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

NCT04700826 | Recruiting Phase 4 DMC

• 2 other identifiers: ERN_20-1747290420
• Study Type: interventional
• Target: 3,000
• Locations: 1 country
• Sites: 1

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.

Conditions

Atrial Fibrillation

Keywords

Atrial fibrillation; anticoagulation; stroke; dementia

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (28)

• 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)

  5 years

• 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)

  5 years

• Incremental cost per quality-adjusted life-years gained from the healthcare perspective.

  5 years

Other Outcomes (8)

• Potential participants located by CPRD

  5 years

• Primary care practices completing sign up

  5 years

• Patients on automated screening successfully recruited

  5 years

Study Arms (2)

Direct Oral anticoagulants (DOAC)

EXPERIMENTAL

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

No anticoagulant therapy (usual care)

NO INTERVENTION

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.

Interventions

Direct Oral Anticoagulants DRUG

choice of DOAC (apixaban, dabigatran, edoxaban or rivaroxaban) according to local practice

Also known as: apixaban, dabigatran, edoxaban or rivaroxaban

Direct Oral anticoagulants (DOAC)

Eligibility Criteria

• Age: 55 Years - 73 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

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

You may not qualify if:

• 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.
• 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.

Sponsors & Collaborators

• University of Birmingham: lead
• Clinical Practice Research Datalink: collaborator
• University Hospital Birmingham NHS Foundation Trust: collaborator
• University of Oxford: collaborator
• London School of Economics and Political Science: collaborator
• Aston University: collaborator

Study Sites (1)

University Hospitals Birmingham

Birmingham, West Midlands, B15 2TH, United Kingdom

RECRUITING

Related Publications (3)

• 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.

  PMID: 36712153 BACKGROUND

• 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.

  PMID: 38839900 BACKGROUND

• 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.

  PMID: 39217497 BACKGROUND

MeSH Terms

Conditions

Atrial Fibrillation; Stroke; Dementia

Interventions

N(4)-oleylcytosine arabinoside; apixaban; Dabigatran; edoxaban; Rivaroxaban

Condition Hierarchy (Ancestors)

Arrhythmias, Cardiac; Heart Diseases; Cardiovascular Diseases; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Neurocognitive Disorders; Mental Disorders

Intervention Hierarchy (Ancestors)

Pyridines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Benzimidazoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Thiophenes; Sulfur Compounds; Organic Chemicals; Morpholines; Oxazines

Study Officials

• Dipak Kotecha

  University of Birmingham and University Hospitals Birmingham NHS Foundation Trust

  PRINCIPAL INVESTIGATOR

• John Camm

  St George's University of London; Chair of DaRe2THINK Independent TSC

  STUDY CHAIR

• Marcus Flather

  Norwich Medical School; Chaire of DaRe2THINK Independent DMC

  STUDY CHAIR

• David Shukla

  Deputy CI; Lead for NIHR West Midlands Primary Care CRN Team

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Alastair Mobley, BSc

CONTACT

+44 121 371 4225; a.mobley@bham.ac.uk

Dipak Kotecha

CONTACT

+44 121 371 4225; d.kotecha@bham.ac.uk

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: 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

Study Record Dates

• First Submitted: December 4, 2020
• First Posted: January 8, 2021
• Study Start: June 1, 2021
• Primary Completion (Estimated): December 1, 2027
• Study Completion (Estimated): January 1, 2031
• Last Updated: May 16, 2025

Record last verified: 2024-12

Data Sharing

• IPD Sharing: Will not share

Locations

GB (1)