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Clinical Medicine Insights: Therapeutics
Volume 10: 1–15
© The Author(s) 2018
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DOI: 10.1177/1179559X18790258
Introduction
Acute upper gastrointestinal haemorrhage continues to be an
important clinical problem. The incidence of non-variceal
acute upper gastrointestinal bleeding is about 85/100 000 per
year in the United Kingdom.1 Although the specific mortality
associated with portal-hypertensive variceal bleeding is higher,2
peptic ulcer bleeding (PUB) is still the commonest cause of
both acute gastro-intestinal (GI) bleeding overall and signifi-
cant bleeding requiring a blood transfusion.2,3 There have been
considerable advances in many aspects of the management of
PUB, but the overall mortality remains significant (around
10%): the advances in therapy being offset by the increasing
age and comorbidity of the patients.
There are several comprehensive, evidence-based guide-
lines supporting the management of PUB,4,5 although com-
prehensive audits and observational studies have shown that
all aspects of management do not always reliably follow guide-
lines.3,6,7 New data are continually becoming available in all
aspects of PUB, and in many cases, these have had insufficient
time to directly inform published guidelines. In addition,
guidelines by their very nature are broad and overarching and
are not optimally positioned for discussion of new and evolv-
ing techniques and management strategies of developments in
specific, niche but important areas.
This narrative review covers important and/or controversial
recent developments in all aspects of PUB. These will be placed
in clinical context to further enhance the management of
patients. The aim is to concisely summarise important evolu-
tions in therapy for generalist physicians and surgeons as well
as highlight important new literature to those with more
focused interests in the area, in particular where this adds to, or
even contradicts, standard guidelines.
The management of ulcer bleeding can be divided for con-
venience into several overlapping areas: recognition, risk assess-
ment, resuscitation, endoscopic and salvage therapies and drug
therapies, both in the acute presentation and primary and sec-
ondary preventive strategies. There are important new devel-
opments in all of these areas (see Figure 1), areas that will be
highlighted include the application of novel prognostic scoring
systems, the peri-procedural pharmacological management of
the patient and co-morbidity, novel endoscopic techniques
(Doppler ultrasound probe, over the scope clips, haemostatic
powders), reassessment of classical endoscopic stigmata and
secondary prevention strategies focused on the management of
polypharmacy and co-morbidity.
Recognition
The presence of blood in the vomitus or melaena passed rec-
tally is usually sufficient to alert a clinician to the presenta-
tion of acute upper GI bleeding and enough to instigate
appropriate management. Sometimes rapid fresh rectal
bleeding presents a dilemma: could this be colonic source or
very rapid transit from an upper GI source? This has impli-
cations for the management. In the United Kingdom,
National Confidential Enquiry into Patient Outcome and
Death (NCEPOD) audit of severe GI bleeding, actual site of
bleeding correlated poorly with the presenting general clini-
cal features and clinical suspicion of the admitting team.3
The presence of a pulse rate greater than the systolic blood
pressure was associated with an upper GI source for fresh
rectal bleeding.3 Further prospective studies examining this
index are required, but it certainly seems reasonable to per-
form a gastroscopy initially, before lower GI endoscopy in
Advances in the Therapy of Bleeding Peptic Ulcer
Ian LP Beales
Department of Gastroenterology, Norfolk and Nor wich University Hospital, Norwich, UK.
ABSTRACT: Peptic ulcer bleeding remains an important medical emergency. Important recent advances are reviewed. These include further
support for a more restrictive transfusion strategy aiming for a target haemoglobin of 70-90 g/L. The Glasgow-Blatchford score remains
the most useful assessment score for identifying the lowest risk patients suitable for outpatient management and predicting the need for
intervention. Newer scores such as the AIMS65 and Progetto Nazionale Emorragia Digestive score (PNED) may be more accurate in predicting
mortality. Pre-endoscopy erythromycin improves outcomes and is underused. A new disposable Doppler probe appears to provide more
accurate determination of both rebleeding risk and the success of endoscopic therapy than purely visual guidance. Over-the-scope clips and
haemostatic powders appear to have some role as endoscopic salvage therapies. Non-H. pylori, non-aspirin/non-steroidal anti-inflammatory
drug (NSAID) ulcers contribute to an increasing percentage of bleeding peptic ulcers and are associated with a high rebleeding rate. The
optimal management of these ulcers remains to be determined.
KEYWORDS: Gastrointestinal haemorrhage, peptic ulcer haemorrhage, endoscopic hemostasis, H pylori, Hemospray, inorganic powder,
anaemia, anticoagulant drugs, non-steroidal anti-inflammatory drugs
RECEIVED: August 5, 2017. ACCEPTED: June 22, 2018.
TYPE: Review
FUNDING: The author (s) received no nancia l suppor t for the research, a uthors hip, and/or
publication of this article.
DECLARATION OF CONFLICTING INTEREST: The autho r(s) declare d no potenti al
conic ts of inter est with re spect to t he resear ch, autho rship, an d/or publ icatio n of this
article.
CORRESPONDING AUTHOR: Ian LP Beales , Depart ment of Gas troente rology, Nor folk
and Nor wich Uni versit y Hospit al, Norw ich NR4 7U Y, UK. Email: i.bea les@uea.ac.uk
790258THP0010.1177/1179559X18790258Clinical Medicine Insights: erapeuticsBeales
review-article2018
2 Clinical Medicine Insights: Therapeutics
these patients showing that degree of circulatory compro-
mise after they have received appropriate resuscitation.
Resuscitation
Despite the high prevalence of PUB, there are few data on any
specifics of fluid resuscitation and general principles on restor-
ing circulating fluid volume and adequacy of organ perfusion
are usually employed, although it seems inevitable that there
will be individual choice in terms of fluids used and rate given.
There is an increasing body of data concerning transfusion
strategies, although they are somewhat difficult to interpret
applied to a dynamic situation, such as significant PUB when
blood forms but one part of an overall fluid resuscitation strat-
egy. Randomised studies in this area are difficult to do, and
hence, the key trial examining blood transfusion strategies was
extremely welcome.8 In common with an increasing body of
data from other critically ill patients, across the spectrum of
medicine including major sepsis9,10 a restrictive blood transfu-
sion strategy seems at least as good as a more traditional liberal
strategy. In the trial,8 a single unit, and then repeated as required,
strategy with a transfusion trigger of 70 g/L to maintain the
haemoglobin at 70-90 g/L was as safe and effective as a more
traditional haemoglobin target of 90-110 g/L. The trial recruited
all comers with upper GI bleeding and was not specifically
designed to look at subgroups by aetiology of bleeding. Mortality
was lower in the restrictive transfusion group (5% vs 9%). Those
with variceal bleeding or Child’s A or B cirrhosis particularly
seemed to benefit from the conservative transfusion strategy
with improved mortality and rebleeding rates. In the subgroup
with PUB, there appeared to be less difference between the two
strategies. The restrictive strategy produced favourable clinical
outcomes: mortality 3% versus 5%, rebleeding 10% versus 17%
Figure 1. Management of peptic ulcer bleeding with recent advances in therapy highlighted.
Beales 3
and surgery 2% versus 6%, although given the small numbers
these were not statistically significant. Recruitment to the trial
was, by necessity, selective excluding those with very severe
bleeding and significant circulatory diseases, which may limit
generalisation to other populations.
There are data showing contrary effects: one study pub-
lished only in abstract form11 examined real-world outcomes
after transfusion for PUB, and showed an association between
with more units transfused and lower death rates. A further
uncontrolled study also from Los Angeles reported that initial
blood transfusion during resuscitation was associated with a
lower risk of death from PUB (odds ratio [OR]: 0.84 (95%
confidence interval [CI]: 0.75-0.94),12 although it is possible
that blood transfusion in this context is more of marker for the
adequacy and aggressiveness of initial fluid resuscitation.
A meta-analysis reported the results of pooling the four
available studies of transfusion strategies in acute upper GI
bleeding, individually these all have different methodologies
and inclusion criteria.13 Not all of the included studies specifi-
cally examined only acutely bleeding peptic ulceration. Overall,
the results favoured a restrictive transfusion strategy: there
were significant reductions in death and length of stay with the
restrictive strategy. Rebleeding rates were also non-significantly
lower in the restrictive group (OR: 0.26; 95% CIs: 0.03-2.10).
A subsequent further meta-analysis including only data on
acute gastrointestinal bleeding from five randomised controlled
trials showed that a restrictive transfusion strategy was associ-
ated with lower all-cause mortality (relative risk: 0.65; 95% CI:
0.44-0.97) and rebleeding (relative risk: 0.58; 95% CI: 0.40-
0.84) without any effect on ischaemic events.14 The exact opti-
mal resuscitation strategy is unclear and always needs to be
individualised to the specific patient. However, the consistency
and biological plausibility of the results, combined with the
costs and potential harm of blood transfusion, mean that it
would seem appropriate to employ a conservative transfusion
strategy for most patients with PUB, while maintaining ade-
quate circulating fluid volumes.
It is important to emphasise that blood-transfusion strate-
gies are but only one component of fluid resuscitation in PUB
and that in the acutely bleeding patient haemoglobin levels
only form one part of the assessment of circulatory instability.
Any choices concerning fluid and blood replacement must be
governed by the need to restore adequate organ perfusion. It
seems that crystalloid fluid resuscitation followed by blood to
maintain the haemoglobin level at 70-90 g/L is most appropri-
ate for most patients, further data are required for those with
severe or critical vascular and circulatory diseases.
Risk Stratification
Many systems that have been used to stratify risks in upper GI
bleeding (see Table 1). Probably the two most widely used and
studied are the Rockall scores (both pre- and post-endoscopy)
and the Glasgow-Blatchford Score (GBS).20 Additional scores
have been proposed. The AIMS65 score has been advocated as
an even simpler score requiring scoring only on a 5-point score
for each of albumin <30 g/L, INR (>1.5), Glasgow Coma score
<14. Systolic blood pressure < 90 mmHg and age > 65. Although
the AIMS65 can reliably predict mortality, it appears less accu-
rate than the GBS in determining the need for interventions
such as blood transfusion or admission to critical care.15,17
A further score, the Progetto Nazionale Emorragia Digestive
score (PNED) system which relies on a rather cumbersome
multipart scoring utilising age, the presence of cancer, renal
failure, American Society of Anaesthesiologists (ASA) grade,
cirrhosis, rebleeding and failure of endoscopic therapy has been
proposed. A large prospective study of over 3000 patients con-
firmed that the GBS clearly performed best in identifying the
lowest risk patients and also in predicting important interven-
tions such as endoscopic therapy or blood transfusion. Although
the PNED and AIMS65 scores were best at predicting mortal-
ity, none of the scores apart from the GBS appeared to be clini-
cally useful in determining either the safety of outpatient
management or the need for endoscopic therapy.15 A GBS
score of 7 or more was best at predicting the need for endo-
scopic treatment.15
Despite the fact that the GBS and Rockall scores have
always been designed to assess somewhat different aspects,
there continues to be studies comparing the clinical utility of
these studies. It should be highlighted that the Rockall scores
assess the mortality risk and were never designed directly as
decision tools (accepting that any risk assessment of the patient
obviously does inform clinical-decision making). In contrast,
the GBS was explicitly designed and validated to detect those
cases not needing intervention (therapeutic endoscopy or blood
transfusion). Thus, not surprisingly, the GBS consistently per-
forms better in identifying lower risk cases, especially those
suitable for safe direct discharge and outpatient manage-
ment.16,21 A recent international validation of the GBS con-
firmed that a score of 0 or 1 is associated with a very low risk of
intervention and hospital admission and emergency endoscopy
is not required.15
Despite the plethora of existing scores, a further model has
recently been proposed based on seven factors: systolic blood
pressure <100 mmHg, syncope, haematemesis, haemoglo-
bin < 100 g/L, blood urea 22.4 mg/dL, estimated glomerular
filtration rate <60 mL/min/1.73 m2, and the use of anti-plate-
let medications.19 In a cohort of Japanese patients, this score
was superior to the pre-endoscopy Rockall and AIMS65 scores
in predicting clinical intervention.19 However, it is requires fur-
ther study and in particular comparison against the GBS before
the exact role in management can be established.
Use of anti-thrombotic agents at the time of upper GI
bleeding does not seem to be associated with adverse outcomes.
A prospective study of 619 patients from North America,
Europe and Asia that required endoscopic intervention con-
firmed that patients taking anti-thrombotics were generally
older with more co-morbidity and hence higher risk scores
(AIMS65, Rockall and Glasgow-Blatchford) but actually had
4 Clinical Medicine Insights: Therapeutics
lower mortality (4% vs 11% and shorter hospital stay (mean of
6.9 days vs 7.9 days) when compared to non-users.22
Cirrhosis is an important independent risk factor for mor-
tality in PUB. A prospective analysis of consecutive cases of
all-cause upper GI bleeding in cirrhotic patients showed that
45-day mortality from PUB (17%) was similar to acute variceal
bleeding (19%), although deaths in both groups were due to
liver failure and not controlled bleeding.23
The timing of emergency endoscopy in acute upper GI
bleeding remains controversial and although immediate endos-
copy (as early as possible) seems theoretically attractive, this
approach has not been supported by evidence. Some studies
have demonstrated that very early endoscopy is not associated
with better outcomes, and in some case worse outcomes have
been reported (although this latter effect could have been an
artefact of the design of the observational studies).24,25 Perhaps
more usefully, those patients with a GBS of 12 or more were
shown (again in an observational study) to have lower mortal-
ity with a presentation to endoscopy time of <13 hours, whereas
in those with lower GBS scores there was no association
between early such endoscopy and clinical benefit.26 These
findings have not been university reproduced, although the ret-
rospective nature of the all the studies conspires against deter-
mining the exact nature of the relationships between timing of
endoscopy and outcomes. Ahn etal reported that urgent (<8
hours from presentation) endoscopy was not associated with
better clinical outcomes than early (8-24 hours) endoscopy.
Although those having early endoscopy tended to have higher
risk scores and higher risk lesions seen at endoscopy, when
analysis was confined to those patients with a higher risk (here
defined as a pre-endoscopy Rockall score of 3 or more), urgent
endoscopy was not associated with any positive or negative
clinical outcomes.27 In contrast, another retrospective study
showed a clear association between urgent (<12 hours) and
adverse outcomes compared to early (12-24 hours). Those
undergoing urgent endoscopy were 5 times more likely to reach
a composite end-point of death, inpatient rebleeding, endo-
scopic, surgical or radiological intervention.28 This effect may
have been influenced by causation bias (those having urgent
endoscopy had higher AIMS65 and GBS) but analysis of the
results according to GBSs is very informative. Interestingly in
this study, urgent timing of endoscopy was not associated with
either better or worse outcomes in higher risk cases (defined as
GBS of 12 or more). However, in the lower risk group (GBS of
<12), urgent endoscopy was clearly associated with worse out-
comes (composite outcome 29% vs 5%, rebleeding 10% vs 3%).
The reasons for this perhaps counter-intuitive association are
unclear. The authors postulate, quite reasonably, this could be
due to inadequate resuscitation of these patients considered
low risk. One further recent retrospective study from Korea29
showed that in higher risk patients (defined as GBS of > 7)
urgent endoscopy (<6 hours) was associated with lower 30-day
mortality (2.5%) than later (6-48 hours) endoscopy (3.8%).
However, this was not associated with any association with
Table 1. Principle risk scores used in acute upper GI bleeding. Showing the components of each score and the main clinical uses. References as
cited in main text.
REQUIRES
ENDOSCOPY
COMPONENTS MAIN USE(S)
Pre-endoscopy Rockall (clinical
Rockall)15,16
No Age, blood pressure, pulse,
comorbidity
Predicts mortality
Post-endoscopy Rockall (full
Rockall)15,16
Yes Age, blood pressure, pulse,
comorbidity, cause of bleeding,
stigmata of recent haemorrhage
Predicts mortality
Glasgow-Blatchford15 -17 No Urea, haemoglobin, blood
pressure, pulse, syncope,
melaena, cirrhosis, heart failure
Predicts the need for inter vention (endoscopic
therapy or blood transfusion).
Accurately identies the lowest risk cases
Identies those suitable for non-admission and
outpatient management.
May have a role in triaging urgency of endoscopy
Abbreviated Glasgow
Blatchford18
No Urea, haemoglobin, blood
pressure, pulse
Predicts the need for inter vention (endoscopic
therapy or blood transfusion)
AIMS6515,17 No Albumin, Glasgow Coma Score,
Systolic Blood pressure, age.
Predicts mortality
PNED15 Yes Presence of cancer, ASA grade,
cirrhosis, rebleeding, failure of
endoscopic therapy
Predicts mortality
Iino19 No Haemoglobin, urea, syncope,
haematemesis, eGFR,
anti-platelet treatment
Predicts need for clinical intervention (limited data)
ASA: American Society of Anaesthesiologists; eGFR: estimated glomerular ltration rate; GI: gastrointestinal.
Beales 5
rebleeding, transfusion requirements, intensive care admission
or hospital stay, all or which are usually associated with mortal-
ity. Although more endoscopic therapy was applied in the
urgent group, this was mainly driven by increased treatment of
oozing Forrest Ib lesions (that are probably not as high risk as
previously believed, as will be discussed subsequently).
The conclusion is that GBS scores can be used effectively to
triage patients not requiring admission. It may also be possible
to detect those that may benefit most relatively early endoscopy
and equally detect those in who very early endoscopy may actu-
ally be associated with harm.
Further modifications of the GBS have also been reported,
omitting the most subjective of the criteria and relying merely
on objective measurable haemodynamics and laboratory values,
omitting the scoring for chronic disease/major co-morbidities,
melaena and syncope, Interestingly, the abbreviated score
seemed to perform as well as the full GBS score and was also
superior to the Rockall scores for predicting the need for clini-
cal intervention.18 Further validation studies are required, but
this may prove to be a useful simple modification to enhance
clinical practice.
In addition to these predominantly clinical scores, the endo-
scopic appearances can provide additional prognostic informa-
tion. Reviewing a large cohort of patients with PUB from Los
Angeles, Camus et al12 showed that ulcer size was an inde-
pendent predictor of 30-day rebleeding and death. Increasing
ulcer size above 10 mm was associated with an increased risk of
death of 1.08 per 10% increase in ulcer size in patients present-
ing de novo with GI bleeding. In existing inpatients compli-
cated by a GI bleed, these effects were magnified with
approximately doubled the absolute mortality risks for the
same size ulcer compared to outpatient presentations. This
once again confirms the poor prognosis for patients having a
PUB while already in hospital for another condition as well as
generally confirming that comorbidity and high-risk endo-
scopic stigmata are associated with a poorer prognosis,2
Although this is an interesting finding, at present, it does
not seem that ulcer size alone will be sufficient to influence
decisions about interventions or second-look endoscopies, but
it would be wise to consider reports of ulcer size when consid-
ering any further descriptions of scoring systems or treatments
that have a bearing on prognosis in PUB.
Endoscopy and Endoscopic erapy
Endoscopy obviously remains the essential haemostatic
modality in PUB. Dual therapy, with adrenaline/epinephrine
infiltration combined with either thermal coagulation with a
bipolar probe or mechanical haemostasis with endoclips
remains the optimal endoscopic therapy advocated in the
major guidelines.4,5 The thermal or mechanical aspects are
the most important and although adrenaline is often used to
clear the endoscopic field it probably adds little to the haemo-
stasis as secured by other means.15 There is a variety of
through-the-scope endoscopic clips available from different
manufacturers, but there are no data showing clear superiority
of any one clip.
Within endoscopy, there are four important recent develop-
ments: Doppler probe-guided lesion assessment and treatment,
the reassessment of the bleeding risk associated with oozing
(Forrest Ib) ulcers, the availability of large over-the-scope clips
and the new haemostatic powders. The exact place of these
new haemostatic methods within the management pathway
requires further assessment but all seem to offer some advan-
tages in certain circumstances, although arguably the Doppler
system offers the greatest change to overall strategies.
Doppler probe assessment of ulcers to detect significant
arterial signals in the ulcer base is not a new technique, having
been reported many years previously.30 However, the lack of
availability of the equipment and lack of convincing evidence
of efficacy at the time, with available endoscopic modalities
rather precluded wider adoption. More recently, there has been
an increase in interest, stimulated by the availability of an easier
to use Doppler unit and disposable relatively low-cost endo-
scopic probes (Vascular Technologies Inc, Nashua, New
Hampshire, USA). Two studies from the same group have
shown initially how Doppler probe assessment is more accurate
than classical endoscopic scoring in predicting rebleeding
risks31 and second in a randomised-trial that Doppler probe-
guided management reduces rebleeding and further interven-
tion compared to standard treatment.32 Doppler assessment
demonstrated that many oozing ulcers (Forrest Ib) are actually
not associated with significant arterial flow into the ulcer (only
46.7% showed a positive Doppler signal) and that these ulcers
are associated with a lower rebleeding rate than typically
assumed. The rate of Doppler-positive arterial flow in oozing
ulcers is actually significantly lower than the prevalence of pos-
itive Doppler signal for active arterial bleeding (not surpris-
ingly 100%), non-bleeding visible vessel (Forrest IIa, 90.7%)
and those with adherent clot (Forrest IIb, 68.4%). Interestingly,
40.5% of ulcers with flat haem spots alone (Forrest IIc) which
are classically associated with a low risk of rebleeding had a
positive arterial Doppler signal, while in clean-based ulcers
(Forrest III) only 8.3% had a positive Doppler signal. Repeating
Doppler assessment post-standard endoscopic treatment
showed a considerable reduction in arterial flow and that per-
sistent arterial inflow was associated with an increased risk of
rebleeding.31
It is interesting to compare these results with those from the
original endoscopic Doppler studies.33 In those Forrest Ia and
Ib were not assessed, as they were actively bleeding, it was
assumed they must have a significant feeder artery, but arterial
inflow was detected in 61% of Forrest IIa, 70% Forrest IIb, 50%
of Forrest IIc and 21% of Forrest III. These are very similar to
those with the new disposable technology, although further
studies particularly on low-risk Forrest III lesions are required.
A subsequent randomised trial compared use of the Doppler
probe to both guide the decision to use endoscopic therapy and
the success of that therapy against standard haemostatic
6 Clinical Medicine Insights: Therapeutics
treatment based purely on endoscopic visualisation.32
Endoscopic therapy was applied based on the presence of a
Doppler signal rather than endoscopic appearance and after
endoscopic therapy, the ulcer was reinterrogated and retreat-
ment applied if an arterial signal was still present. Doppler use
in this manner was associated with a significant reduction in
rebleeding. Rebleeding at 30 days was 8/72 (11.1%) in the
Doppler-treated arm compared to 20/76 (26.3%) in the stand-
ard care group. Residual arterial signal despite maximal endo-
scopic therapy (adrenaline, bipolar probe, through-the-scope
clips) was strongly associated with rebleeding (8/9 cases, 88.9%)
compared to 0/8 (0%) of those that had continued endoscopic
retreatment until the Doppler signal was obliterated.
This technique looks extremely promising. The application
of the Doppler probe allows more accurate definition of the
rebleeding risk of ulcers (it is superior to standard endoscopic
stigmata) and facilitates tracing of the underlying artery for
direction of haemostatic methods and allows post-treatment
reanalysis to define the efficacy of endoscopic therapy. Further
studies in other populations with less experienced and commit-
ted operators are required before widespread adoption and fur-
ther data on the efficacy of this advance are awaited with
interest. Certainly, Doppler-guided therapy has the potential to
dramatically reform the endoscopic approach to PUB. Here, it
is important to note that bipolar coagulation is probably the
optimal method of primary endoscopic haemostasis with the
Doppler probe, clips may be difficult to place over a hidden
feeder artery and may also obstruct further Doppler investiga-
tion because of their position.
These data with the Doppler probe showing that oozing
ulcers (Forrest Ib) are associated with significantly lower risks
of rebleeding post-endoscopic therapy31,32 are in keeping with
a retrospective analysis of data from one of the large studies of
proton-pump inhibitor therapy after endoscopic therapy in
PUB34 and should lead us to reappraise the risks associated
with oozing ulcers. After optimal standard endoscopic treat-
ment, in the placebo-treated arm, rebleeding was much lower
in those with oozing ulcers (4.9%) than in spurting (Forrest Ia,
22.5%), adherent clot (Forrest IIb, 17.6%) and visible vessel
(Forrest IIa, 11.3%). Again supporting the hypothesis that ooz-
ing ulcers tend to have smaller feeding vessels and rebleeding
rates are lower than previously believed on the basis that this
was ‘active bleeding.’ Interestingly, this study also showed that
intravenous esomeprazole did not reduce this already low post-
endoscopic rebleeding rate in the oozing ulcers (compared to
the beneficial effect in the other high-risk stigmata). This sug-
gests that parenteral acid suppression may be withheld from
this group after successful haemostasis and standard oral ther-
apy used instead.34 This reappraisal of the rebleeding rates
associated with classical endoscopic stigmata of recent haem-
orrhage has major implications for the interpretation of exist-
ing studies and the design of future studies. Grouping all active
bleeding groups (Forrest Ia and Ib) together now seems inap-
propriate given the clearly divergent rebleeding risks. Certainly,
all future studies of drug or endoscopic techniques should
stratify effects according to this subdivision of endoscopic
stigmata.
The main limitations of the standard endoscopic clips are
the relatively small size and the limited pressure the jaw can
apply to close tissue and provide mechanical haemostasis. The
much larger and stronger over the scope endoscopic clip
(OTSC; Ovesco Endoscopy,Tubingen, Germany) overcomes
many of these drawbacks. It is able to grasp larger and more
fibrotic areas than standard clips and is able to apply more
pressure onto feeding arteries. The obvious drawbacks of this
are having to preload the clip on the endoscope before intuba-
tion, the much greater unit cost and sometimes the difficulty
passing the clip through the upper oesophageal sphincter. The
OTSC clip is Food and Drug Administration (FDA) approved
and available in many areas, being utilised to close fistulas and
perforations in addition to acute PUB. Several case-series have
reported successful haemostasis with this device when other
endoscopic methods have failed. Honegger et al35 reported
85% success in treating PUB (28/35), although in a smaller
case series haemostatic success was only reported in 4/7 cases
of refractory bleeding peptic ulcer.36 The OTSC clip has also
been used successfully as primary treatment for PUB: Manno
etal37 reported 100% success in 21 cases. A retrospective review
of experience in the quaternary referral practice of the Mayo
Clinic,38 showed an overall success rate of 70.1% (47/67
patients) when used as primary or secondary treatment.
Schmidt etal performed an important, albeit small-sized (66
subjects), randomised trial comparing the OTSC with ‘stand-
ard’ endoscopic methods for recurrent PUB after initial suc-
cessful haemostasis. These results looked somewhat more
impressive in that persistent bleeding at the time of endoscopy
after per-protocol second line haemostasis was significantly
lower in the OTSC arm than standard treatment (6.0% vs
14%), although there was no difference in subsequent rebleed-
ing after successful second-line haemostasis, blood transfusion
requirements or hospital stay.39 It is important to note that
essentially all the ‘standard’ endoscopic therapy used in this
particular study was throughout the scope clips plus epineph-
rine, with very minimal use of thermal coagulation. Slightly
surprisingly for a study focusing on failed initial haemostasis
(given the data from the Doppler studies discussed previously)
approximately 50% of the study cohort compromised oozing
(Forrest Ib) ulcers, where rebleeding is generally much lower.
When the OTSC was applied as rescue therapy after failed
per-protocol endoclips, haemostasis was secured in 100% of
cases. It is also worth noting that no problems with passing the
OTSC (even the larger 12 mm OTSC) into position were
reported. Once again, this does seem a very promising tech-
nique, although the studies have not adequately stratified for
the underlying rebleeding rates of the different ulcer pheno-
types. However, at present, this does seem to be useful second-
line endoscopic technique, although a degree of training is
required to use the equipment effectively in the emergency.
Beales 7
Haemostatic powders are in a similar position. These seem
a promising technology, but not yet supported by comprehen-
sive randomised trial data. There are now several powders
available in various geographical locations, the first available
was Hemospray (Cook Medical) but others are now available,
including Endoclot (Premier Endoscopy Limited), Purastat
(Diagmed Healthcare) and Ankaferd (Ankaferd Drug Inc),
although availability of the different products varies in differ-
ent countries. For example, Hemospray has only recently been
approved for use in the United States (7 May 2018). These are
proprietary mineral, amino acid, herbal or polysaccharide prep-
arations that when sprayed onto a bleeding area through a can-
nula inserted through the channel of an endoscope provoke
rapid haemostasis. The powders appear acts both as a physical
barrier by polymerising upon contact with moisture and a pow-
erful procoagulant by concentrating clotting factors at the site
of application. There are no randomised trials, but several case-
series showing successful haemostasis after failure of first-line
endoscopic therapies showing that several of these powders
may be usefully employed in those most difficult refractory
bleeding ulcers.
In a comprehensive literature review of reported cases,
Hemospray was successful in 88% success in 81 cases of bleed-
ing peptic ulcers.40 A further review showed Hemospray to be
effective in 88% of a total of 234 GI bleeding cases of all causes
(the majority of use as primary [83%] rather than rescue ther-
apy (17%)). However, the overall rebleeding rate was relatively
high at 16.2% within 72 hours, and there are a paucity of data
specifically referring to PUB.41 Even within the 81 cases of
PUB reported, the majority were at the lower-risk end of the
spectrum (62% Forrest Ib) and the true clinical efficacy of
Hemospray still needs to be defined.
Obviously, this method provides no obliteration of the
underlying artery (as clips or bipolar probe do) and the rate of
rebleeding and the subsequent natural history of PUB bleeding
in this context are unknown. Haemostatic powders do not
influence the underlying arterial inflow and by obscuring the
view and access conceivably may reduce definitive haemostasis.
At present, it is unclear if rebleeding rates with highest-risk
stigmata (spurting arteries or those with significant positive
Doppler traces) treated by Hemospray are clinically problem-
atical. The powder application invariably obscures the endo-
scopic view, and perhaps repeat second-look endoscopy will be
required to perform more secure haemostasis. The FDA release
accompanying the approval of Hemosray in the United States
includes data on the success (95% initial haemostasis) but also
warnings about the risk of rebleeding (quoting a figure of 20%
at 30 days).42 At present, this cannot be regarded as a routine
first-line therapy but in some cases can be extremely useful
when other methods have failed. The technique is relatively
easy, although care must be taken to avoid premature exposure
to the powder to liquid, which activates the powder. However,
because the spray does not need to be as precisely targeted as
clips or bipolar probing, it may offer some additional advantages
when access is limited, such as posterior duodenal ulcers or
proximal lesser curve ulcers where is it difficult to obtain direct
approach to the lesion. In the author’s experience, applying this
in a duodenal cap with a rapidly bleeding ulcer is often quite
difficult, but it can be applied for bleeding lesions when other
methods are technically impossible or have failed and may pro-
vide rescue haemostasis in those cases. It is important to note
that the requirement for blood or liquid for effective activation
often reduces the effective use of haemostatic powders on non-
bleeding but protuberant arteries (Forest IIa lesions) which do
merit some form of endoscopic therapy.
Most of the published data about powders concerns
Hemospray and given the very different properties of the dif-
ferent preparations, it would be incorrect to extrapolate between
them. Data are even more preliminary for the other forms of
haemostatic powders. Ankaferd was successful in stopping
bleeding from seven cases of upper GI cancer43 and was
reported to be effective in 26/30 cases of upper GI bleeding of
various causes, although the report does not provide sufficient
data about the risk stratification of the bleeding peptic ulcers
included.44 A further small study examined the use of Ankaferd
as the primary method of endoscopic haemostasis for bleeding
Forrest Ia and Ib lesions (although the relative distributions of
the two was not given) and initial success was seen in 19/26
(73%) with a rebleeding rate of 15.8%.45 Interestingly, other
more standard endoscopic methods could be immediately
applied after failed Ankaferd application and these secured
haemostasis in all cases.
Purastat has been mainly used this far as an adjunct to pre-
vent rebleeding after endoscopic resections such as endoscopic
mucosal resection (EMR) or endoscopic submucosal dissection
(ESD)46 and as it has not been reported to control active arterial
haemorrhage it cannot be recommended at present as either a
primary or rescue therapy for actively bleeding peptic ulcer.
Further studies examining its role as an adjunct after other
forms of endoscopic therapies to prevent rebleeding are awaited
with interest, Endoclot is perhaps more promising. A prelimi-
nary study of its use as rescue therapy 21 cases of upper GI
bleeding refractory to treatment with bipolar probe or standard
through-the scope clips reported immediate haemostatic suc-
cess in all cases (100%) and a rebleeding rate of 4.8%. It should
be noted that the majority of ulcers (76%) treated were oozing
(Forrest Ib) and the efficacy in higher-risk contexts remains to
be explored.47 Further studies reporting the different haemo-
static powders in relation to more standard haemostatic meth-
ods and in ulcers with different bleeding stigmata will help
refine the place of the powders in management (Table 2).
Although endoscopic therapy is effective, rebleeding
remains an important problem is a small subset of patients. The
potential role of interventional radiology as an adjunct to
endoscopic therapy continues to be explored. Lau et al per-
formed a well-designed randomised trial comparing radiologi-
cal embolisation with standard high-quality management in
patients after successful endoscopic haemostasis. Patients with
8 Clinical Medicine Insights: Therapeutics
high-risk ulcers based on clinical criteria (size >20 mm, shock
on presentation, spurting ulcer or haemoglobin <90 g/L on
presentation). Overall, there was no significant effect of adjunc-
tive embolisation (in the intention to treat analysis, rebleeding
occurred in 10.2% of the embolisation group and 11.4% of the
control group) and although transfusion requirements were
lower in the embolisation group, other clinical outcomes were
equivalent. While this study shows that routine post-endos-
copy embolisation is not indicated after successful haemostasis,
post hoc analysis of the study does show some interesting
effects that should be followed up by more focused studies.
Embolisation did seem to reduce rebleeding in ulcers >15 mm
and half of the rebleeding in the embolisation group occurred
in the 18% of the group randomised to active intervention arm
that did not receive effective embolisation. With per protocol
analysis the hazard ratio for rebleeding without embolisation
was 1.89 (95% CI: 0.73-4.92).48
Thus, there are an exciting array of tools becoming available
to assist the assessment and endoscopic treatment of PUB.
Further studies are required to define how best we should use
these together.
Drug erapy
Pre-endoscopy proton pump inhibitor (PPI) infusion is recom-
mended by some guidelines but not universally.15 Although
this treatment seems to downstage the endoscopic appearance
of bleeding ulcers, the effect on objective clinical end-points
such as rebleeding or hospital stay is debateable. In contrast,
post-endoscopy PPI treatment after endoscopic therapy to
high-risk ulcers has been shown repeatedly to be better than
placebo in reducing rebleeding and surgery.49 However, despite
the multitude of studies in this area, the optimal PPI regimen
is unclear. Many clinicians use the original ‘Hong-Kong’ regi-
men (bolus followed by continuous infusion of omeprazole,
pantoprazole or esomeprazole) for 72 hours. Other dose regi-
mens have been shown to be effective, including intermittent
parenteral dosing and even high-dose oral PPI, and it is not
clear what the optimal regimen is50,51 (for full details of the
many different regimens studied please refer to the meta-anal-
yses cited). As previously discussed, the rebleeding rate after
successful endoscopic haemostasis in oozing (Forrest Ib) ulcers
is low and does not seem to be reduced by parenteral high-dose
acid suppression and hence treatment may be rationalised in
those patients to standard oral PPI therapy.34
The Rockall score can be used to focus the use of post-pro-
cedure PPI. Cheng etal52 showed that 11 days high dose oral
esomeprazole (40 mg twice daily), started after endoscopic
therapy and 72 hours iv PPI was superior to once daily esome-
prazole 40 mg (with 40 mg once daily subsequently for both
groups) in preventing rebleeding (10.8% vs 28.7% in the 4-28
days post-index bleed) in patients with a full Rockall score of 6
or more. There was no significance difference in mortality, hos-
pital stay or blood transfused. Thus, there is rationale for treat-
ing the higher risk patients (Rockall 6 or more) with higher
dose PPI for the period after initial stabilisation.
There is sound plausibility and evidence for using prokinet-
ics before endoscopy in upper GI bleeding to clear the stomach
and both improve the endoscopic views and probably improve
safety. While individual underpowered trials have shown
inconsistent results, several recent meta-analyses, including up
to 8 trials (598 subjects), showed that intravenous erythromy-
cin before endoscopy was associated with meaningful clinical
benefit in terms of reduction in need for repeat endoscopy (by
about 50%), improved mucosal visualisation, as well as length
of stay, while metoclopramide seemed to be less effective.53-56
No effect on mortality or utilisation of endoscopic therapy was
reported and the effect of blood transfusion was inconsistent
and not significant.56 Erythromycin is probably underused and
seems to be a simple intervention that would improve out-
comes. The optimal erythromycin regimen is unclear, trials
have used doses ranging from 125 mg to 4 mg/kg, given over
5-30 minutes and starting the gastroscopy 20-90 minutes after
completing the erythromycin.56
Tranexamic acid, used to prevent fibrinolysis of a clot over-
lying an artery is an attractive, simple pre-endoscopy treatment.
Tavakoli etal57 randomised 410 patients presenting with signs
suggestive of PUB to pre-endoscopy treatment with either
intravenous tranexamic acid, intravenous plus nasogastric
tranexamic acid or saline placebos. There was no significant
difference in any clinically meaningful end-point (rebleeding,
mortality, and need for endoscopic intervention). However,
there were no thromboembolic complications reported in the
first week after treatment. The study population was of gener-
ally low-risk PUB (80% clean-based ulcers) and was under-
powered and inappropriately designed to show a clinical effect
of tranexamic acid on the more significant clinical outcomes.
Results of the much larger worldwide HALT-IT study should
shed more light on the role of tranexamic acid.58
Table 2. Haemostatic powders available. Not all preparations are available in all territories. References as cited in main text.
PREPARATION RESULTS IN UPPER GI BLEEDING
Hemospray® (Cook Medical)40, 41 Approximately 90% initial success. 20% rebleeding. Several hundred cases repor ted in the
literature. Most established of the powders.
Endoclot® (Premier Endoscopy)47 Ver y limited data. Haemostasis in 100%. Rebleeding 5%
Ankaferd® (Ankaferd Drug Inc)43,44,45 Very limited data. Success in 70 -90%. Rebleeding 15%
Purastat® (Diagmed Healthcare)46 No data in acute upper GI bleeding and not recommended for use.
Beales 9
The management of concurrent anticoagulation is an
increasing problem for all of those involved in the care of acute
PUB. The use of prothrombin complex concentrate to reverse
the anticoagulation effects of vitamin K antagonists (VKAs)
such as warfarin is well-established.15 The directly acting anti-
coagulants (DOACs), the thrombin antagonist dabigatran and
the factor X inhibitors apixaban, rivaroxaban and eduxoban pre-
sent more of a conundrum. Due to renal clearance of these
drugs, the anticoagulation effect declines relatively rapidly.
However, in some patients, life-threatening bleeding will require
anticoagulation reversal. The first specific reversal agent for
dabigatran (idarucizumab) has just been licenced and available
for clinical use. Although it is expensive, it should be available to
treat significant dabigatran-associated PUB. Idarucizumab is a
monoclonal antibody against dabigatran and will not reverse
the other DOACs.59,60 There are relatively few data concerning
the treatment of upper GI bleeding associated with these agents
and although some guidelines have been produced,61 these have
not been informed by comprehensive studies. Widespread use
of tranexamic acid is not routinely indicated in PUB62 (although
the results of the large worldwide HALT-IT trial are awaited
with interest58), but in this particular situation of DOAC-
induced PUB, the use of tranexamic acid seems reasonable,
albeit not supported by convincing evidence.63 Prothrombin
complex concentrate seems to reverse the anticoagulation effect
of factor X inhibitors in healthy volunteers and should probably
be considered in severe life-threatening bleeding. Although
there are really no data specifically showing an effect in PUB.61,64
A specific antidote to factor Xa inhibitors has been developed
and has recently been shown to rapidly reverse the anticoagu-
lant effect and hopefully will be available for clinical use soon.65
Further studies are needed to better define the management
strategy for anticoagulated patients, especially those taking
DOACs in terms of timing of endoscopy, application of phar-
macological reversal strategies and the specifics of endoscopic
therapies. At present, it would be wise to resuscitate and support
such patients and risk stratify as per standard policies. It will be
important to establish whether different forms of endoscopic
therapies, which cause different degrees of tissue damage (ther-
mal methods versus clips) are preferable in this situation.
Acute upper gastrointestinal bleeding is a significant drain
on the body’s iron stores and many patients are anaemic after
completing initial management. A randomised trial compared
subsequent management strategies in this group with non-
variceal upper GI bleeding (mostly peptic ulcer related). Iron
therapy, either a one-off dose of intravenous ferric carboxymalt-
ose or oral ferrous sulphate 200 mg daily, was more effective
than placebo at restoring haemoglobin levels to normal. After
12 weeks, 17% of iron-treated patients were still anaemic com-
pared to 70% of placebo-treated.66 There was no difference in
the rates of improvement in anaemia between parenteral and
enteral iron groups, although higher ferritin levels were seen in
the parenteral group.66 There was no significant toxicity, and it
seems logical supplemental iron therapy should be used in those
patients with anaemia at the cessation of the peptic ulcer bleed.
Management of Refractory Bleeding
Despite advances in endoscopic and pharmacological thera-
pies, a significant minority of patients experience significant
rebleeding. Surgery has traditionally been regarded as the most
appropriate approach. Increasingly interventional radiology is
been seen and often regarded as the initial therapeutic approach
before surgery. There are no randomised trials to guide therapy,
and it seems unlikely any will be performed. Although not sup-
ported by trial data, endoclips can be placed to mark the site of
bleeding, in those deemed at highest risk of needing embolisa-
tion (most obviously in those with failed endoscopic haemosta-
sis, but in also in those with technically difficult but successful
haemostasis) to facilitate subsequent radiological localisation
and embolisation. If this is available locally.
A number of case series have reported high technical suc-
cess and acceptable complication rates with radiological embo-
lisation for acute PUB,67-69 and it is generally believed that the
overall safety of interventional radiological is significantly bet-
ter than surgery. Hence, most guidelines now advocate radio-
logical embolisation as the rescue therapy of choice. However,
not all studies are concordant with this: single centre observa-
tional studies and a meta-analysis have suggested that rates of
rebleeding are higher following embolisation than surgery and
mortality rates equivalent.70,71 All such studies are somewhat
difficult to interpret because of case mix: as patients undergo-
ing embolisation tended to be older with more co-morbidities.
Where the appropriate skills in interventional radiology are
available, embolisation does seem to provide an effective rescue
tool, but as with many other decisions in these patients, clinical
management should be individualised.
Follow-up and Prevention
An understanding of the major causes of PUB naturally leads
into developing strategies for both primary and secondary pre-
vention. The major and easily ameliorable causes of are PUB
are H pylori and drugs. It is also important to note the apparent
rise in idiopathic (non-H pylori, non-aspirin/non-steroidal
anti-inflammatory drug [NSAID]) ulcers.
Strategies to deal with H pylori need to encompass both the
declining efficacy of eradication therapies and the poor sensitiv-
ity of H pylori testing in the context of PUB.72 Empirical eradi-
cation at the presentation with bleeding is usually advocated in
areas with a high prevalence of H pylori, while an alternative
approach of careful follow-up testing and focused treatment
may be more applicable in areas with a low prevalence of H
pylori-induced ulcers.73 Whichever strategy is followed, H pylori
eradication regimes must be effective in the population being
treated. Fourteen-day courses of four agents (either bismuth
containing or not) are now standard in Europe and the United
States, although 7-day clarithromycin containing regimens are
10 Clinical Medicine Insights: Therapeutics
still used in the United Kingdom in areas with a known low
prevalence of clarithromycin-resistant H pylori (the Maastricht
V guidelines provide a more comprehensive review of H pylori
eradication strategies74). It is essential that all clinicians treating
H pylori are aware of the efficacy of their current treatment regi-
mens and follow up patients assiduously.
For many years, it has been documented that the sensitivity
of all endoscopy-based H pylori tests is lower in acute PUB.72
The reasons for this are not fully determined and are not as
simple as being affected by blood in the lumen. The yield of
biopsy-based tests can be significantly improved by taking
additional biopsies from the gastric body,72 but despite this,
there continues to be a residual false-negative rate. Thus, care-
ful follow-up testing may still be more appropriate in those
initially negative.73 In the acute bleeding setting, 13C urea
breath testing immediately on return from endoscopy appears
to be the most accurate test for H pylori but not surprisingly
many units find this logistically difficult to organise.72 In con-
trast, the faecal antigen test has a high false positive rate in
acute PUB, possibly due to immunological cross-reaction with
blood components in the GI lumen and should not be used for
H pylori testing in the acute setting.72 The diagnostic yield for
H pylori in the context of PUB can be significantly enhanced by
performing any diagnostic testing at least 4 weeks after the
index bleed.75
H pylori can cause bleeding peptic ulcer alone but recent
data have clarified the interactions with other risk factors.76 H
pylori infection appears to increase the risk of PUB, compared
to non-bleeding peptic ulcer in patients also taking NSAIDs
(OR: 2.91; 95% CI: 1.71-4.98) aspirin (OR: 2.23; 95% CI:
1.52-3.38) and non-aspirin anti-platelet agents (OR: 4.37;
95% CI: 1.28-14.99) but not in those taking corticosteroids,
selective serotonin-reuptake inhibitors or anti-coagulants.
These increased risks were not completely ameliorated by con-
current PPI use. Once again, emphasising the importance of
successful H pylori eradication in both primary and secondary
prevention of PUB.
Although aspirin and other antiplatelet agents are clearly
associated with an increased risk of PUB, in many cases these
agents are indicated because of the underlying vascular disease,
and it is now accepted that where indicated aspirin should be
continued (or interrupted for a minimal interval of < 3 days) in
acute PUB.73 A small risk in early rebleeding is more than
compensated by a significantly reduced risk of vascular events
and death. This approach is supported by data from both a rela-
tively small clinical trial and observational follow-up data.77,78
A further non-randomised case-control study from Japan79
compared outcomes from patients with PUB that were taking
antithrombotic medications, which were continued throughout
with those from patients without any anti-thrombotic drug
exposure. Overall, in 346 patients, continuing anti-thrombotic
treatment, which was mainly anti-platelet therapies, was asso-
ciated with a significantly increased risk of rebleeding (13.9%
vs 5.8% within 30 days), but there was no difference in
mortality or other outcomes. In this study, collection of data on
post-bleed thrombotic complications was not rigorous. The
endoscopic therapies applied, the majority either argon plasma
coagulation or injection therapies alone, were probably subop-
timal compared to other studies. The exact proportion of
Forrest Ib ulcers, which as discussed previously have a relatively
low rebleeding rate, were not provided. Thus, generalisation of
these finding is slightly difficult, but overall, these data are con-
sistent with the previous studies suggesting that continuation
of anti-platelet therapies is usually indicated in PUB.
The most appropriate treatment after an aspirin-induced
bleed is aspirin plus a PPI,80 this is superior to the P2Y12
antagonist clopidogrel alone as secondary treatment. There are
less data on the newer P2Y12 antagonists ticagrelor and prasu-
grel, but these are more potent anti-platelet agents and not sur-
prisingly the risk of GI bleeding seems to be higher than
aspirin or clopidogrel.81,82 Follow-up of a large non-randomised
cohort (11 955 patients) after myocardial infarction treated
with percutaneous intervention, where PPI-use (about 18%
overall) was at the physicians’ discretion, showed that while
those treated with a PPI had a higher rate of adverse cardiovas-
cular outcomes (hazard ratio 1.38 (95% CI: 1.21-1.58)), this
was similar between clopidogrel- and prasugrel-treated
patients83 and suggests that this association is due to confound-
ing by indication with higher risk patients receiving gastropro-
tection and not due to a significant effect of PPIs on clopidogrel
pharmacokinetics.73 The rates of clinically significant bleeding
were not significantly different between PPI-treated clopi-
dogrel and prasugrel patients, although interestingly were
numerically lower in the prasugrel group (1.9% vs 4.6%), and
this may reflect underlying confounding in this non-ran-
domised study
Patients with drug-eluting coronary artery stents do need to
continue dual antiplatelet therapy for a year, PPI co-treatment
reduces bleeding in those taking aspirin plus clopidogrel.84
Further subgroup analysis of the COGENT trial confirmed
that omeprazole co-treatment with aspirin-clopidogrel therapy
is similarly effective at reducing GI bleeding in the two main
groups receiving dual-therapy: post-acute myocardial infarc-
tion (upper GI bleeding at 180 days, placebo-treated 1.21%,
omeprazole-treated 0.24%) and after elective percutaneous
intervention (0.73% and 0.23% respectively).7 Importantly,
omeprazole-treatment was not associated with increased
adverse cardiovascular outcomes in any subgroup. Although
the COGENT study was prematurely terminated due to fund-
ing difficulties, these data are very reassuring as to the efficacy
and safety of omeprazole in this situation.
These most recent data do again confirm the clinical safety
and efficacy of PPI co-treatment with clopidogrel-based anti-
thrombotic regimens.85 Although there is undoubtedly a phar-
macokinetic interaction, in that several PPIs, most noticeably
omeprazole, do inhibit the CYPP450 mediated biotransforma-
tion and activation of clopidogrel, this is not translated into a
reduction in clinical efficacy.73 A further detailed study on
Beales 11
these interactions showed that four different PPIs (omepra-
zole, esomeprazole, lansoprazole and rabeprazole (pantopra-
zole was not tested), all had the potential to reduce the
anti-platelet activity of clopidogrel; however, no effect was seen
if rabeprazole was taken 4 hours after the clopidogrel.86
The relative benefits and risks of aspirin plus PPI versus
clopidogrel plus PPI after an aspirin-induced PUB are not
fully defined. However, observational data suggest that aspirin
is safer, more effective and preferable.87,88 An interesting effect
of the increasing use of gastro-protection with anti-platelet
agents is that the incidence of upper GI bleeding has decreased,
but as might be expected, the incidence of lower GI bleeding
has remained stable, so that in patients taking dual antiplatelet
agents with PPI cover the risk of lower GI bleeding is approxi-
mately three times higher than upper GI bleeding.89
In general, PPI co-treatment has been advocated with aspi-
rin for primary and secondary prevention. This has been out-
lined in existing guidelines from the American Heart
Association and the American College of Gastroenterology,
although these are over 10 years old now, they are still generally
applicable.90 While all cases of previous PUB are high-risk and
warrant PPI-secondary prevention. Primary prevention needs
can be stratified according to the number other risk factors
(including age, other antithrombotics, selective serotonin reup-
take inhibitors) and primary prevention focused on those are
highest risk.73 A recent study looking at secondary prevention
in a Chinese population showed that famotidine was equivalent
to rabeprazole.91 Previous data suggested that PPI treatment
was better,92 and until more data in wider populations are avail-
able, PPI treatment continues to remain the treatment of choice.
The importance of primary prevention of PUB was high-
lighted in a population-based study from the United Kingdom.
Follow-up of over 3000 patients starting treatment with an
anti-platelet agent (96% aspirin) without any specific gastro-
protection protocol over 10 years (it is worth noting that choice
of this was at the prescriber’s discretion and only about 25%
received gastroprotection) confirmed that the risk of acute
upper GI bleeding increased substantially with age (age > 75,
hazard ratio [HR]: 4.13 (95% CI: 2.60-6.57) but importantly
demonstrated that these bleeding events in this most elderly
group were far from benign in outcome. The majority of PUBs
(62%) in the over 75 age-group were fatal or associated with
major subsequent disability6 Estimates from these data suggest
that in those patients over 85, the number-needed-to-treat
with a PPI to prevent an aspirin-induced PUB is as low as 25.
In comparison, it may be as high as 338 in subjects under 65.6
Similar to the case with antiplatelet agents, it is now becom-
ing apparent that where indicated early resumption of antico-
agulation for atrial fibrillation after a PUB is beneficial. The
increased risk of rebleeding is compensated by reductions in
stroke and death. The exact optimal time for reintroduction of
anticoagulation after a PUB is unclear. It appears that leaving
reintroduction for 3 months imposes an excessive risk of
thrombotic events,93,94 while very early reintroduction does
increase the rebleeding risk and a compromise of reintroduc-
tion after 7-15 days probably seems to provide the optimal
reduction in thromboembolic events compared to rebleed-
ing.95,96 Data in support of this come from Qureshi etal,97 who
reported on outcomes in 1329 patients with atrial fibrillation
and a warfarin-associated significant gastrointestinal haemor-
rhage (about 50% were from an upper GI source). Restarting
warfarin was clearly associated with better outcomes: reduced
thromboembolism (HR: 0.71; 95% CI: 0.54-0.93) and mortal-
ity (HR: 0.67; 95% CI: 0.54-0.93) but no effect on recurrent
bleeding (HR: 1.120; 95% CI: 0.78-1.86). An analysis by time
of reintroduction of warfarin showed that rebleeding was
higher if restarted less than 7 days after index bleeding and
thromboembolism was higher if restarted after 30 days.
Reintroduction between 7 and 15 days seemed to provide opti-
mal efficacy. More studies specifically examining this effect are
required, particularly focused on PUB.
Previous studies have confirmed that selective COX-2
inhibitors are safer than traditional non-selective NSAIDs in
terms of gastrointestinal complications.73 The combination of
celecoxib plus a PPI is associated with the lowest risk of
rebleeding after an NSAID-induced PUB, when reintroduc-
tion of anti-inflammatory therapy is required.73 However, con-
cerns about the cardiovascular safety of COX-2 inhibitors lead
to many clinicians being reluctant to prescribe these. The pub-
lication of recent data has allowed an important reappraisal of
the role and risk associated with COX-2 inhibitors, particularly
celecoxib.98 A large observational study of real-world practice
showed that the risk of myocardial infarction appeared to be
increased with all cyclo-oxygenase inhibitors and the risk asso-
ciated with naproxen (generally thought to be the safest cardio-
vascular NSAID) was equivalent to other NSAID and that the
increase in risk with celecoxib was also comparable other
agents.99 The risk with the now withdrawn COX-2 inhibitor
rofecoxib was higher. Subsequently, a updated meta-analysis of
outcomes from randomised trials and observational studies of
cyclo-oxygenase inhibitors showed that rofecoxib appeared to
be an outlier with higher risks of myocardial infarction, stroke
and combined cardiovascular outcomes that placebo, other
NSAIDs or other COX-2 inhibitors.100 Celecoxib was not
associated with any increased risk of any cardiovascular end-
point compared separately to placebo, NSAIDs or COX-2
inhibitors and in fact seemed to be associated with a lower risk
of stroke compared to other non-specific NSAIDs. There
seemed to be no correlation between the COX-2 selectivity of
an agent and cardiovascular risks.100
Subsequently, a recent, large randomised study powered spe-
cifically to look at cardiovascular rather than gastrointestinal
outcomes showed no inferiority of celecoxib compared to either
naproxen or ibuprofen (all combined with esomeprazole) and
cardioprotective doses of aspirin as indicated. The PRECISON
trial included over 24 000 subjects with osteoarthritis or rheu-
matoid arthritis and increased cardiovascular risk, with mean
follow-up of 20 months. Overall, cardiovascular adverse
12 Clinical Medicine Insights: Therapeutics
outcome rates were comparable (celecoxib 2.3%, naproxen 2.5%
and ibuprofen 2.7%), but celecoxib was associated with a sig-
nificantly lower incidence of GI side effects (composite GI end-
point celecoxib 1.1%, naproxen 1.5%, ibuprofen 1.6%).101
Subsequently, further detailed analysis of the gastrointestinal
effects of PRECISON have confirmed the overall superior
safety of celecoxib, with significantly lower total clinically sig-
nificant gastrointestinal events even in those also treated with
aspirin and corticosteroids. The number of the individual com-
plications such symptomatic ulcer or ulcer bleeding were low
throughout the study and although numerically in favour of
celecoxib, failed to show statistical significance.102 This suggests
that when clinically indicated celecoxib (in a dose up to 200 mg
daily) plus a full-dose PPI should not be withheld from patients
requiring treatment after a NSAID-induced bleed.98
Although these data on the relative cardiovascular safety of
commonly used COX-inhibitors are very reassuring, the miss-
ing piece of the puzzle has always been which is the most
appropriate anti-inflammatory agent to use with low-dose
aspirin to prevent GI bleeding and yet maintain cardiovascular
safety.73 Initial studies showed that as might be expected add-
ing aspirin to a COX-2 inhibitor ameliorated much of the GI
safety of COX-2 inhibitor compared to a non-specific
NSAID,103 however that end point was based predominantly
on endoscopically detected ulcers in average-risk patients and
not complications such as bleeding.
An important trial (CONCERN) has now demonstrated
that in the highest risk patients, those with a combined aspirin-
NSAID induced peptic ulcer bleed, who need to continue both
therapies, celecoxib plus aspirin plus a PPI is the optimal strat-
egy.104 The Hong Kong group randomised 514 subjects to aspi-
rin plus esomeprazole plus either celecoxib or naproxen. After
18 months follow-up, recurrent PUB was significantly lower in
the celecoxib group (5.6%) than the naproxen group (12.3%).
There was no difference in cardiovascular outcomes, although
these were numerically less common in the naproxen arm.
PPI co-treatment would be usually recommended after a
PUB and primary prevention of PUB in higher risk patients
taking anticoagulants is usually advocated by some guidelines
but not all.73,105–108 Surprisingly there are little data specifically
to support this practice. A recent study showed that omepra-
zole co-treatment did reduce rebleeding in warfarin-treated
patients, although this effect was only apparent in those also
taking anti-platelet drugs or NSAIDs.109 A further observa-
tional study showed that concurrent use of PPIs or H2-receptor
antagonists with anticoagulants were both associated with a
reduced risk of acute upper GI bleeding, and this effect was
most marked in those with a history of peptic ulcer disease.110
Therefore, despite the relative lack of evidence, co-prescription
of gastroprotection with anticoagulant therapy would seem to
be indicated in secondary prevention, for primary prevention, a
case- and risk-based approach seems sensible pending further
data. Those with highest risk of bleeding are most likely to gain
from use of acid suppression.
The rate of GI bleeding with DOACs compared to VKAs
remains controversial. While overall bleeding rates associated
with DOAC use at all sites combined do seem to be lower, this
is mainly driven by a reduction in cerebral bleeding and the rate
of GI bleeding may actually be increased but certainly does not
seem convincingly lower. Several studies have shown either a
higher rate of GI bleeding with DOACs or equivalent rates to
VKAs.111–114 The increased GI bleeding risk of DOACS seems
especially marked in the most elderly (aged over 76).
This effect on GI bleeding may not be unexpected, as most
of the DOACs are taken as active drugs (in contrasts to VKAs)
and relatively higher levels and local anticoagulant effects may
be seen at the level of the gastrointestinal mucosa. The choice
of which, if any, anticoagulant to reintroduce after a PUB cur-
rently needs to be made on an individual basis taking into
account underlying risks and comorbidity, availability of anti-
dotes and patient preferences. The scoring systems for throm-
botic risks in atrial fibrillation (CHADS2-Vasc) and bleeding
risk (HAS-BLED) can give important guidance on the relative
risks of these important outcomes;115 however, there are no
data specifically related to using these scores prospectively to
manage patients influences outcomes.
An increasing number of studies from disparate geographi-
cal regions have shown an important increase in apparently idi-
opathic peptic ulcers as the cause of upper GI bleeding. This
was initially in the Far East, but further studies from the United
Kingdom and Europe have confirmed this. These ‘ideopathic’
ulcers can contribute up to 40% of ulcers in some series and an
even higher proportion of the bleeding peptic ulcers occurring
in hospital inpatients.116–119 Although labelled idiopathic, they
are typically seen in the more elderly population with signifi-
cant comorbidity and these ulcers may represent a marker of
systemic vascular pathology. The importance of recognising
this group lies not only in determining secondary preventive
management of PUB by cause (H pylori, drug, idiopathic) but
in appreciating that this group is associated with a significantly
higher risk of rebleeding compared to other causes (up to 42%
at years). This group also had much higher all-cause mortality
(presumably due to the associated comorbidity [87% mortality
at 7 years]120). Continuing acid suppression is probably the
most logical treatment in this group, but one important study
(albeit observational not randomised) showed that acid sup-
pression did not alter rebleeding or mortality in this group.121
It would be worth exploring other approaches, perhaps with
drugs with other modes of action such as misoprostol as a
mucosal protectant agent, to see if the natural history of these
ulcers can be altered.
Conclusions
Acute PUB remains an important clinical problem, but the man-
agement continues to be refined. Important recent developments
that can be incorporated into practice include the confirmation of
the usefulness of the GBS in determining the lowest risk patients,
who may be safely managed as outpatients. The
Beales 13
Glasgow-Blatchford is most useful for predicting the need for
intervention but another score either the Rockall Score or
AIMS65 should also be assessed as a predictor of mortality to aid
assessment of outcomes. The abbreviated GBS may prove easier
to use clinically, and just as accurate, if supported by further data.
A restrictive transfusion threshold with a trigger of 70 g/L
and a target of 70-90 g/L is appropriate for most patients. Pre-
endoscopy erythromycin is probably under used, and recent
evidence supports wider use to improve endoscopic views. The
addition of high dose oral esomeprazole after initial proton
pump therapy in high-risk cases (Rockall scores of 6 and above)
seems to have a useful benefit in reducing rebleeding. For
endoscopic treatment, the haemostatic powders and over the
scope clips are useful tools when standard modalities are inef-
fective or impractical. The new Doppler equipment and dis-
posable endoscopic Doppler probe appear to be very promising
in more accurately predicting ulcer rebleeding and the success
of endoscopic therapy and are likely to be widely used if further
studies are confirmatory.
Oral iron should be prescribed to anaemic patients after a
PUB episode to enhance normalisation of the haemoglobin
level. Strategies to manage the bleeding episode and prevent
rebleeding, need to include the management of comorbidities
and risks and in at present must include the management of
bleeding associated with all antithrombotic agents, but particu-
larly the DOACs. Specific antidotes are being developed and
are just entering the clinical arena. Recent data suggest that the
cardiovascular risk of celecoxib is not excessive compared to
standard NSAIDs and when used appropriately celecoxib
should once again be a useful tool in the primary and secondary
prevention of PUB. Non-H pylori, non-NSAID ulcers are
becoming an increasing problem with a poor prognosis and
further studies are urgently required to define the safest and
most effective management.
Author Contributions
ILPB conceived the concept of the manuscript, performed the
literature search and literature review, wrote all drafts of the
manuscript and is the guarantor of the paper.
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