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Alan N. Barkun

Non-variceal Upper GI Bleeding. Alan N. Barkun. Division of Gastroenterology McGill University and the McGill University Health Centre Montr é al, Canada. Conflicts of interest. Consultant for: Cook Inc. Boston Scientific Inc. Olympus Inc. OBJECTIVES.

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Alan N. Barkun

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  1. Non-variceal Upper GI Bleeding Alan N. Barkun Division of GastroenterologyMcGill University and the McGill University Health Centre Montréal, Canada

  2. Conflicts of interest • Consultant for: • Cook Inc. • Boston Scientific Inc. • Olympus Inc.

  3. OBJECTIVES • Discuss the management of acute non variceal upper gastrointestinal bleeding • Initial management • Preparation for endoscopy • Endoscopic therapy • Pharmacological therapy • Secondary prophylaxis

  4. Initial management

  5. The Glasgow-Blatchford Bleeding Score • GBS superior to total/clinical Rockall scores (ROC curves, P<0.05) • 123 patients (22%) classified as low risk, with 84 (68%) were managed as outpatients safely • Proportion admitted fell (96% to 71%, p<0·00001) Stanley, Lancet 2008

  6. The Rockall Score Rockall, Lancet 1996

  7. Co-morbidity and UGIB mortality N=16 RCTs, over 30,000 patients Leontiadis, AJG, 2013

  8. Initial resuscitation Hemodynamic status should be assessed immediately upon presentation and resuscitative measures begun as needed (Strong recommendation) Laine, Jensen, AJG 2012

  9. 921 UGIB pts randomized to trfX thresholds of Hgb<7 or 9gm/dL,stratified by cirrhosis 15% vs 51% trfX rates, P<0.001 95% vs 91%*, OR=0.55, 0.33-0.92 Villanueva, NEJM, 2013

  10. Villanueva, NEJM, 2013

  11. 2 issues: a) Generalizability (EGD @6hrs, tight hgb control, 30% cirrhosis; excl CV, massive) b) Power adequacy for Non Variceal UGI Bleeding - awaiting TRIGGER in UK - Rebleeding rates: Lower in restrictive strategy 10 vs 16%, P=0.01, and was similar but not significant in the NVUGIB subgroup (P=0.09) Portal Pressure rose significantly within 5 days w liberal strategy (P<0.03) Villanueva, NEJM, 2013

  12. What about an elevated INR and endoscopy? “In patients on anticoagulants, correction of coagulopathy is recommended but should not delay endoscopy” Platelets >50-100,000 Barkun DDW 2009, Wolf AJG 2007, Baradarian AJG 2004, Choudari Gut, 1994

  13. Meta-analysis of new anticoagulants Thrombin/factor Xa inhibitors not limited by narrow therapeutic window, and do not require routine monitoring of therapeutic target Dabigatran, Rivaroxaban, Apixaban, Edoxaban are currently used or undergoing large-scale evaluation in patients with atrial fibrillation, deep vein thrombosis (DVT)/pulmonary embolism, and DVT prophylaxis Holster, Gastroenterol, 2013

  14. Preparation for endoscopy

  15. IV erythromycin / metoclopramide • Also decreased likelihood of blood in the stomach • No improvements in rebleeding, surgery, mortality, transfused units, or length of stay • Nasogastric lavage – RCT-proven yet requires orogastric insertion of large-bore tube and may compromise the airway Should not be used routinely, but can be used in selected cases

  16. The benefits of early endoscopy • Early endoscopy (first 24 hours) allows for • safe and prompt discharge of patients classified as low risk • improves patient outcomes for patients classified as high risk • reduces resource utilization for patients classified as either low or high risk • Earlier timing for endoscopy (2, 12 hrs RCTs) show no advantage; ?week-end effect? • ? Highly selected very sick bleeders may benefit from earlier intervention? Barkun AIM 2003, 2011, Ananthakrishnan CGH 2009, Cooper GIE 2009, Hearnshaw GUT 2010, Lim Endoscopy 2011

  17. PPI pre-endoscopy for UGI bleeding • Efficacy at best marginal: downgrades lesion, yet does not alter outcomes • so PPI should NOT replace the role of adequate resuscitation and early endoscopy • Can provide PPI before endoscopy or not; more likely to be cost-effective IF: • Delay to endoscopy (over 16 hours) • Patient more likely to be bleeding from • a non variceal source • high-risk lesion (hematemesis, bloody NGT) • If you are going to use, high-dose preferred Sreedharan , Cochrane, 2010; Barkun AN, GI Endosc 2008

  18. Endoscopic therapy

  19. INJECTION http://www.nejm.org/doi/full/10.1056/NEJMra0706113

  20. CONTACT THERMAL THERAPY http://www.nejm.org/doi/full/10.1056/NEJMra0706113

  21. Endoscopic clips

  22. Which is the best modality? 0 Rebleeding Odds Ratio (95% CI) 0.27 Not Injection alone Thermal + Epi vs. Epi alone (2*) 0.38 Clips + Epi vs. Epi alone (3*) Thermal alone or clips alone as good as combination with Epi? 0.79 Thermal + Epi vs. Thermal alone (4*) 1.30 Clips+ Epi vs. Clips alone (2*) *Number of trials 0.2 5 0.5 2 1 • Treat only high-risk lesions • Equivocal data for “adherent clots” Favors dualtherapy Favors monotherapy Calvet Gastroenterology 2004, Marmo Am J Gastro 2007, Sung Gut 2007, Laine CGH 2008, Barkun GIE 2009

  23. Pharmacotherapy

  24. 0.53 Mortality (9*) Effect of PPIs on outcomes inpatients with PUD bleeding Outcome at 30 days after randomization Odds Ratio (95% CI) 0.46 Re-bleeding (19*) 0.59 PPI improve mortality in patients w HRS only if they have initially undergone endoscopic haemostasis (best data for high dose IV: 80mg + 8mg/hour x 3 days) These findings have been confirmed in a “real-life” setting Surgical Intervention (17*) 0 0.5 1 1.5 2 Favors PPI Favors control *Number of trials Modified from Leontiadis et al, The Cochrane Database of Systematic Reviews 2005 + update in 2006; Barkun et al., AJG 2004

  25. Lacking evidence that lower doses are as efficacious as high –dose PPI Individual trials: • Systematic bias in ascertainment of rebleeding? • Questions raised about the adequacy of blinding • Confounding attributable to selective use of second-look • No per-site adjustment Meta-analysis: • Issues of patient population selection • Non superiority, not equivalence Leontiadis, AJG, 2012

  26. PPI double dose x 11 days post hi-dose IV PPI and endo hemostasis for Rockall >6 Among Rockall ≥6, rebleeding was lower double-dose oral PPI than in standard-dose group (4th–28th day: 10.8% vs 28.7%, p=0.002) LOS and pURBC lower Rockall scores <6 than in Rockall ≥6 Cheng H-C, GUT, 2014

  27. “Second-look” endoscopy Routine second-look endoscopy, in which repeat endoscopy is performed 24 h after initial endoscopic hemostatic therapy, is not recommended (Conditional recommendation) Should be reserved for select patients at very high risk of rebleeding (large ulcers, hi-risk locations) Laine AJG, 2012; Barkun AIM 2120

  28. Refractory cases

  29. Emerging endoscopic therapy

  30. Endoscopy findings: clips + injection + Hemostatic powder

  31. Peptic ulcer bleeding Cook Inc., and Brullet et al.

  32. Secondary prophylaxis

  33. How should I diagnose H pylori in this setting?

  34. Diagnostic test performance in the acute setting NPV estimates Best to confirm a negative test outside the acute setting

  35. What about the patients having bled on ASA?

  36. PUB bleeder on ASA – acute management ASA non-adherence/withdrawal carries a 3x risk of major adverse cardiac events The delay to the thrombotic event is usually 7-10 days Immediate reintroduction of ASA in patients with PUB on ASA was recently studied Biondi-Zoccai GG, Eur Heart J, 2006; ; Aguejouf O. Clin Appl Thromb Hemost. 2008 ; Sibon I, Neurology. 2004. Burger W, J Intern Med. 2005; Sung J, Gut (abstract) 2007; Ng, APT, 2004; Sung AIM, 2010, barkun AIM 2010

  37. Risks/benefits of immediate reintroduction of ASA ASA-related bleeding ulcers, N=156 Log rank test P=0.25 Hazard ratio 1.9, 95%CI 0.6-6 ASA discontinuation causes significantly increased CV mortality 10.3% ASA Log rank test, P=0.005 (HR 0.2, 95% CI 0.06-0.6) 5.4% Placebo BUT 12.9% Placebo 1.3% ASA A statistically non significant increase in recurrent PUD bleeding, Sung AIM 2010, Editorial: Barkun AIM 2010

  38. PUB bleeder on ASA – secondary prophylaxis If clopidogrel / dual antiplatelet Rx related bleed, suggest PPI (not H2RA) secondary prophylaxis yet few data; RECOMMENDED BY AHA, ACC, ACG Controversy about a possible “clopidogrel – PPI interaction” is NOT warranted ASA + PPI Clopidogrel alone Rebleeding • Hp eradication

  39. PPI PROPHYLAXIS IN ASA- AND NSAID-RELATED UGIB X-sectional study btw 2000-2009 1093 and 2277 patients had NSAID- and ASA-associated ulcer bleeding At hi-risk: 39% NSAID and 75% ASA Only 41.6% of NSAID bleeders and 30.6% were on prophylaxis Greater appropriate PPI use could reduce bleeding risk by 50%, and improved adherence by 35% Ho, APT, 2013; LeRay, CGH, 2013; Lanas, CGH, 2013

  40. Overall management • ABC’s and adequate resuscitation • Early risk stratification • pre-endoscopy • at early endoscopy Very Low risk patients • discharge home All other patients • admit High-risk patients • Endoscopic hemostasis • Initiate high-dose IV PPI Low-risk patients • Initiate daily dose PPI • Consider secondary prophylaxis • H pylori testing and treating • NSAID/COX2 use • ASA/clopidogrel use*

  41. Conclusions – Non variceal UGIB Established recommendations for the management of patients with NVUGIB Risk stratification, early appropriate endoscopic hemostasis followed by hi-dose PPI (secondary prophylaxis) Hemostatic powders Promising ?Optimal role

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