title: Twice- or once-daily dosing of novel oral anticoagulants for stroke prevention: a fixed-effects meta-analysis with predefined heterogeneity quality criteria.
abstract: BACKGROUND
  A number of novel oral anticoagulants (direct thrombin inhibitors or factor Xa inhibitors) are in clinical use for various indications. The dosing regimens differ between twice-daily and once-daily dosing for the prevention of stroke in patients with atrial fibrillation. With the availability of the results from four phase 3 studies (>70,000 patients), we explored whether twice-daily or once-daily dosing provides better risk-benefit balance among novel oral anticoagulants.
  
  
  METHODS
  We conducted a strict, stepwise, fixed-effects meta-analysis with predefined heterogeneity quality criteria to generate the most appropriate common estimates for twice-daily (BID) or once-daily (QD) dosing regimens. An indirect comparison of these dosing regimens with fixed-effects meta-analysis common estimates (where available), or individual compound results, was done respectively.
  
  
  RESULTS
  Comparing indirectly BID vs QD dosing regimens resulted in hazard ratios (HR [95% confidence interval]) for stroke and systemic embolism of 0.75 (0.58-0.96) for dabigatran 150 mg BID, and 0.91 (0.73-1.13) for apixaban BID vs the QD dosing regimen. For ischemic stroke, the HR of BID vs QD was 0.85 (0.69-1.05). For intracranial hemorrhage, BID vs rivaroxaban QD was 0.57 (0.37-0.88) and, vs edoxaban QD, 0.81 (0.54-1.22). Due to heterogeneity, common estimates for major bleeding QD or BID were not justified, therefore indirect comparison of regimens were not possible. All non-vitamin K antagonist oral anticoagulants reduced all-cause mortality vs warfarin with a HR of 0.90 (0.86-0.96) without differences between regimen.
  
  
  CONCLUSIONS
  Based on the available phase 3 study evidence, the twice-daily dosing regimen of non-vitamin K antagonist oral anticoagulants appears to offer a more balanced risk-benefit profile with respect to stroke prevention and intracranial hemorrhage.
authors.affiliation: Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz, Mainz, Germany; Global Biostatistics and Data Management, Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Clemens
authors.affiliation: Corporate Division Medicine, Global Therapeutic Area Cardiovascular, Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany.
authors.forename: Herbert
authors.initials: H
authors.lastname: Noack
authors.affiliation: Corporate Division Medicine, Global Therapeutic Area Cardiovascular, Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany; Faculty of Medicine Mannheim, University of Heidelberg, Mannheim, Germany.
authors.forename: Martina
authors.initials: M
authors.lastname: Brueckmann
authors.affiliation: University of Birmingham Centre for Cardiovascular Sciences, City Hospital, Birmingham, United Kingdom.
authors.forename: Gregory Y H
authors.initials: GY
authors.lastname: Lip
mesh_terms: D000284:Administration, Oral; D000925:Anticoagulants / Q000008:administration & dosage* / Q000493:pharmacokinetics; D004334:Drug Administration Schedule; D006801:Humans; D011292:Premedication; D020521:Stroke / Q000209:etiology / Q000401:mortality / Q000517:prevention & control*; D016896:Treatment Outcome
chemical_list: D000925:Anticoagulants