Peptic Ulcer Rebleeding An Evidence-Based Management Dr Shirley Yuk-Wah Liu Department of Surgery Prince of Wales Hospital The Chinese University of Hong.

Peptic Ulcer RebleedingAn Evidence-Based Management

Dr Shirley Yuk-Wah LiuDepartment of Surgery

Prince of Wales HospitalThe Chinese University of Hong Kong

Joint Hospital Surgical Grand Round17 January 2009

History of Peptic Ulcer Bleeding

1881Theodor Billroth(1829 – 1894)Father of modern abdominal surgeryFirst gastrectomy

1950-1980sIntroduction of endoscopy

1983Warren and MarshallAssociation of H pyloriwith peptic ulcer

1800 1900 2000

Warren et al. Lancet 1983Marshall et al. Lancet 1983

Mortality of peptic ulcer bleeding

Series Year Cases (n)

Age >60(%)

Age >80(%)

Mortality (%)

Jones1 1940 – 47 687 33 2 9.9

Schiller et al2 1953 – 67 2149 48 8 8.9

Johnston et al3 1967 – 68 817 49 9 10.6

Mayberry et al4 1972 – 78 583 / / 10.3

Katchinski et al5 1984 – 86 1017 63 18 11.8

Rockall et al6 1993 4185 68 27 11.0

1. BMJ 1947;2:441-4462. BMJ 1970;2:7-14

3. BMJ 1973;3:655-6604. Postgrad Med J 1987;57:627-6325. 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

Close monitoring

Bleeding peptic ulcersUrgent OGD

Endoscopic hemostasis

Death

Treatment of rebleeding

Rebleeding 10-15%

Prevention of rebleeding

Prediction of rebleeding

PREDICTION OF ULCER REBLEEDING

Joint Hospital Surgical Grand Round 17 Jan 2009Peptic Ulcer Rebleeding: An Evidence-based Management

Who are at risk of rebleeding?

Evaluation on factors predicting rebleeding after endoscopic hemostasis

10 studies published

Q

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 instability2. comorbid illness3. active bleeding ulcers4. large ulcer size5. ulcers with difficult position

PREVENTION OF ULCER REBLEEDING

Joint Hospital Surgical Grand Round 17 Jan 2009Peptic Ulcer Rebleeding: An Evidence-based Management

To prevent ulcer rebleeding

Adjunctive Acid suppressants

Scheduled second-lookendoscopy

- Is it useful?- Type of drugs: H2-receptor antagonists or PPI- Route of administration: IV or oral- Dosage: high-dose or low-dose

Adjunctive acid suppressive drugs

Green et al. Gastroenterology 1978;74:38-43

80

60

40

20

0

1000 1 2 3 4 5

pH

Platelet disaggregation

Acidic environment

Neutralenvironment

0

20

40

60

80

100Maximum pepsin activity (%)

Gastric juice pH43210

pH 6

• Pepsin can disintegrate the clots on ulcer surface• Pepsin is irreversibly inactivated at pH 6

Adjunctive acid suppressive drugs

1. Is acid suppressive drugs useful?Q

Comparison of PPI to placebo in preventing rebleeding

24 RCT published

First RCT on PPI vs placebo

Daneshmend et al. Br Med J 1992;304:143-147

Lau et al. N Eng J Med 2000;343:310-316

P<0.001 P=NS P=NS

First positive evidence of PPI (IV)

120 patients PPI group

80mg bolus, then 8mg/hr for 72 hrs

120 patients Placebo group

240 patientsForrest class Ia, Ib, IIa

Leontiadis et al. Cochrane Databse Syst Rev 2006;3:CD002094

Systematic review 24 RCTs

4373 patients

19 studies on IV PPI5 studies on oral PPI

1. Is PPI useful?Q

Conclusion point:PPI is useful in reducing rates of

rebleeding, emergency operation & mortality

2. Should we give PPI or H2R antagonists?Q

Gisbert et al. Aliment Pharmacol Ther 2001;15:917-926

Comparison of PPI to H2R antagonists as adjunctive treatment to bleeding ulcers

11 RCT published

Meta-analysis11 RCT

PPI681 patients

H2R antagonist671 patients

2. Should we give PPI or H2R antagonists?Q

Gisbert et al. Aliment Pharmacol Ther 2001;15:917-926

Comparison on rebleedingComparison on emergency operationComparison on mortality

Conclusion pointPPI is more superior to H2R antagonists in reducing

the rates of rebleeding and emergency operation

3. What should be the best route of administration?Q

No RCT performed on direct comparison of oral versus IV PPI

0 RCT published

Oral PPI IV PPI

5 trials658 patients

19 trials3714 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

4. High-dose or low-dose PPIQ

Cheng et al. Dig Dis Sci 2005;502:1194-1201Udd 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 PPI 35.4% 11.6%Low-dose PPI 33.3% 8.2%

P=NS P=0.002

Leontiadis et al. Cochrane Databse Syst Rev 2004;3:CD002094

RebleedingBoth 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 PPIPPI 80mg IV bolus

then 8mg/hr infusion

Low-dose PPIOral PPI or IV PPI dose <120mg/day

6 trials2320 patients

18 trials2052 patients

Conclusion point:High-dose PPI should be the recommended

dosage for bleeding peptic ulcer

4. High-dose or low-dose PPIQ

To prevent ulcer rebleeding

Adjunctive Acid suppressants

Scheduled second-lookendoscopy

Is it useful ?

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;40:34-39Saeed et al. Endoscopy 1996;28:288-294

Rutgeerts et al. Lancet 1997;350:692-696Messmann et al. Endoscopy 1998;30:583-589

Chiu et al. Gut 2003;52:1403-1407

Scheduled second-look endoscopy

Marmo et al. Gastrointest Endosc 2003;57:62-67

Risk reduction NNT P value

Rebleeding 6.2% 16 <0.01

Emergency surgery 1.7% 58 NS

Mortality 1.0% 97 NS

Villanueva et al. Gastrointest Endosc 1994;40:34-39Saeed et al. Endoscopy 1996;28:288-294

Rutgeerts et al. Lancet 1997;350:692-696Messmann et al. Endoscopy 1998;30:583-589

Systematic reviews on 4 RCTs

Scheduled second look endoscopy

P=0.03 P=0.05 P=NS

Chiu et al. Gut 2003;52:1403-1407

Forrest class Ia to IIb bleeding ulcers

Conclusion point:Second-look endoscopy can prevent rebleeding

TREATMENT OF ULCER REBLEEDING

Joint Hospital Surgical Grand Round 17 Jan 2009Peptic Ulcer Rebleeding: An Evidence-based Management

How to treat rebleeding?QA.Endoscopic re-treatment

B. Immediate surgery

C. Angiographic embolization

What is the best treatment option? What type of emergency operations to perform?

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

Factors associated with failed endoscopic re-treatment

Conclusion point:- Decision between surgery or repeat endoscopyshould be selective

Surgery vs Angiographic Embolization

Ripoll et al. J Vasc Interv Radiol 2004;15:447-450

Not enough evidence to concludewhether surgery or embolization is more superior

Q0 RCT published

Only one retrospective comparative study (n=70)

Angiographic embolization vs endoscopic re-treatment

No RCT evidence to compareangiographic embolization to repeat endoscopy

0 RCT published

Q

What type of surgery to do?Conservative surgery Definitive 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

Poxon et al. Br J Surg 1991;178:1344-1345

Multicenter trialConservative surgery: ulcer plication + H2RADefinitive surgery: vagotomy + drainage or gastrectomy

P<0.05 P<0.05

Q What type of surgery to do?

Millat et al. World J Surg 1993;17:568-573

French Association of Surgical Research trial [1978-1988]Conservative surgery: ulcer plication + vagotomyDefinitive surgery: gastrectomy

P<0.05

Q What type of surgery to do?

Results before the era of PPI may not be reliable

ConclusionHigh-dose IV PPI infusion is useful in reducingrebleeding, 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 definitiveSurgery is still controversial

Department of SurgeryThe Chinese University of Hong Kong