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

Overview

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.

Interventions

• Drug Direct Oral Anticoagulants
  choice of DOAC (apixaban, dabigatran, edoxaban or rivaroxaban) according to local practice

Primary outcome measures

• Composite primary endpoint - Time to first event [Time frame: 5 years]

Secondary outcome measures (12)

• Change in cognitive function using the UK Biobank fluid intelligence/reasoning test (mixed-effects repeated measures analysis) [Time frame: 5 years]
• Change in cognitive function using the UK Biobank trail making test (mixed-effects repeated measures analysis) [Time frame: 5 years]
• Change in cognitive function using the UK Biobank symbol digit substitution test (mixed-effects repeated measures analysis) [Time frame: 5 years]
• . Change in cognitive function using the UK Biobank non-verbal fluid reasoning matrices test (mixed-effects repeated measures analysis) [Time frame: 5 years]
• Incremental cost per quality-adjusted life-years gained from the healthcare perspective. [Time frame: 5 years]
• Incremental cost per quality-adjusted life-years gained from the societal perspective. [Time frame: 5 years]
• Time to composite of major adverse cardiovascular events (non-fatal stroke, non-fatal myocardial infarction and cardiovascular death). [Time frame: 5 years]
• Time to any major bleeding or clinically-relevant non-major bleeding that requires hospitalisation. [Time frame: 5 years]
• Time to minor bleeding that requires attention from primary care (any bleeding that leads to a primary care consultation). [Time frame: 5 years]
• Time to haemorrhagic stroke and other types of intracranial bleeding. [Time frame: 5 years]
• Number of all-cause general practice visits. [Time frame: 5 years]
• Number of all-cause hospital admissions. [Time frame: 5 years]

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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Prevention

Study locations

United Kingdom · 1 center

• University Hospitals Birmingham — Birmingham

Publications

• 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
• 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
• 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

Identifiers

NCT: NCT04700826 · ERN_20-1747 · 290420

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗