title: Risk of Substantial Intraocular Bleeding With Novel Oral Anticoagulants: Systematic Review and Meta-analysis.
abstract: OBJECTIVE
  In noninferiority trials, novel oral anticoagulants (NOACs), also known as non-vitamin K oral anticoagulants, were at least noninferior to standard care in the prevention of most prothrombotic conditions. However, differences exist in the safety profile of antithrombotic drugs, and little is known about their intraocular bleeding risk.
  
  
  OBJECTIVE
  To evaluate the risk of substantial intraocular bleeding associated with NOACs.
  
  
  METHODS
  MEDLINE, Cochrane Library, SciELO collection, and Web of Science databases were searched from inception to November 2014, as well as other systematic reviews and regulatory agencies documentation.
  
  
  METHODS
  All phase 3 randomized clinical trials (RCTs) comparing NOACs with any other control that reported intraocular bleeding events.
  
  
  METHODS
  Data were extracted independently by 2 of the authors and pooled using random-effects meta-analysis. Heterogeneity was assessed with the I2 test.
  
  
  METHODS
  Substantial intraocular bleeding was evaluated with pooled risk ratios (RRs) and 95% CIs.
  
  
  RESULTS
  Seventeen RCTs were included. In patients with atrial fibrillation, no difference was identified between NOACs and vitamin K antagonists (RR, 0.84; 95% CI, 0.59-1.19; I2 = 35%; 5 RCTs), and no increased risk was identified compared with acetylsalicylic acid (RR, 14.96; 95% CI, 0.85-262.00; 1 RCT). In patients with venous thromboembolism, no increased risk of substantial intraocular bleeding compared with sequential treatment with low-molecular-weight heparin and a vitamin K antagonist (RR, 0.67; 95% CI, 0.37-1.20; I2 = 0%; 5 RCTs) was identified. Regarding patients who underwent orthopedic surgery, the risk was not different between NOACs and low-molecular-weight heparin (RR, 2.13; 95% CI, 0.22-20.50; I2 = 0%; 5 RCTs).
  
  
  CONCLUSIONS
  Randomized data suggest that no differences exist in the risk of substantial intraocular bleeding between NOACs and other antithrombotic drugs. However, the number of events was scarce so that additional studies from larger databases that monitor patients under conditions of ophthalmologic routine clinical practice should be performed to better characterize the safety profile of NOACs.
authors.affiliation: Clinical Pharmacology Unit, Instituto de Medicina Molecular, Lisbon, Portugal2Laboratory of Clinical Pharmacology and Therapeutics, Faculty of Medicine, University of Lisbon, Lisbon, Portugal3Department of Cardiology, Hospital Garcia de Orta, Almada, Port.
authors.forename: Daniel
authors.initials: D
authors.lastname: Caldeira
authors.affiliation: Department of Ophthalmology, Hospital Santa Maria, Lisbon, Portugal.
authors.forename: Mário
authors.initials: M
authors.lastname: Canastro
authors.affiliation: Laboratory of Clinical Pharmacology and Therapeutics, Faculty of Medicine, University of Lisbon, Lisbon, Portugal.
authors.forename: Márcio
authors.initials: M
authors.lastname: Barra
authors.affiliation: Laboratory of Clinical Pharmacology and Therapeutics, Faculty of Medicine, University of Lisbon, Lisbon, Portugal.
authors.forename: Adriana
authors.initials: A
authors.lastname: Ferreira
authors.affiliation: Clinical Pharmacology Unit, Instituto de Medicina Molecular, Lisbon, Portugal2Laboratory of Clinical Pharmacology and Therapeutics, Faculty of Medicine, University of Lisbon, Lisbon, Portugal5Center for Evidence-Based Medicine, Faculty of Medicine, Univer.
authors.forename: João
authors.initials: J
authors.lastname: Costa
authors.affiliation: Department of Cardiology, Cardiovascular Centre of the University of Lisbon (CCUL), Lisbon Academic Medical Center (CAML), Faculty of Medicine, Lisbon, Portugal.
authors.forename: Fausto J
authors.initials: FJ
authors.lastname: Pinto
authors.affiliation: Clinical Pharmacology Unit, Instituto de Medicina Molecular, Lisbon, Portugal2Laboratory of Clinical Pharmacology and Therapeutics, Faculty of Medicine, University of Lisbon, Lisbon, Portugal.
authors.forename: Joaquim J
authors.initials: JJ
authors.lastname: Ferreira
mesh_terms: D000284:Administration, Oral; D000925:Anticoagulants / Q000009:adverse effects* / Q000627:therapeutic use; D002318:Cardiovascular Diseases / Q000175:diagnosis / Q000188:drug therapy; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005130:Eye Hemorrhage / Q000139:chemically induced* / Q000453:epidemiology* / Q000503:physiopathology; D005260:Female; D006801:Humans; D008297:Male; D015995:Prevalence; D011379:Prognosis; D016032:Randomized Controlled Trials as Topic; D018570:Risk Assessment; D054556:Venous Thromboembolism / Q000188:drug therapy / Q000517:prevention & control*
chemical_list: D000925:Anticoagulants