title: Prevention of stroke and systemic embolism with rivaroxaban compared with warfarin in patients with non-valvular atrial fibrillation and moderate renal impairment.
abstract: OBJECTIVE
  Patients with non-valvular atrial fibrillation (AF) and renal insufficiency are at increased risk for ischaemic stroke and bleeding during anticoagulation. Rivaroxaban, an oral, direct factor Xa inhibitor metabolized predominantly by the liver, preserves the benefit of warfarin for stroke prevention while causing fewer intracranial and fatal haemorrhages.
  
  
  RESULTS
  We randomized 14 264 patients with AF in a double-blind trial to rivaroxaban 20 mg/day [15 mg/day if creatinine clearance (CrCl) 30-49 mL/min] or dose-adjusted warfarin (target international normalized ratio 2.0-3.0). Compared with patients with CrCl >50 mL/min (mean age 73 years), the 2950 (20.7%) patients with CrCl 30-49 mL/min were older (79 years) and had higher event rates irrespective of study treatment. Among those with CrCl 30-49 mL/min, the primary endpoint of stroke or systemic embolism occurred in 2.32 per 100 patient-years with rivaroxaban 15 mg/day vs. 2.77 per 100 patient-years with warfarin [hazard ratio (HR) 0.84; 95% confidence interval (CI) 0.57-1.23] in the per-protocol population. Intention-to-treat analysis yielded similar results (HR 0.86; 95% CI 0.63-1.17) to the per-protocol results. Rates of the principal safety endpoint (major and clinically relevant non-major bleeding: 17.82 vs. 18.28 per 100 patient-years; P = 0.76) and intracranial bleeding (0.71 vs. 0.88 per 100 patient-years; P = 0.54) were similar with rivaroxaban or warfarin. Fatal bleeding (0.28 vs. 0.74% per 100 patient-years; P = 0.047) occurred less often with rivaroxaban.
  
  
  CONCLUSIONS
  Patients with AF and moderate renal insufficiency have higher rates of stroke and bleeding than those with normal renal function. There was no evidence of heterogeneity in treatment effect across dosing groups. Dose adjustment in ROCKET-AF yielded results consistent with the overall trial in comparison with dose-adjusted warfarin.
authors.affiliation: Centre for Cardiovascular Science, University of Edinburgh, 49 Little France Crescent, Edinburgh EH16 4SB, UK. k.a.a.fox@ed.ac.uk
authors.forename: Keith A A
authors.initials: KA
authors.lastname: Fox
authors.forename: Jonathan P
authors.initials: JP
authors.lastname: Piccini
authors.forename: Daniel
authors.initials: D
authors.lastname: Wojdyla
authors.forename: Richard C
authors.initials: RC
authors.lastname: Becker
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Halperin
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Nessel
authors.forename: John F
authors.initials: JF
authors.lastname: Paolini
authors.forename: Graeme J
authors.initials: GJ
authors.lastname: Hankey
authors.forename: Kenneth W
authors.initials: KW
authors.lastname: Mahaffey
authors.forename: Manesh R
authors.initials: MR
authors.lastname: Patel
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Singer
authors.forename: Robert M
authors.initials: RM
authors.lastname: Califf
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000925:Anticoagulants / Q000008:administration & dosage* / Q000009:adverse effects; D001281:Atrial Fibrillation / Q000150:complications*; D004311:Double-Blind Method; D004617:Embolism / Q000517:prevention & control*; D005260:Female; D006470:Hemorrhage / Q000139:chemically induced; D006801:Humans; D008297:Male; D009025:Morpholines / Q000008:administration & dosage / Q000009:adverse effects; D051437:Renal Insufficiency / Q000150:complications*; D000069552:Rivaroxaban; D020521:Stroke / Q000517:prevention & control*; D013876:Thiophenes / Q000008:administration & dosage / Q000009:adverse effects; D016896:Treatment Outcome; D014859:Warfarin / Q000008:administration & dosage / Q000009:adverse effects
chemical_list: D000925:Anticoagulants; D009025:Morpholines; D013876:Thiophenes; D014859:Warfarin; D000069552:Rivaroxaban