1. 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

2. Bleeding peptic ulcer A Change in the Management Strategy
Acute upper GI bleeding
Bleeding peptic ulcers
Primary Endoscopic Hemostasis
Primary Surgical Hemostasis ’s
1990’s
Cook et al. Gastroenterology 1992

3. Bleeding stigmata Visible vessel (IIa) Adherent clot (IIb)
Spurting (Ia)
Oozing (Ib)
Clean base (III)

4. Stigmata of Recent Hemorrhage Significance
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
30-35%
Flat spot
IIc
20%
5-8%
Clean base
III
42%
< 3%
Johnson et al. GIE 1990; Laine et al. NEJM 1994

5. Endoscopic injection of epinephine for ulcer hemostasis
Tamponade effect and vasoconstriction with epinephrine

6. Endoscopic Treatment: Bleeding Ulcer Thermal Therapy
Heater probe
3.2mm [need 2T scope]
2.8mm
Pressure + Heat
Coaptive effect – compress until sealing of vessel

7. Endoscopic Treatment: Bleeding Ulcer Mechanical Therapy
Hemoclip

8. Hemospray (Nanopowder)
Sung et al. Endoscopy 2011

9. Endoscopic Treatment: Bleeding Ulcer Clip meta-analysis - Rebleeding
Sung JJ et al Gut 2007
Clip vs Injection
Clip + injection vs Injection
Clip vs Thermal

10. Endoscopic Treatment: Bleeding Ulcer Single or Combination therapy
STUDY
BALANZO 1990
LOIZOU 1991
SOLLANO 1991
CHUNG 1993
VILLANUEVA 1993
LIN 1993
CHOUDARI 1994
KUBBA 1996
CHUNG 1996
VILLANUEVA 1996
LEE 1997
CHUNG 1997
LIN 1999
CHUNG 1999
GAQRRIDO 2002
PESCATORE 2002
TOATL
WEIGHT (%) PETO OR
Favors combined therapy
Favors epinephrine alone
Calvet et al. Gastro 2004

11. Bleeding peptic ulcers Mortality
Perforation
30 day mortality: a: Bleeding; b: Perforation
Lau JY, Sung JJ et al Digestion 2011

12. Causes of mortality in peptic ulcer bleeding
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
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
Multi-organ failure
110
23.9%
Neurological diseases (Stroke) 25
5.4%
Terminal malignancy
155
33.7%
Unclassified 11
1.9% 12
Sung JJ et al AJG 2009

13. To improve clinical outcomes for bleeding peptic ulcers
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

14. Combining ALL predictive factors for the derivation cohort (AUC 0.842)
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
Chiu et al. Clin Gastroenterol Hepatol 2009

15. Result - Correlation of score with mortality in evaluation cohort

16. Prevention of Rebleeding – PPI Intragastric pH vs platelet disaggregation
ADP, adenosine diphosphate.
ADP 80 60 40 20
100 1 2 3 4 5
pH=6.0
Disaggregation=77%
pH=6.4
Disaggregation=16%
pH=7.3
Disaggregation=0%
Buffer
Elevation of intragastric pH inhibits platelet disaggregation and helps to maintain clotting
The development of a platelet plug is the first step in repairing the breach of a blood vessel. These early platelet plugs can achieve initial haemostasis for several hours but then will disintegrate unless reinforced by a fibrin clot.6
In the in vitro experiment shown in this slide, platelet aggregation was promoted by the addition of adenosine diphosphate, followed by the subsequent application of a buffer solution or dilutions of hydrochloric acid. It shows that, at low pH levels, there is disaggregation of previously aggregated platelets. Moreover, platelet aggregation is also inhibited in an acidic environment. These effects can be overcome by elevating the intragastric pH above 6.0.7
In addition, pepsin in the gastric juice can cause the breakdown of clots, as well as disrupting the mucus/bicarbonate barrier that forms a vital part of the gastroduodenal mucosal defence barrier. However, as shown in the previous slide, this enzyme is inactivated at a pH greater than 4 and irreversibly inactivated when the pH is above 6.4
Elevation of the intragastric pH after initial haemostasis in a patient with a bleeding peptic ulcer will therefore help to maintain clotting and prevent rebleeding – and Nexium® has been shown to be more effective than all other PPIs in elevating the intragastric pH above the critical threshold of 4.8
Time (minutes)
Green et al 1978

17. Prevention of Rebleeding - PPI pepsin activity20 40 60 80
100
Maximum pepsin activity (%)
Gastric juice pH 4 3 2 1
pH 4 is a critical threshold for gastric pepsin activity
Elevation of the intragastric pH above 4 reduces not only the damaging effects of gastric acid but also the activity of the digestive enzyme pepsin in the gastric contents. This is because the activity of pepsin in the gastric juice is pH-dependent, declining rapidly when the pH is raised above 4.4
Thus, in the management of GERD, the critical factor is to maintain the intragastric pH, and hence the intraesophageal pH, above 4 in order to reduce the damaging effects of gastric acid and pepsin on the esophageal mucosa.5 Elevation of the intragastric pH above 4 is also critical in the prevention of stress ulcers and in reducing the risk of lung injury from aspiration of acid contents (patients most at risk are those with an intragastric pH of less than 3.5 and a gastric volume of at least 25 mL). In addition, inhibition of pepsin activity by elevation of the intragastric pH above 4 also plays a key role in preventing rebleeding in the upper GI tract after initial haemostasis, as described in the next slide.
Berstad 1970

18. 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

19. Prevention of peptic ulcer rebleeding Adjunctive high dose PPI infusion
Lau JYW et al NEJM 2000

20. Prevention of peptic ulcer rebleeding Adjunctive high dose PPI infusion
Lau et al. NEJM 2000

21. placebo i.v. for 30 min followed by placebo for 71.5 hours
Study Flow Chart
Intravenous Esomeprazole for Prevention of Peptic Ulcer Re-bleeding: 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, placebo-controlled study at 91 centres in 16 countries
i.v. treatment (72 hours)
Oral treatment (27 days)
esomeprazole i.v. 80 mg over 30 min followed by esomeprazole i.v. 8 mg/h for 71.5 hours
Endoscopic
Haemostasis
Single
Combo
esomeprazole 40 mg qd R
placebo i.v. for 30 min followed by placebo for 71.5 hours

22. Clinically significant rebleeding within 72h, ITT population, n(%)
Esomeprazole
n=375
Placebo n=389
p-value
72 hours
No rebleed
353 (94.1)
349 (89.7)
Rebleed
95% CI
22 (5.9)
3.7 – 8.8
40 (10.3)
7.5 – 13.7
0.0256
Risk reduction: 43%
Sung JY et al, AIM 2009

23. Prevention of ulcer rebleeding Scheduled second endoscopy
OGD : Bleeding peptic ulcers
Primary Endoscopic Hemostasis
Rebleeding (10-20%)
Scheduled second endoscopy
24-48 hours
Treat persistent SRH before rebleeding 23

24. IV PPI infusion or second look endoscopy?

25. Nov 2003 to May 2008 Acute Upper GI Bleeding [556]
Failed hemostasis [11]
Bleeding peptic ulcer [326]
Carcinoma [9]
Primary therapeutic endoscopy [305]
Adjunctive omeprazole infusion [153]
Scheduled 2nd endoscopy [152]
Forrest I, IIa, IIb
Endoscopic Retreatment
Rebleeding
OGD ± Laparotomy
Chiu et al. DDW 2010

26. Results - Rebleeding p = 0.646; OR 1.23 (95% CI 0.51-2.93)
As for the rebleeding rate
8.6% of patients in PPI infusion and 8.8 % of patients in scheduled 2nd OGD rebled
There is no significant difference between the two groups
p = 0.646; OR 1.23 (95% CI )

27. Results – Need of Surgery
Regarding secondary outcomes
6 patients in PPI infusion and 2 patients in scheduled 2nd OGD need surgery on rebleeding
There is no significant difference between the two groups
P =0.51 ; OR = 0.49 (95% CI 0.12 – 2.01)

28. Results – Transfusion, Hospital Stay, Mortality
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
The 30 days mortality, hospital stay and transfusion requirement are also not significantly different between the two groups

29. PPI infusion or scheduled 2nd endoscopy
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

30. Acute Upper GI Hemorrhage
Pre-emptive PPI infusion
OGD : Bleeding peptic ulcers
Primary Endoscopic Hemostasis
Rebleeding (5%)
Adjunctive PPI infusion / Scheduled second endoscopy
Salvage Surgery

32. Preemptive high-dose PPI reduces need of endoscopic treatment
371 UGIB patients randomized to high dose IVPPI or placebo before endoscopy
Lau JY, et al. N Engl J Med. 2007

33. Preemptive high-dose PPI reduces need of endoscopic treatment
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
Hospital stay
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 4
.37
30 day rebleeding 7 5
.52
30 day mortality
.79
Lau JY, et al. N Engl J Med. 2007

34. Transcatheter arterial embolization (TAE)
TAE as an alternative to salvage surgery
Can also act to pre-emptive embolization
Trans-catheter arterial embolization TAE has been proposed as an alternative to surgery. During TAE, a celiac and superior mesenteric angiogram would be performed. In case of contrast extravasation, superselective cannulation of the bleeding vessel followed by angiographic coiling from a distal to proximal manner would be done until extravasation ceased

35. TAE Total: TAE n=32 Surgery n=56
3144 bleeding peptic ulcer from January 2000 to July 2009
1254 (39.9%) required endoscopic hemostasis
1218 (97.1%)
successful hemostasis
36 (2.9%) failed
initial hemostasis
166(13.6%) Rebleeding
13 TAE
23 Surgery
From January 2000 to July 2009, 3144 patients were admitted due to peptic ulcer bleeding patients required endoscopic hemostasis. Among them, 36 patients i.e. 2.9% failed initial hemostasis and 13 of them had TAE and 23 had surgery as salvage. For the rest of the 1218 patients who had initial successful hemostasis, 166, that is 13.6% patients rebled. 52 patients had failed second endoscopic treatment or had a second rebleeding episode. 19 of them had TAE and 33 had surgery. Making a total of 32 patients underwent TAE and 56 patients had surgery during the study period.
52 (31.3%) failed 2nd endoscopic treatment/ 2nd rebleeding
Total:
TAE n=32
Surgery n=56
19 TAE
33 Surgery
Wong TL, Lau JY et al DDW 2010

36. TAE vs Salvage Surgery Outcomes - Rebleeding & Mortality
P = <0.005
P = 0.77
Significantly more patients developed rebleeding after TAE. The rebleeding rate was 40.6% in TAE and 12.5% in surgery group. The all cause mortality in 30 days was the same among the 2 groups.
Wong TL, Lau JY et al DDW 2010

37. TAE vs Salvage Surgery Outcomes
P = 0.09
P = 0.60
P = 0.01
The duration of hospitalization and transfusion requirement were similar in the 2 groups. Significantly more complications were observed among those in surgery group.
Wong TL, Lau JY et al DDW 2010

38. A further step…
Pre-emptive Transcatheter Angiographic Embolization in high risk patients
A prospective RCT is ongoing in PWH…

39. Conclusions
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

40. Advanced Technology Multidisciplinary Clinical Exposure
2 Year Master Programme for Medical and Nursing Professionals
Advanced Technology
Multidisciplinary
Clinical Exposure