Updates in Management of
Non-Variceal Bleeding
Justin CY Wu
Professor, Department of Medicine & Therapeutics,
Institute of Digestive Disease, The Chinese University of Hong Kong
Acute upper GI bleeding
Bleeding peptic ulcers
Primary Surgical
Hemostasis
1970 - 1980’s
2
Primary Endoscopic
Hemostasis
1990’s
Cook et al. Gastroenterology 1992
Visible vessel
(IIa)
Spurting (Ia)
Adherent clot
(IIb)
Oozing (Ib)
Clean base (III)
Endoscopic stigmata
Forrest
Prevalence
Risks of rebleeding
w/o therapy
Acute Spurter
Ia
18%
~ 100%
Acute oozing
Ib
Non-bleeding visible
vessel
IIa
17%
Up to 50%
Non-bleeding adherent
clot
IIb
17%
30-35%
Flat spot
IIc
20%
5-8%
Clean base
III
42%
< 3%
4
Johnson et al. GIE 1990; Laine et al. NEJM 1994
Tamponade effect and vasoconstriction with epinephrine

Heater probe
 3.2mm [need 2T scope]
 2.8mm
 Pressure + Heat
 Coaptive effect – compress until sealing of vessel
6
Hemoclip
7
Sung et al. Endoscopy 2011
Sung JJ et al Gut 2007
Study, Year (Reference)
Clips
(+ injections)
n/N
Clip vs Injection
(a) Clips versus Injections
Simoens, 1997 [10]
Chung, 1999 [11]
Chung, 2000 [12]
Gevers, 2002 [13]
Park 2003 [14]
Chou, 2003 [15]
Shimoda, 2003 [16]
LJubicic, 2004 [17]
2/9
1/41
1/9
7/35
0/16
4/39
4/42
2/31
Injections /
Thermocoagulation
n/N
RR
95% CI
3/9
6/41
4/12
5/34
5/16
11/40
6/42
4/30
RR
95% CI
0.67
0.17
0.33
1.36
0.09
0.37
0.67
0.48
Total (95% CI)
222
224
Total events: 21 (Clips), 44 (Injections)
Test for heterogeneity: Chi-square = 6.88, df = 7 (P = 0.44), I2 = 0%
Test for overall effect: Z = 2.89 (P = 0.004)
[0.14,
[0.02,
[0.04,
[0.48,
[0.01,
[0.13,
[0.20,
[0.10,
3.09]
1.32]
2.50]
3.87]
1.52]
1.07]
2.19]
2.45]
0.49 [0.30, 0.79]
Clip + injection vs Injection
(b) Clips combined with injections versus Injections
Villanueva, 1996 [18]
Simoens, 1997 [10]
Chung, 1999 [11]
Gevers, 2002 [13]
Shimoda, 2003 [16]
Park, 2004 [19]
Lo, 2006 [20]
2/42
2/9
4/42
5/32
3/42
2/23
2/52
7/37
3/9
6/41
5/34
6/42
9/45
11/53
0.25
0.67
0.65
1.06
0.50
0.43
0.19
Total (95% CI)
242
261
Total events: 20 (Clips + Injections), 47 (Injections)
Test for heterogeneity: Chi-square = 4.72, df = 6 (P = 0.58), I2 = 0%
Test for overall effect: Z = 3.03 (P = 0.002)
[0.06,
[0.14,
[0.20,
[0.34,
[0.13,
[0.10,
[0.04,
1.14]
3.09]
2.14]
3.33]
1.87]
1.85]
0.80]
0.47 [0.28, 0.76]
Clip vs Thermal
(c) Clips versus Thermocoagulation with or without Injections
Cipolletta, 2001 [21]
1/56
12/57
Lin, 2002 [22]
3/40
2/40
Lin, 2003 [23]
4/46
3/47
Saltzman, 2005 [24]
4/26
5/21
0.08
1.50
1.36
0.65
Total (95% CI)
168
165
Total events: 12 (Clips), 22 (Thermocoagulation)
Test for heterogeneity: Chi-square = 6.42, df = 3 (P = 0.09), I2 = 53.3%
Test for overall effect: Z = 0.75 (P = 0.45)
9
0.01
0.1
Favours Clips (+ injections)
[0.01,
[0.26,
[0.32,
[0.20,
0.63]
8.50]
5.75]
2.11]
0.65 [0.21, 2.02]
1
10
100
Favours Injections / Thermocoagulation
STUDY
WEIGHT (%)
PETO OR
BALANZO
1990
4.5
0.81
LOIZOU
1991
3.2
0.55
SOLLANO
1991
1.0
0.14
CHUNG
1993
12.8
0.80
VILLANUEVA
1993
4.8
2.01
LIN
1993
6.2
0.33
CHOUDARI
1994
6.3
0.91
KUBBA
1996
7.3
0.23
CHUNG
1996
9.0
0.92
VILLANUEVA
1996
3.9
0.25
LEE
1997
5.3
0.33
CHUNG
1997
9.5
0.39
LIN
1999
5.9
0.27
CHUNG
1999
5.4
0.57
GAQRRIDO
2002
6.1
0.27
PESCATORE
2002
8.7
0.78
100.0
0.53
0.01
TOATL
0.1
Favors combined therapy
10
1
10
100
Favors epinephrine alone
Calvet et al. Gastro 2004
Bleeding

Perforation
30 day mortality: a: Bleeding; b: Perforation
Lau JY, Sung JJ et al Digestion 2011
Mortality cases
N = 577 / 10428
Subcategories
N
Percentage
Bleeding related
Uncontrolled bleeding / rebleeding
31
29.2%
N = 106 (18.4%)
Within 48h after endoscopy
27
25.5%
During surgery for uncontrolled bleeding
3
2.8
Surgical complications or within 1 month after
surgery
31
29.2%
Endoscopy related complication
14
13.2%
Non-bleeding related
Cardiac diseases (ACS, Heart failure)
62
23.5%
N = 460 (79.7%)
Pulmonary diseases (COPD, Pneumonia)
108
23.5%
Multi-organ failure
110
23.9%
Neurological diseases (Stroke)
25
5.4%
Terminal malignancy
155
33.7%
11
1.9%
Unclassified
12
Sung JJ et al AJG 2009

Identification of predictors to adverse
events (including rebleeding & mortality)
 Intensive monitoring and pre-emptive
management

Prevention of rebleeding
 Improvement in post-endoscopy management
 Improve the success rate of primary endoscopic
hemostasis
13
CUHK Outcome Prediction Score
Combining ALL predictive factors for the derivation cohort (AUC 0.842)
Pre-endoscopy factors
1. Age greater than 70 years
2. Presence of listed comorbidities
3. More than one listed comorbidities
4. Hematemesis
5. Initial systolic blood pressure less than 100
mmHg
6. In-hospital bleeders
Post endoscopy factors
1. Presence of Helicobactor pylori
2. Development of rebleeding
3. Need for operation
14
Chiu et al. Clin Gastroenterol Hepatol 2009
15
Aggregation (%)
ADP, adenosine diphosphate.
ADP
pH=6.0
Disaggregation=77%
0
Buffer
20
pH=6.4
Disaggregation=16%
40
60
80
100
pH=7.3
Disaggregation=0%
0
1
2
Time (minutes)
3
4
5
Green et al 1978
16
Maximum pepsin activity
(%)
100
80
60
40
20
0
0
1
2
3
Gastric juice pH
4
Berstad 1970
17

240 patients with bleeding peptic ulcers
 Forrest Ia, Ib, IIa
 Treated by injection + Heater probe

IV Omeprazole infusion vs placebo
 80mg bolus dose
 8mg / hour for 72 hours
 Total dose = 656 mg
18
19
Lau JYW et al NEJM 2000
p = 0.14;
20
p = 0.13
Lau et al. NEJM 2000
Intravenous Esomeprazole for Prevention of Peptic Ulcer Rebleeding: A Multinational, Randomised, Placebo-Controlled Study
Joseph J.Y. Sung1, Alan Barkun2, Ernst J. Kuipers3, Joachim Mössner4, Dennis
Jensen5, Robert Stuart6, James Y. Lau1, Henrik Ahlbom7, Jan Kilhamn7, Tore
Lind7

Randomised, double-blind, placebocontrolled study at 91 centres in 16 countries
i.v. treatment
(72 hours)
Endoscopic
Haemostasis
1.
2.
Single
Combo
R
esomeprazole i.v. 80 mg over 30 min
followed by esomeprazole i.v. 8 mg/h
for 71.5 hours
placebo i.v. for 30 min followed
by placebo for 71.5 hours
Oral treatment
(27 days)
esomeprazole
40 mg qd
72 hours
No rebleed
Rebleed
95% CI
Esomeprazole
n=375
Placebo
n=389
353 (94.1)
349 (89.7)
22 (5.9)
3.7 – 8.8
40 (10.3)
7.5 – 13.7
p-value
0.0256
Risk reduction: 43%
Sung JY et al, AIM 2009
OGD : Bleeding peptic
ulcers
Primary Endoscopic
Hemostasis
Scheduled second endoscopy
24-48 hours
Rebleeding (10-20%)
Treat persistent SRH before rebleeding
23
Nov 2003 to May
2008
Acute Upper GI Bleeding [556]
Bleeding peptic ulcer [326]
Failed
hemostasis [11]
Carcinoma [9]
Primary therapeutic endoscopy
[305]
Scheduled 2nd endoscopy
[152]
Adjunctive omeprazole
infusion [153]
Forrest I, IIa, IIb
Endoscopic Retreatment
Rebleeding
OGD ± Laparotomy
25
Chiu et al. DDW 2010
p = 0.646; OR 1.23 (95% CI 0.51-2.93)
26
P =0.51 ; OR = 0.49 (95% CI 0.12 – 2.01)
27
PPI infusion
[153]
2nd OGD
[152]
p
Mortality (%)
8 (5.2%)
3 (2.0%)
0.22
Hospital stay (days)
6.3
4.4
0.02†
Transfusion (unit)
2.2
1.9
0.39
28

After primary endoscopic hemostasis, PPI infusion
achieved a similar rate of ulcer rebleeding as
compared to scheduled second endoscopy

PPI infusion reduced patients’ discomfort and
endoscopists’ workload from repeating endoscopy

Second endoscopy may have an advantage of
shortening the hospital stay

Second endoscopy should be recommended if PPI
infusion is not available
29
Acute Upper GI Hemorrhage
Pre-emptive PPI infusion
OGD : Bleeding peptic ulcers
Primary Endoscopic
Hemostasis
Adjunctive PPI infusion / Scheduled
second endoscopy
Rebleeding (5%)
Salvage Surgery
30
31
371 UGIB patients randomized to high dose IVPPI or placebo
before endoscopy
Lau JY, et al. N Engl J Med. 2007
Omeprazole
N=179
Placebo
N=190
P value
Blood transfusion
Mean, SD
Median range
1.7, 2.8
0, 0-24
2.2, 3.9
1.5, 0-38
.15
.15
Hospital stay
Mean, SD
Median, range
4.2, 4.9
3, 1-41
5.1, 5.6
3, 0-54
.09
.003
Urgent intervention
2
3
1
Surgery for hemostasis
1
4
.37
30 day rebleeding
7
5
.52
30 day mortality
4
5
.79
Lau JY, et al. N Engl J Med. 2007


TAE as an alternative to salvage surgery
Can also act to pre-emptive embolization
3144 bleeding peptic ulcer from
January 2000 to July 2009
1254 (39.9%) required endoscopic
hemostasis
1218 (97.1%)
successful hemostasis
166(13.6%) Rebleeding
52 (31.3%) failed 2nd endoscopic
treatment/ 2nd rebleeding
19 TAE
33 Surgery
36 (2.9%) failed
initial hemostasis
13 TAE
23 Surgery
Total:
TAE n=32
Surgery n=56
Wong TL, Lau JY et al DDW 2010
P = <0.005
P = 0.77
Wong TL, Lau JY et al DDW 2010
P = 0.09
P = 0.60
P = 0.01
Wong TL, Lau JY et al DDW 2010

Pre-emptive Transcatheter Angiographic
Embolization in high risk patients

A prospective RCT is ongoing in PWH…

Peptic ulcer rebleeding remains one of the
most important clinical catastrophy with
significant mortality

PPI Infusion after endoscopic therapy prevent
ulcer rebleeding

Schedule 2nd endoscopy served as an
alternative when PPI infusion is not available

Pre-emptive Transarterial embolization may
served as an adjunctive measure to prevent
ulcer rebleeding
39
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