Preventing stroke, premature death and cognitive decline in a broader community of patients with atrial fibrillation using healthcare data for pragmatic research (DaRe2THINK)

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? 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. 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. 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. 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. 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.