title: Case fatality of bleeding and recurrent venous thromboembolism during, initial therapy with direct oral anticoagulants: a systematic review.
abstract: BACKGROUND
  The frequency and case fatality of venous thromboembolism (VTE) and major bleeding during the initial 3 months of therapy in those treated for symptomatic VTE with either direct oral anticoagulants (DOACs) or vitamin K antagonists (VKA) are important clinically relevant outcomes. We sought to measure it during the initial months of anticoagulation for symptomatic VTE.
  
  
  METHODS
  We searched MEDLINE, EMBASE, and CENTRAL to identify studies that enrolled patients with acute symptomatic VTE treated with DOACs or VKA and reported data on bleeding, VTE recurrence and death. Studies were evaluated according to a priori inclusion criteria and critically appraised using established internal validity criteria. Single-proportion random-effects models were used to pool estimates.
  
  
  RESULTS
  Of the 2453 citations retrieved, 5 RCTs that enrolled 24,507 patients were included. The rate of major bleeding was 1.8 (95% CI: 1.3-2.5) and 3.1 (95% CI: 2.4-3.9) per 100 patient-years in DOAC and VKA arms, respectively. The rate of VTE recurrence was 3.7 (95% CI: 2.7-4.7) and 4.1 (95% CI: 3.0-5.4) per 100 patient-years of DOAC and VKA, respectively. The case fatality rate of bleeding was significantly higher in the VKA arms 10.4% (95% CI: 6.6-15.4) compared to DOACs 6.1% (95% CI: 2.7-11.7; p value for difference=0.029) with no statistical difference between the case fatalities for recurrent VTE. The rate of death from either definite major bleeding or definite recurrent VTE was 0.27 (95% CI: 0.16-0.40) and 0.46 (95% CI: 0.32-0.63) per 100 patient-years for DOACs and VKAs respectively, resulting in a number needed to treat of 875 for DOACs to prevent one death.
  
  
  CONCLUSIONS
  DOACs are attractive alternatives to VKAs for initial treatment of symptomatic VTE, with lower frequency and case fatality for major bleeding. However, the incremental safety benefit of DOACs over VKAs is small, with large numbers needed to treat.
authors.affiliation: Department of Medicine, University of Alberta, Edmonton, Alberta, Canada. Electronic address: cynthia.wu@ualberta.ca.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Wu
authors.affiliation: Department of Medicine, University of Alberta, Edmonton, Alberta, Canada; Department of Medicine, King Saud University, Riyadh, Saudi Arabia.
authors.forename: Ghazi S
authors.initials: GS
authors.lastname: Alotaibi
authors.affiliation: Department of Medicine, King Saud University, Riyadh, Saudi Arabia.
authors.forename: Khalid
authors.initials: K
authors.lastname: Alsaleh
authors.affiliation: Department of Medicine, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: M
authors.initials: M
authors.lastname: Sean McMurtry
mesh_terms: D000284:Administration, Oral; D000925:Anticoagulants / Q000008:administration & dosage* / Q000009:adverse effects*; D006470:Hemorrhage / Q000139:chemically induced* / Q000401:mortality*; D006801:Humans; D012008:Recurrence; D018570:Risk Assessment; D012307:Risk Factors; D016896:Treatment Outcome; D054556:Venous Thromboembolism / Q000097:blood / Q000188:drug therapy* / Q000401:mortality*; D014812:Vitamin K / Q000037:antagonists & inhibitors
chemical_list: D000925:Anticoagulants; D014812:Vitamin K
keywords: Case fatality; Direct oral anticoagulants; Major bleeding; Mortality; VTE recurrence; Vitamin K antagonists