Title: Neuro-vascular mechanisms of direct oral anticoagulant therapy in younger patients with atrial fibrillation: the DaRe2THINK-NV sub-study
Funder: Medical Research Council

Abstract: Atrial fibrillation (AF) is a common heart rhythm condition that leads to a high chance of stroke, frequent hospital admissions and poor quality of life. Patients also have a much higher risk of cognitive decline (trouble remembering, concentrating or making every-day decisions) and dementia. This may be due to silent ‘micro-strokes’ that gradually damage the brain over time. Blood thinning tablets are used for NHS patients with AF to lower the risk of stroke, but are usually only given to older patients or those with other health issues. This may be too late to avoid dementia._x000D_ _x000D_ DaRe2THINK is a new way of running trials that will use the health data already collected within the NHS for research that benefits the care of patients. Based at GP surgeries across England, this trial will include patients that don’t normally take part in clinical trials, and follow them up without the need for additional visits. The trial, funded by the UK Department of Health, will include 3000 younger patients with AF. On a random basis, each patient will either continue their current treatment, or start a newer type of blood thinning tablet (a direct oral anticoagulant)._x000D_ _x000D_ Whilst the main trial will show whether these blood thinning tablets work to prevent strokes and blood clots, we still need to understand how they work, which patients benefit the most, and why some patients with AF develop dementia. This study within the main trial will help us to understand if these drugs work by preventing damage to the brain, whether they protect the structure of the brain (and so preserve brain function), or if they impact on blood vessels throughout the body._x000D_ _x000D_ 160 patients who are already taking part in DaRe2THINK and live near the West Midlands will be asked to undergo additional tests within a few months of joining the main trial. Half of the patients will be receiving blood thinners, and half from those on their normal medications. The tests include a brain magnet scan which is painless with no x-rays, reaction times and memory tests on a handheld computer, and eye tests. By looking at the blood vessels in the eye with a special camera, we can see what is happening to blood vessels everywhere. In total, these tests will take about 2 hours and will be repeated only once after 3 years. The design of the study has been advised by a Patient and Public Involvement team. Including this study within an existing trial means we can take advantage of the random assignment to blood thinners._x000D_ _x000D_ This study will target an issue of huge importance to patients, our NHS and the social care system. Understanding how blood thinners can prevent these micro-strokes could help doctors to personalise the management of patients, not only with AF, but also similar conditions that affect the blood vessels around the body. Preventing cognitive decline and dementia is a major public health priority for the NHS.

Lay abstract: Research question: To elucidate if the mechanism of action of direct oral anticoagulants (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._x000D_ _x000D_ Background: 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 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 the UK National Institute for Health Research (NIHR)._x000D_ _x000D_ 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._x000D_ _x000D_ Methods: 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 tractography; (2) Structural and functional retinal imaging providing real-time assessment of vascular disease burden; and (3) Cognitive function testing using best-practice methods. Participants with claustrophobia or implanted clips/devices that prohibit the use of MRI will be excluded; all other patients recruited in/near 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 on follow-up MRI or at least moderate WMH, and the key secondary outcome of retinal capillary density of the radial peripapillary capillary network._x000D_ _x000D_ 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._x000D_ _x000D_ Anticipated impact and dissemination: Mechanistic understanding of the role of DOACs in prevention of micro and macro-vascular disease both within and outside the brain could facilitate personalised approaches to prevention of cognitive decline and vascular dementia in younger patients with AF, as well as other multi-system thrombo-inflammatory conditions. Causative assessment of cognitive decline with interval vascular imaging could inform the use of simple preventative measures within NHS primary care. Results will be disseminated through the NIHR Primary Care Clinical Research Network and the PPI team assisted by AF patient support groups.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CARDIOVASCULAR