Justin CY Wu Professor, Department of Medicine & Therapeutics, Institute of Digestive Disease, The Chinese Universi

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. Acute upper GI bleeding Bleeding peptic ulcers Primary Surgical Hemostasis Primary Endoscopic Hemostasis Bleeding peptic ulcerAChange in the Management Strategy 1970 - 1980’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 HemorrhageSignificance 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 UlcerThermal Therapy • Heater probe • 3.2mm [need 2T scope] • 2.8mm • Pressure + Heat • Coaptive effect – compress until sealing of vessel

7. Endoscopic Treatment: Bleeding UlcerMechanical Therapy Hemoclip

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

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

10. 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 0.78 100.00.53 0.01 0.1 1 10 100 Favors combined therapy Favors epinephrine alone Endoscopic Treatment: Bleeding Ulcer Single or Combination therapy Calvet et al. Gastro 2004

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

12. Causes of mortality in peptic ulcer bleeding 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. CUHK Outcome Prediction Score Combining ALL predictive factors for the derivation cohort (AUC 0.842) Chiu et al. Clin Gastroenterol Hepatol 2009

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

16. pH=6.0 Disaggregation=77% 0 20 pH=6.4 Disaggregation=16% 40 60 80 pH=7.3 Disaggregation=0% 100 0 1 2 3 4 5 Prevention of Rebleeding – PPIIntragastric pH vs platelet disaggregation Aggregation (%) ADP, adenosine diphosphate. ADP Buffer Time (minutes) Green et al 1978

17. Maximum pepsin activity(%) 100 80 60 40 20 0 1 2 3 4 0 Gastric juice pH Prevention of Rebleeding - PPIpepsin activity 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 rebleedingAdjunctive high dose PPI infusion Lau JYW et al NEJM 2000

20. Prevention of peptic ulcer rebleedingAdjunctive high dose PPI infusion p = 0.14; p = 0.13 Lau et al. NEJM 2000

21. R 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 minfollowed by esomeprazole i.v. 8 mg/hfor 71.5 hours • Endoscopic • Haemostasis • Single • Combo esomeprazole 40 mg qd placebo i.v. for 30 min followed by placebo for 71.5 hours

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

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

27. Results – Need of Surgery P =0.51 ; OR = 0.49 (95% CI 0.12 – 2.01)

28. Results – Transfusion, Hospital Stay, Mortality

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 Adjunctive PPI infusion / Scheduled second endoscopy Rebleeding (5%) 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 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

35. TAE 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 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 Wong TL, Lau JY et al DDW 2010

37. TAE vs Salvage Surgery Outcomes P = 0.09 P = 0.60 P = 0.01 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. 2 Year Master Programme for Medical and Nursing Professionals Advanced Technology Multidisciplinary Clinical Exposure