title: A meta-analysis of phase III randomized controlled trials with novel oral anticoagulants in atrial fibrillation: comparisons between direct thrombin inhibitors vs. factor Xa inhibitors and different dosing regimens.
abstract: OBJECTIVE
  Previous studies evaluating the ability of novel oral anticoagulants (NOAC) to prevent thromboembolism in patients with non-valvular atrial fibrillation (AF) have identified differences between the efficacy and safety of the drugs tested. Whether these differences reflect differences in direct thrombin or Xa inhibition, different dosing regimens or specific aspects of each agent or trial has not yet been explored.
  
  
  METHODS
  A search was performed on MEDLINE, EMBASE and COCHRANE, and ongoing studies were tracked on clinicaltrials.gov. Phase III randomized controlled trials of direct thrombin inhibitors (DTI) and factor Xa inhibitors (FXaI) vs. warfarin in patients with AF were eligible. Data were pooled using random-effects, according to the Mantel-Haenszel model. Sensitivity analyses were performed on DTI, FXaI, once-daily and twice-daily regimens.
  
  
  RESULTS
  Seven studies were pooled, including a total of 80,290 patients. Both DTI and FXaI outperformed warfarin regarding stroke or systemic embolism, intracranial bleeding, total and cardiovascular mortality. No significant differences were found between DTI and FXaI or between once-daily and twice-daily regimens. Some drugs performed worse than warfarin regarding some secondary endpoints, including: edoxaban 30 mg bid on ischaemic stroke, dabigatran on acute myocardial infarction, dabigatran 150 mg bid and rivaroxaban 20mgod on gastrointestinal bleeding.
  
  
  CONCLUSIONS
  Our pooled data do not support the hypothesis of a significant class-effect of DTI or FXaI, nor the benefit of once-daily vs. twice-daily dosing in the setting of AF, reinforcing that the choice of NOAC should be adapted to the specific patient and focused on the agent itself, rather than the pharmacological class or dosing regimen.
authors.affiliation: Faculty of Medicine, University of Coimbra, Coimbra, Portugal. rui_providencia@yahoo.com
authors.forename: Rui
authors.initials: R
authors.lastname: Providência
authors.forename: Erik Lerkevang
authors.initials: EL
authors.lastname: Grove
authors.forename: Steen
authors.initials: S
authors.lastname: Husted
authors.forename: Sérgio
authors.initials: S
authors.lastname: Barra
authors.forename: Serge
authors.initials: S
authors.lastname: Boveda
authors.forename: João
authors.initials: J
authors.lastname: Morais
mesh_terms: D000284:Administration, Oral; D000368:Aged; D000925:Anticoagulants / Q000008:administration & dosage* / Q000009:adverse effects*; D000991:Antithrombins / Q000008:administration & dosage* / Q000009:adverse effects; D001281:Atrial Fibrillation / Q000453:epidemiology*; D015984:Causality; D017326:Clinical Trials, Phase III as Topic; D015897:Comorbidity; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D065427:Factor Xa Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D005260:Female; D006470:Hemorrhage / Q000139:chemically induced / Q000453:epidemiology; D006801:Humans; D008297:Male; D016032:Randomized Controlled Trials as Topic; D012307:Risk Factors; D020521:Stroke / Q000139:chemically induced; D013923:Thromboembolism / Q000453:epidemiology* / Q000517:prevention & control*; D016896:Treatment Outcome
chemical_list: D000925:Anticoagulants; D000991:Antithrombins; D065427:Factor Xa Inhibitors