Clinical trial NCT04700826: Preventing Stroke, Premature Death and Cognitive Decline in a Broader Community of Patients With Atrial Fibrillation
Official title: 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE4
Conditions: Atrial Fibrillation
Keywords: Atrial fibrillation
anticoagulation
stroke
dementia
Lead sponsor: University of Birmingham
Sponsor class: OTHER
Collaborators: name: Clinical Practice Research Datalink
name: University Hospital Birmingham NHS Foundation Trust
name: University of Oxford
name: London School of Economics and Political Science
name: Aston University
First posted: 2021-01-08
Enrollment: 3000
Sex: ALL
Minimum age (years): 55
Maximum age (years): 73
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention 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
Primary purpose: PREVENTION

Brief summary: 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: 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.

Eligibility criteria: Inclusion Criteria:

1. Diagnosis of AF (previous, current or chronic)
2. Age at enrolment ≥55 years to ≤73 years

Exclusion Criteria based on coding in Primary Care:

1. Prior documented stroke, transient ischaemic attack or systemic thromboembolism.
2. 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.
3. Any prior history of intracranial bleeding.
4. Prior major bleeding requiring hospitalisation in the last 3 years.
5. 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.
6. Estimated glomerular filtration rate \<30 mL/min/1.73m2 measured within the last 12 months.
7. Patients receiving systemic treatment with azole-antimycotics within the last 3 months (ketoconazole, itraconazole, voriconazole and posaconazole).
8. Documented diagnosis of dementia.
9. Hypersensitivity or known intolerance to direct oral anticoagulants.

Exclusion criteria based on review by Primary Care staff:

1. Currently receiving an anticoagulant.
2. Any clinical indication for anticoagulation.
3. Active clinically-significant bleeding.
4. Life expectancy estimated \<2 years.
5. Participant unable or unwilling to provide informed consent for access and linkage of past and future electronic healthcare records.
6. Currently participating in another clinical trial.
7. Women of childbearing potential.

Primary outcomes:
measure: Composite primary endpoint - Time to first event
timeFrame: 5 years
Secondary outcomes:
measure: Change in cognitive function using the UK Biobank fluid intelligence/reasoning test (mixed-effects repeated measures analysis)
timeFrame: 5 years
measure: Change in cognitive function using the UK Biobank trail making test (mixed-effects repeated measures analysis)
timeFrame: 5 years
measure: Change in cognitive function using the UK Biobank symbol digit substitution test (mixed-effects repeated measures analysis)
timeFrame: 5 years
measure: . Change in cognitive function using the UK Biobank non-verbal fluid reasoning matrices test (mixed-effects repeated measures analysis)
timeFrame: 5 years
measure: Incremental cost per quality-adjusted life-years gained from the healthcare perspective.
timeFrame: 5 years
measure: Incremental cost per quality-adjusted life-years gained from the societal perspective.
timeFrame: 5 years
measure: Time to composite of major adverse cardiovascular events (non-fatal stroke, non-fatal myocardial infarction and cardiovascular death).
timeFrame: 5 years
measure: Time to any major bleeding or clinically-relevant non-major bleeding that requires hospitalisation.
timeFrame: 5 years
measure: Time to minor bleeding that requires attention from primary care (any bleeding that leads to a primary care consultation).
timeFrame: 5 years
measure: Time to haemorrhagic stroke and other types of intracranial bleeding.
timeFrame: 5 years
measure: Number of all-cause general practice visits.
timeFrame: 5 years
measure: Number of all-cause hospital admissions.
timeFrame: 5 years
measure: Duration of all-cause hospital admissions.
timeFrame: 5 years
measure: Number of heart failure hospitalisations.
timeFrame: 5 years
measure: Duration of heart failure hospitalisations.
timeFrame: 5 years
measure: Time to all-cause mortality.
timeFrame: 5 years
measure: Time to cardiovascular death
timeFrame: 5 years
measure: Patient-reported quality of life using the Euroqol five-dimensions five-level (EQ-5D-5L) summary index score (mixed-effects repeated measures analysis)
timeFrame: 5 years
measure: Patient-reported quality of life using the EQ-5D-5L visual analogue score (mixed-effects repeated measures analysis)
timeFrame: 5 years
measure: Time to ischaemic cerebrovascular event (stroke and transient ischaemic attacks)
timeFrame: 5 years
measure: Cumulative number of ischaemic cerebrovascular events (stroke and transient ischaemic attacks)
timeFrame: 5 years
measure: Time to any thromboembolic event (including venous and arterial thromboembolism)
timeFrame: 5 years
measure: Time to arterial thromboembolic event
timeFrame: 5 years
measure: Time to venous thromboembolic event
timeFrame: 5 years
measure: Cumulative number of thromboembolic events (including venous and arterial thromboembolism)
timeFrame: 5 years
measure: Time to myocardial infarction
timeFrame: 5 years
measure: Cumulative number of myocardial infarctions
timeFrame: 5 years
measure: Time to vascular dementia
timeFrame: 5 years
Other outcomes:
measure: Potential participants located by CPRD
timeFrame: 5 years
measure: Primary care practices completing sign up
timeFrame: 5 years
measure: Patients on automated screening successfully recruited
timeFrame: 5 years
measure: Rate of patient recruitment
timeFrame: 5 years
measure: Patient reported compliance
timeFrame: 5 years
measure: Repeat prescriptions for DOAC
timeFrame: 5 years
measure: Proportion of participant time-points with missing data for EQ-5D-5L patient-reported quality of life
timeFrame: 5 years
measure: Proportion of participant time-points with missing data for cognitive function using the UK Biobank fluid intelligence/reasoning test
timeFrame: 5 years
Locations:
city: Birmingham
country: United Kingdom
facility: University Hospitals Birmingham
state: West Midlands
Study officials:
affiliation: University of Birmingham and University Hospitals Birmingham NHS Foundation Trust
name: Dipak Kotecha
role: PRINCIPAL_INVESTIGATOR
affiliation: St George's University of London; Chair of DaRe2THINK Independent TSC
name: John Camm
role: STUDY_CHAIR
affiliation: Norwich Medical School; Chaire of DaRe2THINK Independent DMC
name: Marcus Flather
role: STUDY_CHAIR
affiliation: Deputy CI; Lead for NIHR West Midlands Primary Care CRN Team
name: David Shukla
role: PRINCIPAL_INVESTIGATOR
References:
citation: Wang X, Mobley AR, Tica O, Okoth K, Ghosh RE, Myles P, Williams T, Haynes S, Nirantharakumar K, Shukla D, Kotecha D; DaRe2THINK Trial Committees. Systematic approach to outcome assessment from coded electronic healthcare records in the DaRe2THINK NHS-embedded randomized trial. Eur Heart J Digit Health. 2022 Sep 16;3(3):426-436. doi: 10.1093/ehjdh/ztac046. eCollection 2022 Sep.
citation: Mobley AR, Subramanian A, Champsi A, Wang X, Myles P, McGreavy P, Bunting KV, Shukla D, Nirantharakumar K, Kotecha D. Thromboembolic events and vascular dementia in patients with atrial fibrillation and low apparent stroke risk. Nat Med. 2024 Aug;30(8):2288-2294. doi: 10.1038/s41591-024-03049-9. Epub 2024 Jun 5.
citation: Champsi A, Mobley AR, Subramanian A, Nirantharakumar K, Wang X, Shukla D, Bunting KV, Molgaard I, Dwight J, Arroyo RC, Crijns HJGM, Guasti L, Lettino M, Lumbers RT, Maesen B, Rienstra M, Svennberg E, Tica O, Traykov V, Tzeis S, van Gelder I, Kotecha D. Gender and contemporary risk of adverse events in atrial fibrillation. Eur Heart J. 2024 Sep 29;45(36):3707-3717. doi: 10.1093/eurheartj/ehae539.