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Preventing Stroke, Premature Death and Cognitive Decline in a Broader Community of Patients With Atrial Fibrillation (DaRe2THINK)

Primary Purpose

Atrial Fibrillation

Status

Recruiting

Phase

Phase 4

Locations

United Kingdom

Study Type

Interventional

Intervention

Direct Oral Anticoagulants

About this trial

This is an interventional prevention trial for Atrial Fibrillation focused on measuring Atrial fibrillation, anticoagulation, stroke, dementia

Eligibility Criteria

55 Years - 73 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Diagnosis of AF (previous, current or chronic)
Age >=60 years to <=73 years

Exclusion Criteria:

Existing use of an anticoagulant.
Another clinical indication for anticoagulation.
Hypersensitivity or known intolerance to direct oral anticoagulants.
Prior documented stroke, transient ischaemic attack or thromboembolism.
Two or more CHA2DS2-VASc one-point risk factors: Heart failure (confirmed by use of loop diuretic therapy within the last 3 months); Hypertension (confirmed by use of anti-hypertensive therapy within the last 3 months); Age 65 years or older; Diabetes mellitus (confirmed by use of oral antidiabetic therapy or insulin within the last 3 months); Previous myocardial infarction, peripheral artery disease or aortic plaque; and/or Female gender.
Active clinically-significant bleeding
Prior major bleeding, defined as any intracranial bleed, or bleeding that resulted in a drop in haemoglobin ≥2g/dL, required hospitalisation or transfusion.
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 6 months.
Patients receiving systemic treatment with azole-antimycotics within the last 3 months (ketoconazole, itraconazole, voriconazole and posaconazole).
Current diagnosis of dementia.
Life expectancy <2 years.
Unable or unwilling to provide informed consent for access and linkage of past and future electronic healthcare records.

Sites / Locations

University Hospitals BirminghamRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

No Intervention

Arm Label

Direct Oral anticoagulants (DOAC)

No anticoagulant therapy (usual care)

Arm Description

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

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.

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

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 trail making test (mixed-effects repeated measures analysis)

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 non-verbal fluid reasoning matrices test (mixed-effects repeated measures analysis)

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

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

Time to composite of major adverse cardiovascular events (non-fatal stroke, non-fatal myocardial infarction and cardiovascular death).

Time to any major bleeding or clinically-relevant non-major bleeding that requires hospitalisation.

Time to minor bleeding that requires attention from primary care (any bleeding that leads to a primary care consultation).

Time to haemorrhagic stroke and other types of intracranial bleeding.

Number of all-cause general practice visits.

Number of all-cause hospital admissions.

Duration of all-cause hospital admissions.

Number of heart failure hospitalisations.

Duration of heart failure hospitalisations.

Time to all-cause mortality.

Time to cardiovascular death

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

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.

Time to ischaemic cerebrovascular event (stroke and transient ischaemic attacks)

Cumulative number of ischaemic cerebrovascular events (stroke and transient ischaemic attacks)

Time to any thromboembolic event (including venous and arterial thromboembolism)

Time to arterial thromboembolic event

Time to venous thromboembolic event

Cumulative number of thromboembolic events (including venous and arterial thromboembolism)

Time to myocardial infarction

Cumulative number of myocardial infarctions

Time to vascular dementia

Full Information

NCT ID

NCT04700826

First Posted

December 4, 2020

Last Updated

May 9, 2023

Sponsor

University of Birmingham

Collaborators

Clinical Practice Research Datalink, University Hospital Birmingham NHS Foundation Trust, University of Oxford, London School of Economics and Political Science, Aston University

1. Study Identification

Unique Protocol Identification Number

NCT04700826

Brief Title

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

Acronym

DaRe2THINK

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

2. Study Status

Record Verification Date

May 2023

Overall Recruitment Status

Recruiting

Study Start Date

June 1, 2021 (Actual)

Primary Completion Date

January 2026 (Anticipated)

Study Completion Date

January 2031 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

University of Birmingham

Collaborators

Clinical Practice Research Datalink, University Hospital Birmingham NHS Foundation Trust, University of Oxford, London School of Economics and Political Science, Aston University

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Product Manufactured in and Exported from the U.S.

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Atrial Fibrillation

Keywords

Atrial fibrillation, anticoagulation, stroke, dementia

7. Study Design

Primary Purpose

Prevention

Study Phase

Phase 4

Interventional Study Model

Parallel Assignment

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)

Allocation

Randomized

Enrollment

3000 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Direct Oral anticoagulants (DOAC)

Arm Type

Experimental

Arm Description

Arm Title

No anticoagulant therapy (usual care)

Arm Type

No Intervention

Arm Description

Intervention Type

Drug

Intervention Name(s)

Direct Oral Anticoagulants

Other Intervention Name(s)

apixaban, dabigatran, edoxaban or rivaroxaban

Intervention Description

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

Primary Outcome Measure Information:

Title

Composite primary endpoint - Time to first event

Description

Time Frame

5 years

Secondary Outcome Measure Information:

Title

Change in cognitive function using the UK Biobank fluid intelligence/reasoning test (mixed-effects repeated measures analysis)

Description

Change in cognitive function using the UK Biobank fluid intelligence/reasoning test (mixed-effects repeated measures analysis)

Time Frame

5 years

Title

Change in cognitive function using the UK Biobank trail making test (mixed-effects repeated measures analysis)

Description

Change in cognitive function using the UK Biobank trail making test (mixed-effects repeated measures analysis)

Time Frame

5 years

Title

Change in cognitive function using the UK Biobank symbol digit substitution test (mixed-effects repeated measures analysis)

Description

Change in cognitive function using the UK Biobank symbol digit substitution test (mixed-effects repeated measures analysis)

Time Frame

5 years

Title

. Change in cognitive function using the UK Biobank non-verbal fluid reasoning matrices test (mixed-effects repeated measures analysis)

Description

. Change in cognitive function using the UK Biobank non-verbal fluid reasoning matrices test (mixed-effects repeated measures analysis)

Time Frame

5 years

Title

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

Description

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

Time Frame

5 years

Title

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

Description

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

Time Frame

5 years

Title

Time to composite of major adverse cardiovascular events (non-fatal stroke, non-fatal myocardial infarction and cardiovascular death).

Description

Time to composite of major adverse cardiovascular events (non-fatal stroke, non-fatal myocardial infarction and cardiovascular death).

Time Frame

5 years

Title

Time to any major bleeding or clinically-relevant non-major bleeding that requires hospitalisation.

Description

Time to any major bleeding or clinically-relevant non-major bleeding that requires hospitalisation.

Time Frame

5 years

Title

Time to minor bleeding that requires attention from primary care (any bleeding that leads to a primary care consultation).

Description

Time to minor bleeding that requires attention from primary care (any bleeding that leads to a primary care consultation).

Time Frame

5 years

Title

Time to haemorrhagic stroke and other types of intracranial bleeding.

Description

Time to haemorrhagic stroke and other types of intracranial bleeding.

Time Frame

5 years

Title

Number of all-cause general practice visits.

Description

Number of all-cause general practice visits.

Time Frame

5 years

Title

Number of all-cause hospital admissions.

Description

Number of all-cause hospital admissions.

Time Frame

5 years

Title

Duration of all-cause hospital admissions.

Description

Duration of all-cause hospital admissions.

Time Frame

5 years

Title

Number of heart failure hospitalisations.

Description

Number of heart failure hospitalisations.

Time Frame

5 years

Title

Duration of heart failure hospitalisations.

Description

Duration of heart failure hospitalisations.

Time Frame

5 years

Title

Time to all-cause mortality.

Description

Time to all-cause mortality.

Time Frame

5 years

Title

Time to cardiovascular death

Description

Time to cardiovascular death

Time Frame

5 years

Title

Patient-reported quality of life using the Euroqol five-dimensions five-level (EQ-5D-5L) summary index score (mixed-effects repeated measures analysis)

Description

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

Time Frame

5 years

Title

Patient-reported quality of life using the EQ-5D-5L visual analogue score (mixed-effects repeated measures analysis)

Description

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.

Time Frame

5 years

Title

Time to ischaemic cerebrovascular event (stroke and transient ischaemic attacks)

Description

Time to ischaemic cerebrovascular event (stroke and transient ischaemic attacks)

Time Frame

5 years

Title

Cumulative number of ischaemic cerebrovascular events (stroke and transient ischaemic attacks)

Description

Cumulative number of ischaemic cerebrovascular events (stroke and transient ischaemic attacks)

Time Frame

5 years

Title

Time to any thromboembolic event (including venous and arterial thromboembolism)

Description

Time to any thromboembolic event (including venous and arterial thromboembolism)

Time Frame

5 years

Title

Time to arterial thromboembolic event

Description

Time to arterial thromboembolic event

Time Frame

5 years

Title

Time to venous thromboembolic event

Description

Time to venous thromboembolic event

Time Frame

5 years

Title

Cumulative number of thromboembolic events (including venous and arterial thromboembolism)

Description

Cumulative number of thromboembolic events (including venous and arterial thromboembolism)

Time Frame

5 years

Title

Time to myocardial infarction

Description

Time to myocardial infarction

Time Frame

5 years

Title

Cumulative number of myocardial infarctions

Description

Cumulative number of myocardial infarctions

Time Frame

5 years

Title

Time to vascular dementia

Description

Time to vascular dementia

Time Frame

5 years

Other Pre-specified Outcome Measures:

Title

Potential participants located by CPRD

Description

Number/proportion of potential participants located by CPRD and notified to the lead NIHR Clinical Research Network (CRN)

Time Frame

5 years

Title

Primary care practices completing sign up

Description

Number/proportion of primary care practices that have completed sign-up processes

Time Frame

5 years

Title

Patients on automated screening successfully recruited

Description

Number/proportion of patients eligible on automated screening that are successfully recruited

Time Frame

5 years

Title

Rate of patient recruitment

Description

Rate of patient recruitment

Time Frame

5 years

Title

Patient reported compliance

Description

Patient-reported compliance to DOAC therapy in the DOAC arm

Time Frame

5 years

Title

Repeat prescriptions for DOAC

Description

Repeat prescriptions obtained for DOAC therapy

Time Frame

5 years

Title

Proportion of participant time-points with missing data for EQ-5D-5L patient-reported quality of life

Description

Missing data rates for 6-monthly patient-reported Euroqol five-dimensions five-level (EQ-5D-5L) summary index score, with death equivalent to a score of zero

Time Frame

5 years

Title

Proportion of participant time-points with missing data for cognitive function using the UK Biobank fluid intelligence/reasoning test

Description

Missing data rates for yearly patient-reported cognitive function

Time Frame

5 years

10. Eligibility

Sex

All

Minimum Age & Unit of Time

55 Years

Maximum Age & Unit of Time

73 Years

Accepts Healthy Volunteers

Eligibility Criteria

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.

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Alastair Mobley, BSc

Phone

+44 121 371 4225

a.mobley@bham.ac.uk

First Name & Middle Initial & Last Name or Official Title & Degree

Dipak Kotecha

Phone

+44 121 371 4225

d.kotecha@bham.ac.uk

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Dipak Kotecha

Organizational Affiliation

University of Birmingham and University Hospitals Birmingham NHS Foundation Trust

Official's Role

Principal Investigator

First Name & Middle Initial & Last Name & Degree

John Camm

Organizational Affiliation

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

Official's Role

Study Chair

First Name & Middle Initial & Last Name & Degree

Marcus Flather

Organizational Affiliation

Norwich Medical School; Chaire of DaRe2THINK Independent DMC

Official's Role

Study Chair

First Name & Middle Initial & Last Name & Degree

David Shukla

Organizational Affiliation

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

Official's Role

Principal Investigator

Facility Information:

Facility Name

University Hospitals Birmingham

City

Birmingham

State/Province

West Midlands

ZIP/Postal Code

B15 2TH

Country

United Kingdom

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Minnie Ventura

Phone

0121 371 8145

Maximina.Ventura@uhb.nhs.uk

12. IPD Sharing Statement

Plan to Share IPD

Learn more about this trial

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

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