peptic ulcer rebleeding an evidence-based management dr shirley yuk-wah liu department of surgery...
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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
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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
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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
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Close monitoring
Bleeding peptic ulcersUrgent OGD
Endoscopic hemostasis
Death
Treatment of rebleeding
Rebleeding 10-15%
Prevention of rebleeding
Prediction of rebleeding
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PREDICTION OF ULCER REBLEEDING
Joint Hospital Surgical Grand Round 17 Jan 2009Peptic Ulcer Rebleeding: An Evidence-based Management
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Who are at risk of rebleeding?
Evaluation on factors predicting rebleeding after endoscopic hemostasis
10 studies published
Q
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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
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PREVENTION OF ULCER REBLEEDING
Joint Hospital Surgical Grand Round 17 Jan 2009Peptic Ulcer Rebleeding: An Evidence-based Management
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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
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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
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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
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1. Is acid suppressive drugs useful?Q
Comparison of PPI to placebo in preventing rebleeding
24 RCT published
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First RCT on PPI vs placebo
Daneshmend et al. Br Med J 1992;304:143-147
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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
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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
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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
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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
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3. What should be the best route of administration?Q
No RCT performed on direct comparison of oral versus IV PPI
0 RCT published
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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
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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
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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
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To prevent ulcer rebleeding
Adjunctive Acid suppressants
Scheduled second-lookendoscopy
Is it useful ?
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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
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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
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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
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TREATMENT OF ULCER REBLEEDING
Joint Hospital Surgical Grand Round 17 Jan 2009Peptic Ulcer Rebleeding: An Evidence-based Management
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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?
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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
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Factors associated with failed endoscopic re-treatment
Conclusion point:- Decision between surgery or repeat endoscopyshould be selective
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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)
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Angiographic embolization vs endoscopic re-treatment
No RCT evidence to compareangiographic embolization to repeat endoscopy
0 RCT published
Q
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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
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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?
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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
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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
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Department of SurgeryThe Chinese University of Hong Kong