title: Cause of Death and Predictors of All-Cause Mortality in Anticoagulated Patients With Nonvalvular Atrial Fibrillation: Data From ROCKET AF.
abstract: BACKGROUND
  Atrial fibrillation is associated with higher mortality. Identification of causes of death and contemporary risk factors for all-cause mortality may guide interventions.
  
  
  RESULTS
  In the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) study, patients with nonvalvular atrial fibrillation were randomized to rivaroxaban or dose-adjusted warfarin. Cox proportional hazards regression with backward elimination identified factors at randomization that were independently associated with all-cause mortality in the 14 171 participants in the intention-to-treat population. The median age was 73 years, and the mean CHADS2 score was 3.5. Over 1.9 years of median follow-up, 1214 (8.6%) patients died. Kaplan-Meier mortality rates were 4.2% at 1 year and 8.9% at 2 years. The majority of classified deaths (1081) were cardiovascular (72%), whereas only 6% were nonhemorrhagic stroke or systemic embolism. No significant difference in all-cause mortality was observed between the rivaroxaban and warfarin arms (P=0.15). Heart failure (hazard ratio 1.51, 95% CI 1.33-1.70, P<0.0001) and age ≥75 years (hazard ratio 1.69, 95% CI 1.51-1.90, P<0.0001) were associated with higher all-cause mortality. Multiple additional characteristics were independently associated with higher mortality, with decreasing creatinine clearance, chronic obstructive pulmonary disease, male sex, peripheral vascular disease, and diabetes being among the most strongly associated (model C-index 0.677).
  
  
  CONCLUSIONS
  In a large population of patients anticoagulated for nonvalvular atrial fibrillation, ≈7 in 10 deaths were cardiovascular, whereas <1 in 10 deaths were caused by nonhemorrhagic stroke or systemic embolism. Optimal prevention and treatment of heart failure, renal impairment, chronic obstructive pulmonary disease, and diabetes may improve survival.
  
  
  BACKGROUND
  URL: https://www.clinicaltrials.gov/. Unique identifier: NCT00403767.
authors.affiliation: Duke Clinical Research Institute, Duke University Medical Center, Durham, NC sean.pokorney@duke.edu.
authors.forename: Sean D
authors.initials: SD
authors.lastname: Pokorney
authors.affiliation: Duke Clinical Research Institute, Duke University Medical Center, Durham, NC.
authors.forename: Jonathan P
authors.initials: JP
authors.lastname: Piccini
authors.affiliation: Duke Clinical Research Institute, Duke University Medical Center, Durham, NC.
authors.forename: Susanna R
authors.initials: SR
authors.lastname: Stevens
authors.affiliation: Duke Clinical Research Institute, Duke University Medical Center, Durham, NC.
authors.forename: Manesh R
authors.initials: MR
authors.lastname: Patel
authors.affiliation: Duke Clinical Research Institute, Duke University Medical Center, Durham, NC.
authors.forename: Karen S
authors.initials: KS
authors.lastname: Pieper
authors.affiliation: The Cardiovascular Institute, Mount Sinai Medical Center, New York, NY.
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Halperin
authors.affiliation: Division of Electrophysiology, Department of Cardiovascular Medicine, Hospital of the University of Münster, Germany.
authors.forename: Günter
authors.initials: G
authors.lastname: Breithardt
authors.affiliation: Clinical Epidemiology Unit, General Medicine Division, Massachusetts General Hospital, and Harvard Medical School, Boston, MA.
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Singer
authors.affiliation: Department of Neurology, Royal Perth Hospital, Perth, Australia.
authors.forename: Graeme J
authors.initials: GJ
authors.lastname: Hankey
authors.affiliation: Ruprecht-Karls-University, Heidelberg, Germany.
authors.forename: Werner
authors.initials: W
authors.lastname: Hacke
authors.affiliation: Duke Clinical Research Institute, Duke University Medical Center, Durham, NC.
authors.forename: Richard C
authors.initials: RC
authors.lastname: Becker
authors.affiliation: Global Clinical Development, Bayer HealthCare Pharmaceuticals, Inc., Whippany, NJ.
authors.forename: Scott D
authors.initials: SD
authors.lastname: Berkowitz
authors.affiliation: Janssen Research & Development, Raritan, NJ.
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Nessel
authors.affiliation: Department of Medicine, Stanford University, Stanford, CA.
authors.forename: Kenneth W
authors.initials: KW
authors.lastname: Mahaffey
authors.affiliation: University of Edinburgh, and Royal Infirmary of Edinburgh, UK.
authors.forename: Keith A A
authors.initials: KA
authors.lastname: Fox
authors.affiliation: Duke Translational Medicine Institute, Duke University Medical Center, Durham, NC.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Califf
mesh_terms: D000284:Administration, Oral; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000925:Anticoagulants / Q000008:administration & dosage* / Q000009:adverse effects; D001281:Atrial Fibrillation / Q000097:blood / Q000150:complications / Q000175:diagnosis / Q000188:drug therapy* / Q000401:mortality*; D002423:Cause of Death; D015897:Comorbidity; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D065427:Factor Xa Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D005260:Female; D006801:Humans; D057194:Intention to Treat Analysis; D053208:Kaplan-Meier Estimate; D008297:Male; D015999:Multivariate Analysis; D016016:Proportional Hazards Models; D018570:Risk Assessment; D012307:Risk Factors; D000069552:Rivaroxaban / Q000008:administration & dosage* / Q000009:adverse effects; D012737:Sex Factors; D020521:Stroke / Q000175:diagnosis / Q000209:etiology / Q000401:mortality* / Q000517:prevention & control*; D013997:Time Factors; D016896:Treatment Outcome; D014859:Warfarin / Q000008:administration & dosage* / Q000009:adverse effects
chemical_list: D000925:Anticoagulants; D065427:Factor Xa Inhibitors; D014859:Warfarin; D000069552:Rivaroxaban
keywords: atrial fibrillation; mortality; rivaroxaban; stroke; warfarin