Preventing Stroke, Premature Death and Cognitive Decline in a Broader Community of Patients With Atrial Fibrillation

Study Overview
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Brief Summary
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The DaRe2 approach (healthcare Data for pragmatic clinical Research in the NHS - primary 2 secondary) is designed to operationalise efficient, nationwide, primary care approaches for randomised trials embedded within the UK National Health Service (NHS), providing automated screening, targeted patient enrolment and 'no-visit' follow-up through innovations in big data and technology solutions. DaRe2THINK will be the first exemplar of this system, and is appropriately focused on the intersection of key national priorities for healthcare; atrial fibrillation (a heart rhythm condition that will double in prevalence in the next few decades) and the impact this condition has on stroke, thromboembolic events, cognitive impairment and vascular dementia. The trial will test the hypothesis that direct oral anticoagulants (DOACs), now commonly used in older patients with atrial fibrillation (AF), are effective and cost-effective at reducing major adverse clinical events in younger patients at low or intermediate risk of stroke, and can reduce the high rate of cognitive decline. The health technology innovations noted above will allow the investigators to answer this important clinical question, as well as demonstrate the capacity and potential of this system for future, large-scale healthcare-embedded clinical trials for patient benefit.

Detailed Description
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Designed with a Patient and Public Involvement Team, DaRe2THINK is an individual-patient, open-label, event-driven randomised trial with 1:1 allocation to DOAC or no additional therapy (usual care). Automated screening will occur of over 12 million patients in England, with targeted recruitment to practices with eligible patients, regular updates to General Practitioners, simple processes for centre inclusion and patient randomisation, remote e-consent and no additional visits for any patient. The primary outcome is a comprehensive composite of any thromboembolic event, ascertained entirely using electronic healthcare records within both primary and secondary NHS care across the nation. All endpoint data will follow a pre-published coding manual for extracted electronic healthcare data. The key secondary outcome is the change in patient-reported cognitive function, using remote technology solutions to save time for clinical staff and patients. DaRe2THINK will carefully assess and validate safety outcomes relating to major and minor bleeding. A systematic health economic analysis will determine NHS and societal cost-effectiveness of DOAC therapy in this younger population of patients with AF. DaRe2THINK will initially run over a 5-year period (outcomes as listed below), with longer-term outcomes (in particular cardiovascular death, cognitive function and vascular dementia) reassessed at 10 years.

Official Title
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Preventing Stroke, Premature Death and Cognitive Decline in a Broader Community of Patients With Atrial Fibrillation Using Healthcare Data for Pragmatic Research: A Randomised Controlled Trial

Conditions
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Atrial Fibrillation

Intervention / Treatment
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* Drug: Direct Oral Anticoagulants


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of AF (previous, current or chronic) Age at enrolment ≥55 years to ≤73 years Exclusion Criteria based on coding in Primary Care: Prior documented stroke, transient ischaemic attack or systemic thromboembolism. Combination of multiple known risk factors for stroke where oral anticoagulation would ordinarily be started, including: Heart failure; Hypertension; Age 65 years or older; Diabetes mellitus; Previous myocardial infarction, peripheral artery disease or aortic plaque; and/or Female gender. Any prior history of intracranial bleeding. Prior major bleeding requiring hospitalisation in the last 3 years. Condition that poses a significant risk for bleeding (within 12 months) including gastrointestinal ulceration, brain/spinal/ophthalmic injury or surgery, arteriovenous malformations or vascular aneurysms, major intraspinal or intracerebral vascular abnormalities, hepatic disease associated with coagulopathy, known or suspected oesophageal varices, and cancers with high bleeding risk. Estimated glomerular filtration rate <30 mL/min/1.73m2 measured within the last 12 months. Patients receiving systemic treatment with azole-antimycotics within the last 3 months (ketoconazole, itraconazole, voriconazole and posaconazole). Documented diagnosis of dementia. Hypersensitivity or known intolerance to direct oral anticoagulants. Exclusion criteria based on review by Primary Care staff: Currently receiving an anticoagulant. Any clinical indication for anticoagulation. Active clinically-significant bleeding. Life expectancy estimated <2 years. Participant unable or unwilling to provide informed consent for access and linkage of past and future electronic healthcare records. Currently participating in another clinical trial. Women of childbearing potential.

Ages Eligible for Study
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Minimum Age: 55 Years
Maximum Age: 73 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Individual patient, open-label, event driven RCT with 1:1 allocation to DOAC or no additional therapy (usual care). Choice of DOAC (apixaban, dabigatran, edoxaban or rivaroxaban) according to local practice
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Direct Oral anticoagulants (DOAC)<br>Commence DOAC even with low or intermediate risk of stroke or thromboembolism, which could include currently licensed drugs apixaban, dabigatran, edoxaban or rivaroxaban; choice of drug and dose according to local practice guidelines | Drug: Direct Oral Anticoagulants<br>* choice of DOAC (apixaban, dabigatran, edoxaban or rivaroxaban) according to local practice<br>* Other names: apixaban, dabigatran, edoxaban or rivaroxaban;|
| No Intervention: No anticoagulant therapy (usual care)<br>Continuation of usual anticoagulant prescribing practice in patients with AF; e.g. according to National Institute for Health and Care Excellence (NICE), patients with AF should commence oral anticoagulation with a CHA2DS2-VASc score of 2 or above. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Composite primary endpoint - Time to first event | Composite primary endpoint - Time to first event of cardiovascular mortality, ischaemic cerebrovascular events (stroke and transient ischaemic attacks), all thromboembolic events (including venous and arterial thromboembolism), myocardial infarction and vascular dementia | 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in cognitive function using the UK Biobank fluid intelligence/reasoning test (mixed-effects repeated measures analysis) | Change in cognitive function using the UK Biobank fluid intelligence/reasoning test (mixed-effects repeated measures analysis) | 5 years | 
| Change in cognitive function using the UK Biobank trail making test (mixed-effects repeated measures analysis) | Change in cognitive function using the UK Biobank trail making test (mixed-effects repeated measures analysis) | 5 years | 
| Change in cognitive function using the UK Biobank symbol digit substitution test (mixed-effects repeated measures analysis) | Change in cognitive function using the UK Biobank symbol digit substitution test (mixed-effects repeated measures analysis) | 5 years | 
| . Change in cognitive function using the UK Biobank non-verbal fluid reasoning matrices test (mixed-effects repeated measures analysis) | . Change in cognitive function using the UK Biobank non-verbal fluid reasoning matrices test (mixed-effects repeated measures analysis) | 5 years | 
| Incremental cost per quality-adjusted life-years gained from the healthcare perspective. | Incremental cost per quality-adjusted life-years gained from the healthcare perspective. | 5 years | 
| Incremental cost per quality-adjusted life-years gained from the societal perspective. | Incremental cost per quality-adjusted life-years gained from the societal perspective. | 5 years | 
| Time to composite of major adverse cardiovascular events (non-fatal stroke, non-fatal myocardial infarction and cardiovascular death). | Time to composite of major adverse cardiovascular events (non-fatal stroke, non-fatal myocardial infarction and cardiovascular death). | 5 years | 
| Time to any major bleeding or clinically-relevant non-major bleeding that requires hospitalisation. | Time to any major bleeding or clinically-relevant non-major bleeding that requires hospitalisation. | 5 years | 
| Time to minor bleeding that requires attention from primary care (any bleeding that leads to a primary care consultation). | Time to minor bleeding that requires attention from primary care (any bleeding that leads to a primary care consultation). | 5 years | 
| Time to haemorrhagic stroke and other types of intracranial bleeding. | Time to haemorrhagic stroke and other types of intracranial bleeding. | 5 years | 
| Number of all-cause general practice visits. | Number of all-cause general practice visits. | 5 years | 
| Number of all-cause hospital admissions. | Number of all-cause hospital admissions. | 5 years | 
| Duration of all-cause hospital admissions. | Duration of all-cause hospital admissions. | 5 years | 
| Number of heart failure hospitalisations. | Number of heart failure hospitalisations. | 5 years | 
| Duration of heart failure hospitalisations. | Duration of heart failure hospitalisations. | 5 years | 
| Time to all-cause mortality. | Time to all-cause mortality. | 5 years | 
| Time to cardiovascular death | Time to cardiovascular death | 5 years | 
| Patient-reported quality of life using the Euroqol five-dimensions five-level (EQ-5D-5L) summary index score (mixed-effects repeated measures analysis) | Patient-reported quality of life using the Euroqol five-dimensions five-level (EQ-5D-5L) summary index score (mixed-effects repeated measures analysis) Range 0 = death to 1 = complete health | 5 years | 
| Patient-reported quality of life using the EQ-5D-5L visual analogue score (mixed-effects repeated measures analysis) | Patient-reported quality of life using the EQ-5D-5L visual analogue score (mixed-effects repeated measures analysis) Range 0-100, with a higer score indicating better quality of life. | 5 years | 
| Time to ischaemic cerebrovascular event (stroke and transient ischaemic attacks) | Time to ischaemic cerebrovascular event (stroke and transient ischaemic attacks) | 5 years | 
| Cumulative number of ischaemic cerebrovascular events (stroke and transient ischaemic attacks) | Cumulative number of ischaemic cerebrovascular events (stroke and transient ischaemic attacks) | 5 years | 
| Time to any thromboembolic event (including venous and arterial thromboembolism) | Time to any thromboembolic event (including venous and arterial thromboembolism) | 5 years | 
| Time to arterial thromboembolic event | Time to arterial thromboembolic event | 5 years | 
| Time to venous thromboembolic event | Time to venous thromboembolic event | 5 years | 
| Cumulative number of thromboembolic events (including venous and arterial thromboembolism) | Cumulative number of thromboembolic events (including venous and arterial thromboembolism) | 5 years | 
| Time to myocardial infarction | Time to myocardial infarction | 5 years | 
| Cumulative number of myocardial infarctions | Cumulative number of myocardial infarctions | 5 years | 
| Time to vascular dementia | Time to vascular dementia | 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Atrial fibrillation, anticoagulation, stroke, dementia