title: Systemic, noncerebral, arterial embolism in 21,105 patients with atrial fibrillation randomized to edoxaban or warfarin: results from the Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction Study 48 trial.
abstract: BACKGROUND
  Atrial fibrillation (AF) is a major risk factor for stroke and systemic embolism. Trials comparing warfarin with non-vitamin K oral anticoagulants (NOACs) have demonstrated that, when compared with warfarin, the NOACs are at least as effective in preventing stroke, although detailed analyses characterizing systemic embolic events (SEEs) are lacking.
  
  
  RESULTS
  We performed a prespecified analysis in 21,105 patients with AF enrolled in the ENGAGE AF-TIMI 48 trial, which compared 2 once-daily regimens of edoxaban with warfarin for the prevention of stroke and SEE. Of 1,016 patients who met the primary end point, 67 (6.6%) experienced an SEE of which 13% were fatal. Of 73 total SEEs (including recurrent events), 85% involved the extremities, and 41% required a surgical or percutaneous intervention. There were 23 (0.12%/year) SEEs with warfarin versus 15 with higher dose edoxaban (0.08%/year; hazard ratio vs warfarin 0.65; 95% CI 0.34-1.24; P = .19) and 29 with lower dose edoxaban (0.15%/year; hazard ratio vs warfarin 1.24; 95% CI 0.72-2.15; P = .43). In a meta-analysis of 4 warfarin-controlled phase 3 AF trials, NOACs significantly reduced the risk of SEE by 37% (relative risk 0.63; 95% CI 0.43-0.91; P = .01).
  
  
  CONCLUSIONS
  Although considerably less frequent than stroke, systemic embolism is associated with significant morbidity and mortality in patients with AF. Although the overall number of events was too small to show a significant difference in the risk of SEE between edoxaban and warfarin, a meta-analysis of all the NOAC trials demonstrates that NOACs significantly reduce the risk of SEE compared with warfarin.
authors.affiliation: University of Pennsylvania Health System, Philadelphia, PA.
authors.forename: Bram J
authors.initials: BJ
authors.lastname: Geller
authors.affiliation: Brigham and Women's Hospital and Harvard Medical School, Boston, MA.
authors.forename: Robert P
authors.initials: RP
authors.lastname: Giugliano
authors.affiliation: Brigham and Women's Hospital and Harvard Medical School, Boston, MA.
authors.forename: Eugene
authors.initials: E
authors.lastname: Braunwald
authors.affiliation: Brigham and Women's Hospital and Harvard Medical School, Boston, MA.
authors.forename: Sabina A
authors.initials: SA
authors.lastname: Murphy
authors.affiliation: Daiichi-Sankyo Pharma Development, Edison, NJ.
authors.forename: James J
authors.initials: JJ
authors.lastname: Hanyok
authors.affiliation: Daiichi-Sankyo Pharma Development, Edison, NJ.
authors.forename: Jianqing
authors.initials: J
authors.lastname: Jin
authors.affiliation: Daiichi-Sankyo Pharma Development, Edison, NJ.
authors.forename: Michele
authors.initials: M
authors.lastname: Mercuri
authors.affiliation: Brigham and Women's Hospital and Harvard Medical School, Boston, MA.
authors.forename: Elliott M
authors.initials: EM
authors.lastname: Antman
authors.affiliation: Brigham and Women's Hospital and Harvard Medical School, Boston, MA. Electronic address: cruff@partners.org.
authors.forename: Christian T
authors.initials: CT
authors.lastname: Ruff
mesh_terms: D000368:Aged; D000925:Anticoagulants / Q000627:therapeutic use; D001281:Atrial Fibrillation / Q000150:complications* / Q000188:drug therapy / Q000503:physiopathology; D001777:Blood Coagulation; D004311:Double-Blind Method; D004617:Embolism / Q000097:blood / Q000209:etiology / Q000517:prevention & control*; D015951:Factor Xa / Q000627:therapeutic use*; D065427:Factor Xa Inhibitors / Q000627:therapeutic use; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008875:Middle Aged; D009203:Myocardial Infarction / Q000150:complications* / Q000628:therapy; D011725:Pyridines / Q000627:therapeutic use*; D012189:Retrospective Studies; D013844:Thiazoles / Q000627:therapeutic use*; D015912:Thrombolytic Therapy / Q000379:methods*; D016896:Treatment Outcome; D014859:Warfarin / Q000627:therapeutic use*
chemical_list: D000925:Anticoagulants; D065427:Factor Xa Inhibitors; D011725:Pyridines; D013844:Thiazoles; D014859:Warfarin; D015951:Factor Xa; C552171:edoxaban