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

NCT ID: NCT04700826

Last Updated: 2025-05-16

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE4
• Total Enrollment: 3000 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2021-06-01
• Study Completion Date: 2031-01-31

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.

Conditions

Atrial Fibrillation

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: PREVENTION
• Blinding Strategy: NONE

Study Groups

Direct Oral anticoagulants (DOAC)

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

Group Type: EXPERIMENTAL

Direct Oral Anticoagulants

Intervention Type: DRUG

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

No anticoagulant therapy (usual care)

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.

Group Type: NO_INTERVENTION

No interventions assigned to this group

Interventions

Direct Oral Anticoagulants

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

Intervention Type: DRUG

Other Intervention Names

apixaban, dabigatran, edoxaban or rivaroxaban

Eligibility Criteria

Inclusion Criteria

1. Diagnosis of AF (previous, current or chronic)

2. Age at enrolment ≥55 years to ≤73 years

Exclusion Criteria

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.

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.

• Minimum Eligible Age: 55 Years
• Maximum Eligible Age: 73 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Clinical Practice Research Datalink

OTHER_GOV

Sponsor Role: collaborator

University Hospital Birmingham NHS Foundation Trust

OTHER

Sponsor Role: collaborator

University of Oxford

OTHER

Sponsor Role: collaborator

London School of Economics and Political Science

OTHER

Sponsor Role: collaborator

Aston University

OTHER

Sponsor Role: collaborator

University of Birmingham

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Dipak Kotecha

Role: PRINCIPAL_INVESTIGATOR

University of Birmingham and University Hospitals Birmingham NHS Foundation Trust

John Camm

Role: STUDY_CHAIR

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

Marcus Flather

Role: STUDY_CHAIR

Norwich Medical School; Chaire of DaRe2THINK Independent DMC

David Shukla

Role: PRINCIPAL_INVESTIGATOR

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

Locations

University Hospitals Birmingham

Birmingham, West Midlands, United Kingdom

Site Status: RECRUITING

Countries

United Kingdom

Central Contacts

Alastair Mobley, BSc

Role: CONTACT

a.mobley@bham.ac.uk

+44 121 371 4225

Dipak Kotecha

Role: CONTACT

d.kotecha@bham.ac.uk

+44 121 371 4225

Facility Contacts

Minnie Ventura

Role: primary

Maximina.Ventura@uhb.nhs.uk

0121 371 8145

References

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.

Reference Type: BACKGROUND

PMID: 36712153 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 38839900 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 39217497 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Other Identifiers

290420

Identifier Type: OTHER

Identifier Source: secondary_id

ERN_20-1747

Identifier Type: -

Identifier Source: org_study_id