title: Major Bleeding and Hemorrhagic Stroke With Direct Oral Anticoagulants in Patients With Renal Failure: Systematic Review and Meta-Analysis of Randomized Trials.
abstract: BACKGROUND
  Direct oral anticoagulants (DOACs) are used as an alternative for traditional antithrombotic therapy. However, the safety profile of DOACs in patients with renal failure (RF) has not been determined.
  
  
  METHODS
  A systematic review was performed assessing the reported safety of DOACs compared with vitamin K antagonists (VKAs) in patients with RF and estimated creatinine clearance (eCrCL) < 50 mL/min and eCrCL 50 to 80 mL/min. MEDLINE, EMBASE, Cochrane, and the Clinical Trials Registry (ClinicalTrials.gov) were searched for randomized clinical trials up to November 2015. The data were pooled by using both traditional frequentist and Bayesian random effects models.
  
  
  RESULTS
  Nine trials met the inclusion criteria. Among 94,897 participants, 54,667 (58%) had RF. Compared with VKAs, DOACs were associated with a significantly decreased risk for major bleeding in patients with eCrCL 50 to 80 mL/min (risk ratio, 0.87 [95% CI, 0.81-0.93]) and a nonsignificant decrease in the risk for major bleeding in patients with eCrCL < 50 mL/min (risk ratio, 0.83 [95% CI, 0.68-1.02]); there was evidence of significant heterogeneity. Indirect comparisons, using Bayesian network analysis, indicated that apixaban was associated with a decreased rate of major bleeding compared with other DOACs in patients with eCrCL < 50 mL/min. DOACs were associated with a significant decrease in the risk for hemorrhagic stroke compared with VKAs in patients with eCrCL < 50 mL/min and 50 to 80 mL/min.
  
  
  CONCLUSIONS
  As a class, DOACs are associated with a reduced risk for hemorrhagic stroke compared with VKAs in patients with RF. However, DOACs may differ from each other in their relative risk for major bleeding in patients with eCrCL < 50 mL/min.
  
  
  BACKGROUND
  PROSPERO registry; No.: CRD42014013730; URL: http://www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD42014013730.
authors.affiliation: Division of Clinical Pharmacy, Institute for Drug Research, School of Pharmacy, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel; Department of Cardiology, Hadassah University Hospital, Jerusalem, Israel.
authors.forename: Bruria Hirsh
authors.initials: BH
authors.lastname: Raccah
authors.affiliation: Division of Clinical Pharmacy, Institute for Drug Research, School of Pharmacy, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel; Department of Medicine, Hadassah University Hospital, Jerusalem, Israel.
authors.forename: Amichai
authors.initials: A
authors.lastname: Perlman
authors.affiliation: Department of Cardiology, Hadassah University Hospital, Jerusalem, Israel.
authors.forename: Haim D
authors.initials: HD
authors.lastname: Danenberg
authors.affiliation: Department of Cardiology, Hadassah University Hospital, Jerusalem, Israel.
authors.forename: Arthur
authors.initials: A
authors.lastname: Pollak
authors.affiliation: Department of Medicine, Division of Clinical Pharmacology, Hadassah University Hospital, Jerusalem, Israel.
authors.forename: Mordechai
authors.initials: M
authors.lastname: Muszkat
authors.affiliation: Division of Clinical Pharmacy, Institute for Drug Research, School of Pharmacy, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel. Electronic address: ilan.matok@ekmd.huji.ac.il.
authors.forename: Ilan
authors.initials: I
authors.lastname: Matok
mesh_terms: D000284:Administration, Oral; D000925:Anticoagulants / Q000008:administration & dosage / Q000009:adverse effects; D000991:Antithrombins / Q000008:administration & dosage / Q000009:adverse effects; D006470:Hemorrhage / Q000139:chemically induced / Q000517:prevention & control; D006801:Humans; D020300:Intracranial Hemorrhages / Q000139:chemically induced / Q000517:prevention & control; D016032:Randomized Controlled Trials as Topic; D051437:Renal Insufficiency / Q000150:complications*; D020379:Risk Adjustment / Q000379:methods; D013923:Thromboembolism / Q000209:etiology / Q000517:prevention & control
chemical_list: D000925:Anticoagulants; D000991:Antithrombins
keywords: DVT; antithrombotic therapy; atrial fibrillation; pulmonary embolism; stroke