title: Systematic review with meta-analysis: the risk of major gastrointestinal bleeding with non-vitamin K antagonist oral anticoagulants.
abstract: BACKGROUND
  Gastrointestinal (GI) bleeding is a common complication among anticoagulated patients. Non-vitamin K antagonist oral anticoagulants (NOACs) are associated with increased risk of GI (major and clinically relevant non-major) bleeding. However, more information is needed regarding severe events.
  
  
  OBJECTIVE
  To evaluate the risk of NOACs major GI bleeding.
  
  
  METHODS
  We searched for phase III randomised clinical trials (RCT) evaluating NOACs (apixaban, dabigatran, edoxaban and rivaroxaban) and reporting major GI bleeding events, in MEDLINE, Cochrane Library, SciELO collection and Web of Science databases (July 2015). Meta-analysis was performed to estimate risk ratio (RR) and 95% confidence intervals (95% CIs). Heterogeneity was assessed with the I(2) test.
  
  
  RESULTS
  A total of 23 studies were included. Among patients with atrial fibrillation, the risk of major GI bleeding was not different between NOACs and vitamin K antagonists (VKA) (RR 1.08, 95% CI 0.85-1.36, I(2)  = 78%; 5 RCTs) or acetylsalicylic acid (RR 0.78, 95% CI 0.36-1.72; 1 RCT). Similar results were found for patients undergoing orthopaedic surgery and those with venous thromboembolism. NOACs were not found to increase the risk compared to low-molecular-weight heparin (LWMH) alone (RR 1.42, 95% CI 0.55-3.71, I(2)  = 7%; 8 RCTs), the sequential treatment with LMWH-VKA (RR 0.77, 95% CI 0.49-1.21, I(2)  = 43%; 7 RCTs) or placebo (RR 1.48, 95% CI 0.15-14.84, I(2)  = 21%; 2 RCTs).
  
  
  CONCLUSIONS
  Despite previous evidence supporting the association of non-vitamin K antagonist oral anticoagulants and overall GI bleeding, non-vitamin K antagonist oral anticoagulants are not associated with increased risk of major GI bleeding compared to other anticoagulant drugs (with known increased risk of these events).
authors.affiliation: Clinical Pharmacology Unit, Instituto de Medicina Molecular, Lisbon, Portugal.|Laboratory of Clinical Pharmacology and Therapeutics, Faculty of Medicine, University of Lisbon, Lisbon, Portugal.|Cardiology Department, Hospital Garcia de Orta, Almada, Portugal.
authors.forename: D
authors.identifier: http://orcid.org/0000-0002-2520-5673
authors.initials: D
authors.lastname: Caldeira
authors.affiliation: Clinical Pharmacology Unit, Instituto de Medicina Molecular, Lisbon, Portugal.
authors.forename: M
authors.initials: M
authors.lastname: Barra
authors.affiliation: Clinical Pharmacology Unit, Instituto de Medicina Molecular, Lisbon, Portugal.
authors.forename: A
authors.initials: A
authors.lastname: Ferreira
authors.affiliation: Clinical Pharmacology Unit, Instituto de Medicina Molecular, Lisbon, Portugal.
authors.forename: A
authors.initials: A
authors.lastname: Rocha
authors.affiliation: Clinical Pharmacology Unit, Instituto de Medicina Molecular, Lisbon, Portugal.
authors.forename: A
authors.initials: A
authors.lastname: Augusto
authors.affiliation: Cardiology Department, Faculty of Medicine, CCUL, CAML, Lisbon, Portugal.
authors.forename: F J
authors.initials: FJ
authors.lastname: Pinto
authors.affiliation: Clinical Pharmacology Unit, Instituto de Medicina Molecular, Lisbon, Portugal.|Laboratory of Clinical Pharmacology and Therapeutics, Faculty of Medicine, University of Lisbon, Lisbon, Portugal.|Center for Evidence-Based Medicine, Faculty of Medicine, University of Lisbon, Lisbon, Portugal.|Portuguese Collaborating Center of the IberoAmerican Cochrane Network, Faculty of Medicine, University of Lisbon, Lisbon, Portugal.
authors.forename: J
authors.initials: J
authors.lastname: Costa
authors.affiliation: Clinical Pharmacology Unit, Instituto de Medicina Molecular, Lisbon, Portugal.|Laboratory of Clinical Pharmacology and Therapeutics, Faculty of Medicine, University of Lisbon, Lisbon, Portugal.
authors.forename: J J
authors.initials: JJ
authors.lastname: Ferreira
mesh_terms: D000925:Anticoagulants / Q000008:administration & dosage / Q000009:adverse effects*; D006471:Gastrointestinal Hemorrhage / Q000139:chemically induced*; D006495:Heparin, Low-Molecular-Weight / Q000009:adverse effects* / Q000627:therapeutic use; D006801:Humans; D016017:Odds Ratio; D016032:Randomized Controlled Trials as Topic; D054556:Venous Thromboembolism / Q000188:drug therapy
chemical_list: D000925:Anticoagulants; D006495:Heparin, Low-Molecular-Weight