Information for Healthcare Professionals

Research question

To elucidate if the mechanism of action of DOACs to preserve cognitive function in patients with atrial fibrillation (AF) is due to the prevention of cerebral white matter lesions, reduction in incident silent brain infarcts, protection of cognitive neural tracts, or an overall decrease in the burden of vascular disease.


AF is the most common heart rhythm abnormality, expected to double in prevalence in the next few decades, and leading to considerable burdens on the NHS and society.  AF has a major impact on stroke, cognitive decline and vascular dementia, which are all key public health concerns.  The newer direct oral anticoagulants (DOACs), if started at an earlier age, could provide protection against these adverse outcomes.  This will be tested in DaRe2THINK, an innovative and NHS-embedded primary care trial funded by NIHR-HTA.

Aims and objectives

In this sub-study, we aim to explain the reasons for cognitive decline and development of vascular dementia in patients with AF, and determine the mechanism of action of DOACs, separating out the effects on cerebrovascular disease from overall vascular disease burden. 


DaRe2THINK is an individual-patient, open-label, event-driven randomised trial with 1:1 allocation to DOAC or no additional therapy (usual care), supported by extensive Patient and Public Involvement (PPI).  The trial will use automated and targeted screening through NHS Primary Care, remote enrolment, and outcomes derived from NHS electronic records.  This sub-study will recruit 160 patients from the 3000 that will be randomised in DaRe2THINK, with visits at baseline and 3-years comprising: (1) Structural and functional brain magnetic resonance imaging (MRI) demonstrating change in white matter hyperintensities (WMH), cerebral infarction and connectivity/tractography; (2) Structural and functional retinal imaging providing real-time assessment of vascular disease burden; and (3) Cognitive function testing using gold-standard methods.  Participants with claustrophobia or implanted clips/devices that prohibit the use of MRI will be excluded; all other patients recruited in the West Midlands will be approached consecutively until recruitment is completed.  Sample size is based on the number of participants required for the primary outcome of new cerebral infarction or at least moderate WMH, and the key secondary outcome of retinal capillary density of the radial peripapillary capillary network. 

Timelines for delivery

Total duration 48 months, including a 6-month period for baseline scans within 3 months of patient randomisation, and 4-6 months for follow-up scans after a 3-year interval.   

Inclusion and Exclusion Criteria

Inclusion Criteria:

Consents to join DaRe2THINK-NV within 3 months of randomisation in DaRe2THINK. 

Exclusion Criteria:

  1. Claustrophobia prohibiting the use of MRI. 
  2. Contraindication to MRI scanning due to implanted metal clips or devices with the potential to cause tissue damage in a magnetic field (e.g. aneurysm clips and certain cardiac pacemakers). 
  3. Weight over 30 stone or 190 kg (maximum limit for MRI scanner).