Subscribe to RSS
DOI: 10.1055/a-1369-5274
Endoscopic diagnosis and management of nonvariceal upper gastrointestinal hemorrhage (NVUGIH): European Society of Gastrointestinal Endoscopy (ESGE) Guideline – Update 2021
![](https://www.thieme-connect.de/media/endoscopy/202103/lookinside/thumbnails/20468_10-1055-a-1369-5274-1.jpg)
MAIN RECOMMENDATIONS
1 ESGE recommends in patients with acute upper gastrointestinal hemorrhage (UGIH) the use of the Glasgow–Blatchford Score (GBS) for pre-endoscopy risk stratification. Patients with GBS ≤ 1 are at very low risk of rebleeding, mortality within 30 days, or needing hospital-based intervention and can be safely managed as outpatients with outpatient endoscopy.
Strong recommendation, moderate quality evidence.
2 ESGE recommends that in patients with acute UGIH who are taking low-dose aspirin as monotherapy for secondary cardiovascular prophylaxis, aspirin should not be interrupted. If for any reason it is interrupted, aspirin should be re-started as soon as possible, preferably within 3–5 days.
Strong recommendation, moderate quality evidence.
3 ESGE recommends that following hemodynamic resuscitation, early (≤ 24 hours) upper gastrointestinal (GI) endoscopy should be performed.
Strong recommendation, high quality evidence.
4 ESGE does not recommend urgent (≤ 12 hours) upper GI endoscopy since as compared to early endoscopy, patient outcomes are not improved.
Strong recommendation, high quality evidence.
5 ESGE recommends for patients with actively bleeding ulcers (FIa, FIb), combination therapy using epinephrine injection plus a second hemostasis modality (contact thermal or mechanical therapy).
Strong recommendation, high quality evidence.
6 ESGE recommends for patients with an ulcer with a nonbleeding visible vessel (FIIa), contact or noncontact thermal therapy, mechanical therapy, or injection of a sclerosing agent, each as monotherapy or in combination with epinephrine injection.
Strong recommendation, high quality evidence.
7 ESGE suggests that in patients with persistent bleeding refractory to standard hemostasis modalities, the use of a topical hemostatic spray/powder or cap-mounted clip should be considered.
Weak recommendation, low quality evidence.
8 ESGE recommends that for patients with clinical evidence of recurrent peptic ulcer hemorrhage, use of a cap-mounted clip should be considered. In the case of failure of this second attempt at endoscopic hemostasis, transcatheter angiographic embolization (TAE) should be considered. Surgery is indicated when TAE is not locally available or after failed TAE.
Strong recommendation, moderate quality evidence.
9 ESGE recommends high dose proton pump inhibitor (PPI) therapy for patients who receive endoscopic hemostasis and for patients with FIIb ulcer stigmata (adherent clot) not treated endoscopically.
(a) PPI therapy should be administered as an intravenous bolus followed by continuous infusion (e. g., 80 mg then 8 mg/hour) for 72 hours post endoscopy.
(b) High dose PPI therapies given as intravenous bolus dosing (twice-daily) or in oral formulation (twice-daily) can be considered as alternative regimens.
Strong recommendation, high quality evidence.
10 ESGE recommends that in patients who require ongoing anticoagulation therapy following acute NVUGIH (e. g., peptic ulcer hemorrhage), anticoagulation should be resumed as soon as the bleeding has been controlled, preferably within or soon after 7 days of the bleeding event, based on thromboembolic risk. The rapid onset of action of direct oral anticoagulants (DOACS), as compared to vitamin K antagonists (VKAs), must be considered in this context.
Strong recommendation, low quality evidence.
Publication History
Article published online:
10 February 2021
© 2021. European Society of Gastrointestinal Endoscopy. All rights reserved.
Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany
-
References
- 1 Oakland K. Changing epidemiology and etiology of upper and lower gastrointestinal bleeding. Best Pract Res Clin Gastroenterol 2019; 42/43: 1-6
- 2 Gralnek IM, Dumonceau JM, Kuipers EJ. et al. Diagnosis and management of nonvariceal upper gastrointestinal hemorrhage: European Society of Gastrointestinal Endoscopy (ESGE) Guideline. Endoscopy 2015; 47: 1-46
- 3 Guyatt GH, Oxman AD, Vist GE. et al. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ 2008; 336: 924-926
- 4 Hassan C, Ponchon T, Bisschops R. et al. European Society of Gastrointestinal Endoscopy (ESGE) Publications Policy – Update 2020. Endoscopy 2020; 52: 123-126
- 5 Baradarian R, Ramdhaney S, Chapalamadugu R. et al. Early intensive resuscitation of patients with upper gastrointestinal bleeding decreases mortality. Am J Gastroenterol 2004; 99: 619-622
- 6 Lu B, Li MQ, Li JQ. The use of limited fluid resuscitation and blood pressure-controlling drugs in the treatment of acute upper gastrointestinal hemorrhage concomitant with hemorrhagic shock. Cell Biochem Biophys 2015; 72: 461-463
- 7 Kwan I, Bunn F, Chinnock P. et al. Timing and volume of fluid administration for patients with bleeding. Cochrane Database Syst Rev 2014; CD002245
- 8 Duan C, Li T, Liu L. Efficacy of limited fluid resuscitation in patients with hemorrhagic shock: a meta-analysis. Int J Clin Exp Med 2015; 8: 11645-11656
- 9 Carrick MM, Morrison CA, Tapia NM. et al. Intraoperative hypotensive resuscitation for patients undergoing laparotomy or thoracotomy for trauma: Early termination of a randomized prospective clinical trial. J Trauma Acute Care Surg 2016; 80: 886-896
- 10 Lewis SR, Pritchard MW, Evans DJ. et al. Colloids versus crystalloids for fluid resuscitation in critically ill people. Cochrane Database Syst Rev 2018; 8: CD000567
- 11 Hammond DA, Lam SW, Rech MA. et al. Balanced crystalloids versus saline in critically ill adults: a systematic review and meta-analysis. Ann Pharmacother 2020; 54: 5-13
- 12 Semler MW, Self WH, Wanderer JP. et al. Balanced crystalloids versus saline in critically ill adults. N Engl J Med 2018; 378: 829-839
- 13 Villanueva C, Colomo A, Bosch A. et al. Transfusion strategies for acute upper gastrointestinal bleeding. N Engl J Med 2013; 368: 11-21
- 14 Jairath V, Kahan BC, Gray A. et al. Restrictive versus liberal blood transfusion for acute upper gastrointestinal bleeding (TRIGGER): a pragmatic, open-label, cluster randomised feasibility trial. Lancet Lond Engl 2015; 386: 137-144
- 15 Barkun AN, Almadi M, Kuipers EJ. et al. Management of nonvariceal upper gastrointestinal bleeding: guideline recommendations from the international consensus group. Ann Intern Med 2019; 171: 805-822
- 16 Odutayo A, Desborough MJR, Trivella M. et al. Restrictive versus liberal blood transfusion for gastrointestinal bleeding: a systematic review and meta-analysis of randomised controlled trials. Lancet Gastroenterol Hepatol 2017; 2: 354-360
- 17 Carson JL, Stanworth SJ, Roubinian N. et al. Transfusion thresholds and other strategies for guiding allogeneic red blood cell transfusion. Cochrane Database Syst Rev 2016; 10: CD002042
- 18 Docherty AB, O’Donnell R, Brunskill S. et al. Effect of restrictive versus liberal transfusion strategies on outcomes in patients with cardiovascular disease in a non-cardiac surgery setting: systematic review and meta-analysis. BMJ 2016; 352: i1351
- 19 Blatchford O, Murray WR, Blatchford M. A risk score to predict need for treatment for upper-gastrointestinal haemorrhage. Lancet 2000; 356: 1318-1321
- 20 Rockall TA, Logan RF, Devlin HB. et al. Risk assessment after acute upper gastrointestinal haemorrhage. Gut 1996; 38: 316-321
- 21 Saltzman JR, Tabak YP, Hyett BH. et al. A simple risk score accurately predicts in-hospital mortality, length of stay, and cost in acute upper GI bleeding. Gastrointest Endosc 2011; 74: 1215-1224
- 22 Laursen SB, Dalton HR, Murray IA. et al. Performance of new thresholds of the Glasgow Blatchford score in managing patients with upper gastrointestinal bleeding. Clin Gastroenterol Hepatol 2015; 13: 115-121
- 23 Ramaekers R, Mukarram M, Smith CAM. et al. The predictive value of pre-endoscopic risk scores to predict adverse outcomes in emergency department patients with upper gastrointestinal bleeding: a systematic review. Acad Emerg Med 2016; 23: 1218-1227
- 24 Stanley AJ, Laine L, Dalton HR. et al. International gastrointestinal bleeding consortium. comparison of risk scoring systems for patients presenting with upper gastrointestinal bleeding: international multicentre prospective study. BMJ 2017; 356: i6432
- 25 Stanley AJ, Ashley D, Dalton HR. et al. Outpatient management of patients with low-risk upper-gastrointestinal haemorrhage: multicentre validation and prospective evaluation. Lancet 2009; 373: 42-47
- 26 Girardin M, Bertolini D, Ditisheim S. et al. Use of Glasgow-Blatchford bleeding score reduces hospital stay duration and costs for patients with low-risk upper GI bleeding. Endosc Int Open 2014; 2: E74-E79
- 27 Sung JJY, Lau JYW, Ching JYL. et al. Continuation of low dose aspirin therapy in peptic ulcer bleeding: a randomized trial. Ann Intern Med 2010; 152: 1-9
- 28 Derogar M, Sandblom G, Lundell L. et al. Discontinuation of low dose aspirin therapy after peptic ulcer bleeding increases risk of death and acute cardiovascular events. Clin Gastroenterol Hepatol 2013; 11: 38-42
- 29 Kim SY, Hyun JJ, Suh SJ. et al. Risk of vascular thrombotic events following discontinuation of anti-thrombotics after peptic ulcer bleeding. J Clin Gastroenterol 2016; 50: e40-e44
- 30 Wang XX, Dong B, Hong B. et al. Long-term prognosis in patients continuing taking anti-thrombotics after peptic ulcer bleeding. World J Gastroenterol 2017; 23: 723-729
- 31 Siau K, Hannah JL, Hodson J. et al. Stopping antithrombotic therapy after acute upper gastrointestinal bleeding is associated with reduced survival. Postgrad Med J 2018; 94: 137-142
- 32 Burger W, Chemnitius JM, Kneissl GD. et al. Low-dose aspirin for secondary cardiovascular prevention – cardiovascular risks after its perioperative withdrawal versus bleeding risks with its continuation – review and meta-analysis. J Intern Med 2005; 257: 399-414
- 33 Sung JJ, Chiu PW, Chan FKL. et al. Asia-Pacific working group consensus on non-variceal upper gastrointestinal bleeding: an update 2018. Gut 2018; 67: 1757-1768
- 34 Sostres C, Marcén B, Laredo V. et al. Risk of rebleeding, vascular events and death after gastrointestinal bleeding in anticoagulant and/or antiplatelet users. Aliment Pharmacol Ther 2019; 50: 919-929
- 35 Patrono C, Morais J, Baigent C. et al. Antiplatelet agents for the treatment and prevention of coronary atherothrombosis. J Am Coll Cardiol 2017; 70: 1760-1776
- 36 Eisenberg MJ, Richard PR, Libersan D. et al. Safety of short-term discontinuation of antiplatelet therapy in patients with drug-eluting stents. Circulation 2009; 119: 1634-42
- 37 Ramos GP, Binder M, Hampel P. et al. Outcomes of endoscopic intervention for overt GI bleeding in severe thrombocytopenia. Gastrointest Endosc 2018; 88: 55-61
- 38 Zakko L, Rustagi T, Douglas M. et al. No benefit from platelet transfusion for gastrointestinal bleeding in patients taking antiplatelet agents. Clin Gastroenterol Hepatol 2017; 15: 46-52
- 39 Bennett C, Klingenberg SL, Langholz E, Gluud LL. Tranexamic acid for upper gastrointestinal bleeding. Cochrane Database of Systematic Reviews 2014; 11 DOI: 10.1002/14651858.CD006640.pub3.
- 40 Stollings JL, Landsperger JS, Semler MW. et al. Tranexamic acid for refractory gastrointestinal bleeds: A cohort study. J Crit Care 2018; 43: 128-132
- 41 Tavakoli N, Mokhtare M, Agah S. et al. Comparison of the efficacy of intravenous tranexamic acid with and without topical administration versus placebo in urgent endoscopy rate for acute gastrointestinal bleeding: A double-blind randomized controlled trial. United European Gastroenterol J 2018; 646-654
- 42 Twum-Barimah E, Abdelgadir I, Gordon M. et al. Systematic review with meta-analysis: the efficacy of tranexamic acid in upper gastrointestinal bleeding. Aliment Pharmacol Ther 2020; 51: 1004-1013
- 43 Roberts I, Shakur-Still H, Afolabi A. et al. Effects of a high-dose 24-h infusion of tranexamic acid on death and thromboembolic events in patients with acute gastrointestinal bleeding (HALT-IT): an international randomised, double-blind, placebo-controlled trial. Lancet 2020; 395: 1927-1936
- 44 Lanas A, Dumonceau JM, Hunt RH. et al. Non-variceal upper gastrointestinal bleeding. Nat Rev Dis Primers 2018; 4: 18020 DOI: 10.1038/nrdp.2018.20.
- 45 Lanas-Gimeno A, Lanas A. Risk of gastrointestinal bleeding during anticoagulant treatment. Expert Opin Drug Saf 2017; 16: 673-685
- 46 Choudari CP, Rajgopal C, Palmer KR. Acute gastrointestinal haemorrhage in anticoagulated patients: diagnoses and response to endoscopic treatment. Gut 1994; 35: 464-466
- 47 Rubin TA, Murdoch M, Nelson DB. Acute GI bleeding in the setting of supratherapeutic international normalized ratio in patients taking warfarin: endoscopic diagnosis, clinical management, and outcomes. Gastrointest Endosc 2003; 58: 369-373
- 48 Wolf AT, Wasan SK, Saltzman JR. Impact of anticoagulation on rebleeding following endoscopic therapy for nonvariceal upper gastrointestinal hemorrhage. Am J Gastroenterol 2007; 102: 290-296
- 49 Nagata N, Sakurai T, Moriyasu S. et al. Impact of INR monitoring, reversal agent use, heparin bridging, and anticoagulant interruption on rebleeding and thromboembolism in acute gastrointestinal bleeding. PLoS One 2017; 12: e0183423
- 50 Sarode R, Milling Jr. TJ, Refaai MA. et al. Efficacy and safety of a 4-factor prothrombin complex concentrate in patients on vitamin K antagonists presenting with major bleeding: a randomized, plasma-controlled, phase IIIb study. Circulation 2013; 128: 1234-1243
- 51 Goldstein JN, Refaai MA, Milling Jr. TJ. et al. Four-factor prothrombin complex concentrate versus plasma for rapid vitamin K antagonist reversal in patients needing urgent surgical or invasive interventions: a phase 3b, open-label, non-inferiority, randomised trial. Lancet 2015; 385: 2077-2087
- 52 Shim CN, Chung HS, Park JC. et al. Is endoscopic therapy safe for upper gastrointestinal bleeding in anticoagulated patients with supratherapeutic international normalized ratios?. Am J Ther 2016; 23: e995-e1003
- 53 Peloquin JM, Seraj SM, King LY. et al. Diagnostic and therapeutic yield of endoscopy in patients with elevated INR and gastrointestinal bleeding. Am J Med 2016; 129: 628-634
- 54 Holbrook A, Schulman S, Witt DM. et al. Evidence-based management of anticoagulant therapy: Antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141: e152S-184S
- 55 Sin JH, Berger K, Lesch CA. Four-factor prothrombin complex concentrate for life-threatening bleeds or emergent surgery: A retrospective evaluation. J Crit Care 2016; 36: 166-172
- 56 Subramaniam K, Spilsbury K, Ayonrinde OT. et al. Red blood cell transfusion is associated with further bleeding and fresh-frozen plasma with mortality in nonvariceal upper gastrointestinal bleeding. Transfusion 2016; 56: 816-826
- 57 Fabricius R, Svenningsen P, Hillingsø J. et al. Effect of transfusion strategy in acute non-variceal upper gastrointestinal bleeding: a nationwide study of 5861 hospital admissions in Denmark. World J Surg 2016; 40: 1129-36
- 58 Karaca MA, Erbil B, Ozmen MM. Use and effectiveness of prothrombin complex concentrates vs fresh frozen plasma in gastrointestinal hemorrhage due to warfarin usage in the ED. Am J Emerg Med 2014; 32: 660-664
- 59 Zatta A, McQuilten Z, Kandane-Rathnayake R. et al. The Australian and New Zealand Haemostasis Registry: ten years of data on off-licence use of recombinant activated factor VII. Blood Transfus 2015; 13: 86-99
- 60 Liesenfeld KH, Gruenenfelder F, Clemens A. Enhanced elimination of dabigatran: Identifying the appropriate patient for the use of continuous venovenous hemodialysis instead of intermittent hemodialysis – A simulation analysis. J Clin Pharmacol 2016; 56: 597-608
- 61 Dager WE, Banares L. Reversing the anticoagulation effects of dabigatran. Hosp Pract 2017; 45: 29-38
- 62 Schulman S, Ritchie B, Nahirniak S. et al. Reversal of dabigatran-associated major bleeding with activated prothrombin concentrate: A prospective cohort study. Thromb Res 2017; 152: 44-48
- 63 Pollack CV, Reilly PA, van Ryn J. et al. Idarucizumab for dabigatran reversal – full cohort analysis. N Engl J Med 2017; 377: 431-441
- 64 Deutsch D, Boustiere C, Ferrari E. et al. Direct oral anticoagulants and digestive bleeding: therapeutic management and preventive measures. Therap Adv Gastroenterol 2017; 10: 495-505
- 65 Heidbuchel H, Verhamme P, Alings M. et al. Updated European Heart Rhythm Association practical guide on the use of non-vitamin-K antagonist anticoagulants in patients with non-valvular atrial fibrillation: Executive summary. Eur Heart J 2017; 38: 2137-2149
- 66 Connolly SJ, Milling TJ, Eikelboom JW. et al. Andexanet alfa for acute major bleeding associated with factor Xa inhibitors. N Engl J Med 2016; 375: 1131-1141
- 67 Ansell JE, Bakhru SH, Laulicht BE. et al. Single-dose ciraparantag safely and completely reverses anticoagulant effects of edoxaban. Thromb Haemost 2017; 117: 238-245
- 68 Sreedharan A, Martin J, Leontiadis GI. et al. Proton pump inhibitor treatment initiated prior to endoscopic diagnosis in upper gastrointestinal bleeding. Cochrane Database Syst Rev 2010; 7: CD005415
- 69 Barkun AN, Bardou M, Kuipers EJ. et al. International consensus recommendations on the management of patients with nonvariceal upper gastrointestinal bleeding. Ann Intern Med 2010; 152: 101-13
- 70 Siau K, Hearnshaw S, Stanley AJ. et al. British Society of Gastroenterology (BSG)-led Multisociety consensus care bundle for the early clinical management of acute upper gastrointestinal bleeding. Frontline Gastroenterol 2020; 11: 311-323
- 71 Raptis S, Dollinger HC, von Berger L. et al. Effects of somatostatin on gastric secretion and gastrin release in man. Digestion 1975; 13: 15-26
- 72 Riha HM, Wilkinson R, Twilla J. et al. Octreotide added to a proton pump inhibitor versus a proton pump inhibitor alone in nonvariceal upper-gastrointestinal bleeds. Ann Pharmacother 2019; 53: 794-800
- 73 Kessel B, Olsha O, Younis A. et al. Evaluation of nasogastric tubes to enable differentiation between upper and lower gastrointestinal bleeding in unselected patients with melena. Eur J Emerg Med 2016; 23: 71-73
- 74 Machlab S, Garcia-Iglesias P, Martinez-Bauer E. et al. Diagnostic utility of nasogastric tube aspiration and the ratio of blood urea nitrogen to creatinine for distinguishing upper and lower gastrointestinal tract bleeding. Emergencias 2018; 30: 419-423
- 75 Rockey DC, Ahn C, de Melo SW. Randomized pragmatic trial of nasogastric tube placement in patients with upper gastrointestinal tract bleeding. J Investig Med 2017; 65: 759-764
- 76 Chaudhuri D, Bishay K, Tandon P. et al. Prophylactic endotracheal intubation in critically ill patients with upper gastrointestinal bleed: a systematic review and meta-analysis. JGH Open 2019; DOI: 10.1002/jgh3.12195.
- 77 Alshamsi F, Jaeschke R, Baw B. et al. Prophylactic endotracheal intubation in patients with upper gastrointestinal bleeding undergoing endoscopy: a systematic review and meta-analysis. Saudi J Med Med Sci 2017; 5: 201-209
- 78 Almashhrawi AA, Rahman R, Jersak ST. et al. Prophylactic tracheal intubation for upper GI bleeding: a meta-analysis. World J Metaanal 2015; 3: 4-10
- 79 Perisetti A, Kopel J, Shredi A. et al. Prophylactic pre-esophagogastroduodenoscopy tracheal intubation in patients with upper gastrointestinal bleeding. Proc (Bayl Univ Med Cent) 2019; 32: 22-25
- 80 Enestvedt BK, Gralnek IM, Mattek N. et al. An evaluation of endoscopic indications and findings related to non-variceal upper-GI hemorrhage in a large multicenter consortium. Gastrointest Endosc 2008; 67: 422-429
- 81 Hearnshaw SA, Logan RF, Lowe D. et al. Use of endoscopy for management of acute upper gastrointestinal bleeding in the UK: results of a nationwide audit. Gut 2010; 59: 1022-1029
- 82 Bai Y, Guo JF, Li ZS. Meta-analysis: erythromycin before endoscopy for acute upper gastrointestinal bleeding. Aliment Pharmacol Ther 2011; 34: 166-171
- 83 Szary NM, Gupta R, Choudhary A. et al. Erythromycin prior to endoscopy in acute upper gastrointestinal bleeding: a meta-analysis. Scand J Gastroenterol 2011; 46: 920-924
- 84 Theivanayagam S, Lim RG, Cobell WJ. et al. Administration of erythromycin before endoscopy in upper gastrointestinal bleeding: a meta-analysis of randomized controlled trials. Saudi J Gastroenterol 2013; 19: 205-210
- 85 Barkun AN, Bardou M, Martel M. et al. Prokinetics in acute upper GI bleeding: a meta-analysis. Gastrointest Endosc 2010; 72: 1138-1145
- 86 Rahman R, Nguyen DL, Sohail U. et al. Pre-endoscopic erythromycin administration in upper gastrointestinal bleeding: an updated meta-analysis and systematic review. Ann Gastroenterol 2016; 29: 312-317
- 87 Winstead NS, Wilcox CM. Erythromycin prior to endoscopy for acute upper gastrointestinal haemorrhage: a cost–effectiveness analysis. Aliment Pharmacol Ther 2007; 26: 1371-1377
- 88 Gomes T, Mamdani MM, Juurlink DN. Macrolide-induced digoxin toxicity: a population-based study. Clin Pharmacol Ther 2009; 86: 383-386
- 89 Rowan C, Brinker AD, Nourjah P. et al. Rhabdomyolysis reports show interaction between simvastatin and CYP3A4 inhibitors. Pharmacoepidemiol Drug Saf 2009; 18: 301-309
- 90 Alexandrino G, Domingues TD, Carvalho R. et al. Endoscopy in patients with acute upper gastrointestinal bleeding. Clin Endosc 2019; 52: 47-52
- 91 Ahn DW, Park YS, Lee SH. et al. Clinical outcome of acute nonvariceal upper gastrointestinal bleeding after hours: the role of urgent endoscopy. Korean J Intern Med 2016; 31: 470-478
- 92 Garg SK, Anugwom C, Campbell J. et al. Early esophagogastroduodenoscopy in upper gastrointestinal bleeding: a nationwide study. Endosc Int Open 2017; 5: E376-E386
- 93 Siau K, Hodson J, Ingram R. et al. Time to endoscopy for acute upper gastrointestinal bleeding: results from a prospective multicentre trainee-led audit. United European Gastroenterol J 2019; 7: 199-209
- 94 Jeong N, Kim KS, Jung YS. et al. Delayed endoscopy is associated with increased mortality in upper gastrointestinal hemorrhage. Am J Emerg Med 2019; 37: 277-280
- 95 Xia XF, Chiu PWY, Tsoi KKF. et al. The effect of off-hours hospital admission on mortality and clinical outcomes for patients with upper gastrointestinal hemorrhage: a systematic review and meta-analysis of 20 cohorts. United European Gastroenterol J 2018; 6: 367-381
- 96 Cho SH, Lee YS, Kim YJ. et al. Outcomes and role of urgent endoscopy in high-risk patients with acute nonvariceal gastrointestinal bleeding. Clin Gastroenterol Hepatol 2018; 16: 370-377
- 97 Kumar NL, Cohen AJ, Nayor J. et al. Timing of upper endoscopy influences outcomes in patients with acute nonvariceal upper GI bleeding. Gastrointest Endosc 2017; 85: 945-952
- 98 Lau JYW, Yu Y, Tang RSY. et al. Timing of endoscopy for acute upper gastrointestinal bleeding. N Engl J Med 2020; 382: 1299-1308
- 99 Laursen SB, Leontiadis GI, Stanley AJ. et al. Relationship between timing of endoscopy and mortality in patients with peptic ulcer bleeding: a nationwide cohort study. Gastrointest Endosc 2017; 85: 936-944
- 100 Matsuura S, Sakata Y, Tsuruoka N. et al. Outcomes of patients undergoing endoscopic hemostasis for the upper gastrointestinal bleeding were not influenced by the hospital emergency visits: a situation prevailing in Japan. Digestion 2018; 97: 260-266
- 101 Shih P, Liu S, Li S. et al. Weekend effect in upper gastrointestinal bleeding: a systematic review and meta-analysis. PeerJ 2018; 6: e428
- 102 Forrest JA, Finlayson ND, Shearman DJ. Endoscopy in gastrointestinal bleeding. Lancet 1974; 2: 394-397
- 103 Elmunzer BJ, Young SD, Inadomi JM. et al. Systematic review of the predictors of recurrent hemorrhage after endoscopic hemostatic therapy for bleeding peptic ulcers. Am J Gastroenterol 2008; 103: 2625-2632
- 104 Lau JY, Sung JJ, Chan AC. et al. Stigmata of hemorrhage in bleeding peptic ulcers: an interobserver agreement study among international experts. Gastrointest Endosc 1997; 46: 33-36
- 105 Mondardini A, Barletti C, Rocca G. et al. Non-variceal upper gastrointestinal bleeding and Forrest’s classification: diagnostic agreement between endoscopists from the same area. Endoscopy 1998; 30: 508-512
- 106 Jensen DM, Eklund S, Persson T. et al. Reassessment of rebleeding risk of Forrest IB (oozing) peptic ulcer bleeding in a large international randomized trial. Am J Gastroenterol 2017; 112: 441-446
- 107 Jensen DM, Ohning GV, Kovacs TO. et al. Doppler endoscopic probe as a guide to risk stratification and definitive hemostasis of peptic ulcer bleeding. Gastrointest Endosc 2016; 83: 129-136
- 108 Camus M, Jensen DM, Kovacs TO. et al. Independent risk factors of 30-day outcomes in 1,264 patients with peptic ulcer bleeding in the USA: large ulcers do worse. Aliment Pharmacol Ther 2016; 43: 1080-1089
- 109 Lolle I, Møller MH, Rosenstock SJ. Association between ulcer site and outcome in complicated peptic ulcer disease: a Danish nationwide cohort study. Scand J Gastroenterol 2016; 51: 1165-1171
- 110 Wong RC, Chak A, Kobayashi K. et al. Role of Doppler US in acute peptic ulcer hemorrhage: can it predict failure of endoscopic therapy?. Gastrointest Endosc 2000; 52: 315-321
- 111 Jensen DM, Kovacs TOG, Ohning GV. et al. Doppler endoscopic probe monitoring of blood flow improves risk stratification and outcomes of patients with severe nonvariceal upper gastrointestinal hemorrhage. Gastroenterology 2017; 152: 1310-1318
- 112 Kantowski M, Schoepfer AM, Settmacher U. et al. Assessment of endoscopic doppler to guide hemostasis in high risk peptic ulcer bleeding. Scand J Gastroenterol 2018; 53: 1311-1318
- 113 Barkun AN, Adam V, Wong RCK. Use of doppler probe in nonvariceal upper-gastrointestinal bleeding is less costly and more effective than standard of care. Clin Gastroenterol Hepatol 2019; 17: 2463-2470
- 114 Marya NB, Jawaid S, Foley A. et al. A randomized controlled trial comparing efficacy of early video capsule endoscopy with standard of care in the approach to non-hematemesis GI bleeding (with videos). Gastrointest Endosc 2019; 89: 33-43
- 115 Pérez-Cuadrado Robles EE, Bebia Conesa P, Esteban Delgado P. et al. Emergency double-balloon enteroscopy combined with real-time viewing of capsule endoscopy: A feasible combined approach in acute overt-obscure gastrointestinal bleeding?. Dig Endosc 2015; 27: 338-344
- 116 Schlag C, Menzel C, Nennstiel S. et al. Emergency video capsule endoscopy in patients with acute severe GI bleeding and negative upper endoscopy results. Gastrointest Endosc 2015; 81: 889-895
- 117 Ching H, Hale MF, Sidhu R. et al. Magnetically assisted capsule endoscopy in suspected acute upper GI bleeding versus esophagogastroduodenoscopy in detecting focal lesions. Gastrointest Endosc 2019; 90: 430-439
- 118 Schmidt A, Zimmermann M, Bauder M. et al. Novel telemetric sensor capsule for EGD urgency triage: a feasibility study. Endosc Int Open 2019; 07: E774-E781
- 119 Laine L, McQuaid KR. Endoscopic therapy for bleeding ulcers: an evidence-based approach based on meta-analyses of randomized controlled trials. Clin Gastroenterol Hepatol 2009; 7: 33-47
- 120 Barkun AN, Martel M, Toubouti Y. et al. Endoscopic hemostasis in peptic ulcer bleeding for patients with high-risk lesions: a series of meta-analyses. Gastrointest Endosc 2009; 69: 786-799
- 121 Sung JJ, Tsoi KK, Lai LH. et al. Endoscopic clipping versus injection and thermo-coagulation in the treatment of non-variceal upper gastrointestinal bleeding: a meta-analysis. Gut 2007; 56: 1364-1373
- 122 Marmo R, Rotondano G, Piscopo R. et al. Dual therapy versus monotherapy in the endoscopic treatment of high-risk bleeding ulcers: a meta-analysis of controlled trials. Am J Gastroenterol 2007; 102: 279-289
- 123 Vergara M, Bennett C, Calvet X. et al. Epinephrine injection versus epinephrine injection and a second endoscopic method in high risk bleeding ulcers. Cochrane Database Syst Rev 2014; 10: CD005584
- 124 Baracat F, Moura E, Bernardo W. et al. Endoscopic hemostasis for peptic ulcer bleeding: systematic review and meta-analyses of randomized controlled trials. Surg Endosc 2016; 2155-2168
- 125 Shi K, Shen Z, Zhu G. et al. Systematic review with network meta-analysis: dual therapy for high-risk bleeding peptic ulcers. BMC Gastroenterology 2017; 55 DOI: 10.1186/s12876-017-0610-0.
- 126 Kim JW, Jang JY, Lee CK. et al. Comparison of hemostatic forceps with soft coagulation versus argon plasma coagulation for bleeding peptic ulcer – a randomized trial. Endoscopy 2015; 47: 680-687
- 127 Kyaw M, Tse Y, Ang D. et al. Embolization versus surgery for peptic ulcer bleeding after failed endoscopic hemostasis: A meta-analysis. Endoscopy International Open 2014; 2 DOI: 10.1055/s-0034-1365235.
- 128 Beggs AD, Dilworth MP, Powell SL. et al. A systematic review of transarterial embolization versus emergency surgery in treatment of major nonvariceal upper gastrointestinal bleeding. Clinical and Experimental Gastroenterology 2014; 7: 93-104
- 129 Tarasconi A, Baiocchi G, Pattonieri V. et al. Transcatheter arterial embolization versus surgery for refractory non-variceal upper gastrointestinal bleeding: A meta-analysis. World J Emerg Surgery 2014; 14: 1-13
- 130 Sverden E, Mattsson F, Lindstrom D. et al. Transcatheter arterial embolization compared with surgery for uncontrolled peptic ulcer bleeding. A population-based cohort study. Ann Surg 2019; 269: 304-309
- 131 Park JS, Kim HK, Shin YW. et al. Novel hemostatic adhesive powder for nonvariceal upper gastrointestinal bleeding. Endosc Int Open 2019; 07: E1763-E1767
- 132 Alzoubaidi D, Hussein M, Rusu R. et al. Outcomes from an international multicenter registry of patients with acute gastrointestinal bleeding undergoing endoscopic therapy with Hemospray. Dig Endosc 2020; 32: 96-105
- 133 Baracat F, Hourneaux de Moura D, Brunaldi V. et al. Randomized controlled trial of hemostatic powder versus endoscopic clipping for non‑variceal upper gastrointestinal bleeding. Surg Endosc 2020; 34: 317-324
- 134 Barkun AN, Adam V, Lu Y. et al. Using Hemospray improves the cost-effectiveness ratio in the management of upper gastrointestinal nonvariceal bleeding. J Clin Gastroenterol 2018; 52: 36-44
- 135 Wedi E, Fischer A, Hochberger J. et al. Multicenter evaluation of first-line endoscopic treatment with the OTSC in acute non-variceal upper gastrointestinal bleeding and comparison with the Rockall cohort: the FLETRock study. Surg Endosc 2018; 32: 307-314
- 136 Manta R, Galloro G, Mangiafico S. et al. First-line endoscopic treatment with over-the-scope clips in patients with either upper or lower gastrointestinal bleeding: a multicenter study. Endosc Int Open 2018; 06: E1317-E1321
- 137 Brandler J, Buttar N, Baruah A. et al. Efficacy of over-the-scope clips in management of high-risk gastrointestinal bleeding. Clin Gastroenterol Hepatol 2018; 16: 690-696
- 138 Chandrasekar VT, Sharma P, Desai M. et al. Efficacy and safety of over-the-scope clips for gastrointestinal bleeding: a systematic review and meta-analysis. Endoscopy 2019; 51: 941-949
- 139 Goelder S, Messmann H, Neuhaus L. et al. Over-the-scope clip in peptic ulcer bleeding: clinical success in primary and secondary treatment and factors associated with treatment failure. Endoscopy International Open 2019; 7: E846-E854
- 140 Kobara H, Hirohito M, Tsutomu M. et al. Over-the-scope-clips: A review of 1517 cases over 9 years. J Gastroenterol Hepatol 2019; 34: 22-30
- 141 Richter-Schrag HJ, Thimme R, Glatz T. et al. First-line endoscopic treatment with over-the-scope clips significantly improves the primary failure and rebleeding rates in high-risk gastrointestinal bleeding: A single-center experience with 100 cases. World J Gastroenterol 2016; 22: 9162-9171
- 142 Asokkumar R, Ngu JH, Soetikno R. et al. Use of over-the-scope-clip (OTSC) improves outcomes of high-risk adverse outcome (HR-AO) non-variceal upper gastrointestinal bleeding (NVUGIB). Endoscopy International Open 2018; 06: E789-E796
- 143 Lamberts R, Halm U, Koch A. et al. Use of over-the-scope-clips (OTSC) for hemostasis in gastrointestinal bleeding in patients under antithrombotic therapy. Endosc Int Open 2017; 05: E324-E330
- 144 Wedi E, Hochberger J, Gonzalez S. et al. One hundred and one over-the-scope-clip applications for severe gastrointestinal bleeding, leaks and fistula. World J Gastroenterol 2016; 22: 1844-1853
- 145 Jensen DM, Kovacs TOG, Ghassemi KA. et al. Randomized controlled trial of over-the-scope clip as initial treatment of severe non-variceal upper gastrointestinal bleeding. Clin Gastroenterol Hepatol 2020; DOI: 10.1016/j.cgh.2020.08.046.
- 146 Schmidt A, Caca K, Goelder S. et al. Over-the-scope clips are more effective than standard endoscopic therapy for patients with recurrent bleeding of peptic ulcers. Gastroenterology 2018; 155: 674-686
- 147 Arima S, Sakata Y, Ogata S. et al. Evaluation of hemostasis with soft coagulation using endoscopic hemostatic forceps in comparison with metallic hemoclips for bleeding gastric ulcers: a prospective, randomized trial. J Gastroenterol 2010; 45: 501-505
- 148 Kataoka M, Kawai T, Hayama Y. et al. Comparison of hemostasis using bipolar hemostatic forceps with hemostasis by endoscopic hemoclipping for nonvariceal upper gastrointestinal bleeding in a prospective non-randomized trial. Surg Endosc 2013; 27: 3035-3038
- 149 Nunoue T, Takenaka R, Hori K. et al. A randomized trial of monopolar soft-mode coagulation versus heater probe thermocoagulation for peptic ulcer bleeding. J Clin Gastroenterol 2015; 49: 472-476
- 150 Kim JW, Jang JY, Lee CK. et al. Comparison of hemostatic forceps with soft coagulation versus argon plasma coagulation for bleeding peptic ulcer – a randomized trial. Endoscopy 2015; 47: 680-687
- 151 Toka B, Eminler AT, Karacaer C. et al. Comparison of monopolar hemostatic forceps with soft coagulation versus hemoclip for peptic ulcer bleeding: a randomized trial (with video). Gastrointest Endosc 2019; 89: 792-802
- 152 Neumann I, Letelier LM, Rada G. et al. Comparison of different regimens of proton pump inhibitors for acute peptic ulcer bleeding. Cochrane Database Syst Rev 2013; 6: 007999 DOI: 10.1002/14651858.CD007999.
- 153 Sgourakis G, Chatzidakis G, Poulou A. et al. High-dose vs. low-dose proton pump inhibitors post-endoscopic hemostasis in patients with bleeding peptic ulcer. a meta-analysis and meta-regression analysis. Turk J Gastroenterol 2018; 29: 22-31
- 154 Sachar H, Vaidya K, Laine L. Intermittent vs continuous proton pump inhibitor therapy for high-risk bleeding ulcers: a systematic review and meta-analysis. JAMA Intern Med 2014; 174: 1755-1762
- 155 Javid G, Zargar SA, U-Saif R. et al. Comparison of po or IV proton pump inhibitors on 72-h intragastric pH in bleeding peptic ulcer. J Gastroenterol Hepatol 2009; 24: 1236-1243
- 156 Sung JJ, Suen BY, Wu JC. et al. Effects of intravenous and oral esomeprazole in the prevention of recurrent bleeding from peptic ulcers after endoscopic therapy. Am J Gastroenterol 2014; 109: 1005-1010
- 157 El Ouali S, Barkun AN, Wyse J. et al. Is routine second-look endoscopy effective after endoscopic hemostasis in acute peptic ulcer bleeding?. A meta-analysis. Gastrointest Endosc 2012; 76: 283-292
- 158 Imperiale TF, Kong N. Second look endoscopy for bleeding peptic ulcer disease: a decision and cost-effectiveness analysis. J Clin Gastroenterol 2012; 46: 71-75
- 159 Chiu PWY, Joeng HKM, Choi CLY. et al. High-dose omeprazole infusion compared with scheduled second-look endoscopy for prevention of peptic ulcer rebleeding: a randomized controlled trial. Endoscopy 2016; 48: 717-22
- 160 Park SJ, Park H, Lee YC. et al. Effect of scheduled second-look endoscopy on peptic ulcer bleeding: a prospective randomized multicenter trial. Gastrointest Endos 2018; 87: 457-465
- 161 Laine L, Spiegel B, Rostom A. et al. Methodology for randomized trials of patients with nonvariceal upper gastrointestinal bleeding: recommendations from an international consensus conference. Am J Gastroenterol 2010; 105: 540-550
- 162 Lau JYW, Sung JJY, Lam YH. et al. Endoscopic retreatment compared with surgery in patients with recurrent bleeding after initial endoscopic control of bleeding ulcer. N Engl J Med 1999; 340: 751-756
- 163 Haddara S, Jacques J, Lecleire S. et al. A novel hemostatic powder for upper gastrointestinal bleeding: a multicenter study (the “GRAPHE” registry). Endoscopy 2016; 48: 1084-1095
- 164 Rodríguez de Santiago E, Burgos-Santamaría D, Pérez-Carazo L. et al. Hemostatic spray powder TC-325 for GI bleeding in a nationwide study: survival and predictors of failure via competing risks analysis. Gastrointest Endosc 2019; 90: 581-590
- 165 Lau JYW, Pittayanon R, Wong KT. et al. Prophylactic angiographic embolisation after endoscopic control of bleeding to high-risk peptic ulcers: a randomised controlled trial. Gut 2019; 68: 796-803
- 166 Gisbert JP, Khorrami S, Carballo F. et al. Meta-analysis: Helicobacter pylori eradication therapy vs. anti-secretory non-eradication therapy for the prevention of recurrent bleeding from peptic ulcer. Aliment Pharmacol Ther 2004; 19: 617-629
- 167 Ford AC, Delaney BC, Forman D. et al. Eradication therapy in Helicobacter pylori positive peptic ulcer disease: systematic review and economic analysis. Am J Gastroenterol 2004; 99: 1833-55
- 168 Gisbert JP, Calvet X, Cosme A. et al. Long-term follow-up of 1,000 patients cured of Helicobacter pylori infection following an episode of peptic ulcer bleeding. Am J Gastroenterol 2012; 107: 1197-1204
- 169 Ford AC, Gurusamy KS, Delaney B. et al. Eradication therapy for peptic ulcer disease in Helicobacter pylori-positive people. Cochrane Database Syst Rev 2016; 4: CD003840
- 170 Chang SS, Hu HY. Helicobacter pylori eradication within 120 days is associated with decreased complicated recurrent peptic ulcers in peptic ulcer bleeding patients. Gut Liver 2015; 9: 346-352
- 171 Hung KW, Knotts RM, Faye AS. et al. Factors associated with adherence to Helicobacter pylori testing during hospitalization for bleeding peptic ulcer disease. Clin Gastroenterol Hepatol 2020; 18: 1091-1098
- 172 Sverdén E, Brusselaers N, Wahlin K. et al. Time latencies of Helicobacter pylori eradication after peptic ulcer and risk of recurrent ulcer, ulcer adverse events, and gastric cancer: a population-based cohort study. Gastrointest Endosc 2018; 88: 242-250
- 173 Gisbert JP, Abraira V. Accuracy of Helicobacter pylori diagnostic tests in patients with bleeding peptic ulcer: a systematic review and meta-analysis. Am J Gastroenterol 2006; 101: 848-863
- 174 Sánchez-Delgado J, Gené E, Suárez D. et al. Has H. pylori prevalence in bleeding peptic ulcer been underestimated? A meta-regression. Am J Gastroenterol 2011; 106: 398-405
- 175 Lim LG, Ho KY, So JB. et al. Diagnosis and treatment of Helicobacter pylori for peptic ulcer bleeding in clinical practice – factors associated with non-diagnosis and non-treatment, and diagnostic yield in various settings. Turk J Gastroenterol 2014; 25: 157-161
- 176 Lanas A, Garcia-Rodriguez LA, Arroyo MT. et al. Effect of anti-secretory drugs and nitrates on the risk of ulcer bleeding associated with nonsteroidal anti-inflammatory drugs, antiplatelet agents, and anticoagulants. Am J Gastroenterol 2007; 102: 507-515
- 177 Bhatt DL, Scheiman J, Abraham NS. et al. ACCF/ACG/AHA 2008 expert consensus document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use: a report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents. Circulation 2008; 118: 1894-1909
- 178 Kwok CS, Nijar RS, Loke YK. Effects of proton pump inhibitors on adverse gastrointestinal events in patients receiving clopidogrel: a systematic review and meta-analysis. Drug Saf 2011; 34: 47-57
- 179 Chen J, Chen SY, Lian JJ. et al. Pharmacodynamic impacts of proton pump inhibitors on the efficacy of clopidogrel in vivo – a systematic review. Clin Cardiol 2013; 36: 184-189
- 180 Kwok CS, Loke YK. Meta-analysis: the effects of proton pump inhibitors on cardiovascular events and mortality in patients receiving clopidogrel. Aliment Pharmacol Ther 2010; 31: 810-823
- 181 Siller-Matula JM, Jilma B, Schror K. et al. Effect of proton pump inhibitors on clinical outcome in patients treated with clopidogrel: a systematic review and meta-analysis. J Thromb Haemost 2010; 8: 2624-2641
- 182 Cardoso RN, Benjo AM, DiNicolantonio JJ. et al. Incidence of cardiovascular events and gastrointestinal bleeding in patients receiving clopidogrel with and without proton pump inhibitors: an updated meta-analysis. Open Heart 2015; 2: e000248.2
- 183 Witt DM, Delate T, Garcia DA. et al. Risk of thromboembolism, recurrent hemorrhage, and death after warfarin therapy interruption for gastrointestinal tract bleeding. Arch Intern Med 2012; 172: 1484-1491
- 184 Lee JK, Kang HW, Kim SG. et al. Risks related with withholding and resuming anticoagulation in patients with non-variceal upper gastrointestinal bleeding while on warfarin therapy. Int J Clin Pract 2012; 66: 64-68
- 185 Qureshi W, Mittal C, Patsias I. et al. Restarting anticoagulation and outcomes after major gastrointestinal bleeding in atrial fibrillation. Am J Cardiol 2014; 113: 662-668
- 186 Staerk L, Lip GY, Olesen JB. et al. Stroke and recurrent haemorrhage associated with antithrombotic treatment after gastrointestinal bleeding in patients with atrial fibrillation: nationwide cohort study. BMJ 2015; 351: h5876
- 187 Kido K, Scalese MJ. Management of oral anticoagulation therapy after gastrointestinal bleeding: whether to, when to, and how to restart an anticoagulation therapy. Ann Pharmacother 2017; 51: 1000-1007
- 188 Majeed A, Wallvik N, Eriksson J. et al. Optimal timing of vitamin K antagonist resumption after upper gastrointestinal bleeding. A risk modelling analysis. Thromb Haemost 2017; 117: 491-499
- 189 Hernandez I, Zhang Y, Brooks MM. et al. Anticoagulation use and clinical outcomes after major bleeding on dabigatran or warfarin in atrial fibrillation. Stroke 2017; 48: 159-166
- 190 Granger CB, Alexander JH, McMurray JJV. et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011; 365: 981-992
- 191 Lip GY, Nieuwlaat R, Pisters R. et al. Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: the euro heart survey on atrial fibrillation. Chest 2010; 137: 263-272
- 192 Sandhu RK, Bakal JA, Ezekowitz JA. et al. Risk stratification schemes, anticoagulation use and outcomes: the risk-treatment paradox in patients with newly diagnosed non-valvular atrial fibrillation. Heart 2011; 97: 2046-2050
- 193 Pisters R, Lane DA, Nieuwlaat R. et al. A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation. Chest 2010; 138: 1093-100
- 194 Lanas A, Garcia-Rodriguez LA, Arroyo MT. et al. Effect of antisecretory drugs and nitrates on the risk of ulcer bleeding associated with nonsteroidal anti-inflammatory drugs, antiplatelet agents, and anticoagulants. Am J Gastroenterol 2007; 102: 507-515
- 195 Masso Gonzalez EL, Garcia Rodriguez LA. Proton pump inhibitors reduce the long-term risk of recurrent upper gastrointestinal bleeding: An observational study. Aliment Pharmacol Ther 2008; 28: 629-637
- 196 Lin KJ, Hernandez-Diaz S, Garcia Rodriguez LA. Acid suppressants reduce risk of gastrointestinal bleeding in patients on antithrombotic or anti-inflammatory therapy. Gastroenterology 2011; 141: 71-79
- 197 Chan EW, Lau WC, Leung WK. et al. Prevention of dabigatran-related gastrointestinal bleeding with gastroprotective agents: A population-based study. Gastroenterology 2015; 149: 586-595
- 198 Ray WA, Chung CP, Murray KT. et al. Association of proton pump inhibitors with reduced risk of warfarin-related serious upper gastrointestinal bleeding. Gastroenterology 2016; 151: 1105-1112
- 199 Moayyedi P, Eikelboom JW, Bosch J. et al. Pantoprazole to prevent gastroduodenal events in patients receiving rivaroxaban and/or aspirin in a randomized, double-blind, placebo-controlled trial. Gastroenterology 2019; 157: 403-412
- 200 Chan EW, Lau WC, Leung WK. et al. Prevention of dabigatran-related gastrointestinal bleeding with gastroprotective agents: A population-based study. Gastroenterology 2015; 149: 586-595