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

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

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.

Study Overview

• Status: Recruiting
• Conditions: Atrial Fibrillation
• Intervention / Treatment: Drug: Direct Oral Anticoagulants

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.

• Study Type: Interventional
• Enrollment (Anticipated): 3000
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Dipak Kotecha; Phone Number: +44 121 371 4225; Email: d.kotecha@bham.ac.uk
• Study Contact Backup: Name: Alastair Mobley, BSc; Phone Number: +44 121 371 4225; Email: a.mobley@bham.ac.uk

Study Locations

• United Kingdom
  • West Midlands
    • Birmingham, West Midlands, United Kingdom, B15 2TH
      • Recruiting
      • University Hospitals Birmingham
      • Contact: Minnie Ventura; Phone Number: 0121 371 8145; Email: Maximina.Ventura@uhb.nhs.uk

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 60 years to 73 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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	Drug: Direct Oral Anticoagulants; choice of DOAC (apixaban, dabigatran, edoxaban or rivaroxaban) according to local practice; Other Names: apixaban, dabigatran, edoxaban or rivaroxaban
No Intervention: 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.

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Potential participants located by CPRD	Number/proportion of potential participants located by CPRD and notified to the lead NIHR Clinical Research Network (CRN)	5 years
Primary care practices completing sign up	Number/proportion of primary care practices that have completed sign-up processes	5 years
Patients on automated screening successfully recruited	Number/proportion of patients eligible on automated screening that are successfully recruited	5 years
Rate of patient recruitment	Rate of patient recruitment	5 years
Patient reported compliance	Patient-reported compliance to DOAC therapy in the DOAC arm	5 years
Repeat prescriptions for DOAC	Repeat prescriptions obtained for DOAC therapy	5 years
Proportion of participant time-points with missing data for EQ-5D-5L patient-reported quality of life	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	5 years
Proportion of participant time-points with missing data for cognitive function using the UK Biobank fluid intelligence/reasoning test	Missing data rates for yearly patient-reported cognitive function	5 years

Collaborators and Investigators

• Sponsor: University of Birmingham
• Collaborators: University of Oxford; University Hospital Birmingham NHS Foundation Trust; London School of Economics and Political Science; Aston University; Clinical Practice Research Datalink
• Investigators: Principal Investigator: Dipak Kotecha, University of Birmingham and University Hospitals Birmingham NHS Foundation Trust; Study Chair: 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; Principal Investigator: David Shukla, Deputy CI; Lead for NIHR West Midlands Primary Care CRN Team

Study record dates

Study Major Dates

• Study Start (Actual): June 1, 2021
• Primary Completion (Anticipated): January 1, 2026
• Study Completion (Anticipated): January 1, 2031

Study Registration Dates

• First Submitted: December 4, 2020
• First Submitted That Met QC Criteria: January 7, 2021
• First Posted (Actual): January 8, 2021

Study Record Updates

• Last Update Posted (Estimate): May 11, 2023
• Last Update Submitted That Met QC Criteria: May 9, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Keywords: dementia; Atrial fibrillation; stroke; anticoagulation
• Additional Relevant MeSH Terms: Mental Disorders; Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Neurocognitive Disorders; Arrhythmias, Cardiac; Cognition Disorders; Atrial Fibrillation; Cognitive Dysfunction; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protease Inhibitors; Factor Xa Inhibitors; Antithrombins; Serine Proteinase Inhibitors; Rivaroxaban; Dabigatran; Apixaban; Edoxaban; Anticoagulants
• Other Study ID Numbers: ERN_20-1747; 290420 (Other Identifier: IRAS)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No