title: Causes of Death in Anticoagulated Patients With Atrial Fibrillation.
abstract: BACKGROUND
  Oral anticoagulation reduces the risk of mortality in atrial fibrillation (AF), but examination of the causes of death is essential to design new strategies to further reduce the high mortality rates observed in this population.
  
  
  OBJECTIVE
  The authors sought to analyze and compare causes of death in patients receiving direct oral anticoagulants (DOAC) or warfarin for prevention of stroke and systemic embolism (SE) in AF.
  
  
  METHODS
  The authors systematically searched for randomized trials of DOAC versus warfarin for prevention of stroke/SE in AF. The main outcome was mortality and independently adjudicated specific causes of death. The authors used the random effects model of meta-analysis to combine the studies.
  
  
  RESULTS
  71,683 patients from 4 trials were included (134,046 patient-years of follow-up). A total of 6,206 patients (9%) died during follow-up. Adjusted mortality rate was 4.72%/year (95% confidence interval [CI]: 4.19 to 5.28). Cardiac deaths accounted for 46% of all deaths, whereas nonhemorrhagic stroke/SE and hemorrhage-related deaths represented 5.7% and 5.6% of the total mortality, respectively. Compared with patients who were alive, those who died had more frequent history of heart failure (odds ratio [OR]: 1.75; 95% CI: 1.25 to 2.44), permanent/persistent AF (OR: 1.38; 95% CI: 1.25 to 1.52) and diabetes (OR: 1.37; 95% CI: 1.11 to 1.68); were more frequently male (OR: 1.24; 95% CI: 1.13 to 1.37) and older (mean difference 3.2 years; 95% CI: 1.6 to 4.8); and had a lower creatinine clearance (-9.9 ml/min; 95% CI: -11.3 to -8.4). There was a small, but significant, reduction in all-cause mortality with the DOAC versus warfarin (difference -0.42%/year; 95% CI: -0.66 to -0.18), mainly driven by a reduction in fatal bleedings.
  
  
  CONCLUSIONS
  In contemporary AF trials, most deaths were cardiac-related, whereas stroke and bleeding represented only a small subset of deaths. Interventions beyond anticoagulation are needed to further reduce mortality in AF.
authors.affiliation: Division of Pharmacology and Clinical Drug Evaluation, Spanish Agency for Medicines and Medical Devices (AEMPS), Madrid, Spain. Electronic address: agomezo@aemps.es.
authors.forename: Antonio
authors.initials: A
authors.lastname: Gómez-Outes
authors.affiliation: Department of Clinical Pharmacology, Hospital Clínico San Carlos, Madrid, Spain.
authors.forename: Julián
authors.initials: J
authors.lastname: Lagunar-Ruíz
authors.affiliation: Department of Clinical Pharmacology, Hospital Clínico San Carlos, Madrid, Spain; Department of Pharmacology, Universidad Complutense, Madrid, Spain.
authors.forename: Ana-Isabel
authors.initials: AI
authors.lastname: Terleira-Fernández
authors.affiliation: Department of Clinical Pharmacology, Hospital Clinic, Barcelona, Spain.
authors.forename: Gonzalo
authors.initials: G
authors.lastname: Calvo-Rojas
authors.affiliation: Division of Pharmacology and Clinical Drug Evaluation, Spanish Agency for Medicines and Medical Devices (AEMPS), Madrid, Spain.
authors.forename: Maria Luisa
authors.initials: ML
authors.lastname: Suárez-Gea
authors.affiliation: Department of Clinical Pharmacology, Hospital Clínico San Carlos, Madrid, Spain; Department of Pharmacology, Universidad Complutense, Madrid, Spain.
authors.forename: Emilio
authors.initials: E
authors.lastname: Vargas-Castrillón
mesh_terms: D000284:Administration, Oral; D000368:Aged; D000925:Anticoagulants / Q000627:therapeutic use*; D001281:Atrial Fibrillation / Q000150:complications / Q000188:drug therapy / Q000401:mortality*; D002423:Cause of Death / Q000639:trends; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D012042:Registries; D012189:Retrospective Studies; D020521:Stroke / Q000209:etiology / Q000401:mortality* / Q000517:prevention & control; D015996:Survival Rate / Q000639:trends; D014481:United States / Q000453:epidemiology
chemical_list: D000925:Anticoagulants
keywords: apixaban; atrial fibrillation; dabigatran; rivaroxaban; stroke; warfarin