title: Apixaban 5 mg Twice Daily and Clinical Outcomes in Patients With Atrial Fibrillation and Advanced Age, Low Body Weight, or High Creatinine: A Secondary Analysis of a Randomized Clinical Trial.
abstract: In the Apixaban for Reduction of Stroke and Other Thromboembolic Complications in Atrial Fibrillation (ARISTOTLE) trial, the standard dose of apixaban was 5 mg twice daily; patients with at least 2 dose-reduction criteria-80 years or older, weight 60 kg or less, and creatinine level 1.5 mg/dL or higher-received a reduced dose of apixaban of 2.5 mg twice daily. Little is known about patients with 1 dose-reduction criterion who received the 5 mg twice daily dose of apixaban.
  
  
  
  To determine the frequency of 1 dose-reduction criterion and whether the effects of the 5 mg twice daily dose of apixaban on stroke or systemic embolism and bleeding varied among patients with 1 or no dose-reduction criteria.
  
  
  
  Among 18 201 patients in the ARISTOTLE trial, 17 322 were included in this analysis. Annualized event rates of stroke or systemic embolism and major bleeding and hazard ratios (HRs) and 95% CIs were evaluated. Interactions between the effects of apixaban vs warfarin and the presence of 1 or no dose-reduction criteria were assessed. The first patient was enrolled in the ARISTOTLE trial on December 19, 2006, and follow-up was completed on January 30, 2011. Data were analyzed from January 2015 to May 30, 2016.
  
  
  
  Analysis of major bleeding included events during study drug treatment. Analysis of stroke or systemic embolism was based on intention to treat.
  
  
  
  Of the patients with 1 or no dose-reduction criteria assigned to receive the 5 mg twice daily dose of apixaban or warfarin, 3966 had 1 dose-reduction criterion; these patients had higher rates of stroke or systemic embolism (HR, 1.47; 95% CI, 1.20-1.81) and major bleeding (HR, 1.89; 95% CI, 1.62-2.20) compared with those with no dose-reduction criteria (n = 13 356). The benefit of the 5 mg twice daily dose of apixaban (n = 8665) compared with warfarin (n = 8657) on stroke or systemic embolism in patients with 1 dose-reduction criterion (HR, 0.94; 95% CI, 0.66-1.32) and no dose-reduction criterion (HR, 0.77; 95% CI, 0.62-0.97) were similar (P for interaction = .36). Similarly, the benefit of 5 mg twice daily dose of apixaban compared with warfarin on major bleeding in patients with 1 dose-reduction criterion (HR, 0.68; 95% CI, 0.53-0.87) and no dose-reduction criterion (HR, 0.72; 95% CI, 0.60-0.86) were similar (P for interaction = .71). Similar patterns were seen for each dose-reduction criterion and across the spectrum of age, body weight, creatinine level, and creatinine clearance.
  
  
  
  Patients with atrial fibrillation and isolated advanced age, low body weight, or renal dysfunction have a higher risk of stroke or systemic embolism and major bleeding but show consistent benefits with the 5 mg twice daily dose of apixaban vs warfarin compared with patients without these characteristics. The 5 mg twice daily dose of apixaban is safe, efficacious, and appropriate for patients with only 1 dose-reduction criterion.
  
  
  
  clinicaltrials.gov Identifier: NCT00412984.
authors.affiliation: Duke Clinical Research Institute, Duke Health, Durham, North Carolina.
authors.forename: John H
authors.initials: JH
authors.lastname: Alexander
authors.affiliation: Uppsala Clinical Research Center, Uppsala University, Uppsala, Sweden.
authors.forename: Ulrika
authors.initials: U
authors.lastname: Andersson
authors.affiliation: Duke Clinical Research Institute, Duke Health, Durham, North Carolina.
authors.forename: Renato D
authors.initials: RD
authors.lastname: Lopes
authors.affiliation: Uppsala Clinical Research Center, Uppsala University, Uppsala, Sweden.
authors.forename: Ziad
authors.initials: Z
authors.lastname: Hijazi
authors.affiliation: Division of Clinical Electrophysiology, Goethe University, Frankfurt, Germany.
authors.forename: Stefan H
authors.initials: SH
authors.lastname: Hohnloser
authors.affiliation: Division of Cardiology, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Justin A
authors.initials: JA
authors.lastname: Ezekowitz
authors.affiliation: Department of Cardiology, Oslo University Hospital and University of Oslo, Oslo, Norway.
authors.forename: Sigrun
authors.initials: S
authors.lastname: Halvorsen
authors.affiliation: Bristol-Myers Squibb, Princeton, New Jersey.
authors.forename: Michael
authors.initials: M
authors.lastname: Hanna
authors.affiliation: Department of Medicine, University of Cape Town, Cape Town, South Africa.
authors.forename: Patrick
authors.initials: P
authors.lastname: Commerford
authors.affiliation: Institute of Cardiology, Warsaw, Poland.
authors.forename: Witold
authors.initials: W
authors.lastname: Ruzyllo
authors.affiliation: Third Department of Medicine, Cardiology and Emergency Medicine, Wilhelminenspital, Vienna, Austria.
authors.forename: Kurt
authors.initials: K
authors.lastname: Huber
authors.affiliation: Duke Clinical Research Institute, Duke Health, Durham, North Carolina.
authors.forename: Sana M
authors.initials: SM
authors.lastname: Al-Khatib
authors.affiliation: Duke Clinical Research Institute, Duke Health, Durham, North Carolina.
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Granger
authors.affiliation: Uppsala Clinical Research Center, Uppsala University, Uppsala, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Wallentin
mesh_terms: D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000925:Anticoagulants / Q000008:administration & dosage* / Q000009:adverse effects; D001281:Atrial Fibrillation / Q000188:drug therapy*; D001835:Body Weight; D003404:Creatinine / Q000378:metabolism*; D004617:Embolism; D005260:Female; D006470:Hemorrhage; D006801:Humans; D008297:Male; D011720:Pyrazoles / Q000008:administration & dosage* / Q000009:adverse effects; D011728:Pyridones / Q000008:administration & dosage* / Q000009:adverse effects; D020521:Stroke; D016896:Treatment Outcome
chemical_list: D000925:Anticoagulants; D011720:Pyrazoles; D011728:Pyridones; C522181:apixaban; D003404:Creatinine