Background:

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.

Objective:

To determine the best oral anticoagulant/s for prevention of stroke in AF and for primary prevention, treatment and secondary prevention of VTE.

Design:

Four systematic reviews, network meta-analyses (NMAs) and cost-effectiveness analyses (CEAs) of randomised controlled trials.

Setting:

Hospital (VTE primary prevention and acute treatment) and primary care/anticoagulation clinics (AF and VTE secondary prevention).

Participants:

Patients eligible for anticoagulation with warfarin (stroke prevention in AF, acute treatment or secondary prevention of VTE) or LMWH (primary prevention of VTE).

Interventions:

NOACs, warfarin and LMWH, together with other interventions (antiplatelet therapy, placebo) evaluated in the evidence network.

Main outcome measures:

Efficacy Stroke, symptomatic VTE, symptomatic deep-vein thrombosis and symptomatic pulmonary embolism. Safety Major bleeding, clinically relevant bleeding and intracranial haemorrhage. We also considered myocardial infarction and all-cause mortality and evaluated cost-effectiveness.

Data sources:

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.

Review methods:

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.

Results:

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.

Conclusions:

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.

Limitations:

These relate mainly to shortfalls in the primary data: in particular, there were no head-to-head comparisons between different NOAC drugs.

Future work:

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.

Study registration:

This study is registered as PROSPERO CRD42013005324, CRD42013005331 and CRD42013005330.

Funding:

The National Institute for Health Research Health Technology Assessment programme.

Article history

The research reported in this issue of the journal was funded by the HTA programme as project number 11/92/17. The contractual start date was in October 2013. The draft report began editorial review in May 2015 and was accepted for publication in December 2015. The authors have been wholly responsible for all data collection, analysis and interpretation, and for writing up their work. The HTA editors and publisher have tried to ensure the accuracy of the authors’ report and would like to thank the reviewers for their constructive comments on the draft document. However, they do not accept liability for damages or losses arising from material published in this report.

Declared competing interests of authors

Jonathan AC Sterne was a National Institute for Health Research (NIHR) Health Technology Assessment Clinical Trial Board member from 2010 to 2014 and is a NIHR Senior Investigator (award NF-SI-0611-10168). Chris Salisbury is a NIHR Health Services and Delivery Research Board member, and also reports receipt of a research grant from NIHR. Howard HZ Thom reports personal fees for consultancy work from Novartis Pharma, Eli Lilly and company, and ICON Plc, all outside this work. Sofia Dias reports grants from NIHR, Novartis and Pfizer, all outside this work. Diane Eaton reports other from Boehringer Ingelheim, Pfizer, Bayer, Leo Pharmaceuticals and Bristol-Myers Squib, outside the submitted work, and AntiCoagulation Europe (ACE), a registered charity, the aims of which include raising awareness of the risk and prevention of thrombosis, and providing information, education and support to people who are on anticoagulation therapy for any duration, including long term for those with chronic conditions. Diane Eaton works with ACE in an associate consultant capacity in the role of Project Development Manager. She has over 40 years of personal experience of anticoagulation therapy and represents ACE as a patient expert at the National Institute for Health and Care Excellence (NICE). On behalf of the charity, she has provided the patient perspective for the submissions for the technology appraisals for the novel oral anticoagulants (NOACs) and Diagnostic Guidance for Coagulometers over a 4-year period. Please note that the financial information has been prepared by Eve Knight, Chief Executive of AntiCoagulation Europe, for the purpose of inclusion in this document.