1. Peptic Ulcer Rebleeding An Evidence-Based Management Dr Shirley Yuk-Wah Liu Department of Surgery Prince of Wales Hospital The Chinese University of Hong Kong Joint Hospital Surgical Grand Round 17 January 2009

2. History of Peptic Ulcer Bleeding 1881 Theodor Billroth (1829 – 1894) Father of modern abdominal surgery First gastrectomy 1950-1980s Introduction of endoscopy 1983 Warren and Marshall Association of H pylori with peptic ulcer 180019002000 Warren et al. Lancet 1983 Marshall et al. Lancet 1983

3. Mortality of peptic ulcer bleeding SeriesYearCases (n) Age >60 (%) Age >80 (%) Mortality (%) Jones 1 1940 – 476873329.9 Schiller et al 2 1953 – 6721494888.9 Johnston et al 3 1967 – 6881749910.6 Mayberry et al 4 1972 – 78583//10.3 Katchinski et al 5 1984 – 861017631811.8 Rockall et al 6 19934185682711.0 1. BMJ 1947;2:441-446 2. BMJ 1970;2:7-14 3. BMJ 1973;3:655-660 4. Postgrad Med J 1987;57:627-632 5. Postgrad Med J 1989;65:913-917 6. BMJ 1995;311:222-226 Peptic ulcer rebleeding is the most important predictor of mortality Van Leerdam et al. Am J Gastroenterol 2003;98:1494-1499

4. Close monitoring Bleeding peptic ulcers Urgent OGD Endoscopic hemostasis Death Treatment of rebleeding Rebleeding 10-15% Prevention of rebleeding Prediction of rebleeding

5. P REDICTION OF ULCER REBLEEDING Joint Hospital Surgical Grand Round 17 Jan 2009 Peptic Ulcer Rebleeding: An Evidence-based Management

6. Who are at risk of rebleeding? Evaluation on factors predicting rebleeding after endoscopic hemostasis 10 studies published Q

7. Predictive factors of rebleeding Elmunzer et al. Am J Gastroenterol 2008;103:2625-2632 Meta-analysis Clinical Endoscopic Independent predictive factors for rebleeding: 1. hemodynamic instability 2. comorbid illness 3. active bleeding ulcers 4. large ulcer size 5. ulcers with difficult position

8. P REVENTION OF ULCER REBLEEDING Joint Hospital Surgical Grand Round 17 Jan 2009 Peptic Ulcer Rebleeding: An Evidence-based Management

9. To prevent ulcer rebleeding Adjunctive Acid suppressants Scheduled second-look endoscopy - Is it useful? - Type of drugs: H 2 -receptor antagonists or PPI - Route of administration: IV or oral - Dosage: high-dose or low-dose

10. Adjunctive acid suppressive drugs Green et al. Gastroenterology 1978;74:38-43 80 60 40 20 0 100 012345 pH Platelet disaggregation Acidic environment Neutral environment

11. 0 20 40 60 80 100 Maximum pepsin activity (%) Gastric juice pH 4321 0 pH 6 Pepsin can disintegrate the clots on ulcer surface Pepsin is irreversibly inactivated at pH 6 Adjunctive acid suppressive drugs

12. 1. Is acid suppressive drugs useful? Q Comparison of PPI to placebo in preventing rebleeding 24 RCT published

13. First RCT on PPI vs placebo Daneshmend et al. Br Med J 1992;304:143-147

14. Lau et al. N Eng J Med 2000;343:310-316 P<0.001P=NS First positive evidence of PPI (IV) 120 patients PPI group 80mg bolus, then 8mg/hr for 72 hrs 120 patients Placebo group 240 patients Forrest class Ia, Ib, IIa

15. Leontiadis et al. Cochrane Databse Syst Rev 2006;3:CD002094 Systematic review 24 RCTs 4373 patients 19 studies on IV PPI 5 studies on oral PPI 1. Is PPI useful? Q Conclusion point: PPI is useful in reducing rates of rebleeding, emergency operation & mortality

16. 2. Should we give PPI or H 2 R antagonists? Q Gisbert et al. Aliment Pharmacol Ther 2001;15:917-926 Comparison of PPI to H 2 R antagonists as adjunctive treatment to bleeding ulcers 11 RCT published Meta-analysis 11 RCT PPI 681 patients H 2 R antagonist 671 patients

17. 2. Should we give PPI or H 2 R antagonists? Q Gisbert et al. Aliment Pharmacol Ther 2001;15:917-926 Comparison on rebleedingComparison on emergency operationComparison on mortality Conclusion point PPI is more superior to H2R antagonists in reducing the rates of rebleeding and emergency operation

18. 3. What should be the best route of administration? Q No RCT performed on direct comparison of oral versus IV PPI 0 RCT published

19. Oral PPI IV PPI 5 trials 658 patients 19 trials 3714 patients Meta-regression analysis: No difference on - Rebleeding - Emergency operation - Mortality Leontiadis et al. Cochrane Databse Syst Rev 2006;3:CD002094 Evidence is still inconclusive of which route is better 3. What should be the best route of administration? Q

20. 4. High-dose or low-dose PPI Q Cheng et al. Dig Dis Sci 2005;502:1194-1201 Udd et al. Scand J Gastroenterol 2001;36:1332-1338 High-dose PPI vs low-dose PPI 2 RCT published Rebleeding rate Cheng 2005 (n=105) Udd 2001 (n=142) High-dose PPI35.4%11.6% Low-dose PPI33.3%8.2% P=NSP=0.002

21. Leontiadis et al. Cochrane Databse Syst Rev 2004;3:CD002094 Rebleeding Both significantly reduced Emergency surgery 36/1149 (3.1%)59/1171 (5.0%) Only high-dose PPI significantly reduce the need OR=0.61, 95% C.I. 0.40-0.93, P=0.02 High-dose PPI PPI 80mg IV bolus then 8mg/hr infusion Low-dose PPI Oral PPI or IV PPI dose <120mg/day 6 trials 2320 patients 18 trials 2052 patients Conclusion point: High-dose PPI should be the recommended dosage for bleeding peptic ulcer 4. High-dose or low-dose PPI Q

22. To prevent ulcer rebleeding Adjunctive Acid suppressants Scheduled second-look endoscopy Is it useful ?

23. Scheduled second-look endoscopy Rationale – To treat before clinical rebleeding occurs – To perform second-look OGD within 16 – 24 hours after primary endoscopic hemostasis Villanueva et al. Gastrointest Endosc 1994;40:34-39 Saeed et al. Endoscopy 1996;28:288-294 Rutgeerts et al. Lancet 1997;350:692-696 Messmann et al. Endoscopy 1998;30:583-589 Chiu et al. Gut 2003;52:1403-1407

24. Scheduled second-look endoscopy Marmo et al. Gastrointest Endosc 2003;57:62-67 Risk reductionNNTP value Rebleeding6.2%16<0.01 Emergency surgery1.7%58NS Mortality1.0%97NS Villanueva et al. Gastrointest Endosc 1994;40:34-39 Saeed et al. Endoscopy 1996;28:288-294 Rutgeerts et al. Lancet 1997;350:692-696 Messmann et al. Endoscopy 1998;30:583-589 Systematic reviews on 4 RCTs

25. Scheduled second look endoscopy P=0.03P=0.05P=NS Chiu et al. Gut 2003;52:1403-1407 Forrest class Ia to IIb bleeding ulcers Conclusion point: Second-look endoscopy can prevent rebleeding

26. T REATMENT OF ULCER REBLEEDING Joint Hospital Surgical Grand Round 17 Jan 2009 Peptic Ulcer Rebleeding: An Evidence-based Management

27. How to treat rebleeding? Q A.Endoscopic re-treatment B. Immediate surgery C. Angiographic embolization What is the best treatment option? What type of emergency operations to perform?

28. Surgery vs endoscopic re-treatment Lau et al. N Eng J Med 1999;340:751-756 - 1169 patients with bleeding ulcers requiring endoscopic hemostasis - 92 patients (8.7%) developed rebleeding P=0.03 P=0.27 P=0.59 P=0.16 P=0.37 1 RCT published Q

29. Factors associated with failed endoscopic re-treatment Conclusion point: - Decision between surgery or repeat endoscopy should be selective

30. Surgery vs Angiographic Embolization Ripoll et al. J Vasc Interv Radiol 2004;15:447-450 Not enough evidence to conclude whether surgery or embolization is more superior Q 0 RCT published Only one retrospective comparative study (n=70)

31. Angiographic embolization vs endoscopic re-treatment No RCT evidence to compare angiographic embolization to repeat endoscopy 0 RCT published Q

32. What type of surgery to do? Conservative surgeryDefinitive surgery Lau et al. Best Pract Res Clin Gastroenterol 2000;14:505-518 - Ulcer plication - Ulcer excision Stop bleeding - Vagotomy +/- drainage - Partial gastrectomy Prevent rebleeding 2 RCT published Q

33. Poxon et al. Br J Surg 1991;178:1344-1345 Multicenter trial Conservative surgery: ulcer plication + H2RA Definitive surgery: vagotomy + drainage or gastrectomy P<0.05 Q What type of surgery to do?

34. Millat et al. World J Surg 1993;17:568-573 French Association of Surgical Research trial [1978-1988] Conservative surgery: ulcer plication + vagotomy Definitive surgery: gastrectomy P<0.05 Q What type of surgery to do? Results before the era of PPI may not be reliable

35. Conclusion High-dose IV PPI infusion is useful in reducing rebleeding, emergency operation and mortality Second-look endoscopy is useful in preventing rebleeding in high-risk patients Both endoscopic re-treatment and surgery should be selectively applied to rebleeding patients The choice between conservative and definitive Surgery is still controversial

36. Department of Surgery The Chinese University of Hong Kong