Justin CY WuProfessor, Department of Medicine & Therapeutics,

Institute of Digestive Disease, The Chinese University of Hong Kong

Updates in Management of

Non-Variceal Bleeding

Cook et al. Gastroenterology 1992

Acute upper GI bleeding

Acute upper GI bleeding

Bleeding peptic ulcers

Bleeding peptic ulcers

Primary Endoscopic Hemostasis

Primary Endoscopic Hemostasis

Primary Surgical Hemostasis

Primary Surgical Hemostasis

1970 - 1980’s

1990’s

2

Spurting (Ia) Adherent clot (IIb)

Visible vessel (IIa)

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%

Johnson et al. GIE 1990; Laine et al. NEJM 19944

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

7

Hemoclip

Sung et al. Endoscopy 2011

Study, Year (Reference)RR RR

n/N n/N 95% CI 95% CI

Favours Injections / ThermocoagulationFavours Clips (+ injections)

(a) Clips versus Injections

(b) Clips combined with injections versus Injections

(c) Clips versus Thermocoagulation with or without Injections

Simoens, 1997 [10] 2/9 3/9 0.67 [0.14, 3.09] Chung, 1999 [11] 1/41 6/41 0.17 [0.02, 1.32] Chung, 2000 [12] 1/9 4/12 0.33 [0.04, 2.50] Gevers, 2002 [13] 7/35 5/34 1.36 [0.48, 3.87] Park 2003 [14] 0/16 5/16 0.09 [0.01, 1.52] Chou, 2003 [15] 4/39 11/40 0.37 [0.13, 1.07] Shimoda, 2003 [16] 4/42 6/42 0.67 [0.20, 2.19] LJubicic, 2004 [17] 2/31 4/30 0.48 [0.10, 2.45]

Total (95% CI) 222 224 0.49 [0.30, 0.79]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)

Villanueva, 1996 [18] 2/42 7/37 0.25 [0.06, 1.14] Simoens, 1997 [10] 2/9 3/9 0.67 [0.14, 3.09] Chung, 1999 [11] 4/42 6/41 0.65 [0.20, 2.14] Gevers, 2002 [13] 5/32 5/34 1.06 [0.34, 3.33] Shimoda, 2003 [16] 3/42 6/42 0.50 [0.13, 1.87] Park, 2004 [19] 2/23 9/45 0.43 [0.10, 1.85] Lo, 2006 [20] 2/52 11/53 0.19 [0.04, 0.80]

Total (95% CI) 242 261 0.47 [0.28, 0.76]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)

Cipolletta, 2001 [21] 1/56 12/57 0.08 [0.01, 0.63] Lin, 2002 [22] 3/40 2/40 1.50 [0.26, 8.50] Lin, 2003 [23] 4/46 3/47 1.36 [0.32, 5.75] Saltzman, 2005 [24] 4/26 5/21 0.65 [0.20, 2.11]

Total (95% CI) 168 165 0.65 [0.21, 2.02]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)

0.01 0.1 1 10 100

Clips (+ injections)

Injections / Thermocoagulation

9

Clip vs InjectionClip vs Injection

Clip + injection vs InjectionClip + injection vs Injection

Clip vs ThermalClip vs Thermal

Sung JJ et al Gut 2007

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

4.5 0.81

3.2 0.55

1.0 0.14

12.8 0.80

4.8 2.01

6.2 0.33

6.3 0.91

7.3 0.23

9.0 0.92

3.9 0.25

5.3 0.33

9.5 0.39

5.9 0.27

5.4 0.57

6.1 0.27

8.7 0.78

100.0 0.530.01 0.1 1 10 100

Favors combined therapy

Favors epinephrine alone

Calvet et al. Gastro 200410

30 day mortality: a: Bleeding; b: Perforation

Bleeding Perforation

Lau JY, Sung JJ et al Digestion 2011

12

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%

Unclassified 11 1.9%

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 hemostasis13

Combining ALL predictive factors for the derivation cohort (AUC 0.842)

14

CUHK Outcome Prediction Score

Chiu et al. Clin Gastroenterol Hepatol 2009

15

Time (minutes)

ADP, adenosine diphosphate.

Green et al 1978

Aggregation (%)

0

80

60

40

20

0

1001 2 3 4 5

pH=6.0Disaggregation=77%

pH=6.4Disaggregation=16%

pH=7.3Disaggregation=0%

Buffer

ADP

16

Berstad 1970

0

20

40

60

80

100

Maximum pepsin activity(%)

Gastric juice pH43210

17

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

Lau JYW et al NEJM 200019

p = 0.14; p = 0.13

Lau et al. NEJM 200020

Randomised, double-blind, placebo-controlled study at 91 centres in 16 countries

RResomeprazo

le 40 mg qd

esomeprazole

40 mg qd

i.v. treatment(72 hours)

Oral treatment(27 days)

EndoscopicHaemostasi

s

1. Single2. Combo

EndoscopicHaemostasi

s

1. Single2. Combo

esomeprazole i.v. 80 mg over 30 min

followed by esomeprazole i.v. 8 mg/h

for 71.5 hours

esomeprazole i.v. 80 mg over 30 min

followed by esomeprazole i.v. 8 mg/h

for 71.5 hoursplacebo i.v. for 30 min followed

by placebo for 71.5 hoursplacebo i.v. for 30 min followed

by placebo for 71.5 hours

Intravenous Esomeprazole for Prevention of Peptic Ulcer Re-bleeding: A Multinational, Randomised, Placebo-Controlled Study

Intravenous Esomeprazole for Prevention of Peptic Ulcer Re-bleeding: A Multinational, Randomised, Placebo-Controlled StudyJoseph J.Y. SungJoseph J.Y. Sung11, Alan Barkun, Alan Barkun22, Ernst J. Kuipers, Ernst J. Kuipers33, Joachim , Joachim

MössnerMössner44, Dennis Jensen, Dennis Jensen55, Robert Stuart, Robert Stuart66, James Y. Lau, James Y. Lau11, , Henrik AhlbomHenrik Ahlbom77, Jan Kilhamn, Jan Kilhamn77, Tore Lind, Tore Lind77

Esomeprazolen=375

Placebon=389

72 hours 353 (94.1)

22 (5.95.9)3.7 – 8.8

No rebleed

p-value

Rebleed95% CI

349 (89.7)

40 (10.310.3)7.5 – 13.7

0.02560.0256

Risk reduction: 43%

Sung JY et al, AIM 2009

OGD : Bleeding peptic ulcers

OGD : Bleeding peptic ulcers

Primary Endoscopic Hemostasis

Primary Endoscopic Hemostasis

Rebleeding (10-20%)

Rebleeding (10-20%)

Scheduled second endoscopy

24-48 hours

Scheduled second endoscopy

24-48 hours

Treat persistent SRH before rebleedingTreat persistent SRH before rebleeding

23

Acute Upper GI Bleeding [556]Acute Upper GI Bleeding [556]

Bleeding peptic ulcer [326]

Bleeding peptic ulcer [326]

Primary therapeutic endoscopy [305]

Primary therapeutic endoscopy [305]

Adjunctive omeprazole

infusion [153]

Adjunctive omeprazole

infusion [153]

Scheduled 2nd endoscopy [152]

Scheduled 2nd endoscopy [152]

Failed hemostasis

[11]

Failed hemostasis

[11]

Forrest I, IIa, IIb

Endoscopic Retreatment

Forrest I, IIa, IIb

Endoscopic Retreatment

RebleedingRebleeding

OGD ± LaparotomyOGD ± Laparotomy

Nov 2003 to May 2008

Carcinoma [9]

Carcinoma [9]

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

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 available29

OGD : Bleeding peptic ulcers

OGD : Bleeding peptic ulcers

Primary Endoscopic Hemostasis

Primary Endoscopic Hemostasis

Rebleeding (5%)Rebleeding (5%)

Salvage SurgerySalvage Surgery

Adjunctive PPI infusion / Scheduled second

endoscopy

30

Pre-emptive PPI infusionPre-emptive PPI infusion

Acute Upper GI Hemorrhage

Acute Upper GI Hemorrhage

31

Lau JY, et al. N Engl J Med. 2007

371 UGIB patients randomized to high dose IVPPI or placebo before endoscopy

OmeprazoleN=179

PlaceboN=190

P value

Blood transfusion Mean, SD Median range

1.7, 2.80, 0-24

2.2, 3.91.5, 0-

38

.15

.15

Hospital stay Mean, SD Median, range

4.2, 4.93, 1-41

5.1, 5.63, 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 .79Lau JY, et al. N Engl J Med. 2007

TAE as an alternative to salvage surgery Can also act to pre-emptive embolization

1254 (39.9%) required endoscopic hemostasis1254 (39.9%) required endoscopic hemostasis

3144 bleeding peptic ulcer from January 2000 to July

2009

3144 bleeding peptic ulcer from January 2000 to July

2009

1218 (97.1%) successful hemostasis

1218 (97.1%) successful hemostasis

36 (2.9%) failed initial hemostasis 36 (2.9%) failed

initial hemostasis

166(13.6%) Rebleeding166(13.6%) Rebleeding

52 (31.3%) failed 2nd endoscopic treatment/ 2nd

rebleeding

52 (31.3%) failed 2nd endoscopic treatment/ 2nd

rebleeding

19 TAE19 TAE 33 Surgery

33 Surgery

13 TAE13

TAE23 Surgery23 Surgery

Total:TAE n=32Surgery

n=56

Total:TAE n=32Surgery

n=56Wong TL, Lau JY et al DDW 2010

P = <0.005P = 0.77

Wong TL, Lau JY et al DDW 2010

P = 0.09P = 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…

39

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

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