Transcript Slide 1

Non-variceal Upper
GI Bleeding
Alan N. Barkun
Division of Gastroenterology
McGill University and the McGill
University Health Centre
Montréal, Canada
Conflicts of interest

Consultant for:
Cook Inc.
 Boston Scientific Inc.
 Olympus Inc.

OBJECTIVES

Discuss the management of acute non
variceal upper gastrointestinal bleeding
Initial management
 Preparation for endoscopy
 Endoscopic therapy
 Pharmacological therapy
 Secondary prophylaxis
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INITIAL MANAGEMENT
The Glasgow-Blatchford
Bleeding Score
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GBS superior to
total/clinical Rockall
scores (ROC curves,
P<0.05)
123 patients (22%)
classified as low risk,
with 84 (68%) were
managed as
outpatients safely
Proportion admitted
fell (96% to 71%,
p<0·00001)
Stanley, Lancet 2008
The Rockall Score
Variable
Score
1
0
2
Age (yrs)
< 60
60-79
≥ 80
Comorbidity
No or mild
coexisting
Moderate
coexisting
(e.g.,
hypertension)
Severe coexisting
(e.g., CHF)
Hemodynamic
status
No shock
P < 100
Syst BP ≥ 100
P ≥ 100 plus
Sys BP ≥ 100
Hypotension
Diagnosis
MW tear,
All other
normal
diagnosis
endoscopy with
no blood seen
Malignancy of UGI
tract
Major stigmata
of recent
hemorrhage
None or dark
spot
Blood in UGI tract
Adherent clot,
visible or spurting
vessel
3
Life
threatening
(e.g., RF)
Rockall, Lancet 1996
Co-morbidity and UGIB
mortality
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N=16 RCTs, over 30,000 patients
Leontiadis, AJG, 2013
Initial resuscitation
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Hemodynamic status should be
assessed immediately upon
presentation and resuscitative
measures begun as needed (Strong
recommendation)
Laine, Jensen, AJG 2012
921 UGIB pts randomized to trfX thresholds of Hgb<7 or 9gm/dL,
stratified by cirrhosis
15% vs 51% trfX rates, P<0.001
95% vs 91%*, OR=0.55, 0.33-0.92
Villanueva, NEJM, 2013
Villanueva, NEJM, 2013
2 issues:
a) Generalizability (EGD @6hrs, tight hgb control, 30% cirrhosis;
excl CV, massive)
b) Power adequacy for Non Variceal UGI Bleeding
- awaiting TRIGGER in UK -
Rebleeding rates: Lower in restrictive strategy 10 vs 16%, P=0.01,
and was similar but not significant in the NVUGIB subgroup (P=0.09)
Portal Pressure rose significantly within 5 days w liberal strategy (P<0.03)
Villanueva, NEJM, 2013
What about an elevated INR and
endoscopy?
“In patients on anticoagulants, correction
of coagulopathy is recommended but
should not delay endoscopy”
Platelets >50-100,000
Barkun DDW 2009, Wolf AJG 2007, Baradarian AJG 2004, Choudari Gut, 1994
Meta-analysis of new
anticoagulants
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Thrombin/factor Xa inhibitors not
limited by narrow therapeutic window,
and do not require routine monitoring
of therapeutic target
Dabigatran, Rivaroxaban, Apixaban,
Edoxaban are currently used or
undergoing large-scale evaluation in
patients with atrial fibrillation, deep
vein thrombosis (DVT)/pulmonary
embolism, and DVT prophylaxis
Holster, Gastroenterol, 2013
PREPARATION FOR
ENDOSCOPY
IV erythromycin / metoclopramide
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Nasogastric lavage – RCT-proven yet requires
orogastric insertion of large-bore tube and may
compromise the airway
Should not be used routinely, but can be used in selected cases
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Also decreased likelihood of blood in the stomach
No improvements in rebleeding, surgery,
mortality, transfused units, or length of stay
The benefits of early endoscopy
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Early endoscopy (first 24 hours) allows for
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safe and prompt discharge of patients classified
as low risk
improves patient outcomes for patients classified
as high risk
reduces resource utilization for patients classified
as either low or high risk
Earlier timing for endoscopy (2, 12 hrs RCTs)
show no advantage; ?week-end effect?
? Highly selected very sick bleeders may
benefit from earlier intervention?
Barkun AIM 2003, 2011, Ananthakrishnan CGH 2009, Cooper GIE 2009, Hearnshaw GUT 2010, Lim Endoscopy 2011
PPI pre-endoscopy for UGI
bleeding
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Efficacy at best marginal: downgrades lesion, yet
does not alter outcomes
so PPI should NOT replace the role of adequate
resuscitation and early endoscopy
Can provide PPI before endoscopy or not; more
likely to be cost-effective IF:
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Delay to endoscopy (over 16 hours)
Patient more likely to be bleeding from
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a non variceal source
high-risk lesion (hematemesis, bloody NGT)
If you are going to use, high-dose preferred
Sreedharan , Cochrane, 2010; Barkun AN, GI Endosc 2008
ENDOSCOPIC THERAPY
INJECTION
http://www.nejm.org/doi/full/10.1056/NEJMra0706113
CONTACT THERMAL
THERAPY
http://www.nejm.org/doi/full/10.1056/NEJMra0706113
Endoscopic clips
Which is the best modality?
Rebleeding
Odds Ratio (95% CI)
Not
Injection alone
Thermal + Epi vs. Epi alone (2*)
0.27
0.38
Clips + Epi vs. Epi alone (3*)
Thermal alone
or clips alone
as good as
combination
with Epi?
0.79
Thermal + Epi vs. Thermal alone (4*)
1.30
Clips+ Epi vs. Clips alone (2*)
*Number of trials
 Treat only high-risk lesions
 Equivocal data for “adherent clots”
0.2
0.5
Favors dual
therapy
1
2
5
Favors
monotherapy
Calvet Gastroenterology 2004, Marmo Am J Gastro 2007, Sung Gut 2007, Laine CGH 2008, Barkun GIE 2009
PHARMACOTHERAPY
Effect of PPIs on outcomes in
patients with PUD bleeding
Outcome at 30 days after randomization
Odds Ratio (95% CI)
0.53
Mortality (9*)
0.46
Re-bleeding (19*)
0.59
PPISurgical
improve
mortality
Intervention
(17*) in patients w HRS only if they
have initially undergone endoscopic haemostasis (best
data for high dose IV: 80mg + 8mg/hour x 3 days)
These findings have been confirmed
in a “real-life” setting
0
*Number of trials
0.5
Favors PPI
1
1.5
2
Favors control
Modified from Leontiadis et al, The Cochrane Database of Systematic
Reviews 2005 + update in 2006; Barkun et al., AJG 2004
Lacking evidence that lower doses
are as efficacious as high –dose PPI
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Individual trials:
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Systematic bias in ascertainment of rebleeding?
Questions raised about the adequacy of blinding
Confounding attributable to selective use of
second-look
No per-site adjustment
Meta-analysis:
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Issues of patient population selection
Non superiority, not equivalence
Leontiadis, AJG, 2012
PPI double dose x 11 days post hidose IV PPI and endo hemostasis for
Rockall >6
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Among Rockall ≥6,
rebleeding was
lower double-dose
oral PPI than in
standard-dose
group (4th–28th day:
10.8% vs 28.7%,
p=0.002)
LOS and pURBC
lower Rockall
scores <6 than in
Rockall ≥6
Cheng H-C, GUT, 2014
“Second-look” endoscopy
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Routine second-look endoscopy, in
which repeat endoscopy is performed
24 h after initial endoscopic hemostatic
therapy, is not recommended
(Conditional recommendation)
Should be reserved for select patients
at very high risk of rebleeding (large
ulcers, hi-risk locations)
Laine AJG, 2012; Barkun AIM 2120
REFRACTORY CASES
EMERGING ENDOSCOPIC
THERAPY
Endoscopy findings:
clips + injection + Hemostatic
powder
Peptic ulcer bleeding
Cook Inc., and Brullet et al.
SECONDARY PROPHYLAXIS
How should I diagnose H pylori in
this setting?
Diagnostic test performance in
the acute setting
100
NPV estimates
90
80
70
60
50
+ve Predictive value
-ve Predictive value
40
30
20
10
0
Serology
Rapid
Urease
Histology
Culture
Urea
Breath
Stool
antigen
Best to confirm a negative test outside the acute setting
What about the patients having bled
on ASA?
PUB bleeder on ASA – acute
management
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ASA non-adherence/withdrawal carries a 3x
risk of major adverse cardiac events
The delay to the thrombotic event is usually
7-10 days
Immediate reintroduction of ASA in patients
with PUB on ASA was recently studied
Biondi-Zoccai GG, Eur Heart J, 2006; ; Aguejouf O. Clin Appl Thromb Hemost. 2008 ; Sibon I,
Neurology. 2004. Burger W, J Intern Med. 2005; Sung J, Gut (abstract) 2007; Ng, APT, 2004;
Sung AIM, 2010, barkun AIM 2010
Risks/benefits of immediate
reintroduction of ASA
ASA-related bleeding ulcers,
N=156
ASA discontinuation causes significantly
increased CV mortality
Log rank test P=0.25
Hazard ratio 1.9, 95%CI 0.6-6
Log rank test, P=0.005
(HR 0.2, 95% CI 0.06-0.6)
ASA 10.3%
Placebo 5.4%
BUT
Placebo 12.9%
ASA
1.3%
A statistically non significant increase
in recurrent PUD bleeding,
Sung AIM 2010, Editorial: Barkun AIM 2010
PUB bleeder on ASA –
secondary prophylaxis
 Hp eradication
Experimental
Study or Subgroup
Events
Control
Odds Ratio
Total Events Total Weight
M-H, Fixed, 95% CI
Chan 2005
1
159
13
161
57.3%
0.07 [0.01, 0.56]
Lai 2006
0
86
9
84
42.7%
0.05 [0.00, 0.80]
245 100.0%
0.06 [0.01, 0.32]
Total (95% CI)
Total events
245
1
0.01
Test for overall effect: Z = 3.30 (P = 0.0010)
Rebleeding
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M-H, Fixed, 95% CI
22
Heterogeneity: Chi² = 0.06, df = 1 (P = 0.80); I² = 0%
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Odds Ratio
0.1
1
10
Favours experimental Favours control
ASA + PPI
100
Clopidogrel alone
If clopidogrel / dual antiplatelet Rx related bleed,
suggest PPI (not H2RA) secondary prophylaxis yet
few data; RECOMMENDED BY AHA, ACC, ACG
Controversy about a possible “clopidogrel – PPI
interaction” is NOT warranted
PPI PROPHYLAXIS IN ASAAND NSAID-RELATED UGIB
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X-sectional study btw 2000-2009
1093 and 2277 patients had NSAID- and
ASA-associated ulcer bleeding
At hi-risk: 39% NSAID and 75% ASA
Only 41.6% of NSAID bleeders and
30.6% were on prophylaxis
Greater appropriate PPI use could
reduce bleeding risk by 50%, and
improved adherence by 35%
Ho, APT, 2013; LeRay, CGH, 2013; Lanas, CGH, 2013
Overall management
ABC’s and adequate resuscitation
 Early risk stratification
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Very Low risk patients
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discharge home
pre-endoscopy
at early endoscopy
All other patients
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admit
High-risk patients
Low-risk patients
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Endoscopic hemostasis
Initiate high-dose IV PPI
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Initiate daily dose PPI
Consider secondary prophylaxis
H pylori testing and treating
NSAID/COX2 use
ASA/clopidogrel use*
Conclusions – Non variceal
UGIB
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Established recommendations for
the management of patients with
NVUGIB
Risk stratification, early appropriate
endoscopic hemostasis followed by
hi-dose PPI (secondary prophylaxis)
Hemostatic powders
 Promising
 ?Optimal
role