title: Risk of insomnia with non-vitamin K oral anticoagulants: systematic review and meta-analysis.
abstract: OBJECTIVE
  Insomnia is an important adverse event of mechanical thromboprophylaxis. This sleep disorder has been reported as one of the commonest adverse events of the new oral anti-Xa anticoagulant darexaban, with similar rates to mechanical thromboprophylaxis in a randomized controlled trial (RCT). However, the perceived effect could have been biased because it was an open-label RCT. Therefore, we aimed to review the incidence of insomnia with non-vitamin K antagonist oral anticoagulants (NOACs).
  
  
  METHODS
  We performed a systematic review and meta-analysis of Phase III RCTs. Electronic databases MEDLINE and CENTRAL (inception to September 2013) were searched as well as review articles and references of included studies. We included phase III RCTs which compared NOACs with any other control group. Data were analyzed and pooled to estimate risk ratio (RR) with 95% confidence intervals (95%CI) for insomnia using inverse variance method. Statistical heterogeneity was evaluated with I(2) test.
  
  
  RESULTS
  We included seven studies (two apixaban RCTs, two dabigatran RCTs, one darexaban RCTs, and two rivaroxaban RCTs), enrolling a total of 23,023 patients. Overall, NOACs were not associated to an increased risk of insomnia: RR 0.94 (95%CI 0.83-1.08; I(2) = 0%). In blinded studies (six studies), NOACs also did not show increased risk of insomnia (RR 0.94, 95%CI 0.83-1.08; I(2) = 0%). Results were similar irrespective of the comparators.
  
  
  CONCLUSIONS
  NOACs (apixaban, dabigatran, darexaban, rivaroxaban) did not show increased risk of insomnia. Results according to study design (blinded vs. open-label trials) overlap the main analysis.
authors.affiliation: Laboratory of Clinical Pharmacology and Therapeutics, Faculty of Medicine, University of Lisbon, Lisbon, Portugal, dgcaldeira@hotmail.com.
authors.forename: Daniel
authors.initials: D
authors.lastname: Caldeira
authors.forename: Márcio
authors.initials: M
authors.lastname: Barra
authors.forename: Ana Teresa
authors.initials: AT
authors.lastname: Santos
authors.forename: Daisy
authors.initials: D
authors.lastname: de Abreu
authors.forename: João
authors.initials: J
authors.lastname: Costa
authors.forename: Joaquim J
authors.initials: JJ
authors.lastname: Ferreira
mesh_terms: D000284:Administration, Oral; D000925:Anticoagulants / Q000009:adverse effects* / Q000627:therapeutic use; D001381:Azepines / Q000009:adverse effects / Q000627:therapeutic use; D001549:Benzamides / Q000009:adverse effects / Q000627:therapeutic use; D017326:Clinical Trials, Phase III as Topic; D006801:Humans; D016032:Randomized Controlled Trials as Topic; D007319:Sleep Initiation and Maintenance Disorders / Q000139:chemically induced*; D013927:Thrombosis / Q000188:drug therapy*; D014812:Vitamin K / Q000037:antagonists & inhibitors
chemical_list: D000925:Anticoagulants; D001381:Azepines; D001549:Benzamides; D014812:Vitamin K; C569750:darexaban