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Non-Variceal Upper Gastrointestinal Bleeding
Non-Variceal Upper Gastrointestinal Bleeding
Gastrointestinal bleeding is a medical emergency and In this Primer, we focus on NVUGIB in the com-
represents the most common cause of hospitalizations munity setting, which is more common and less severe
associated with digestive diseases in most countries1,2. than NVUGIB in inpatient hospital settings, which
Upper gastrointestinal bleeding (UGIB) is defined by occurs in association with hospitalizations due to other
any gastrointestinal bleeding above the ligament of Treitz, serious conditions (such as neurological, renal, cardiac,
which includes the oesophagus, stomach and proximal pulmonary, metabolic, traumatic or septic conditions).
duodenum. By contrast, middle and lower gastrointesti- Although both conditions are life threatening, the
nal bleeding originate in the small bowel below the liga- mortality associated with NVUGIB is fourfold higher
ment of Treitz or in the colorectum3. UGIB events can be in patients who develop bleeding in the hospital than in
classified as non-variceal UGIB (NVUGIB) and variceal those who develop bleeding in the community setting 4,5.
UGIB (VUGIB). NVUGIB is most often caused by peptic
ulcers (a break of the mucosal barrier that exposes the Epidemiology
submucosa to the damaging effects of acid and pepsin The most common cause of NVUGIB is gastroduo
present in the gastroduodenal lumen), which are com- denal peptic ulcers followed by gastroduodenal ero-
monly associated with Helicobacter pylori infection and sions, p eptic oesophageal lesions (oesophagitis or
Correspondence to A.L.
the use of NSAIDs (including aspirin doses of ≥500 mg) oesophageal ulcers), vascular lesions (such as Dieulafoy
Service of Digestive Diseases, or low-dose aspirin (LDA; which is a dose of ≤325 mg but lesions; a medical condition associated with an abnormal
University Clinic Hospital is typically 75–100 mg). By contrast, VUGIB is caused by tortuous arteriole that penetrates into the gastrointesti
Lozano Blesa, University oesophageal or gastric varices (dilated submucosal veins), nal mucosa) and vascular ectasias such as angiodys
of Zaragoza, IIS Aragón,
which are usually associated with chronic liver diseases plasia (a small vascular malformation in the gut)),
Zaragoza, Spain.
alanas@unizar.es and/or portal hypertension. The incidence of NVUGIB Mallory–Weiss tears (lacerations in the mucosa at the
in most countries is fivefold higher than that of VUGIB gastro-oesophageal junction that occur associated with
Article number: 18020
doi:10.1038/nrdp.2018.20 (BOX 1), and NVUGIB represents a serious clinical recurrent vomiting often after excessive alcohol intake
Published online 19 Apr 2018 challenge with considerable mortality 4. or a heavy meal) and, less often, neoplastic lesions6,7.
was threefold higher in Mexico, twofold higher in vascular lesions and neoplastic lesions. Whatever the
Argentina and Chile and only slightly higher in Taiwan cause, exposure of the underlying blood vessels to
and Singapore, whereas no difference was observed in the action of acid and pepsin further erodes the vessel
Hong Kong. wall and interferes with blood coagulation3 (FIG. 2).
Despite these improvements, mortality associ
ated with NVUGIB remains high, with values varying Mucosal damage
between different studies and stable, non-decreasing H. pylori infection. Mucosal damage and ulcer forma-
v alues over time in some countries (for example, tion are considered to be consequences of the inter
Spain)17. A systematic review of 18 studies showed action between H. pylori and the host immune response.
mortality of NVUGIB ranging from 1.1% in Japan to H. pylori strains show genetic diversity, but those that
11% in Denmark, although most studies included in exhibit a cag pathogenic island encoding virulence fac-
the review placed that figure closer to 5%35. These dis- tors such as cytotoxicity-associated immunodominant
crepancies in the reported mortality of NVUGIB are antigen (CagA), vacuolating cytotoxin autotransporter
attributable to differences in study methodologies and (VacA), blood group antigen-binding adhesin (BabA)
populations studied. or outer inflammatory protein adhesin (OipA) strongly
Improvement in NVUGIB outcomes is likely due induce the host immune response3,37,38. This immune
to factors such as advances in endoscopic and med- response is initiated in the gastric epithelium, where
ical management and improvements in emergency these bacterial virulence factors elicit an intracellu-
and critical care or geriatric medicine8,10,11. Risk factors lar cascade of events that activate kinases involved in
for mortality linked to NVUGIB include increased the regulation of cell growth and differentiation and the
age, comorbidities (such as respiratory or cardiac nuclear factor-κB (NF-κB) signalling pathway. Cytokines
insufficiency, renal failure and sepsis), severe haemo that have a key role in the immune and inflammatory
dynamic instability or development of further bleed- response to H. pylori infection include IL‑1β, IL‑1 recep-
ing 36. However, at present, most deaths associated with tor antagonist protein (IL1RN), tumour necrosis factor
NVUGIB are not due to uncontrolled bleeding but are (TNF), IL‑6, IL‑8 and IL‑10 (REFS 3,38).
the consequence of complications induced by bleeding H. pylori induces different types of lesions in the
(for example, organ failure), comorbidities or older age4. lining of the stomach and duodenum, most commonly
mild asymptomatic gastritis. Pan-gastritis is associ-
Mechanisms/pathophysiology ated with hyposecretion of gastric acid and is linked
The mechanisms involved in the development of to the development of gastric ulcers. However, some
NVUGIB are not well understood. The mucosal barrier patients develop an antrum-predominant gastritis that
and submucosal blood vessels must be damaged for is associated with duodenal ulcers and increased gastric
the bleeding event to occur. Disruption of the mucosal acid secretion due to hypersecretion of gastrin and
barrier is commonly associated with H. pylori infection hyposecretion of somatostatin3,39. Gastric acid hyper
and/or NSAID or LDA use, but exposure of the blood secretion in antrum-predominant gastritis is associated
vessels to the luminal content can also be the conse- with the development of gastric metaplasia in the duo-
quence of causes such as Mallory–Weis syndrome, denal bulb, which may be colonized by H. pylori and
favour ulcer formation3,40.
Box 1 | Variceal upper gastrointestinal bleeding NSAID and LDA use. Studies have shown that NSAIDs
and LDA induce damage to the gastroduodenal mucosa
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
by both systemic and local effects41. Locally, NSAIDs
often involves vomiting large amounts of ‘fresh’ red blood. The first-line therapy and LDA can decrease the hydrophobicity of the
combines vasoactive drugs and variceal ligation. Drugs with vasoactive properties, mucous layer owing to their amphiphilic properties,
such as terlipressin, somatostatin or octreotide, should be given as soon as acute VUGIB thereby exposing the underlying epithelium to luminal
is suspected. Upper gastrointestinal endoscopy should be performed within the first acid and pepsin. NSAIDs also uncouple mitochondrial
12 hours after admission once haemodynamic stability has been achieved to ascertain oxidative phosphorylation in the epithelial cells, lead-
the cause of haemorrhage; when VUGIB is confirmed, ligation should be performed ing to cellular dysfunction with decreased levels of ATP
within the same procedure. Early pre-emptive insertion of a covered (that is, with fabric and glutathione, mitochondrial swelling, generation
or graft material over the metal structure) transjugular intrahepatic portosystemic of free radicals, calcium release into the cytosol and,
shunt to treat portal hypertension should be considered in patients with high risk of
eventually, loss of integrity of tight junctions, apoptosis
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
and cell death, all contributing to increased mucosal
stomach should be used in cases of uncontrolled bleeding as a temporary measure permeability and disruption.
(<24 hours) until definitive treatment can be instituted. Removable, covered and The local effects of NSAIDs depend on their acid
self-expanding oesophageal stents are a promising alternative to balloon tamponade. dissociation constant; acidic NSAIDs are not ionized
Eventually, liver transplantation should be considered when bleeding is not controlled at the low pH of the gastric lumen and can, therefore,
after transjugular intrahepatic portosystemic shunt insertion and when liver function be absorbed by epithelial cells, where they become
has deteriorated. Peptic ulcer bleeding (that is, non-variceal bleeding) in patients with ‘trapped’ because of the neutral intracellular pH. The
cirrhosis has a mortality similar to that of VUGIB with a similar incidence of ability of an NSAID to uncouple mitochondrial oxid
complications and decompensation of liver disease, which account for a great ative phosphorylation (that is, its uncoupling potency)
proportion of fatalities201,202.
is also directly proportional to its acid dissociation
constant, with acidic NSAIDs being the most potent. enzymes are present in abundance in the gastric lumen;
Consequently, use of acidic NSAIDs (including aspirin) these circumstances make the stomach and proximal
may need to be combined with proton pump inhibitors duodenum a hostile environment that facilitates contin-
(PPIs) in some high-risk patients (see below); non-acidic ued bleeding once the blood vessel is breached. Thus, the
NSAIDs (such as paracetamol) are considered safer for medical treatment of bleeding lesions aims at attempt-
the gastrointestinal tract 41. ing to keep the gastric pH above the proteolytic range
Systemically, NSAIDs contribute to mucosal dam- for pepsin (that is, pH >6). Current medical treatment
age by inhibiting the prostaglandin secretion associated with a high-dose PPI is able to achieve this pH target45–47.
with cyclooxygenase 1 (COX1; also known as PTGS1) As PPIs suppress acid secretion by covalent binding of
and COX2. The reduction in prostaglandin levels dis- the protonated drug to activated proton pumps, which
rupts the mucosal barrier as prostaglandins stimulate are at rest in the cytoplasm in the fasting patient, the
mucous and bicarbonate secretion by epithelial cells, use of PPI therapy provides highly effective pH control
inhibit acid secretion and promote cell proliferation following endoscopic treatment.
and mucosal blood flow. The ischaemic effect of NSAIDs Some studies have shown clinical benefits of main-
leads to increased leukocyte adherence, damaging blood taining an intragastric pH >6 during the bleeding epi-
vessels. The gastric mucosa is especially sensitive to the sode. A meta-analysis48 showed a significant decrease in
reduced COX1‑derived prostaglandin levels compared further bleeding, need for surgery and mortality among
with other segments of the gastrointestinal tract 42 for patients with high-risk bleeding ulcers after endoscopic
reasons that are not yet clear. COX2 is not expressed in therapy and high-dose continuous infusion with PPIs
the absence of a pre-existing lesion or H. pylori infec- when compared with placebo.
tion. However, given that H. pylori infections are fre-
quent, many patients who take NSAIDs or LDA may Inhibition of platelets. In addition to mucosal damage,
be infected, which seems to exacerbate the potential NSAIDs and LDA might also contribute to bleeding by
damaging effects of these drugs41,43. inhibiting the formation of thromboxane A2 in platelets.
Platelet COX1‑derived thromboxane A2 is activated to
Bleeding control bleeding following damage to blood vessels
Role of pH. The coagulation system is extremely sen- (FIG. 2). A similar mechanism has been proposed for
sitive to minor pH changes. In vitro studies show that non-aspirin antiplatelet agents49.
coagulation becomes abnormal at pH 6.8, platelet Some have questioned the mucosal-damaging
aggregation reduces by >50% at pH 6.4 and platelet capacity of LDA and have suggested that the role of LDA
aggregation and plasma coagulation are abolished and in NVUGIB is mainly due to its antiplatelet effect. In this
previously aggregated platelets disaggregate at a pH <5.9 context, the antiplatelet effect would be similar to that
(REF. 44). In addition, an increase in pH to 6.8 (or even of anticoagulants such as vitamin K antagonists, which
slightly higher) induces platelet aggregation, calcium do not produce mucosal damage but may induce severe
release and serotonin release from the platelets as well bleeding of gastrointestinal lesions caused by other
as normalization of the blood clotting time (meas- agents (such as NSAIDs and H. pylori). If so, LDA and
ured using prothrombin and partial thromboplastin non-aspirin antiplatelet agents would induce bleeding
times)44 (FIG. 3). only in patients with pre-existing lesions. This hypoth
Pepsin, a proteolytic enzyme that becomes activated esis is supported by one study involving individuals with
at pH <6, further enhances platelet disaggregation and osteoarthritis, in whom the rate of peptic ulcers did
clot disintegration44. Acid, pepsin and other proteolytic 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
0 LDA can damage the gastrointestinal mucosa42.
Change in the incidence of NVUGIB (%)
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
↓ 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.
Aggregation (%)
60
ment has not been systematically evaluated but should
50 be considered in patients with one or more risk factor
40
when using NSAIDs or LDA67; however, prevention is
rarely required for low-risk patients. Acid suppression
30 with antisecretory drugs is recommended in the pres-
pH 6.8
20 ence of risk factors; PPIs are preferred and are superior
ADP
to histamine H2 receptor antagonists67. Prostaglandins
10 A
(such as misoprostol) are cytoprotective and effec-
pH 5.9
0 tive in reducing acid secretion, but at the expense of
adverse events that reduce their tolerability 67. In those
0 1 2 3 4 5 who have a history of peptic ulcers, the risk associ-
Time (minutes) ated with NSAID use can be modified first by treating
Figure 3 | Effects of an acidic environment on platelet H. pylori infection if present and then by switching to a
Nature Reviews | Disease Primers
aggregation. At pH 7.4, platelet aggregation induced by COX2‑selective NSAID. Eradication of H. pylori infec-
ADP is normal and occurs rapidly. Arrow A denotes the tion in those taking NSAIDs or LDA can considerably
time point at which the pH of plasma is decreased by the reduce, although not abolish, the risk of ulcers, bleeding
addition of hydrochloric acid in an experimental setting. or re‑bleeding events68,69.
At pH 6.8, platelet aggregation is negatively affected, Concomitant NSAID treatment with several other
and at pH 5.9, it is completely abolished. Adapted with drugs increases the risk of developing gastrointestinal
permission from REF. 44. bleeding 64,66,70 (BOX 2; FIG. 5), but the risk might be modi
fied by co‑treatment with antisecretory drugs. Indeed,
whereas platelet and clotting dysfunction, platelet–vessel use of omeprazole (a PPI) while continuing clopidogrel
interaction and haemodynamic instability are mech- treatment decreases the number of gastrointestinal
anisms involved in end-stage renal disease-associated bleeding events without an increase in cardiovascular
gastrointestinal bleeding 62. Most of these conditions adverse events71. Monitoring international normal-
are also associated with poor nutritional s tatus, which, ized ratio (INR; a parameter used to standardize pro
together with the common use of LDA, antiplatelet thera thrombin time) is indicated when a PPI is started or
pies, anticoagulants and NSAIDs in these conditions, stopped in patients on vitamin K antagonists. Indeed,
may contribute to gastrointestinal mucosa damage. the metabolism of PPIs involves the hepatic cytochrome
Most of these mechanisms, especially those related to P450 (CYP) enzyme system, which might affect metabo
altered microperfusion, hypoxia, free radical concen- lism or activation of drugs taken concomitantly. How
tration and pH, are also involved in diffuse mucosal different PPIs interact with different CYPs might inform
damage or stress ulcers in patients needing respiratory PPI choice. For example, the selection of pantoprazole
assistance in the intensive care setting 60,61 (FIG. 4). and rabeprazole rather than other PPIs has been recom-
mended in patients taking vitamin K antagonists, but the
Diagnosis, screening and prevention real clinical impact of this recommendation remains to
Prevention be shown72. The identification of polymorphisms lead-
Risk stratification. Prevention of bleeding events is the ing to poor metabolism of PPIs in the CYP2C19 gene
best clinical approach in NVUGIB. A careful medical in a Japanese population could be predictive of adverse
history, physical examination and laboratory investi events73. These findings could also be extended to other
gations provide the basis to identify risk factors and populations, but additional studies are needed. To date,
comorbid conditions (BOX 2) and to select a sound pre- no interaction has been reported with novel direct oral
vention strategy, which should balance the benefits anticoagulants (DOACs) and CYP enzymes. When using
and risks of preventive measures. In NSAID and LDA corticosteroids, PPI treatment should be considered if an
users, balancing risks is especially important when individual has a history of peptic ulcers or in the case
cardiovascular and gastrointestinal risk factors are both of combined corticosteroid and NSAID or LDA use67.
present. Some risk factors can be easily identified and Identification of a history of uncomplicated or com-
prevented or discontinued63,64, whereas others are not plicated ulcers should prompt a test-and-treat strategy
(such as advanced age or the presence of comorbidi- for H. pylori infection to prevent a first-bleeding or
ties)59 (FIG. 4). The risk of developing bleeding increases re‑bleeding event 74,75. Identification of H. pylori infec-
with the presence and number of risk factors, in addi- tion during a bleeding event represents a clinical chal-
tion to NSAID and LDA use, and appreciation of these lenge, as an invasive test such as urease testing during
factors offers the opportunity to stratify patients into the endoscopic procedure may provide false-negative
risk categories65,66. Those taking NSAIDs or LDA with results owing to the presence of blood in the gastric
no other identified risk factors are at low risk of ulcer lumen, inadequate sampling or the previous use of PPIs.
Histological analysis and/or culture of biopsy speci- colon cannot be excluded. Caution should be taken to
mens may also provide false-negative results76. In this exclude oral or nasopharyngeal sources of bleeding as
clinical scenario, the presence of H. pylori infection patients who swallow fresh blood might present with
should be tested or retested if negative after ulcer healing haematemesis or melena. The probability that a patient
(4–8 weeks after the bleeding event) with patients being has NVUGIB is higher when melena is observed on
off PPI for at least 7 days and no antibiotic therapy the rectal examination than with patient-reported history
month before. A positive test should prompt eradication of melena or the presence of blood clots in the stool77.
therapy with a confirmatory negative test performed The initial assessment and management of these
at least 1 month after therapy 3,75,76. patients is focused on emergency assessment and
stabilization protocols aimed at restoring and protect-
Diagnosis ing the airway and maintaining the circulation followed
In clinical practice, the diagnosis and management of by NVUGIB-specific pre-endoscopic assessment and
NVUGIB are intermingled. Following resuscitation and interventions. In a minority of patients who present with
initial assessment, pre-endoscopic management is per- large-volume haematemesis and/or diminished level of
formed followed by endoscopic diagnosis and endoscopic consciousness, orotracheal intubation should be consid-
management. For example, medical treatment with, for ered to protect the airway and to facilitate initial resusci
example, PPIs, is often started before endoscopic diag tation and subsequent endoscopy in the emergency
nosis and treatment. In this Primer, we d iscuss the setting. Blood should be drawn during catheter insertion
diagnosis and management options separately. to analyse complete blood count, INR, electrolytes, urea,
albumin, creatinine and liver enzymes. Additional blood
Initial, pre-endoscopic assessment. The presentation of tests or investigations can be performed depending on
overt NVUGIB varies considerably from asymptomatic the underlying comorbidities5,78.
outpatients with melena (black faeces due to the pres- During initial resuscitation, a directed history and
ence of blood) to those presenting with large-volume physical exam is conducted and aimed at ascertaining
haematemesis (vomiting of blood), passage of ‘fresh’ red the potential aetiology for the gastrointestinal bleeding
blood, severe hypotension and a compromised airway. and identifying important risk factors and comorbidi
The presence of haematemesis indicates that the source ties that modify survival and warrant lowered thresh-
of the bleeding is the upper gastrointestinal tract (above olds for transfusion or early endoscopy. A digital
the ligament of Treitz), whereas the source of bleeding rectal examination enables verification of the presence
in most individuals with melena is also the upper gastro of either melena or blood and may avoid unnecessary
intestinal tract (90%), but the small bowel and ascending confirmatory tests79.
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.
Each patient presenting with NVUGIB should have usually not be delayed until the action of the anticoagu-
pre-endoscopic risk stratification. Among the different lant is completely reversed. An INR <2.5 is adequate and
risk-scoring systems (BOX 3), the Glasgow–Blatchford enables successful endoscopic management if needed5,81.
Score (GBS) performs well80 and is used globally. The The decision to stop and when to resume antiplatelet
GBS performs better at predicting intervention, compli- anticoagulant agents at the time of NVUGIB is difficult
cations or death than the full (preadmission and post- and should be guided by post-endoscopy risk assess-
endoscopy) Rockall score, the admission Rockall score, ment and consultation with a cardiologist (discussed in
the AIMS65 score and the Progetto Nazionale Emorragia detail below).
Digestiva (PNED) score80. The PNED and AIMS65 scores
perform best at predicting mortality 80. In general, high- Endoscopy. Endoscopy is essential to reveal the cause of
risk patients are those who present with hypotension, NVUGIB, and early upper gastrointestinal endoscopy
vomiting of bright red (fresh) blood, passage of red blood within 24 hours of presentation improves patient out-
per rectum (in the setting of NVUGIB) and/or have con- comes82–84. Several studies have found no differences in
siderable comorbidities and are of advanced age. These outcomes between patients who undergo early endoscopy
patients have an increased risk of mortality and require and those undergoing very early endoscopy (<12 hours of
careful assessment and early management. patient presentation)85–87. Nevertheless, controversy per-
In individuals who develop NVUGIB when on anti- sists because very early endoscopy reveals active bleed-
platelet or anticoagulation therapy to prevent cardio ing stigmata and need of endoscopic treatment of lesions
vascular events, this treatment should generally be without evidence of reduction of the risk of re-bleeding
stopped and/or reversed. However, endoscopy should or improved survival88,89.
Endoscopy should be used to diagnose the cause of
the bleeding and evaluate stigmata of recent haemorrhage
Box 2 | Risk factors for increased bleeding risk (such as active bleeding, a visible blood vessel, presence of
clots or red or black spots covering the ulcer lesion) and to
Drugs classify them according the Forrest classification, which
• Compared with non-use, NSAID use increases the risk of developing non-variceal enables patient selection for endoscopic treatment and
upper gastrointestinal bleeding (NVUGIB) fourfold, and low-dose aspirin (LDA) use stratification of the risks of re-bleeding, surgery and mor-
increases the risk twofold3,66,203. The risk progressively increases with increasing drug
tality 90–92 (TABLE 1). Of note, the interobserver agreement
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 for the Forrest classification is low to moderate93. Vigorous
clinical practice and seems to be higher in drugs with longer half-lives, slow-release water irrigation on the ulcer base is r ecommended to
formulations or cyclooxygenase 1 (COX1) selectivity; COX2‑selective antagonists improve the accuracy of Forrest classification.
have been associated with lower NVUGIB risk67. Endoscopic treatment should be provided to patients
• Anticoagulants and non-aspirin antiplatelet agentsa (such as clopidogrel) increase the with bleeding of Forrest types Ia, Ib and IIa. A meta-
risk of NVUGIB twofold204. analysis of randomized clinical trials (RCTs) confirmed
• Other drugsa (such as serotonin reuptake inhibitors70, metamizole, calcium channel that endoscopic therapy was effective in preventing per-
blockers and aldosterone antagonists) have also been associated with NVUGIB, but sistent or recurrent bleeding in Forrest types Ia and Ib
less consistently. (relative risk (RR) 0.29, 95% CI 0.20–0.43; n umber
• Combined use of NSAIDs (both unselective COX inhibitors and COX2‑selective needed to treat (NNT) 2, 95% CI 2–2) and Forrest
inhibitors) with LDA, thienopyridine antiplatelet agents (for example, clopidogrel), type IIa (RR 0.49, 95% CI 0.40–0.59; NNT 5, 95% CI 4–6)
warfarin, novel antiplatelet drugs (for example, prasugrel and ticagrelor), direct oral compared with no endoscopic therapy 94. The necessity
anticoagulants, corticosteroids67 or serotonin reuptake inhibitors70 increases the risk for endoscopic treatment in patients with Forrest type IIb
of NVUGIB. Combining NSAIDs and aldosterone antagonists might increase the risk of bleeding, which is defined as a lesion with a clot that is
developing NVUGIB more than the risk associated with individual drug use64,66,70. red, maroon or black in colour and amorphous in texture
Gastrointestinal comorbidities and that cannot be dislodged by suction or forceful water
• Eradication of Helicobacter pylori infection before NSAID use reduces ulcer risk by irrigation, remains controversial. The above-mentioned
2.8‑fold and ulcer bleeding risk by 6.4‑fold205. meta-analysis showed no benefit for endoscopic ther-
• The single most important risk factor for bleeding is a history of ulcer complications, apy in Forrest type IIb bleeding 94; however, the studies
especially in patients treated with NSAIDs or LDA67. included showed significant heterogeneity, with two
• A history of uncomplicated ulcers increases the risk of complications; eradication of concluding that there was a beneficial effect of com-
H. pylori may not reduce the risk completely in patients treated with NSAIDs or LDA67. bining therapeutic endoscopy with intravenous PPI
• History of dyspepsia, which may be a marker of underlying peptic ulcer disease, therapy compared with PPI alone95,96. Thus, at present,
increases the risk of NVUGIB. the approach to managing patients with Forrest type IIb
Other comorbidities bleeding should be determined on a case‑by‑case
basis, considering, among others, medical resources,
• Bleeding risk increases with age; >75 years of age is considered high risk67.
endoscopist experience and patient status.
• Concomitant disability; for example, the prevalence of gastrointestinal bleeding
Stigmata of recent haemorrhage, which are visible
events is higher in those with rheumatoid arthritis than in those with
osteoarthritis65,206. on endoscopy, have been used for decades to make risk
stratification and treatment decisions in NVUGIB, but
• The risk of NVUGIB increases with an increasing number of comorbidities65,66.
Doppler assessments of arterial blood flow in the gastro-
a
These drugs do not induce damage to the gastrointestinal tract; patients must have lesions intestinal wall, which can be measured using endoscopy,
caused by other aetiology.
could revolutionize the field. Detection rates of arterial
SSRIs + nsNSAIDs
(OR 0.65; 95% CI 0.26–1.62), when routine second-look
Calcium antagonists
Calcium antagonists + nsNSAIDs endoscopy was performed compared with an as‑needed
Aldosterone antagonists endoscopy 102. Further analysis showed that any protec-
Aldosterone antagonists + nsNSAIDs tive effect for second-look endoscopy was limited to
Anticoagulants high-risk patients (that is, those with active bleeding at
Anticoagulants + nsNSAIDs
index endoscopy). In addition, scheduled second-look
Non-aspirin antiplatelet agents
Non-aspirin antiplatelet agents + nsNSAIDs endoscopy is cost effective only in patients at high risk of
recurrent ulcer bleeding, defined as those with high-risk
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14
endoscopic stigmata103.
Relative risk
Figure 5 | Risk of developing NVUGIB associated withNature certainReviews Diseaserisk
drugs. |Relative Primers Management
and 95% CIs of developing non-variceal upper gastrointestinal bleeding (NVUGIB) Initial, pre-endoscopic management
associated with the use of various types of drugs alone or combined with non-selective Peripheral intravenous access should be obtained soon
NSAIDs (nsNSAIDS) compared with no drug use. Based on data reported in European
after or at the same time as initial assessment and be
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, of sufficient size to allow rapid blood transfusion if
selective serotonin reuptake inhibitor. required. Resuscitation with crystalloid fluid should be
guided by the haemodynamic status of the patient. The
decision to provide additional blood transfusion should
signals on ulcer bases using a Doppler probe in patients be individualized on the basis of the patient’s clinical
with Forrest type Ia bleeding are high (100%) but are status and should take ongoing bleeding, haemoglobin
lower in those with Forrest types Ib (46.7%), IIa (90.7%), level and presence of underlying comorbidities that
IIb (68.4%), IIc (40.5%) and III (8.3%) bleeding 97. These make the patient sensitive to reduced oxygen-carrying
data could explain the finding that patients with Forrest capacity into consideration. In general, a restrictive
type Ib bleeding had a very low re-bleeding rate after blood transfusion strategy is recommended. Guidelines5
successful endoscopic haemostasis in a recent RCT, typically recommend blood transfusion for patients who
although both Forrest types Ia and Ib are often included have a haemoglobin level <70 g per litre and recommend
together as ‘active bleeding’ (REF. 98). Furthermore, the targeting a haemoglobin value of 70–90 g per litre104.
use of the Doppler probe facilitates tracing of the under- These targets can be individualized for patients who are
lying artery for effective endoscopic haemostasis, which sensitive to low oxygen-carrying capacity, but overtrans-
improves patient outcomes99. fusion should be avoided as it can be associated with
Recently, iatrogenic ulcers following mucosal or sub- harm (such as congestive heart failure)5,78.
mucosal endoscopic tumour resection have become a Guidelines recommend administration of intra
substantial cause of NVUGIB, especially in east Asia, venous high-dose PPI pre-endoscopy to stabilize clots,
where endoscopic tumour resection for upper gastro downgrade endoscopic stigmata of recent haemorrhage
intestinal neoplasia is more frequent than in other parts and reduce the need for endoscopic therapy 5,10,78.
of the world100. Although evidence is limited, endoscopic However, the use of intravenous pre-endoscopy PPIs has
evaluation and management of bleeding from these not shown reductions in the rates of re-bleeding, surgi-
ulcers should be considered on a similar basis to those cal intervention or mortality in meta-analyses, therefore,
with peptic ulcers100. Literature regarding endoscopic its use should not delay endoscopy 5,78,105,106. The use of
evaluation and management methods for bleeding from pre-endoscopy PPIs is considered to be cost effective in
other causes such as Mallory–Weiss tear, oesophagitis, high-risk patients and in low-risk patients with expected
erosive gastritis, duodenitis, vascular abnormalities, short hospitalizations or outpatient management 107. The
anastomotic wounds after surgery and upper gastro cost effectiveness of pre-endoscopic intravenous PPIs
intestinal neoplasia are sparse. Spontaneous haemostasis is likely maximized in patients with the likelihood of
is usually achieved in these conditions, and endoscopic a high-risk lesion on initial assessment or in those in
treatment should be considered only in cases of active whom a delay in endoscopic therapy is expected. By con-
bleeding101. In cases of curative-intent treatment for neo- trast, post-endoscopy intravenous PPI use reduces the
plastic lesion, endoscopic or surgical removal of the entire risk of re-bleeding and need for surgical intervention
lesion should be prioritized over endoscopic h aemostasis (see below).
to control bleeding. Guidelines do not support the routine use of
somatostatin or somatostatin analogues (aimed mainly
Second-look endoscopy. Re-bleeding after endoscopic at splanchnic vasoconstriction) or tranexamic acid
treatment occurs in 10–15% of individuals with PUB (an antifibrinolytic agent) in NVUGIB. Although not
and results in a twofold to fivefold increase in mortality 5. routinely recommended, a single dose of the antibiotic
erythromycin 30–120 minutes before endoscopy, Over-the-scope clip (OTSC system; OVESCO
especially in those with severe and ongoing bleeding, Endos copy AG, Tübingen, Germany) and haemo-
can improve endoscopic visualization, reduce the need static powders such as TC‑325 (Haemospray; Cook
for blood transfusion and second-look endoscopy and Medical, Bloomington, IN, USA) and the EndoClot
reduce the length of hospitalization5,78,108. polysaccharide haemostatic system (EndoClot Plus,
Santa Clara, CA, USA) are newly developed devices or
Endoscopic management substances with promising outcomes, but they still lack
Various modalities to achieve endoscopic haemostasis sufficient data to draw robust conclusions concerning
aimed at stopping active bleeding in those with UGIB efficacy 116–118. Over-the-scope clips overcome the limita
associated with peptic ulcers or other causes exist and tions of haemoclips, such as smaller size and lower
are detailed in BOX 4. capacity to include the whole lesion and induce pres-
sure, and are good options for salvage or rescue endo-
PUB. Meta-analyses show that injection therapy with scopic haemostasis interventions after conventional
solutions other than adrenaline, thermal therapy and endoscopic therapies have failed before surgical or
haemoclip therapy (BOX 4) are all effective methods for radiological intervention. Haemostatic powders mainly
achieving haemostasis in PUB with no single modality act as a tamponade and a physical barrier from factors
being superior 109–114. For high-risk PUB, adrenaline plus such as gastric acid and might be more effective than
any second haemostasis modality (except spray ther- conventional endoscopic therapies in cases in which
apy) significantly reduced re-bleeding (OR 0.53; 95% CI targeting the bleeding point is difficult. Notably, bleed-
0.35 – 0.81) and need for emergency surgery (OR 0.68; ing duodenal ulcers at the posterior wall may require
95% CI 0.50 – 0.93), but not mortality, as compared with subsequent vigilance after endoscopic therapy; if the
adrenaline injection monotherapy 113. Thus, if adrenaline gastroduodenal artery is affected, radiological coiling
injection is used to treat PUB with high-risk stigmata, or surgery may be needed to stop the bleeding 1.
it should be used only in combination with a second
endoscopic haemostasis modality. The use of soft coagu Non-PUB NVUGIB. For NVUGIB other than PUB,
lation using haemostatic forceps (FIG. 6) has become endoscopic haemostasis should be selected according
more frequent along with development of endoscopic to the nature of the disease, severity of bleeding and
submucosal dissection115. preference of the endoscopist because of the low quality
of evidence and scarcity of comparative data. Bleeding clot formation44,127,128. A meta-analysis of RCTs found a
associated with Mallory–Weiss tears is u sually self- significant reduction in re-bleeding (RR 0.40, 95% CI
limited, and endoscopic haemostasis would be applied 0.28–0.59; NNT 12, 95% CI 10–18), surgery (RR 0.43,
only when active bleeding is detected. Among various 95% CI 0.24–0.76; NNT 28, 95% CI 21–67) and mor-
endoscopic haemostatic modalities, haemoclip and tality (RR 0.41, 95% CI 0.20–0.84; NNT 45, 95% CI
band ligation therapy are preferred as they achieve 33–167) with intravenous post-endoscopic PPI ther-
haemostasis and closing of the mucosal tear without apy (bolus injection followed by continuous infusion
thermal damage to the thinner lacerated tissue119,120. versus placebo or no treatment for 72 hours after endo-
Endoscopic haemostasis to control bleeding associated scopic therapy)94. High-dose intravenous omeprazole
with vascular abnormalities is usually carried out using (a PPI) was superior to intravenous administration
coagulation therapy such as argon plasma coagula- of ranitidine (a histamine H 2 receptor antagonist)
tion, laser therapy or radiofrequency ablation. Argon in maintaining gastric pH >6 (percentage of time
plasma coagulation is especially useful for lesions that gastric pH <6 in the study period was 15.3 ± 5.9%
are spread (for example, gastric antral vascular ectasia (mean ± standard deviation) for omeprazole versus
(longitudinal antral folds converging on the pylorus 61.8 ± 5.6% (mean ± standard deviation) for ranitidine,
that contain visible columns of tortuous red ectatic P <0.0001)45.
vessels)) or for multiple lesions (arteriovenous malfor- Given the cost of continuous intravenous ther-
mations or telangiectases) as its coagulation depth is apy, less costly intermittent (including oral) therapy
uniform and the risk of perforation is lower than that is a logical consideration, although a recent study
of laser therapy 121. has shown that the timing or dosing of PPI has little
For patients with a few or localized lesions, haemo- impact on cost, much less than efficient triage and dis-
stasis using mechanical therapy or injection therapy are charge of patients129,130. Several meta-analyses found
also applicable. As a new approach for refractory gastric that intermittent PPI use was non-inferior compared
antral vascular ectasia, radiofrequency ablation using with bolus plus continuous infusion of PPIs in terms
the HALO90 Ablation Catheter System (Covidien GI of re-bleeding (at 3, 7 and 30 days), the need for blood
Solutions, Sunnyvale, CA, USA) has been tested with transfusion and urgent intervention and mortality 131,132.
promising outcomes122–125. In Dieulafoy lesions, either Intermittent oral PPI may be as effective in pH control
mechanical therapy (such as band ligation) or haemo- as equivalent doses of intravenous PPIs given intermit-
clips are considered to be the first-line treatment tently. Both oral and intravenous PPIs (lansoprazole)
and over-the-scope clips are a rescue treatment for given intermittently achieved similar pH control during
refractory cases126. the study period (percentage time gastric pH <6 was
67.8 ± 4.5% (mean ± standard error) for intravenous PPI
Medical therapy after endoscopy versus 64.8 ± 4.2% (mean ± standard error) for oral PPI),
The goals of medical treatment are to reduce the risk although intravenous PPI increased pH to >6 sooner
of re-bleeding while healing the ulcer and preventing than oral PPI (by 1 hour)47, but the ranges are wide.
long-term recurrence. The rationale for raising intra- Thus, intermittent, high-dose PPIs given at least twice
gastric pH to >6 is based on studies that demonstrated daily are an option, using oral PPIs in patients able to
that acidity affects platelet aggregation and destabilizes tolerate oral medications94.
Patients with PUB have an unacceptably high Another meta-analysis also found that the combination
rate of recurrent bleeding. In an RCT of patients with of selective COX2 inhibitors plus PPIs provides the best
H. pylori-associated PUB, the rate of recurrent bleed- gastrointestinal protection, followed by selective COX2
ing after 12‑month follow‑up was 27% in patients who inhibitors alone and non-selective NSAIDs plus PPI136.
did not undergo H. pylori eradication therapy com- Thus, the current best practice for those patients with a
pared with 0% in those who did133. H. pylori eradication PUB who must remain on NSAIDs is that they should
is more effective than long-term maintenance anti receive a COX2‑selective NSAID at the lowest effective
secretory therapy in reducing recurrence; a systematic dose plus PPI therapy 68,69.
review of studies assessing re-bleeding in patients with
documented H. pylori eradication revealed a 1.1% inci- Recurrent bleeding
dence of re-bleeding over mean follow‑up periods of In patients with clinical evidence of re-bleeding, repeat
11–53 months. However, the re-bleeding rate in patients upper endoscopy should be performed with haemostasis
who did not undergo H. pylori eradication therapy but of high-risk endoscopic stigmata of haemorrhage, if pres-
were maintained with long-term antisecretory therapy ent. A seminal RCT comparing endoscopic therapy with
was 5.6%134. These findings set the current Cochrane rec- surgery for recurrent PUB following successful initial
ommendations to test all patients with PUB for H. pylori endoscopic control of PUB showed that 73% of patients
and provide eradication therapy if needed134. randomly assigned to endoscopic re-treatment had long-
When patients have to use NSAIDs after PUB, RCTs term control of their bleeding and avoided surgery com-
have shown that maintenance PPI therapy significantly pared with 93.1% of surgery-treated patients137. Patients
lowers the risk of recurrent ulcer bleeding at 6 months in the endoscopy group had a lower rate of complica-
compared with H. pylori eradication alone (4.4% ver- tions than those in the surgery group (14.5% versus 36%;
sus 18.8%, P = 0.005; NNT = 7) 68,135. In a 12‑month P = 0.03)137. If further bleeding occurs following a second
double-blind study, patients taking celecoxib (a COX2 endoscopic treatment, transcatheter angiographic embo-
inhibitor) plus twice-daily PPI had fewer recurrent lization or surgery should be considered5,10,11. In those
ulcer bleeding events than those taking celecoxib plus with PUB after failed endoscopic haemostasis, a higher
placebo (0% versus 8.9%, P = 0.0004; NNT = 12)69. re-bleeding rate was observed following transcatheter
is not recommended (high cost and 11% thromboembo- Finally, activated charcoal can also be used in the case
lism risk)160. FIGURE 8 summarizes commonly accepted of a recent (≤3 hours) overdose and when no emergency
recommendations for patients on vitamin K antagonists UGIB endoscopy is contemplated169–171.
who develop NVUGIB161–163. Haemostatic agents such as PCCs or activated PCCs
have been shown to be effective at restoring coagula-
DOACs. DOACs target single enzymes of the coagu- tion in patients with NVUGIB who are taking DOACs,
lation process; apixaban, edoxaban and rivaroxaban although evidence is limited172–174. By contrast, FFP is
inhibit factor Xa whereas dabigatran directly inhibits not recommended as clotting factors are 25‑fold more
thrombin72. Plasma monitoring of coagulation factors dilute than in PPCs, and very large volumes are required
is not needed, which is a clinical advantage over vita- to overwhelm the binding capacity of DOACs. The most
min K antagonists. However, unlike vitamin K antago promising therapeutic options rely on the availability
nists and dabigatran, anti-factor Xa agents currently of reversal agents, which could be used in the case of
have no widely available reversal agents, are not yet life-threatening gastrointestinal bleeding, but reliable data
approved and normalization of clotting factor levels are needed because of the risk of thromboembolism175,176.
takes 12–24 hours164. Dabigatran has a specific antidote (idarucizumab), which
Routine coagulation tests may be conducted, but works effectively in minutes with thromboembolism and
they are unreliable (BOX 5). Renal function should be a rebound effect reported in 6.8% and 23% of patients,
monitored as it is frequently compromised in those respectively 171. In this cohort study 171, including patients
with UGIB on DOACs, and aggressive fluid replace- who had uncontrolled bleeding (45.5% of whom had
ment may be needed to maintain renal function165,166. gastrointestinal bleeding and 32.6% had intracranial
Creatinine clearance enables the estimation of the per- haemorrhage), the median maximum percentage reversal
sisting DOAC effect 167. Haemodialysis can be of help of dabigatran was 100% on the basis of either the diluted
for dabigatran clearance treatment only but requires thrombin time or the ecarin clotting time; the median
haemodynamic stability. Prolonged continuous haemo- time to cessation of bleeding was 2.5 hours. In those
dialysis may help to prevent bleeding rebound effects168. undergoing emergency procedures, haemostasis was
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.
Determine INR
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 dabigatran offers similar protection against thrombo
procedure (1.6 hours after idarucizumab administration). embolism with less re-bleeding than warfarin after
At 90 days, thrombotic events had occurred in 6.3% and major bleeding 185. With respect to timing, although it
7.4% of patients and the mortality was 18.8% and 18.9% is still a matter of debate, warfarin should be restarted
in those with uncontrolled bleeding and those under- 7–14 days following NVUGIB on the basis of a single
going emergency surgery, respectively. Rebound effects available study, whereas DOACs act more rapidly 186.
may occur for up to 6 days and require repeat dosing 177. If early anticoagulation is indicated (for example, in
The costs of these compounds may hamper the use in those with a high thromboe mbolic risk), a bridge
clinical practice. Other investigational antidotes include approach with heparin may be used. A recent joint con-
andexanet alfa (for anti-factor Xa agents) and ciraparan- sensus document composed by several international
tag (for many DOACs)178,179. FIGURE 9 summarizes cardiology societies advocates an earlier resumption
current recommendations167,176,180. of vitamin K antagonists — within the first week for
patients with atrial f ibrillation associated with valvular
Continuing therapy following bleeding control. Once heart disease187.
the bleeding event has been controlled, the decision to
resume anticoagulation should involve a multidisci Quality of life
plinary team and the patient; the need for anticoagu At the time of an NVUGIB, symptoms can include
lants should be reassessed using available risk scores (for vomiting of blood and blood in stools, abdominal pain,
example, CHA2DS2‑VASc and HAS-BLED)181,182. The chest pain, cramping, burning, fatigue, dizziness, palpi
implementation of alternative management (for example, tations and diarrhoea. Thus, the burden on patients
ablation therapy for atrial fibrillation or catheter-based during a bleeding event and hospitalization is con-
atrial appendage occlusion), change of anticoagulants siderable, and health-related quality of life (HRQOL)
(for example, apixaban may have a lower risk of gastro- is substantially impaired105,188,189. A negative associ
intestinal bleeding than other DOACs in indirect com- ation exists between the number of symptoms experi-
parison studies)72 and optimization of treatment (for enced by patients and self-reported levels of HRQOL189.
example, PPI, H. pylori eradication, stricter INR control Impairment to physical health accounts for most of
or DOAC dose adaptation) should also be considered. the decrement in HRQOL experienced by individuals
Data, mostly involving vitamin K antagonists72,183, show at the time of a bleeding event. Issues with mobility,
that resuming oral anticoagulation is associated with a performing daily activities, pain and discomfort have
lower mortality despite more frequent major bleeding 184. all been more frequently cited by patients than issues
A recent study involving 1,539 patients suggested that with a nxiety and depression, and following hospital
Box 5 | Coagulation tests for DOACs NVUGIB can have a substantial impact on other
aspects of quality of life (QOL) in patients and their
Results of routine coagulation tests in patients taking families. Patients can require many days of informal
direct oral anticoagulants (DOACs) are unreliable and care from family members at home during the first
vary depending on the reagents used. Approximately
few weeks following a bleeding event190. In providing
20% of patients who take dabigatran have a normal
this help, caregivers must take time away from their
activated partial thromboplastin time213,214. However,
the American Society of Hematology states in its usual activities, which may incur costs (financial or
practice guide that dabigatran is unlikely to contribute otherwise). In addition, for patients who are in paid
to bleeding if partial thromboplastin time is normal215. employment at the time of NVUGIB, an immediate
Similar findings have been reported with prothrombin return to work is unlikely, resulting in a loss of working
time for rivaroxaban216. In some specialized laboratories, hours and possible earnings190. The consequences of
activity assays calibrated to the specific drug can be NVUGIB can, therefore, be substantial and wide rang-
performed (that is, diluted thrombin time specific ing, affecting aspects of HRQOL and QOL for patients
for dabigatran and anti-factor Xa assays specific for and their families.
rivaroxaban, apixaban and edoxaban)217.
Outlook
NVUGIB is one of the most frequent causes of hos-
admission for NVUGIB, patients have reported levels pitalization, morbidity and mortality associated with
of general and physical fatigue to be considerably higher digestive diseases. Despite the important advances
than mental and motivational fatigue105,188,190. observed in the field, the management of patients with
With clinically effective endoscopic, surgical and NVUGIB has become ever more challenging owing to
medical therapies to stop and prevent bleeding, many an ageing population with comorbidities and complex
physical symptoms can be resolved and improvements therapies. PUB remains the main cause of NVUGIB, and
in HRQOL following the bleeding event can be r ealized. most advances in NVUGIB have been focused on this
The few studies taking repeated HRQOL measures pathology. However, the face and profile of NVUGIB
from patients who have had an NVUGIB have shown events are changing, which demands new approaches in
a significant reduction in symptoms and improvements prevention, diagnosis and therapy 9,23.
in the physical dimensions of health following discharge
compared with during the hospital stay 105,188,189. Management
The long-term consequences of an NVUGIB for From a pathogenetic point of view and in addition to
patients often include anaemia, which is associated the appropriate endoscopic management of bleeding
with fatigue, heart palpitations, pallor and shortness lesions, stabilization of the clotting process in the acidic
of breath191. The already high prevalence of anaemia environment of the upper gastrointestinal tract is a goal
(50–80%)192,193 in patients discharged from the hospital that should be achieved for the successful control of
following a bleeding event is likely to increase, with more the bleeding event. Although the route of administra-
restrictive blood transfusion strategies being adopted for tion and best dosing regimen are still matters of debate,
NVUGIB104,194,195. Iron supplementation in the months there is consensus that PPIs are the drug of choice. The
following an NVUGIB can help increase haemoglobin development of new compounds such as a new class
levels and correct anaemia, but little is known about of potassium-competitive acid blockers may facilitate
whether this directly translates into improvements in emergency treatment of NVUGIB as they have a faster
HRQOL196. One small study in 97 patients diagnosed onset and greater, more consistent and longer acid
with anaemia following NVUGIB showed that 6 months control198 than PPIs.
after the NVUGIB, the proportion of patients who Endoscopic diagnosis and treatment of gastro
reached the normalized HRQOL score was higher and intestinal bleeding lesions probably represent the most
general and physical fatigue levels were lower in those important advances in the control of bleeding events.
patients for whom anaemia had been resolved than Innovation in endoscopic techniques continues to
in those with persistent anaemia; differences at other provide new tools for the management of NVUGIB.
time points were non-significant 188. Iron supplemen- New therapies with compounds or devices that can be
tation can be provided intravenously before discharge, safely applied during the endoscopic procedures or new
which will reduce the time to recover to appropriate diagnostic tools such as the endoscopic Doppler probe
haemoglobin levels197. that can improve the localization of the blood vessel
HRQOL generally follows an upward trajectory in responsible for the bleeding 97 will probably be imple-
the weeks and months following hospital discharge mented in our routine clinical practice in the future
for NVUGIB. However, a return to general popula- once they prove to be safe and useful in clinical trials.
tion normal levels seems unlikely, probably because Patients with ongoing bleeding despite initial volume
of the considerable role of pre-existing comorbidi- restitution could benefit from very early endoscopy
ties and their associated treatments in the aetiology (<12 hours or even <6 hours), but this should be clarified
of NVUGIB105,188–190. For patients with NVUGIB, the in future studies. New studies should also define whether
increased risk of re-bleeding associated with NSAIDs routine second-look endoscopy can be performed in
and antiplatelet and anticoagulant therapies must be selected patients at high risk of therapeutic failure after
carefully considered when planning subsequent care. first-line therapy.
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National Audit of Acute Upper Gastrointestinal tests: a comprehensive assessment using in vitro is an adviser to Aralez Pharmaceuticals. All other authors
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