title: Risk of renal failure with the non-vitamin K antagonist oral anticoagulants: systematic review and meta-analysis.
abstract: OBJECTIVE
  Vitamin K antagonists (VKA)-related nephropathy is a novel entity characterized by acute kidney injury related to International Normalized Ratio supratherapeutic levels. Non-vitamin K antagonists oral anticoagulants (NOACs) have a predictable dose-response relationship and an improved safety profile. We hypothesized that these drugs do not have an increased risk of incident renal failure, which may be detrimental for the use of NOACs.
  
  
  METHODS
  Systematic review and meta-analysis of phase III randomized controlled trials (RCTs). Trials were searched through Medline, Cochrane Library and public assessment reports in August 2014. Primary outcome was renal failure. NOACs were evaluated against any comparator. Random-effects meta-analysis was performed by default, and pooled estimates were expressed as Risk Ratio (RR) and 95%CI. Heterogeneity was evaluated with I(2) test.
  
  
  RESULTS
  Ten RCTs fulfilled inclusion criteria (one apixaban RCT, three dabigatran RCTs, and six rivaroxaban RCTs), enrolling 75 100 patients. Overall NOACs did not increase the risk of renal failure with an RR 0.96, 95%CI 0.88-1.05 compared with VKA or Low-molecular weight heparin (LMWH), without significant statistical heterogeneity (I(2)  = 3.5%). Compared with VKA, NOACs did not increase the risk of renal failure (RR 0.96, 95%CI 0.87-1.07; I(2)  = 17.8%; six RCTs). Rivaroxaban did not show differences in the incidence of renal failure compared with LMWH (RR 1.20, 95%CI 0.37-3.94; four trials), but there was an increased risk of creatinine elevation RR 1.25, 95%CI 1.08-1.45; I(2)  = 0%.
  
  
  CONCLUSIONS
  NOACs had a similar risk of renal failure compared with VKA/LMWH in phase III RCTs. Post-marketing surveillance should be warranted.
authors.affiliation: Clinical Pharmacology Unit, Instituto de Medicina Molecular, Lisbon, Portugal.|Laboratory of Clinical Pharmacology and Therapeutics, Faculty of Medicine, University of Lisbon, Portugal.|Cardiology Department, Hospital Garcia de Orta, Almada, Portugal.
authors.forename: Daniel
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: Nilza
authors.initials: N
authors.lastname: Gonçalves
authors.affiliation: Cardiology Department, CCUL, CAML, Faculty of Medicine, University of Lisbon, Lisbon, Portugal.
authors.forename: Fausto 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, Portugal.|Evidence Based Medicine Centre, Faculty of Medicine, University of Lisbon, Portugal.|Portuguese Collaborating Centre of the Cochrane Iberoamerican Network, Faculty of Medicine, University of Lisbon, Portugal.
authors.forename: João
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, Portugal.
authors.forename: Joaquim J
authors.initials: JJ
authors.lastname: Ferreira
mesh_terms: D000284:Administration, Oral; D000925:Anticoagulants / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D017326:Clinical Trials, Phase III as Topic; D006801:Humans; D019934:International Normalized Ratio; D016032:Randomized Controlled Trials as Topic; D051437:Renal Insufficiency / Q000139:chemically induced*; D018570:Risk Assessment; D014812:Vitamin K / Q000037:antagonists & inhibitors
chemical_list: D000925:Anticoagulants; D014812:Vitamin K
keywords: anti-IIa; anti-Xa; anticoagulants; meta-analysis; pharmacoepidemiology; renal failure