title: Oral anticoagulants for primary prevention, treatment and secondary prevention of venous thromboembolic disease, and for prevention of stroke in atrial fibrillation: systematic review, network meta-analysis and cost-effectiveness analysis.
abstract: Warfarin is effective for stroke prevention in atrial fibrillation (AF), but anticoagulation is underused in clinical care. The risk of venous thromboembolic disease during hospitalisation can be reduced by low-molecular-weight heparin (LMWH): warfarin is the most frequently prescribed anticoagulant for treatment and secondary prevention of venous thromboembolism (VTE). Warfarin-related bleeding is a major reason for hospitalisation for adverse drug effects. Warfarin is cheap but therapeutic monitoring increases treatment costs. Novel oral anticoagulants (NOACs) have more rapid onset and offset of action than warfarin, and more predictable dosing requirements.
  
  
  
  To determine the best oral anticoagulant/s for prevention of stroke in AF and for primary prevention, treatment and secondary prevention of VTE.
  
  
  
  Four systematic reviews, network meta-analyses (NMAs) and cost-effectiveness analyses (CEAs) of randomised controlled trials.
  
  
  
  Hospital (VTE primary prevention and acute treatment) and primary care/anticoagulation clinics (AF and VTE secondary prevention).
  
  
  
  Patients eligible for anticoagulation with warfarin (stroke prevention in AF, acute treatment or secondary prevention of VTE) or LMWH (primary prevention of VTE).
  
  
  
  NOACs, warfarin and LMWH, together with other interventions (antiplatelet therapy, placebo) evaluated in the evidence network.
  
  
  
  EfficacyStroke, symptomatic VTE, symptomatic deep-vein thrombosis and symptomatic pulmonary embolism.SafetyMajor bleeding, clinically relevant bleeding and intracranial haemorrhage. We also considered myocardial infarction and all-cause mortality and evaluated cost-effectiveness.
  
  
  
  MEDLINE and PREMEDLINE In-Process & Other Non-Indexed Citations, EMBASE and The Cochrane Library, reference lists of published NMAs and trial registries. We searched MEDLINE and PREMEDLINE In-Process & Other Non-Indexed Citations, EMBASE and The Cochrane Library. The stroke prevention in AF review search was run on the 12 March 2014 and updated on 15 September 2014, and covered the period 2010 to September 2014. The search for the three reviews in VTE was run on the 19 March 2014, updated on 15 September 2014, and covered the period 2008 to September 2014.
  
  
  
  Two reviewers screened search results, extracted and checked data, and assessed risk of bias. For each outcome we conducted standard meta-analysis and NMA. We evaluated cost-effectiveness using discrete-time Markov models.
  
  
  
  Apixaban (Eliquis®, Bristol-Myers Squibb, USA; Pfizer, USA) [5 mg bd (twice daily)] was ranked as among the best interventions for stroke prevention in AF, and had the highest expected net benefit. Edoxaban (Lixiana®, Daiichi Sankyo, Japan) [60 mg od (once daily)] was ranked second for major bleeding and all-cause mortality. Neither the clinical effectiveness analysis nor the CEA provided strong evidence that NOACs should replace postoperative LMWH in primary prevention of VTE. For acute treatment and secondary prevention of VTE, we found little evidence that NOACs offer an efficacy advantage over warfarin, but the risk of bleeding complications was lower for some NOACs than for warfarin. For a willingness-to-pay threshold of > £5000, apixaban (5 mg bd) had the highest expected net benefit for acute treatment of VTE. Aspirin or no pharmacotherapy were likely to be the most cost-effective interventions for secondary prevention of VTE: our results suggest that it is not cost-effective to prescribe NOACs or warfarin for this indication.
  
  
  
  NOACs have advantages over warfarin in patients with AF, but we found no strong evidence that they should replace warfarin or LMWH in primary prevention, treatment or secondary prevention of VTE.
  
  
  
  These relate mainly to shortfalls in the primary data: in particular, there were no head-to-head comparisons between different NOAC drugs.
  
  
  
  Calculating the expected value of sample information to clarify whether or not it would be justifiable to fund one or more head-to-head trials.
  
  
  
  This study is registered as PROSPERO CRD42013005324, CRD42013005331 and CRD42013005330.
  
  
  
  The National Institute for Health Research Health Technology Assessment programme.
authors.affiliation: School of Social and Community Medicine, University of Bristol, Bristol, UK.
authors.forename: Jonathan Ac
authors.initials: JA
authors.lastname: Sterne
authors.affiliation: University College London Hospitals, NHS, London, UK.|Royal National Orthopaedic Hospital, NHS, London, UK.
authors.forename: Pritesh N
authors.initials: PN
authors.lastname: Bodalia
authors.affiliation: School of Social and Community Medicine, University of Bristol, Bristol, UK.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Bryden
authors.affiliation: School of Social and Community Medicine, University of Bristol, Bristol, UK.
authors.forename: Philippa A
authors.initials: PA
authors.lastname: Davies
authors.affiliation: School of Social and Community Medicine, University of Bristol, Bristol, UK.
authors.forename: Jose A
authors.initials: JA
authors.lastname: López-López
authors.affiliation: School of Social and Community Medicine, University of Bristol, Bristol, UK.
authors.forename: George N
authors.initials: GN
authors.lastname: Okoli
authors.affiliation: School of Social and Community Medicine, University of Bristol, Bristol, UK.
authors.forename: Howard Hz
authors.initials: HH
authors.lastname: Thom
authors.affiliation: School of Social and Community Medicine, University of Bristol, Bristol, UK.
authors.forename: Deborah M
authors.initials: DM
authors.lastname: Caldwell
authors.affiliation: School of Social and Community Medicine, University of Bristol, Bristol, UK.
authors.forename: Sofia
authors.initials: S
authors.lastname: Dias
authors.affiliation: AntiCoagulation Europe, Bromley, UK.
authors.forename: Diane
authors.initials: D
authors.lastname: Eaton
authors.affiliation: School of Social and Community Medicine, University of Bristol, Bristol, UK.
authors.forename: Julian Pt
authors.initials: JP
authors.lastname: Higgins
authors.affiliation: School of Social and Community Medicine, University of Bristol, Bristol, UK.
authors.forename: Will
authors.initials: W
authors.lastname: Hollingworth
authors.affiliation: School of Social and Community Medicine, University of Bristol, Bristol, UK.
authors.forename: Chris
authors.initials: C
authors.lastname: Salisbury
authors.affiliation: School of Social and Community Medicine, University of Bristol, Bristol, UK.
authors.forename: Jelena
authors.initials: J
authors.lastname: Savović
authors.affiliation: University College London, London, UK.|London School of Hygiene and Tropical Medicine, London, UK.
authors.forename: Reecha
authors.initials: R
authors.lastname: Sofat
authors.affiliation: Thrombosis UK, Llanwrda, UK.
authors.forename: Annya
authors.initials: A
authors.lastname: Stephens-Boal
authors.affiliation: School of Social and Community Medicine, University of Bristol, Bristol, UK.
authors.forename: Nicky J
authors.initials: NJ
authors.lastname: Welton
authors.affiliation: University College London, London, UK.|London School of Hygiene and Tropical Medicine, London, UK.
authors.forename: Aroon D
authors.initials: AD
authors.lastname: Hingorani
mesh_terms: D017677:Age Distribution; D000368:Aged; D000369:Aged, 80 and over; D000925:Anticoagulants / Q000008:administration & dosage*; D001281:Atrial Fibrillation / Q000175:diagnosis*; D001794:Blood Pressure; D003362:Cost-Benefit Analysis; D004562:Electrocardiography; D005260:Female; D006801:Humans; D008297:Male; D008390:Markov Chains; D008403:Mass Screening / Q000191:economics* / Q000379:methods* / Q000592:standards; D017059:Models, Econometric; D064887:Observational Studies as Topic; D011320:Primary Health Care; D011674:Pulse; D055502:Secondary Prevention; D012680:Sensitivity and Specificity; D013222:State Medicine / Q000191:economics; D020521:Stroke / Q000517:prevention & control*; D006113:United Kingdom; D054556:Venous Thromboembolism / Q000517:prevention & control*
chemical_list: D000925:Anticoagulants