Title: Preventing stroke, premature death and cognitive decline in a broader community of patients with atrial fibrillation using healthcare data for pragmatic research (DaRe2THINK)
Funder: Department of Health and Social Care

Abstract: The National Health Service (NHS) is unlike any other in the world, caring for people throughout their lives both in the community and in hospitals. At the heart of DaRe2THINK is that health data collected within these services can be used for the benefit of patients. Clinical trials are an important way to understand how new treatments can be used in the NHS, but many trials struggle to find the right patients, or be relevant to their needs. The DaRe2 approach (healthcare Data for pragmatic clinical Research in the NHS – primary 2 secondary) will test a new way of running trials based at General Practitioner (GP) surgeries using routine NHS information. We will include patients that don’t normally take part in clinical trials and follow them up without the need to revisit their GP or attend hospital. This approach could improve the health and well-being of those treated by the NHS, whilst reducing the time needed from staff and patients to engage in important research._x000D_ _x000D_ As an example of this new system, DaRe2THINK will target an issue of huge importance to patients, our NHS and the social care system. 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 (anticoagulants) greatly reduce the number of patients with AF that will suffer a stroke, but are usually only given to older patients or those with other health issues. This may be too late to avoid dementia. It also leaves those younger than 65 years, and some patients aged 65-75 without treatment that could prevent these devastating complications._x000D_ _x000D_ A new class of blood thinning tablets are now widely used in the NHS which are more convenient for patients to take, and have a lower risk of bleeding than older treatments. These drugs could provide an effective way to prevent strokes, brain damage and dementia in later life for a broader group of patients, but this needs to be tested in a clinical trial. With the support of a Patient and Public Involvement Team and a national network of research nurses and GPs, the trial will include 3,000 patients from up to 600 GP surgeries across England. Each patient will either continue their current treatment or start an additional blood thinning tablet on a random basis. Patients will be followed up automatically within the NHS to look at the difference in those who suffer from strokes, blood clots, heart attacks, other problems with the blood vessels and dementia. Patients will self-report their memory, reaction times and quality of life using simple questionnaires through their mobile phone or the internet, again without needing to revisit their doctor._x000D_ _x000D_ DaRe2THINK will answer important questions for a growing number of patients with AF. The combination of information from the community as well as hospitals across the NHS will allow us to see whether these blood thinning tablets should be prescribed more widely. DaRe2THINK will allow us to develop and improve this new clinical trial system so that future research in the NHS will continue to benefit those patients most in need.

Lay abstract: Research question: Using an efficient, nationwide, primary care approach for an NHS-embedded randomised controlled trial (RCT), does direct oral anticoagulant (DOAC) therapy reduce premature death, stroke and other thromboembolic consequences of atrial fibrillation (AF) in younger patients, including prevention of cognitive decline and vascular dementia?_x000D_ _x000D_ Background: Current RCT methodology often leads to recruitment of highly selected participants with less diversity than the clinical population, and challenges with enrolment and retention of patients. New RCT approaches are needed that can realise the value of the world-leading data quality and infrastructure of the NHS. AF is the most common heart rhythm abnormality, expected to double in prevalence in the next few decades, and leads to a considerable burden for patients and society at-large. In particular, the impact of stroke, cognitive decline and vascular dementia are all major public health concerns._x000D_ _x000D_ Aims and objectives: DaRe2THINK will test the hypothesis that DOACs are effective and cost-effective in patients with AF at low or intermediate risk of stroke by using an ambitious and innovative data-enabled approach through the Clinical Practice Research Datalink (CPRD) in Primary Care General Practices across England._x000D_ _x000D_ Methods: Individual-patient, open-label, event-driven RCT with 1:1 allocation to DOAC or no additional therapy (usual care). Automated screening of over 12 million patients, with targeted recruitment to practices with eligible patients, regular updates to General Practitioners, simple processes for centre inclusion and patient randomisation, and no additional visits after baseline for any patient. The primary outcome is a comprehensive composite of any thromboembolic event, including cardiovascular mortality, ischaemic stroke, pulmonary or venous thromboembolism, myocardial infarction and vascular dementia, ascertained entirely using electronic healthcare records within both primary and secondary NHS care. The key secondary outcome is the change in cognitive function, using technology solutions to provide ‘no-visit’ patient-reported follow-up, saving time for clinical staff and patients. We will carefully assess and validate safety outcomes relating to major and minor bleeding, and a systematic health economic analysis will determine NHS and societal cost-effectiveness._x000D_ _x000D_ Timelines for delivery: Total duration 60 months, including 3-stage internal pilot (8 months), patient recruitment (total 24 months), and additional 36 months follow-up for primary and secondary outcomes._x000D_ _x000D_ Anticipated impact and dissemination: DaRe2THINK will demonstrate the operational capabilities of using the NHS record for interventional research. We will recruit a diverse, population-relevant cohort using automated nationwide screening, prioritisation of centres with recruitable patients, and remote technology-enhanced follow-up. These innovations will allow us to answer a key question for 21st century healthcare relating to an increasingly common condition with considerable burden on patient quality of life, the health of the nation and our economy. Current and future impacts from AF and vascular dementia will be unsustainable unless we can expand prevention. DaRe2THINK will develop close collaboration between the NIHR Clinical Research Network, CPRD, patient groups, academic institutions and the NHS to address this and future evidence-gaps in clinical practice.

Research activity codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING;6.1 PHARMACEUTICALS
Health categories: CARDIOVASCULAR;NEUROLOGICAL;STROKE