Read the DaRe2THINK protocol (DOCX, 2.30 Mb)
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Using an efficient, nationwide, primary care approach for an NHS-embedded randomised controlled trial (RCT), does direct oral anticoagulant (DOAC) therapy reduce premature death, stroke and other thromboembolic consequences of atrial fibrillation (AF) in younger patients, including prevention of cognitive decline and vascular dementia?
Current RCT methodology often leads to recruitment of highly selected participants with less diversity than the clinical population, and challenges with enrolment and retention of patients. New RCT approaches are needed that can realise the value of the world-leading data quality and infrastructure of the NHS. AF is the most common heart rhythm abnormality, expected to double in prevalence in the next few decades, and leads to a considerable burden for patients and society at-large. In particular, the impact of stroke, cognitive decline and vascular dementia are all major public health concerns.
Aims and objectives
DaRe2THINK will test the hypothesis that DOACs are effective and cost-effective in patients with AF at low or intermediate risk of stroke by using an ambitious and innovative data-enabled approach through the Clinical Practice Research Datalink (CPRD) in Primary Care General Practices across England.
Individual-patient, open-label, event-driven RCT with 1:1 allocation to DOAC or no additional therapy (usual care). Automated screening of over 12 million patients, with targeted recruitment to practices with eligible patients, regular updates to General Practitioners, simple processes for centre inclusion and patient randomisation, and no additional visits after baseline for any patient. The primary outcome is a comprehensive composite of any thromboembolic event, including cardiovascular mortality, ischaemic stroke, pulmonary or venous thromboembolism, myocardial infarction and vascular dementia, ascertained entirely using electronic healthcare records within both primary and secondary NHS care. The key secondary outcome is the change in cognitive function, using technology solutions to provide ‘no-visit’ patient-reported follow-up, saving time for clinical staff and patients. We will carefully assess and validate safety outcomes relating to major and minor bleeding, and a systematic health economic analysis will determine NHS and societal cost-effectiveness.
Timelines for delivery
Total duration 60 months, including 3-stage internal pilot (8 months), patient recruitment (24 months), and additional 36 months follow-up for primary and secondary outcomes. A further outcome assessment at 10 years will specifically target development of vascular dementia.
Anticipated impact and dissemination
DaRe2THINK will demonstrate the operational capabilities of using the NHS record for interventional research. We will recruit a diverse, population-relevant cohort using automated nationwide screening, prioritisation of centres with recruitable patients, and remote technology-enhanced follow-up. These innovations will allow us to answer a key question for 21st century healthcare relating to an increasingly common condition with considerable burden on patient quality of life, the health of the nation and our economy. Current and future impacts from AF and vascular dementia will be unsustainable unless we can expand prevention. DaRe2THINK will develop close collaboration between the NIHR Clinical Research Network, CPRD, patient groups, academic institutions and the NHS to address this and future evidence-gaps in clinical practice
Inclusion and Exclusion Criteria
- Diagnosis of AF (previous, current or chronic)
- Age at enrolment ≥60 years to ≤73 years
- 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.
What are the benefits for joining CPRD
- CPRD currently includes 1,337 practices in England (15% of all General Practices)
- Contribute to evidence-based medicine
- Ensure your patient population is represented in research evidence informing clinical guidance and best practice
- Earn extra income for the practice by taking part in questionnaires and clinical studies
- Your patients can take part in clinical studies
- Receive regular practice-level prescribing and patient safety quality improvement (QI) reports including patient case-finding and national practice benchmarking
- Case reviews from QI reports, questionnaires and research contribute towards annual appraisals and revalidation
How can you join CPRD and the trial?
Joining is an easy, one-off process following which data automatically flows to CPRD
If you and your General Practice currently use EMIS health as your patient medical record system and you are interested in taking part in DaRe2THINK please fill in a CPRD Practice Joining form
Alastair Mobley, Trial Manager, firstname.lastname@example.org