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Non-variceal upper gastrointestinal bleeding

Abstract

Non-variceal upper gastrointestinal bleeding (NVUGIB) is bleeding that develops in the oesophagus, stomach or proximal duodenum. Peptic ulcers, caused by Helicobacter pylori infection or use of NSAIDs and low-dose aspirin (LDA), are the most common cause. Although the incidence and mortality associated with NVUGIB have been decreasing owing to considerable advances in the prevention and management of NVUGIB over the past 20 years, it remains a common clinical problem with an annual incidence of 67 per 100,000 individuals in the United States in 2012. NVUGIB is a medical emergency, and mortality is in the range 1–5%. After resuscitation and initial assessment, early (within 24 hours) diagnostic and therapeutic endoscopy together with intragastric pH control with proton pump inhibitors (PPIs) form the basis of treatment. With a growing ageing population treated with antiplatelet and/or anticoagulant medications, the clinical management of NVUGIB is complex as the risk between gastrointestinal bleeding events and adverse cardiovascular events needs to be balanced. The best clinical approach includes identification of risk factors and prevention of bleeding; available strategies include continuous treatment with PPIs or H. pylori eradication in those at increased risk of developing NVUGIB. Treatment with PPIs and/or use of cyclooxygenase-2-selective NSAIDs should be implemented in those patients at risk of NVUGIB who need NSAIDs and/or LDA.

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Figure 1: The decline in incidence of NVUGIB over time.
Figure 2: Mechanisms of upper gastrointestinal bleeding induced by NSAIDs, LDA or H. pylori infection.
Figure 3: Effects of an acidic environment on platelet aggregation.
Figure 4: Complex pathophysiology of NVUGIB.
Figure 5: Risk of developing NVUGIB associated with certain drugs.
Figure 6: Management of using soft coagulation.
Figure 7: Management of NVUGIB in those using antiplatelet agents.
Figure 8: Management of NVUGIB in those using vitamin K antagonists.
Figure 9: Management of NVUGIB in those on DOACs.

References

  1. Laine, L. Upper gastrointestinal bleeding due to a peptic ulcer. N. Engl. J. Med. 374, 2367–2376 (2016).

    PubMed  Google Scholar 

  2. Gralnek, I. M., Neeman, Z. & Strate, L. L. Acute lower gastrointestinal bleeding. N. Engl. J. Med. 376, 1054–1063 (2017).

    PubMed  Google Scholar 

  3. Lanas, A. & Chan, F. K. Peptic ulcer disease. Lancet 390, 613–624 (2017).

    PubMed  Google Scholar 

  4. Sung, J. J. et al. Causes of mortality in patients with peptic ulcer bleeding: a prospective cohort study of 10,428 cases. Am. J. Gastroenterol. 105, 84–89 (2010).

    PubMed  Google Scholar 

  5. Gralnek, I. M. et al. Diagnosis and management of nonvariceal upper gastrointestinal hemorrhage: European Society of Gastrointestinal Endoscopy (ESGE) Guideline. Endoscopy 47, a1–a46 (2015). This paper presents the most recent European guidelines based on the best available evidence for the complete management of NVUGIB.

    PubMed  Google Scholar 

  6. Rotondano, G. Epidemiology and diagnosis of acute nonvariceal upper gastrointestinal bleeding. Gastroenterol. Clin. North Am. 43, 643–663 (2014).

    PubMed  Google Scholar 

  7. Hreinsson, J. P., Kalaitzakis, E., Gudmundsson, S. & Björnsson, E. S. Upper gastrointestinal bleeding: incidence, etiology and outcomes in a population-based setting. Scand. J. Gastroenterol. 48, 439–447 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Gralnek, I. M., Barkun, A. N. & Bardou, M. Management of acute bleeding from a peptic ulcer. N. Engl. J. Med. 359, 928–937 (2008).

    CAS  PubMed  Google Scholar 

  9. Laine, L., Yang, H., Chang, S. C. & Datto, C. Trends for incidence of hospitalization and death due to GI complications in the United States from 2001 to 2009. Am. J. Gastroenterol. 107, 1190–1195 (2012).

    PubMed  Google Scholar 

  10. Laine, L. & Jensen, D. M. Management of patients with ulcer bleeding. Am. J. Gastroenterol. 107, 345–360 (2012).

    CAS  PubMed  Google Scholar 

  11. Lau, J. Y. et al. Challenges in the management of acute peptic ulcer bleeding. Lancet 381, 2033–2043 (2013).

    PubMed  Google Scholar 

  12. Quan, S. et al. Upper-gastrointestinal bleeding secondary to peptic ulcer disease: incidence and outcomes. World J. Gastroenterol. 20, 17568–17577 (2014).

    PubMed  PubMed Central  Google Scholar 

  13. Tielleman, T., Bujanda, D. & Cryer, B. Epidemiology and risk factors for upper gastrointestinal bleeding. Gastrointest. Endosc. Clin. N. Am. 25, 415–428 (2015).

    PubMed  Google Scholar 

  14. Everhart, J. E. & Ruhl, C. E. Burden of digestive diseases in the United States part I: overall and upper gastrointestinal diseases. Gastroenterology 136, 376–386 (2009).

    PubMed  Google Scholar 

  15. Wuerth, B. A. & Rockey, D. C. Changing epidemiology of upper gastrointestinal hemorrhage in the last decade: a nationwide analysis. Dig. Dis. Sci. (2017).

  16. van Leerdam, M. E. et al. Acute upper GI bleeding: did anything change? Time trend analysis of incidence and outcome of acute upper GI bleeding between 1993/1994 and 2000. Am. J. Gastroenterol. 98, 1494–1499 (2003).

    CAS  PubMed  Google Scholar 

  17. Lanas, A. et al. A nationwide study of mortality associated with hospital admission due to severe gastrointestinal events and those associated with nonsteroidal antiinflammatory drug use. Am. J. Gastroenterol. 100, 1685–1693 (2005).

    CAS  PubMed  Google Scholar 

  18. Ahsberg, K., Ye, W., Lu, Y., Zheng, Z. & Staël von Holstein, C. Hospitalisation of and mortality from bleeding peptic ulcer in Sweden: a nationwide time-trend analysis. Aliment. Pharmacol. Ther. 33, 578–584 (2011).

    CAS  PubMed  Google Scholar 

  19. Cavallaro, L. G. et al. Time trends and outcome of gastrointestinal bleeding in the Veneto region: a retrospective population based study from 2001 to 2010. Dig. Liver Dis. 46, 313–317 (2014).

    PubMed  Google Scholar 

  20. Sonnenberg, A. Time trends of ulcer mortality in non-European countries. Am. J. Gastroenterol. 102, 1101–1107 (2007).

    PubMed  Google Scholar 

  21. Wollenman, C. S., Chason, R., Reisch, J. S. & Rockey, D. C. Impact of ethnicity in upper gastrointestinal hemorrhage. J. Clin. Gastroenterol. 48, 343–350 (2014).

    PubMed  PubMed Central  Google Scholar 

  22. Irwin, J., Ferguson, R., Weilert, F. & Smith, A. Incidence of upper gastrointestinal haemorrhage in Maori and New Zealand European ethnic groups, 2001–2010. Intern. Med. J. 44, 735–741 (2014).

    CAS  PubMed  Google Scholar 

  23. Lanas, A. et al. The changing face of hospitalisation due to gastrointestinal bleeding and perforation. Aliment. Pharmacol. Ther. 33, 585–591 (2011).

    CAS  PubMed  Google Scholar 

  24. Papatheodoridis, G. V., Sougioultzis, S. & Archimandritis, A. J. Effects of Helicobacter pylori and nonsteroidal anti-inflammatory drugs on peptic ulcer disease: a systematic review. Clin. Gastroenterol. Hepatol. 4, 130–142 (2006).

    PubMed  Google Scholar 

  25. Gisbert, J. P. & Calvet, X. Review article: Helicobacter pylori-negative duodenal ulcer disease. Aliment. Pharmacol. Ther. 30, 791–815 (2009).

    CAS  PubMed  Google Scholar 

  26. Charpignon, C. et al. Peptic ulcer disease: one in five is related to neither Helicobacter pylori nor aspirin/NSAID intake. Aliment. Pharmacol. Ther. 38, 946–954 (2013).

    CAS  PubMed  Google Scholar 

  27. Chan, H. L. et al. Is non-Helicobacter pylori, non-NSAID peptic ulcer a common cause of upper GI bleeding? A prospective study of 977 patients. Gastrointest. Endosc. 53, 438–442 (2001).

    CAS  PubMed  Google Scholar 

  28. Yoon, H., Kim, S. G., Jung, H. C. & Song, I. S. High recurrence rate of idiopathic peptic ulcers in long-term follow-up. Gut Liver 7, 175–181 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Wong, G. L. et al. Gastroprotective therapy does not improve outcomes of patients with Helicobacter pylori-negative idiopathic bleeding ulcers. Clin. Gastroenterol. Hepatol. 10, 1124–1129 (2012).

    CAS  PubMed  Google Scholar 

  30. Wong, G. L. et al. High incidence of mortality and recurrent bleeding in patients with Helicobacter pylori-negative idiopathic bleeding ulcers. Gastroenterology 137, 525–531 (2009).

    PubMed  Google Scholar 

  31. Iijima, K., Kanno, T., Koike, T. & Shimosegawa, T. Helicobacter pylori-negative, non-steroidal anti-inflammatory drug: negative idiopathic ulcers in Asia. World J. Gastroenterol. 20, 706–713 (2014).

    PubMed  PubMed Central  Google Scholar 

  32. Crooks, C., Card, T. & West, J. Reductions in 28-day mortality following hospital admission for upper gastrointestinal hemorrhage. Gastroenterology 141, 62–70 (2011).

    PubMed  PubMed Central  Google Scholar 

  33. Abougergi, M. S., Travis, A. C. & Saltzman, J. R. The in-hospital mortality rate for upper GI hemorrhage has decreased over 2 decades in the United States: a nationwide analysis. Gastrointest. Endosc. 81, 882–888.e1 (2015).

    PubMed  Google Scholar 

  34. Taefi, A., Cho, W. K. & Nouraie, M. Decreasing trend of upper gastrointestinal bleeding mortality risk over three decades. Dig. Dis. Sci. 58, 2940–2948 (2013).

    PubMed  Google Scholar 

  35. Jairath, V., Martel, M., Logan, R. F. & Barkun, A. N. Why do mortality rates for nonvariceal upper gastrointestinal bleeding differ around the world? A systematic review of cohort studies. Can. J. Gastroenterol. 26, 537–543 (2012).

    PubMed  PubMed Central  Google Scholar 

  36. Sostres, C. & Lanas, A. Epidemiology and demographics of upper gastrointestinal bleeding: prevalence, incidence, and mortality. Gastrointest. Endosc. Clin. N. Am. 21, 567–581 (2011).

    PubMed  Google Scholar 

  37. Wang, F., Meng, W., Wang, B. & Qiao, L. Helicobacter pylori-induced gastric inflammation and gastric cancer. Cancer Lett. 345, 196–202 (2014).

    CAS  PubMed  Google Scholar 

  38. Datta De, D. & Roychoudhury, S. To be or not to be: The host genetic factor and beyond in Helicobacter pylori mediated gastro-duodenal diseases. World J. Gastroenterol. 21, 2883–2895 (2015).

    PubMed  PubMed Central  Google Scholar 

  39. Zaki, M. et al. H. pylori acutely inhibits gastric secretion by activating CGRP sensory neurons coupled to stimulation of somatostatin and inhibition of histamine secretion. Am. J. Physiol. Gastrointest. Liver Physiol. 304, G715–722 (2013).

    CAS  PubMed  Google Scholar 

  40. Moss, S. F., Legon, S., Bishop, A. E., Polak, J. M. & Calam, J. Effect of Helicobacter pylori on gastric somatostatin in duodenal ulcer disease. Lancet 340, 930–932 (1992).

    CAS  PubMed  Google Scholar 

  41. Bjarnason, I. et al. Mechanisms of damage to the gastrointestinal tract from nonsteroidal anti-inflammatory drugs. Gastroenterology 154, 500–514 (2018).

    CAS  PubMed  Google Scholar 

  42. Cryer, B. & Feldman, M. Effects of very low dose daily, long-term aspirin therapy on gastric, duodenal, and rectal prostaglandin levels and on mucosal injury in healthy humans. Gastroenterology 117, 17–25 (1999).

    CAS  PubMed  Google Scholar 

  43. Sostres, C. et al. Peptic ulcer bleeding risk. The role of Helicobacter pylori infection in NSAID/low-dose aspirin users. Am. J. Gastroenterol. 110, 684–689 (2015).

    CAS  PubMed  Google Scholar 

  44. Green, F. W., Kaplan, M. M., Curtis, L. E. & Levine, P. H. Effect of acid and pepsin on blood coagulation and platelet aggregation. A possible contributor prolonged gastroduodenal mucosal hemorrhage. Gastroenterology 74, 38–43 (1978).

    CAS  PubMed  Google Scholar 

  45. Lanas, A. et al. Effect of parenteral omeprazole and ranitidine on gastric pH and the outcome of bleeding peptic ulcer. J. Clin. Gastroenterol. 21, 103–106 (1995).

    CAS  PubMed  Google Scholar 

  46. van Rensburg, C. J. et al. Intragastric pH during continuous infusion with pantoprazole in patients with bleeding peptic ulcer. Am. J. Gastroenterol. 98, 2635–2641 (2003).

    CAS  PubMed  Google Scholar 

  47. Laine, L., Shah, A. & Bemanian, S. Intragastric pH with oral versus intravenous bolus plus infusion proton-pump inhibitor therapy in patients with bleeding ulcers. Gastroenterology 134, 1836–1841 (2008).

    PubMed  Google Scholar 

  48. Bardou, M., Toubouti, Y., Benhaberou-Brun, D., Rahme, E. & Barkun, A. N. Meta-analysis: proton-pump inhibition in high-risk patients with acute peptic ulcer bleeding. Aliment. Pharmacol. Ther. 21, 677–686 (2005).

    CAS  PubMed  Google Scholar 

  49. Halvorsen, S. et al. Management of antithrombotic therapy after bleeding in patients with coronary artery disease and/or atrial fibrillation: expert consensus paper of the European Society of Cardiology Working Group on Thrombosis. Eur. Heart J. 38, 1455–1462 (2017).

    CAS  PubMed  Google Scholar 

  50. Laine, L., Maller, E. S., Yu, C., Quan, H. & Simon, T. Ulcer formation with low-dose enteric-coated aspirin and the effect of COX-2 selective inhibition: a double-blind trial. Gastroenterology 127, 395–402 (2004).

    CAS  PubMed  Google Scholar 

  51. Hernández-Díaz, S. & García Rodríguez, L. A. Cardioprotective aspirin users and their excess risk of upper gastrointestinal complications. BMC Med. 4, 22 (2006).

    PubMed  PubMed Central  Google Scholar 

  52. Lanas, A. I. et al. Aspirin related gastrointestinal bleeders have an exaggerated bleeding time response due to aspirin use. Gut 39, 654–660 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. García-González, M. A. et al. Association of interleukin 1 gene family polymorphisms with duodenal ulcer disease. Clin. Exp. Immunol. 134, 525–531 (2003).

    PubMed  PubMed Central  Google Scholar 

  54. Okada, M. et al. Circumferential distribution and location of Mallory-Weiss tears: recent trends. Endosc. Int. Open 3, E418–424 (2015).

    PubMed  PubMed Central  Google Scholar 

  55. Cherednikov, E. F., Kunin, A. A., Cherednikov, E. E. & Moiseeva, N. S. The role of etiopathogenetic aspects in prediction and prevention of discontinuous-hemorrhagic (Mallory-Weiss) syndrome. EPMA J. 7, 7 (2016).

    PubMed  PubMed Central  Google Scholar 

  56. Baxter, M. & Aly, E. H. Dieulafoy's lesion: current trends in diagnosis and management. Ann. R. Coll. Surg. Engl. 92, 548–554 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Sami, S. S., Al-Araji, S. A. & Ragunath, K. Review article: gastrointestinal angiodysplasia - pathogenesis, diagnosis and management. Aliment. Pharmacol. Ther. 39, 15–34 (2014).

    CAS  PubMed  Google Scholar 

  58. Kim, D. B. et al. Analysis of risk factor and clinical characteristics of angiodysplasia presenting as upper gastrointestinal bleeding. Kor. J. Intern. Med. 31, 669–677 (2016).

    CAS  Google Scholar 

  59. Crooks, C. J., West, J. & Card, T. R. Comorbidities affect risk of nonvariceal upper gastrointestinal bleeding. Gastroenterology 144, 1384–1393.e2 (2013).

    PubMed  PubMed Central  Google Scholar 

  60. De Backer, D., Creteur, J., Dubois, M. J., Sakr, Y. & Vincent, J. L. Microvascular alterations in patients with acute severe heart failure and cardiogenic shock. Am. Heart J. 147, 91–99 (2004).

    PubMed  Google Scholar 

  61. Huang, K. W. et al. Chronic obstructive pulmonary disease: an independent risk factor for peptic ulcer bleeding: a nationwide population-based study. Aliment. Pharmacol. Ther. 35, 796–802 (2012).

    PubMed  Google Scholar 

  62. Luo, J. C. et al. Incidence of bleeding from gastroduodenal ulcers in patients with end-stage renal disease receiving hemodialysis. CMAJ 183, E1345–E1351 (2011).

    PubMed  PubMed Central  Google Scholar 

  63. Hunt, R. H., Lanas, A., Stichtenoth, D. O. & Scarpignato, C. Myths and facts in the use of anti-inflammatory drugs. Ann. Med. 41, 423–437 (2009).

    CAS  PubMed  Google Scholar 

  64. Masclee, G. M. et al. Risk of upper gastrointestinal bleeding from different drug combinations. Gastroenterology 147, 784–792.e9 (2014).

    CAS  PubMed  Google Scholar 

  65. Laine, L. et al. Stratifying the risk of NSAID-related upper gastrointestinal clinical events: results of a double-blind outcomes study in patients with rheumatoid arthritis. Gastroenterology 123, 1006–1012 (2002).

    CAS  PubMed  Google Scholar 

  66. Lanas, A. & Hunt, R. Prevention of anti-inflammatory drug-induced gastrointestinal damage: benefits and risks of therapeutic strategies. Ann. Med. 38, 415–428 (2006).

    CAS  PubMed  Google Scholar 

  67. Scarpignato, C. et al. Safe prescribing of non-steroidal anti-inflammatory drugs in patients with osteoarthritis — an expert consensus addressing benefits as well as gastrointestinal and cardiovascular risks. BMC Med. 13, 55 (2015).

    PubMed  PubMed Central  Google Scholar 

  68. Chan, F. K. et al. Preventing recurrent upper gastrointestinal bleeding in patients with Helicobacter pylori infection who are taking low-dose aspirin or naproxen. N. Engl. J. Med. 344, 967–973 (2001).

    CAS  PubMed  Google Scholar 

  69. Chan, F. K. et al. Combination of a cyclo-oxygenase-2 inhibitor and a proton-pump inhibitor for prevention of recurrent ulcer bleeding in patients at very high risk: a double-blind, randomised trial. Lancet 369, 1621–1626 (2007). This article presents the first RCT that demonstrated the combination of a COX2 inhibitor and a PPI is the best strategy to reduce the risk of recurrent PUB in patients at very high risk (that is, those who have had a previous ulcer bleeding event) who need NSAIDs.

    CAS  PubMed  Google Scholar 

  70. Anglin, R. et al. Risk of upper gastrointestinal bleeding with selective serotonin reuptake inhibitors with or without concurrent nonsteroidal anti-inflammatory use: a systematic review and meta-analysis. Am. J. Gastroenterol. 109, 811–819 (2014).

    CAS  PubMed  Google Scholar 

  71. Bhatt, D. L. et al. Clopidogrel with or without omeprazole in coronary artery disease. N. Engl. J. Med. 363, 1909–1917 (2010). This is the only double-blind RCT that tested both cardiovascular and gastrointestinal events in patients who receive clopidogrel plus LDA and omeprazole versus clopidogrel and LDA. Omeprazole reduced the number of gastrointestinal events and did not increase the risk of cardiovascular events.

    CAS  PubMed  Google Scholar 

  72. Lanas-Gimeno, A. & Lanas, A. Risk of gastrointestinal bleeding during anticoagulant treatment. Expert Opin. Drug Saf 16, 673–685 (2017).

    CAS  PubMed  Google Scholar 

  73. Nuki, Y. et al. The influence of CYP2C19 polymorphisms on exacerbating effect of rabeprazole in celecoxib-induced small bowel injury. Aliment. Pharmacol. Ther. 46, 331–336 (2017).

    CAS  PubMed  Google Scholar 

  74. Moayyedi, P. M. et al. ACG and CAG Clinical Guideline: Management of Dyspepsia. Am. J. Gastroenterol. 112, 988–1013 (2017).

    CAS  PubMed  Google Scholar 

  75. Malfertheiner, P. et al. Management of Helicobacter pylori infection-the Maastricht V/Florence Consensus Report. Gut 66, 6–30 (2017).

    CAS  PubMed  Google Scholar 

  76. Huang, T. C. & Lee, C. L. Diagnosis, treatment, and outcome in patients with bleeding peptic ulcers and Helicobacter pylori infections. Biomed. Res. Int. 2014, 658108 (2014).

    PubMed  PubMed Central  Google Scholar 

  77. Srygley, F. D., Gerardo, C. J., Tran, T. & Fisher, D. A. Does this patient have a severe upper gastrointestinal bleed? JAMA 307, 1072–1079 (2012).

    CAS  PubMed  Google Scholar 

  78. Barkun, A. et al. International consensus recommendations on the management of patients with nonvariceal upper gastrointestinal bleeding. Ann. Intern. Med. 152, 101–113 (2010).

    PubMed  Google Scholar 

  79. Shrestha, M. P., Borgstrom, M. & Trowers, E. Digital rectal examination reduces hospital admissions, endoscopies, and medical therapy in patients with acute gastrointestinal bleeding. Am. J. Med. 130, 819–825 (2017).

    PubMed  Google Scholar 

  80. Stanley, A. J. et al. Comparison of risk scoring systems for patients presenting with upper gastrointestinal bleeding: international multicentre prospective study. BMJ 356, i6432 (2017). This prospective study of 3,012 consecutive patients analysed the predictive accuracy and clinical utility of five risk-scoring systems in the assessment of patients with NVUGIB. The GBS was the best of all, showing high accuracy at predicting the need for hospital-based intervention or death.

    PubMed  PubMed Central  Google Scholar 

  81. Wolf, A. T., Wasan, S. K. & Saltzman, J. R. Impact of anticoagulation on rebleeding following endoscopic therapy for nonvariceal upper gastrointestinal hemorrhage. Am. J. Gastroenterol. 102, 290–296 (2007).

    PubMed  Google Scholar 

  82. Jairath, V. et al. Outcomes following acute nonvariceal upper gastrointestinal bleeding in relation to time to endoscopy: results from a nationwide study. Endoscopy 44, 723–730 (2012).

    CAS  PubMed  Google Scholar 

  83. Hearnshaw, S. A. et al. Use of endoscopy for management of acute upper gastrointestinal bleeding in the UK: results of a nationwide audit. Gut 59, 1022–1029 (2010).

    PubMed  Google Scholar 

  84. Sarin, N., Monga, N. & Adams, P. C. Time to endoscopy and outcomes in upper gastrointestinal bleeding. Can. J. Gastroenterol. 23, 489–493 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Targownik, L. E., Murthy, S., Keyvani, L. & Leeson, S. The role of rapid endoscopy for high-risk patients with acute nonvariceal upper gastrointestinal bleeding. Can. J. Gastroenterol. 21, 425–429 (2007).

    PubMed  PubMed Central  Google Scholar 

  86. Tai, C. M. et al. High-risk ED patients with nonvariceal upper gastrointestinal hemorrhage undergoing emergency or urgent endoscopy: a retrospective analysis. Am. J. Emerg. Med. 25, 273–278 (2007).

    PubMed  Google Scholar 

  87. Spiegel, B. M., Vakil, N. B. & Ofman, J. J. Endoscopy for acute nonvariceal upper gastrointestinal tract hemorrhage: is sooner better? A systematic review. Arch. Intern. Med. 161, 1393–1404 (2001).

    CAS  PubMed  Google Scholar 

  88. Tsoi, K. K., Ma, T. K. & Sung, J. J. Endoscopy for upper gastrointestinal bleeding: how urgent is it? Nat. Rev. Gastroenterol. Hepatol. 6, 463–469 (2009).

    PubMed  Google Scholar 

  89. Kumar, N. L., Cohen, A. J., Nayor, J., Claggett, B. L. & Saltzman, J. R. Timing of upper endoscopy influences outcomes in patients with acute nonvariceal upper GI bleeding. Gastrointest. Endosc. 85, 945–952.e1 (2017).

    PubMed  Google Scholar 

  90. Forrest, J. A., Finlayson, N. D. & Shearman, D. J. Endoscopy in gastrointestinal bleeding. Lancet 2, 394–397 (1974).

    CAS  PubMed  Google Scholar 

  91. Heldwein, W., Schreiner, J., Pedrazzoli, J. & Lehnert, P. Is the Forrest classification a useful tool for planning endoscopic therapy of bleeding peptic ulcers? Endoscopy 21, 258–262 (1989).

    CAS  PubMed  Google Scholar 

  92. Lau, J. Y. et al. The evolution of stigmata of hemorrhage in bleeding peptic ulcers: a sequential endoscopic study. Endoscopy 30, 513–518 (1998).

    CAS  PubMed  Google Scholar 

  93. Lau, J. Y. et al. Stigmata of hemorrhage in bleeding peptic ulcers: an interobserver agreement study among international experts. Gastrointest. Endosc. 46, 33–36 (1997).

    CAS  PubMed  Google Scholar 

  94. Laine, L. & McQuaid, K. R. Endoscopic therapy for bleeding ulcers: an evidence-based approach based on meta-analyses of randomized controlled trials. Clin. Gastroenterol. Hepatol. 7, 33–47 (2009). This meta-analysis of RCTs determined the best endoscopic treatment of patients with bleeding ulcers.

    PubMed  Google Scholar 

  95. Sung, J. J. et al. The effect of endoscopic therapy in patients receiving omeprazole for bleeding ulcers with nonbleeding visible vessels or adherent clots: a randomized comparison. Ann. Intern. Med. 139, 237–243 (2003).

    CAS  PubMed  Google Scholar 

  96. Jensen, D. M. et al. Randomized trial of medical or endoscopic therapy to prevent recurrent ulcer hemorrhage in patients with adherent clots. Gastroenterology 123, 407–413 (2002).

    PubMed  Google Scholar 

  97. Jensen, D. M. et al. Doppler endoscopic probe as a guide to risk stratification and definitive hemostasis of peptic ulcer bleeding. Gastrointest. Endosc. 83, 129–136 (2016).

    PubMed  Google Scholar 

  98. Jensen, D. M. et al. Reassessment of rebleeding risk of Forrest IB (oozing) peptic ulcer bleeding in a large international randomized trial. Am. J. Gastroenterol. 112, 441–446 (2017).

    PubMed  PubMed Central  Google Scholar 

  99. Jensen, D. M. et al. Doppler endoscopic probe monitoring of blood flow improves risk stratification and outcomes of patients with severe nonvariceal upper gastrointestinal hemorrhage. Gastroenterology 152, 1310–1318.e1 (2017).

    PubMed  PubMed Central  Google Scholar 

  100. Fujishiro, M. et al. Current managements and outcomes of peptic and artificial ulcer bleeding in Japan. Dig. Endosc. 22 (Suppl. 1), S9–S14 (2010).

    PubMed  Google Scholar 

  101. Fujishiro, M. et al. Guidelines for endoscopic management of non-variceal upper gastrointestinal bleeding. Dig. Endosc. 28, 363–378 (2016).

    PubMed  Google Scholar 

  102. El Ouali, S. et al. Is routine second-look endoscopy effective after endoscopic hemostasis in acute peptic ulcer bleeding? A meta-analysis. Gastrointest. Endosc. 76, 283–292 (2012). This meta-analysis of randomized trials concluded that in unselected patients and in the era of high-dose PPI, second-look endoscopy does not offer significant benefit.

    PubMed  Google Scholar 

  103. Imperiale, T. F. & Kong, N. Second-look endoscopy for bleeding peptic ulcer disease: a decision-effectiveness and cost-effectiveness analysis. J. Clin. Gastroenterol. 46, e71–e75 (2012).

    PubMed  PubMed Central  Google Scholar 

  104. Villanueva, C. et al. Transfusion strategies for acute upper gastrointestinal bleeding. N. Engl. J. Med. 368, 11–21 (2013). This seminal study shows that, compared with a liberal blood transfusion policy, a restrictive blood transfusion policy in patients with UGIB is associated with better survival.

    CAS  PubMed  Google Scholar 

  105. Leontiadis, G. I. et al. Systematic reviews of the clinical effectiveness and cost-effectiveness of proton pump inhibitors in acute upper gastrointestinal bleeding. Health Technol. Assess. 11, 1–164 (2007).

    Google Scholar 

  106. Sreedharan, A. et al. Proton pump inhibitor treatment initiated prior to endoscopic diagnosis in upper gastrointestinal bleeding. Cochrane Database Syst. Rev. 7, CD005415 (2010).

    Google Scholar 

  107. Al-Sabah, S. et al. Cost-effectiveness of proton-pump inhibition before endoscopy in upper gastrointestinal bleeding. Clin. Gastroenterol. Hepatol. 6, 418–425 (2008).

    PubMed  Google Scholar 

  108. Theivanayagam, S. et al. Administration of erythromycin before endoscopy in upper gastrointestinal bleeding: a meta-analysis of randomized controlled trials. Saudi J. Gastroenterol. 19, 205–210 (2013).

    PubMed  PubMed Central  Google Scholar 

  109. Barkun, A. N., Martel, M., Toubouti, Y., Rahme, E. & Bardou, M. Endoscopic hemostasis in peptic ulcer bleeding for patients with high-risk lesions: a series of meta-analyses. Gastrointest. Endosc. 69, 786–799 (2009).

    PubMed  Google Scholar 

  110. Sung, J. J., Tsoi, K. K., Lai, L. H., Wu, J. C. & Lau, J. Y. Endoscopic clipping versus injection and thermo-coagulation in the treatment of non-variceal upper gastrointestinal bleeding: a meta-analysis. Gut 56, 1364–1373 (2007).

    PubMed  PubMed Central  Google Scholar 

  111. Calvet, X., Vergara, M., Brullet, E., Gisbert, J. P. & Campo, R. Addition of a second endoscopic treatment following epinephrine injection improves outcome in high-risk bleeding ulcers. Gastroenterology 126, 441–450 (2004).

    PubMed  Google Scholar 

  112. Marmo, 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. 102, 279–289 (2007).

    PubMed  Google Scholar 

  113. Vergara, M., Bennett, C., Calvet, X. & Gisbert, J. P. Epinephrine injection versus epinephrine injection and a second endoscopic method in high-risk bleeding ulcers. Cochrane Database Syst. Rev. 2, CD005584 (2014).

    Google Scholar 

  114. Hwang, J. H. et al. The role of endoscopy in the management of acute non-variceal upper GI bleeding. Gastrointest. Endosc. 75, 1132–1138 (2012).

    PubMed  Google Scholar 

  115. Fujishiro, M. et al. Retrospective multicenter study concerning electrocautery forceps with soft coagulation for nonmalignant gastroduodenal ulcer bleeding in Japan. Dig. Endosc. 22 (Suppl. 1), S15–S18 (2010).

    PubMed  Google Scholar 

  116. Wedi, E. et al. Use of the over-the-scope-clip (OTSC) in non-variceal upper gastrointestinal bleeding in patients with severe cardiovascular comorbidities: a retrospective study. Endosc. Int. Open 5, E875–E882 (2017).

    PubMed  PubMed Central  Google Scholar 

  117. Prei, J. C. et al. EndoClot polysaccharide hemostatic system in nonvariceal gastrointestinal bleeding: results of a prospective multicenter observational pilot study. J. Clin. Gastroenterol. 50, e95–e100 (2016).

    PubMed  Google Scholar 

  118. Haddara, S. et al. A novel hemostatic powder for upper gastrointestinal bleeding: a multicenter study (the “GRAPHE” registry). Endoscopy 48, 1084–1095 (2016).

    PubMed  Google Scholar 

  119. Lecleire, S. et al. Endoscopic band ligation could decrease recurrent bleeding in Mallory-Weiss syndrome as compared to haemostasis by hemoclips plus epinephrine. Aliment. Pharmacol. Ther. 30, 399–405 (2009).

    CAS  PubMed  Google Scholar 

  120. Yamaguchi, Y. et al. Endoscopic hemoclipping for upper GI bleeding due to Mallory-Weiss syndrome. Gastrointest. Endosc. 53, 427–430 (2001).

    CAS  PubMed  Google Scholar 

  121. Silverstein, F. E. et al. Argon versus neodymium YAG laser photocoagulation of experimental canine gastric ulcers. Gastroenterology 77, 491–496 (1979).

    CAS  PubMed  Google Scholar 

  122. Kwan, V. et al. Argon plasma coagulation in the management of symptomatic gastrointestinal vascular lesions: experience in 100 consecutive patients with long-term follow-up. Am. J. Gastroenterol. 101, 58–63 (2006).

    CAS  PubMed  Google Scholar 

  123. Sargeant, I. R., Loizou, L. A., Rampton, D., Tulloch, M. & Bown, S. G. Laser ablation of upper gastrointestinal vascular ectasias: long term results. Gut 34, 470–475 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  124. Zulli, C. et al. Refractory gastric antral vascular ectasia: a new endoscopic approach. Eur. Rev. Med. Pharmacol. Sci. 19, 4119–4122 (2015).

    CAS  PubMed  Google Scholar 

  125. Maida, M., Camilleri, S., Manganaro, M., Garufi, S. & Scarpulla, G. Radiofrequency ablation for treatment of refractory gastric antral vascular ectasia: a systematic review of the literature. Gastroenterol. Res. Pract. 2017, 5609647 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. Park, C. H. et al. A prospective, randomized trial of endoscopic band ligation versus endoscopic hemoclip placement for bleeding gastric Dieulafoy's lesions. Endoscopy 36, 677–681 (2004).

    CAS  PubMed  Google Scholar 

  127. Chaimoff, C., Creter, D. & Djaldetti, M. The effect of pH on platelet and coagulation factor activities. Am. J. Surg. 136, 257–259 (1978).

    CAS  PubMed  Google Scholar 

  128. Vorder Bruegge, W. F. & Peura, D. A. Stress-related mucosal damage: review of drug therapy. J. Clin. Gastroenterol. 12 (Suppl. 2), S35–S40 (1990).

    PubMed  Google Scholar 

  129. Peterson, K. & Bjorkman, D. J. Editorial: Intravenous proton pump inhibitors for bleeding peptic ulcer: what is the most cost-effective approach? Am. J. Gastroenterol. 111, 1399–1401 (2016).

    PubMed  Google Scholar 

  130. Lu, Y., Adam, V., Teich, V. & Barkun, A. Timing or dosing of intravenous proton pump inhibitors in acute upper gastrointestinal bleeding has low impact on costs. Am. J. Gastroenterol. 111, 1389–1398 (2016).

    CAS  PubMed  Google Scholar 

  131. Sachar, H., Vaidya, K. & Laine, L. Intermittent versus continuous proton pump inhibitor therapy for high-risk bleeding ulcers: a systematic review and meta-analysis. JAMA Intern. Med. 174, 1755–1762 (2014). This meta-analysis of available RCTs shows that intermittent PPI therapy is comparable to the current guideline-recommended regimen of intravenous bolus plus a continuous infusion in patients with endoscopically treated high-risk bleeding ulcers.

    PubMed  PubMed Central  Google Scholar 

  132. Jian, Z. et al. Is the era of intravenous proton pump inhibitors coming to an end in patients with bleeding peptic ulcers? Meta-analysis of the published literature. Br. J. Clin. Pharmacol. 82, 880–889 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  133. Jaspersen, D. et al. Helicobacter pylori eradication reduces the rate of rebleeding in ulcer hemorrhage. Gastrointest. Endosc. 41, 5–7 (1995).

    CAS  PubMed  Google Scholar 

  134. Gisbert, J. P. et al. H. pylori eradication therapy versus antisecretory non-eradication therapy (with or without long-term maintenance antisecretory therapy) for the prevention of recurrent bleeding from peptic ulcer. Cochrane Database Syst. Rev. 2, CD004062 (2004).

    Google Scholar 

  135. Sung, J. J. et al. Intravenous esomeprazole for prevention of recurrent peptic ulcer bleeding: a randomized trial. Ann. Intern. Med. 150, 455–464 (2009).

    PubMed  Google Scholar 

  136. Yuan, J. Q. et al. Systematic review with network meta-analysis: comparative effectiveness and safety of strategies for preventing NSAID-associated gastrointestinal toxicity. Aliment. Pharmacol. Ther. 43, 1262–1275 (2016).

    CAS  PubMed  Google Scholar 

  137. Lau, J. Y. et al. Endoscopic retreatment compared with surgery in patients with recurrent bleeding after initial endoscopic control of bleeding ulcers. N. Engl. J. Med. 340, 751–756 (1999).

    CAS  PubMed  Google Scholar 

  138. Kyaw, M., Tse, Y., Ang, D., Ang, T. L. & Lau, J. Embolization versus surgery for peptic ulcer bleeding after failed endoscopic hemostasis: a meta-analysis. Endosc. Int. Open 2, E6–E14 (2014).

    PubMed  PubMed Central  Google Scholar 

  139. Beggs, A. D., Dilworth, M. P., Powell, S. L., Atherton, H. & Griffiths, E. A. A systematic review of transarterial embolization versus emergency surgery in treatment of major nonvariceal upper gastrointestinal bleeding. Clin. Exp. Gastroenterol. 7, 93–104 (2014).

    PubMed  PubMed Central  Google Scholar 

  140. Sung, J. J. et al. Early clinical experience of the safety and effectiveness of Hemospray in achieving hemostasis in patients with acute peptic ulcer bleeding. Endoscopy 43, 291–295 (2011).

    CAS  PubMed  Google Scholar 

  141. Smith, L. A. et al. Hemospray application in nonvariceal upper gastrointestinal bleeding: results of the Survey to Evaluate the Application of Hemospray in the Luminal Tract. J. Clin. Gastroenterol. 48, e89–92 (2014).

    PubMed  Google Scholar 

  142. Manta, R. et al. Over-the-scope clip (OTSC) represents an effective endoscopic treatment for acute GI bleeding after failure of conventional techniques. Surg. Endosc. 27, 3162–3164 (2013).

    PubMed  Google Scholar 

  143. Manno, M. et al. First-line endoscopic treatment with OTSC in patients with high-risk non-variceal upper gastrointestinal bleeding: preliminary experience in 40 cases. Surg. Endosc. 30, 2026–2029 (2016).

    PubMed  Google Scholar 

  144. Sung, J. J. et al. Continuation of low-dose aspirin therapy in peptic ulcer bleeding: a randomized trial. Ann. Intern. Med. 152, 1–9 (2010). This RCT is the first to show that, compared with withholding LDA, continuation and no interruption of LDA in patients who develop NVUGIB is associated with a lower 30-day mortality (mostly owing to cardiovascular events) at the expense of a minor and nonsignificant increase of gastrointestinal bleeding.

  145. Derogar, M. et al. Discontinuation of low-dose aspirin therapy after peptic ulcer bleeding increases risk of death and acute cardiovascular events. Clin. Gastroenterol. Hepatol. 11, 38–42 (2013).

    CAS  PubMed  Google Scholar 

  146. Kim, S. Y. et al. Risk of vascular thrombotic events following discontinuation of antithrombotics after peptic ulcer bleeding. J. Clin. Gastroenterol. 50, e40–e44 (2016).

    CAS  PubMed  Google Scholar 

  147. Burger, W., Chemnitius, J. M., Kneissl, G. D. & Rücker, G. 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. 257, 399–414 (2005).

    CAS  PubMed  Google Scholar 

  148. Choudari, C. P., Rajgopal, C. & Palmer, K. R. Acute gastrointestinal haemorrhage in anticoagulated patients: diagnoses and response to endoscopic treatment. Gut 35, 464–466 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  149. Rubin, T. A., Murdoch, M. & Nelson, D. B. Acute GI bleeding in the setting of supratherapeutic international normalized ratio in patients taking warfarin: endoscopic diagnosis, clinical management, and outcomes. Gastrointest. Endosc. 58, 369–373 (2003).

    PubMed  Google Scholar 

  150. Peloquin, J. M. et al. Diagnostic and therapeutic yield of endoscopy in patients with elevated INR and gastrointestinal bleeding. Am. J. Med. 129, 628–634 (2016).

    PubMed  Google Scholar 

  151. Holbrook, A. 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 141 (Suppl.), e152S–e184S (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  152. Britt, R. B. & Brown, J. N. Characterizing the severe reactions of parenteral vitamin K1. Clin. Appl. Thromb. Hemost 24, 5–12 (2018).

    CAS  PubMed  Google Scholar 

  153. Dhakal, P., Rayamajhi, S., Verma, V., Gundabolu, K. & Bhatt, V. R. Reversal of anticoagulation and management of bleeding in patients on anticoagulants. Clin. Appl. Thromb. Hemost. 23, 410–415 (2017).

    CAS  PubMed  Google Scholar 

  154. Chai-Adisaksopha, C. et al. Prothrombin complex concentrates versus fresh frozen plasma for warfarin reversal. A systematic review and meta-analysis. Thromb. Haemost. 116, 879–890 (2016).

    PubMed  Google Scholar 

  155. Voils, S. A. & Baird, B. Systematic review: 3-factor versus 4-factor prothrombin complex concentrate for warfarin reversal: does it matter? Thromb. Res. 130, 833–840 (2012).

    CAS  PubMed  Google Scholar 

  156. Voils, S. A., Holder, M. C., Premraj, S., Catlin, J. R. & Allen, B. R. Comparative effectiveness of 3- versus 4-factor prothrombin complex concentrate for emergent warfarin reversal. Thromb. Res. 136, 595–598 (2015).

    CAS  PubMed  Google Scholar 

  157. Kuroski, J. E. & Young, S. Comparison of the safety and efficacy between 3-factor and 4-factor prothrombin complex concentrates for the reversal of warfarin. Am. J. Emergency Med. 35, 871–874 (2017).

    Google Scholar 

  158. Majeed, A. et al. Management and outcomes of major bleeding during treatment with dabigatran or warfarin. Circulation 128, 2325–2332 (2013).

    CAS  PubMed  Google Scholar 

  159. Steiner, T., Rosand, J. & Diringer, M. Intracerebral hemorrhage associated with oral anticoagulant therapy: current practices and unresolved questions. Stroke 37, 256–262 (2006).

    CAS  PubMed  Google Scholar 

  160. Zatta, A. et al. The Australian and New Zealand Haemostasis Registry: ten years of data on off-licence use of recombinant activated factor VII. Blood Transfus 13, 86–99 (2015).

    PubMed  PubMed Central  Google Scholar 

  161. Witt, D. M., Clark, N. P., Kaatz, S., Schnurr, T. & Ansell, J. E. Guidance for the practical management of warfarin therapy in the treatment of venous thromboembolism. J. Thromb. Thrombolysis 41, 187–205 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  162. Makris, M. et al. Guideline on the management of bleeding in patients on antithrombotic agents. Br. J. Haematol. 160, 35–46 (2013).

    CAS  PubMed  Google Scholar 

  163. Radaelli, F. et al. Management of anticoagulation in patients with acute gastrointestinal bleeding. Dig. Liver Dis. 47, 621–627 (2015).

    PubMed  Google Scholar 

  164. Lubetsky, A. et al. Comparison of oral versus intravenous phytonadione (vitamin K1) in patients with excessive anticoagulation: a prospective randomized controlled study. Arch. Intern. Med. 163, 2469–2473 (2003).

    CAS  PubMed  Google Scholar 

  165. Heublein, V., Pannach, S., Daschkow, K., Tittl, L. & Beyer-Westendorf, J. Gastrointestinal endoscopy in patients receiving novel direct oral anticoagulants: results from the prospective Dresden NOAC registry. J. Gastroenterol. 53, 236–246 (2018).

    PubMed  Google Scholar 

  166. Bouget, J. & Oger, E. Emergency admissions for major haemorrhage associated with direct oral anticoagulants. Thromb. Res. 136, 1190–1194 (2015).

    CAS  PubMed  Google Scholar 

  167. Abraham, N. S. & Horsley-Silva, J. L. Gastrointestinal bleeding secondary to the new anticoagulants. Curr. Opin. Gastroenterol. 32, 474–480 (2016).

    CAS  PubMed  Google Scholar 

  168. Liesenfeld, K.-H., 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. 56, 597–608 (2016).

    CAS  PubMed  Google Scholar 

  169. van Ryn, J., Sieger, P., Kink-Eiband, M., Gansser, D. & Clemens, A. Adsorption of dabigatran etexilate in water or dabigatran in pooled human plasma by activated charcoal in vitro. Blood 114, 1065–1065 (2009).

    Google Scholar 

  170. Wang, X. et al. Effect of activated charcoal on apixaban pharmacokinetics in healthy subjects. Am. J. Cardiovasc. Drugs 14, 147–154 (2013).

    CAS  PubMed Central  Google Scholar 

  171. Pollack, C. V. et al. Idarucizumab for dabigatran reversal — full cohort analysis. N. Engl. J. Med. 377, 431–441 (2017). This large cohort study is the first to show the high efficacy and safety of the infusion of idarucizumab for dabigatran reversal in patients who had either uncontrolled bleeding or the need to undergo an urgent procedure.

    CAS  PubMed  Google Scholar 

  172. Dager, W. E. & Banares, L. Reversing the anticoagulation effects of dabigatran. Hosp. Pract. 45, 29–38 (2017).

    Google Scholar 

  173. Schulman, S. et al. Reversal of dabigatran-associated major bleeding with activated prothrombin concentrate: a prospective cohort study. Thromb. Res. 152, 44–48 (2017).

    CAS  PubMed  Google Scholar 

  174. Zahir, H. et al. Edoxaban effects on bleeding following punch biopsy and reversal by a 4-factor prothrombin complex concentrate. Circulation 131, 82–90 (2015).

    CAS  PubMed  Google Scholar 

  175. Deutsch, D. et al. Direct oral anticoagulants and digestive bleeding: therapeutic management and preventive measures. Therap. Adv. Gastroenterol. 10, 495–505 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  176. Heidbuchel, H. 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. 38, 2137–2149 (2017).

    CAS  PubMed  Google Scholar 

  177. Rottenstreich, A., Jahshan, N., Avraham, L. & Kalish, Y. Idarucizumab for dabigatran reversal — does one dose fit all? Thromb. Res. 146, 103–104 (2016).

    CAS  PubMed  Google Scholar 

  178. Connolly, S. J. et al. Andexanet alfa for acute major bleeding associated with factor Xa inhibitors. N. Engl. J. Med. 375, 1131–1141 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  179. Ansell, J. E. et al. Single-dose ciraparantag safely and completely reverses anticoagulant effects of edoxaban. Thromb. Haemost. 117, 238–245 (2017).

    PubMed  PubMed Central  Google Scholar 

  180. Chatterjee, P. & Weitz, J. I. Assessment and management of gastrointestinal hemorrhage in the setting of direct oral anticoagulants: the hematology perspective. Am. J. Gastroenterol. Suppl. 3, 29–35 (2016).

    CAS  Google Scholar 

  181. Qureshi, W. T. & Nasir, U. Restarting oral anticoagulation among patients with atrial fibrillation with gastrointestinal bleeding was associated with lower risk of all-cause mortality and thromboembolism. Evid. Based Med. 21, 152 (2016).

    PubMed  Google Scholar 

  182. Zulkifly, H., Lip, G. Y. H. & Lane, D. A. Bleeding risk scores in atrial fibrillation and venous thromboembolism. Am. J. Cardiol. 120, 1139–1145 (2017).

    PubMed  Google Scholar 

  183. Scott, M. J., Veitch, A. & Thachil, J. Reintroduction of anti-thrombotic therapy after a gastrointestinal haemorrhage: if and when? Br. J. Haematol. 177, 185–197 (2017).

    PubMed  Google Scholar 

  184. Staerk, L. et al. Stroke and recurrent haemorrhage associated with antithrombotic treatment after gastrointestinal bleeding in patients with atrial fibrillation: nationwide cohort study. BMJ 351, h5876 (2015).

    PubMed  PubMed Central  Google Scholar 

  185. Hernandez, I., Zhang, Y., Brooks, M. M., Chin, P. K. L. & Saba, S. Anticoagulation use and clinical outcomes after major bleeding on dabigatran or warfarin in atrial fibrillation. Stroke 48, 159–166 (2017).

    CAS  PubMed  Google Scholar 

  186. Qureshi, W. et al. Restarting anticoagulation and outcomes after major gastrointestinal bleeding in atrial fibrillation. Am. J. Cardiol. 113, 662–668 (2014).

    CAS  PubMed  Google Scholar 

  187. Lip, G. Y. H. et al. Antithrombotic therapy in atrial fibrillation associated with valvular heart disease: a joint consensus document from the European Heart Rhythm Association (EHRA) and European Society of Cardiology Working Group on Thrombosis, endorsed by the ESC Working Group on Valvular Heart Disease, Cardiac Arrhythmia Society of Southern Africa (CASSA), Heart Rhythm Society (HRS), Asia Pacific Heart Rhythm Society (APHRS), South African Heart (SA Heart) Association and Sociedad Latinoamericana de Estimulación Cardíaca y Electrofisiología (SOLEACE). Europace 19, 1757–1758 (2017).

    PubMed  Google Scholar 

  188. Bager, P. & Dahlerup, J. F. Patient-reported outcomes after acute nonvariceal upper gastrointestinal hemorrhage. Scand. J. Gastroenterol. 49, 909–916 (2014).

    PubMed  Google Scholar 

  189. Sousa, K. H. & Williamson, A. Symptom status and health-related quality of life: clinical relevance. J. Adv. Nurs. 42, 571–577 (2003).

    PubMed  Google Scholar 

  190. Campbell, H. E. et al. Costs and quality of life associated with acute upper gastrointestinal bleeding in the UK: cohort analysis of patients in a cluster randomised trial. BMJ Open 5, e007230 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  191. World Health Organization. Haemoglobin concentrations for the diagnosis of anaemia and assessment of severity. WHOhttp://www.who.int/vmnis/indicators/haemoglobin/en/ (2011).

  192. Mearin, F. et al. Open questions and misconceptions in the diagnosis and management of anemia in patients with gastrointestinal bleeding. Gastroenterol. Hepatol. 41, 63–76 (2018).

    PubMed  Google Scholar 

  193. Lee, J. M. et al. Discharge hemoglobin and outcome in patients with acute nonvariceal upper gastrointestinal bleeding. Endosc. Int. Open 4, E865–869 (2016).

    PubMed  PubMed Central  Google Scholar 

  194. Bager, P. & Dahlerup, J. F. Lack of follow-up of anaemia after discharge from an upper gastrointestinal bleeding centre. Danish Med. J. 60, A4583 (2013).

    Google Scholar 

  195. Jairath, V. et al. Restrictive versus liberal blood transfusion for acute upper gastrointestinal bleeding (TRIGGER): a pragmatic, open-label, cluster randomised feasibility trial. Lancet 386, 137–144 (2015).

    PubMed  Google Scholar 

  196. Bager, P. & Dahlerup, J. F. Randomised clinical trial: oral versus intravenous iron after upper gastrointestinal haemorrhage — a placebo-controlled study. Aliment. Pharmacol. Ther. 39, 176–187 (2014).

    CAS  PubMed  Google Scholar 

  197. De Franceschi, L., Iolascon, A., Taher, A. & Cappellini, M. D. Clinical management of iron deficiency anemia in adults: systemic review on advances in diagnosis and treatment. Eur. J. Intern. Med. 42, 16–23 (2017).

    CAS  PubMed  Google Scholar 

  198. Hunt, R. H. & Scarpignato, C. Potassium-competitive acid blockers (P-CABs): are they finally ready for prime time in acid-related disease? Clin. Transl Gastroenterol. 6, e119 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  199. Casado-Arroyo, R. et al. Underutilization of gastroprotection for at-risk patients undergoing percutaneous coronary intervention: Spain compared with the United States. Aliment. Pharmacol. Ther. 32, 689–695 (2010).

    CAS  PubMed  Google Scholar 

  200. Lanas, A. et al. Variability in the management of nonvariceal upper gastrointestinal bleeding in Europe: an observational study. Adv. Ther. 29, 1026–1036 (2012).

    PubMed  Google Scholar 

  201. Ardevol, A. et al. Survival of patients with cirrhosis and acute peptic ulcer bleeding compared with variceal bleeding using current first-line therapies. Hepatologyhttps://doi.org/10.1002/hep.29370 (2018).

    CAS  PubMed  Google Scholar 

  202. Mallet, M., Rudler, M. & Thabut, D. Variceal bleeding in cirrhotic patients. Gastroenterol. Rep. 5, 185–192 (2017).

    Google Scholar 

  203. Hunt, R. H. & Bazzoli, F. Review article: should NSAID/low-dose aspirin takers be tested routinely for H. pylori infection and treated if positive? Implications for primary risk of ulcer and ulcer relapse after initial healing. Aliment. Pharmacol. Ther. 19 (Suppl. 1), 9–16 (2004).

    PubMed  Google Scholar 

  204. Lanas, Á. et al. Risk of upper and lower gastrointestinal bleeding in patients taking nonsteroidal anti-inflammatory drugs, antiplatelet agents, or anticoagulants. Clin. Gastroenterol. Hepatol. 13, 906–912.e2 (2015).

    PubMed  Google Scholar 

  205. Chan, F. K. et al. Eradication of Helicobacter pylori and risk of peptic ulcers in patients starting long-term treatment with non-steroidal anti-inflammatory drugs: a randomised trial. Lancet 359, 9–13 (2002).

    CAS  PubMed  Google Scholar 

  206. Scarpignato, C. & Hunt, R. H. Nonsteroidal antiinflammatory drug-related injury to the gastrointestinal tract: clinical picture, pathogenesis, and prevention. Gastroenterol. Clin. North Am. 39, 433–464 (2010).

    PubMed  Google Scholar 

  207. Blatchford, O., Murray, W. R. & Blatchford, M. A risk score to predict need for treatment for upper-gastrointestinal haemorrhage. Lancet 356, 1318–1321 (2000).

    CAS  PubMed  Google Scholar 

  208. Rockall, T. A., Logan, R. F., Devlin, H. B. & Northfield, T. C. Incidence of and mortality from acute upper gastrointestinal haemorrhage in the United Kingdom. Steering Committee and members of the National Audit of Acute Upper Gastrointestinal Haemorrhage. BMJ 311, 222–226 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  209. Hyett, B. H. et al. The AIMS65 score compared with the Glasgow-Blatchford score in predicting outcomes in upper GI bleeding. Gastrointest. Endosc. 77, 551–557 (2013).

    PubMed  Google Scholar 

  210. Saltzman, J. R. et al. A simple risk score accurately predicts in-hospital mortality, length of stay, and cost in acute upper GI bleeding. Gastrointest. Endosc. 74, 1215–1224 (2011).

    PubMed  Google Scholar 

  211. Marmo, R. et al. Predicting mortality in non-variceal upper gastrointestinal bleeders: validation of the Italian PNED score and prospective comparison with the Rockall score. Am. J. Gastroenterol. 105, 1284–1291 (2010).

    PubMed  Google Scholar 

  212. Rockall, T. A., Logan, R. F., Devlin, H. B. & Northfield, T. C. Risk assessment after acute upper gastrointestinal haemorrhage. Gut 38, 316–321 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  213. Adcock, D. M. & Gosselin, R. Direct Oral anticoagulantDOACs) in the laboratory: 2015 review. Thromb. Res. 136, 7–12 (2015).

    CAS  PubMed  Google Scholar 

  214. Gosselin, R. C. et al. Evaluating the use of commercial drug-specific calibrators for determining PT and APTT reagent sensitivity to dabigatran and rivaroxaban. Thromb. Haemost. 113, 77–84 (2015).

    CAS  PubMed  Google Scholar 

  215. The American Society of Hemotology. Clinical practice guide on antithrombotic drug dosing and management of antithrombotic drug-associated bleeding complications in adults. Clot Connecthttp://files.www.clotconnect.org/healthcare-professionals/resources-for-health-care-professionals/AnticoagPocketGuide-1.pdf (2014).

  216. Bonar, R. et al. The effect of the direct factor Xa inhibitors apixaban and rivaroxaban on haemostasis tests: a comprehensive assessment using in vitro and ex vivo samples. Pathology 48, 60–71 (2016).

    CAS  PubMed  Google Scholar 

  217. Douxfils, J. & Gosselin, R. C. Laboratory assessment of direct oral anticoagulants. Semin. Thromb. Hemost. 43, 277–290 (2017).

    CAS  PubMed  Google Scholar 

  218. Lanas, A. et al. Time trends and impact of upper and lower gastrointestinal bleeding and perforation in clinical practice. Am. J. Gastroenterol. 104, 1633–1641 (2009).

    PubMed  Google Scholar 

  219. Pérez-Aisa, M. A., Del Pino, D., Siles, M. & Lanas, A. Clinical trends in ulcer diagnosis in a population with high prevalence of Helicobacter pylori infection. Aliment. Pharmacol. Ther. 21, 65–72 (2005).

    PubMed  Google Scholar 

  220. Klein, A. & Gralnek, I. M. Acute, nonvariceal upper gastrointestinal bleeding. Curr. Opin. Crit. Care 21, 154–162 (2015).

    PubMed  Google Scholar 

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Acknowledgements

A.L. declares that his work on this manuscript was partially funded by a grant from the Spanish Instituto de Salud Carlos III PI/PI08/1301 and “Fondo Europeo de Desarrollo Regional (FEDER) de la Unión Europea. – Una manera de hacer Europa –”. The authors thank M. Fujishiro, The University of Tokyo Hospital, for the images used in Fig. 6.

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Introduction (A.L.); Epidemiology (C.V.); Mechanisms/pathophysiology (A.L. and R.H.H.); Diagnosis, screening and prevention (R.H.H., A.L., A.R. and M.F.); Management (J.J.Y.S., I.M.G., J.M.S. and J.-M.D.); Quality of life (H.E.C.); Outlook (all authors); Overview of the Primer (A.L.).

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Correspondence to Angel Lanas.

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A.L. is an adviser to Bayer Healthcare and Bayer AG. J.M.S. is an adviser to Aralez Pharmaceuticals. All other authors declare no competing interest.

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Lanas, A., Dumonceau, JM., Hunt, R. et al. Non-variceal upper gastrointestinal bleeding. Nat Rev Dis Primers 4, 18020 (2018). https://doi.org/10.1038/nrdp.2018.20

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