospital stay 105,188,189.
The long-term consequences of an NVUGIB for
patients often include anaemia, which is associated
with fatigue, heart palpitations, pallor and shortness
of breath191. The already high prevalence of anaemia
(50–80%)192,193 in patients discharged from the hospital
following a bleeding event is likely to increase, with more
restrictive blood transfusion strategies being adopted for
NVUGIB104,194,195. Iron supplementation in the months
following an NVUGIB can help increase haemoglobin
levels and correct anaemia, but little is known about
whether this directly translates into improvements in
HRQOL196. One small study in 97 patients diagnosed
with anaemia following NVUGIB showed that 6 months
after the NVUGIB, the proportion of patients who
reached the normalized HRQOL score was higher and
general and physical fatigue levels were lower in those
patients for whom anaemia had been resolved than
in those with persistent anaemia; differences at other
time points were non-significant 188. Iron supplemen-
tation can be provided intravenously before discharge,
which will reduce the time to recover to appropriate
haemoglobin levels197.
HRQOL generally follows an upward trajectory in
the weeks and months following hospital discharge
for NVUGIB. However, a return to general popula-
tion normal levels seems unlikely, probably because
of the considerable role of pre-existing comorbidi-
ties and their associated treatments in the aetiology
of NVUGIB105,188–190. For patients with NVUGIB, the
increased risk of re-bleeding associated with NSAIDs
and antiplatelet and anticoagulant therapies must be
carefully considered when planning subsequent care.
NVUGIB can have a substantial impact on other
aspects of quality of life (QOL) in patients and their
families. Patients can require many days of informal
care from family members at home during the first
few weeks following a bleeding event190. In providing
this help, caregivers must take time away from their
usual activities, which may incur costs (financial or
otherwise). In addition, for patients who are in paid
employment at the time of NVUGIB, an immediate
return to work is unlikely, resulting in a loss of working
hours and possible earnings190. The consequences of
NVUGIB can, therefore, be substantial and wide rang-
ing, affecting aspects of HRQOL and QOL for patients
and their families.
Outlook
NVUGIB is one of the most frequent causes of hos-
pitalization, morbidity and mortality associated with
digestive diseases. Despite the important advances
observed in the field, the management of patients with
NVUGIB has become ever more challenging owing to
an ageing population with comorbidities and complex
therapies. PUB remains the main cause of NVUGIB, and
most advances in NVUGIB have been focused on this
pathology. However, the face and profile of NVUGIB
events are changing, which demands new approaches in
­prevention, diagnosis and therapy 9,23.
Management
From a pathogenetic point of view and in addition to
the appropriate endoscopic management of bleeding
lesions, stabilization of the clotting process in the acidic
environment of the upper gastrointestinal tract is a goal
that should be achieved for the successful control of
the bleeding event. Although the route of administra-
tion and best dosing regimen are still matters of debate,
there is consensus that PPIs are the drug of choice. The
development of new compounds such as a new class
of potassium-competitive acid blockers may facilitate
emergency treatment of NVUGIB as they have a faster
onset and greater, more consistent and longer acid
­control198 than PPIs.
Endoscopic diagnosis and treatment of gastro­
intestinal bleeding lesions probably represent the most
important advances in the control of bleeding events.
Innovation in endoscopic techniques continues to
provide new tools for the management of NVUGIB.
New therapies with compounds or devices that can be
safely applied during the endoscopic procedures or new
diagnostic tools such as the endoscopic Doppler probe
that can improve the localization of the blood vessel
responsible for the bleeding 97 will probably be imple-
mented in our routine clinical practice in the future
once they prove to be safe and useful in clinical trials.
Patients with ongoing bleeding despite initial volume
restitution could benefit from very early endoscopy
(<12 hours or even <6 hours), but this should be clarified
in future studies. New studies should also define whether
­routine second-look endoscopy can be performed in
selected patients at high risk of therapeutic failure after
first-line therapy.

16 | ARTICLE NUMBER 18020 | VOLUME 4 www.nature.com/nrdp

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 PRIMER

UGIB in patients taking DOACs Prognostic scoring systems

Several prognostic scores have been developed to facili­
Inquire about type and last dose of DOAC
tate the clinical decision path at the time of emergency
Blood sample to measure creatinine and specific coagulation test (if available) admission before and/or after endoscopy. When sev-
eral prognostic scores are used or proposed, or when
they are infrequently used in most emergency rooms200,
Mild Moderate to severe bleeding Life-threatening bleeding the logical conclusion is to assume that none of them
bleeding or ongoing bleeding despite
adequate measures
fulfils all demands required by the clinicians. The GBS
Undergo measures to control seems to be the best at predicting most outcomes but
mild bleeding plus not mortality. A low GBS score (0–1) would mandate
• Aggressive fluid replacement Undergo measures to ambulatory treatment, but few patients present at
• Consider charcoal (DOAC overdose control moderate or severe
<3 hours) bleeding plus
emergency rooms with such a low score, which limits
For dabigatran, consider • For dabigatran: its impact. With new statistical approaches, learning
Delay or • Haemodialysis intravenous idarucizumab machines and artificial intelligence systems, efforts
interrupt • Intravenous idarucizumab • For anti-factor Xaa: should be made to find the best tool to predict the best
DOAC For anti-factor Xaa, consider four-factor PCC four-factor PCC management approach.
Figure 9 | Management of NVUGIB in those on DOACs. Nature
DirectReviews | Disease Primers
oral anticoagulant
(DOAC) treatment should be withheld in patients with an ongoing non-variceal upper Prognosis
gastrointestinal bleeding (NVUGIB) episode. Depending on the severity of bleeding and Although overall mortality associated with NVUGIB
the specific DOAC taken, other measures might be needed. UGIB, upper gastrointestinal has declined over time owing to a parallel decrease in
bleeding. aIf idarucizumab is not available (in case of dabigatran use) or the patient is the number of events, mortality linked to the bleeding
treated with anti-factor Xa, use four‑factor prothrombin complex concentrate (PCC). event itself is resistant because the majority of patients
Algorithm based on expert consensus and recommendations of the European Hearth with NVUGIB die from non-bleeding-related causes4.
Rhythm Association167,176,180. Clearly, further improvements of this outcome will be
a challenge and probably require a multidisciplinary
Patients on antiplatelet or anticoagulation agents approach by specialized teams.
The clearest changes are the progressive decline in Finally, one aspect often overlooked and rarely
H. pylori-related PUB in developed countries and a pro- investigated is the prognosis of patients with NVUGIB
gressive increase in elderly patients with NVUGIB, who beyond the event. Thus far, little attention has been
often take antiplatelet and anticoagulant agents. These paid to the QOL of patients following a gastrointesti-
changes demand specific approaches in both prevention nal bleeding event because this aspect requires con-
and therapeutic management owing to the increased tact to be maintained with patients and actions to be
risk of thromboembolic events when these therapies implemented after hospital discharge. The appropriate
are withheld during a bleeding event. In our experience, management of anaemia and iron deficiency has the
the proportion of patients with this problem is growing. potential to directly affect the QOL and performance of
The new DOACs will progressively replace vitamin K most patients. Implications for physical health, mobility,
antagonists, and the development of agents to reverse performance of daily activities, pain, discomfort, ­anxiety
each specific DOAC will be a challenge in terms of the and depression following hospital admission and dis-
appropriate management and costs. The opportunity charge have not been as adequately investigated and
to improve adherence to guideline recommendations are as important to patients and families as the bleed-
for PPI prophylaxis for those patients on antiplatelet ing itself. These aspects need to be featured within our
and/or anticoagulant therapy remains a challenge in daily agenda when ­considering the appropriate management
­clinical practice199. of patients105,188,190.

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Acknowledgements
A.L. declares that his work on this manuscript was partially
funded by a grant from the Spanish Instituto de Salud Carlos
III PI/PI08/1301 and “Fondo Europeo de Desarrollo Regional
(FEDER) de la Unión Europea. – Una manera de hacer Europa
–”. The authors thank M. Fujishiro, The University of Tokyo
Hospital, for the images used in Fig. 6.
Author contributions
Introduction (A.L.); Epidemiology (C.V.); Mechanisms/
pathophysiology (A.L. and R.H.H.); Diagnosis, screening and
prevention (R.H.H., A.L., A.R. and M.F.); Management
(J.J.Y.S., I.M.G., J.M.S. and J.-M.D.); Quality of life (H.E.C.);
Outlook (all authors); Overview of the Primer (A.L.).
Competing interests
A.L. is an adviser to Bayer Healthcare and Bayer AG. J.M.S.
is an adviser to Aralez Pharmaceuticals. All other authors
declare no competing interest.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional
claims in published maps and institutional affiliations.
Reviewer information
Nature Reviews Disease Primers thanks E.J. Kuipers,
P. Malfertheiner, R. Marmo, F. Radaelli and other, anonymous
reviewer(s) for their contribution to the peer review of
this work.
How to cite this Primer
Lanas, A. et al. Non-variceal upper gastrointestinal bleeding.
Nat. Rev. Dis. Primers 4, 18020 (2018).

NATURE REVIEWS | DISEASE PRIMERS VOLUME 4 | ARTICLE NUMBER 18020 | 21

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