<jats:sec id="abs1-1"><jats:title>Background</jats:title><jats:p>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.</jats:p></jats:sec><jats:sec id="abs1-2"><jats:title>Objective</jats:title><jats:p>To determine the best oral anticoagulant/s for prevention of stroke in AF and for primary prevention, treatment and secondary prevention of VTE.</jats:p></jats:sec><jats:sec id="abs1-3"><jats:title>Design</jats:title><jats:p>Four systematic reviews, network meta-analyses (NMAs) and cost-effectiveness analyses (CEAs) of randomised controlled trials.</jats:p></jats:sec><jats:sec id="abs1-4"><jats:title>Setting</jats:title><jats:p>Hospital (VTE primary prevention and acute treatment) and primary care/anticoagulation clinics (AF and VTE secondary prevention).</jats:p></jats:sec><jats:sec id="abs1-5"><jats:title>Participants</jats:title><jats:p>Patients eligible for anticoagulation with warfarin (stroke prevention in AF, acute treatment or secondary prevention of VTE) or LMWH (primary prevention of VTE).</jats:p></jats:sec><jats:sec id="abs1-6"><jats:title>Interventions</jats:title><jats:p>NOACs, warfarin and LMWH, together with other interventions (antiplatelet therapy, placebo) evaluated in the evidence network.</jats:p></jats:sec><jats:sec id="abs1-7"><jats:title>Main outcome measures</jats:title><jats:p><jats:italic>Efficacy</jats:italic> Stroke, symptomatic VTE, symptomatic deep-vein thrombosis and symptomatic pulmonary embolism.<jats:italic>Safety</jats:italic> Major bleeding, clinically relevant bleeding and intracranial haemorrhage. We also considered myocardial infarction and all-cause mortality and evaluated cost-effectiveness.</jats:p></jats:sec><jats:sec id="abs1-8"><jats:title>Data sources</jats:title><jats:p>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.</jats:p></jats:sec><jats:sec id="abs1-9"><jats:title>Review methods</jats:title><jats:p>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.</jats:p></jats:sec><jats:sec id="abs1-10"><jats:title>Results</jats:title><jats:p>Apixaban (Eliquis<jats:sup>®</jats:sup>, 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<jats:sup>®</jats:sup>, 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.</jats:p></jats:sec><jats:sec id="abs1-11"><jats:title>Conclusions</jats:title><jats:p>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.</jats:p></jats:sec><jats:sec id="abs1-12"><jats:title>Limitations</jats:title><jats:p>These relate mainly to shortfalls in the primary data: in particular, there were no head-to-head comparisons between different NOAC drugs.</jats:p></jats:sec><jats:sec id="abs1-13"><jats:title>Future work</jats:title><jats:p>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.</jats:p></jats:sec><jats:sec id="abs1-14"><jats:title>Study registration</jats:title><jats:p>This study is registered as PROSPERO CRD42013005324, CRD42013005331 and CRD42013005330.</jats:p></jats:sec><jats:sec id="abs1-15"><jats:title>Funding</jats:title><jats:p>The National Institute for Health Research Health Technology Assessment programme.</jats:p></jats:sec>