title: Case Fatality Rates of Recurrent Thromboembolism and Bleeding in Patients Receiving Direct Oral Anticoagulants for the Initial and Extended Treatment of Venous Thromboembolism: A Systematic Review.
abstract: BACKGROUND
  In patients with venous thromboembolism (VTE), the study of the case fatality rate (CFR) of VTE recurrences and bleeding complications may be of help to balance the risks and benefits of anticoagulant therapy.
  
  
  OBJECTIVE
  To investigate the CFR with the direct oral anticoagulants (DOACs; dabigatran, rivaroxaban, apixaban, and edoxaban) in patients with VTE.
  
  
  METHODS
  We conducted a systematic review and meta-analysis of randomized clinical trials testing the DOACs versus standard initial treatment of VTE (parenteral anticoagulant for ≥5 days plus vitamin K antagonists [VKAs] for ≥3 months) and DOACs versus placebo or VKA for extended treatment. Two investigators independently extracted the data. A random effects meta-analysis was conducted using StatsDirect software.
  
  
  RESULTS
  Overall, 10 trials in 35 029 patients were included. During initial treatment, the rate of recurrent VTE per 100 patient-years (%/yr) and CFR (%) was similar in patients receiving DOACs or standard therapy (4.1%/yr vs 4.4%/yr; P = .21 and 16% vs 13%; P = .61, respectively). However, major bleeding (1.8%/yr vs 3.1%/yr; P = .003), fatal bleeding (0.1%/yr vs 0.3%/yr; P = .02), and CFR (6% vs 10%; P = .18) were lower with DOACs than with standard therapy. During extended treatment, both all-cause mortality and recurrent VTE per 100 patient-years were lower with DOACs than with placebo (0.6%/yr vs 1.1%/yr; P = .01 and 1.9%/yr vs 10.9%/yr; P < .0001, respectively), but there were no statistical differences between treatments on CFR of VTE recurrences (P = .17). No fatal bleeding events were reported during extended treatment.
  
  
  CONCLUSIONS
  The use of DOACs was associated with fewer major and fatal bleedings and corresponding CFR than standard initial treatment of VTE, and fewer recurrent VTEs and mortality than placebo during extended therapy, although the CFR of recurrent VTE was not reduced.
authors: Division of Pharmacology and Clinical Evaluation, Spanish Agency for Medicines and Medical Devices (AEMPS), Madrid, Spain agomezo@aemps.es.
authors: Antonio
authors: A
authors: Gómez-Outes
authors: Hematology Service, University Clinic of Navarra, Pamplona, Spain.
authors: Ramón
authors: R
authors: Lecumberri
authors: Division of Pharmacology and Clinical Evaluation, Spanish Agency for Medicines and Medical Devices (AEMPS), Madrid, Spain.
authors: M Luisa
authors: ML
authors: Suárez-Gea
authors: Department of Clinical Pharmacology, Hospital Clínico San Carlos, Madrid, Spain Department of Pharmacology, Universidad Complutense, Madrid, Spain.
authors: Ana-Isabel
authors: AI
authors: Terleira-Fernández
authors: Department of Internal Medicine, Hospital Universitari Germans Trias i Pujol, Badalona, Barcelona, Spain.
authors: Manuel
authors: M
authors: Monreal
authors: Department of Clinical Pharmacology, Hospital Clínico San Carlos, Madrid, Spain Department of Pharmacology, Universidad Complutense, Madrid, Spain.
authors: Emilio
authors: E
authors: Vargas-Castrillón
mesh_terms: D000284:Administration, Oral; D000925:Anticoagulants / Q000009:adverse effects* / Q000627:therapeutic use*; D006470:Hemorrhage / Q000139:chemically induced / Q000401:mortality*; D006801:Humans; D016032:Randomized Controlled Trials as Topic; D012008:Recurrence; D054556:Venous Thromboembolism / Q000188:drug therapy* / Q000401:mortality*
chemical_list: D000925:Anticoagulants
keywords: anticoagulants; bleeding; case fatality rate; deep vein thrombosis; pulmonary embolism; recurrent event