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Trial registered on ANZCTR


Registration number
ACTRN12623000949684p
Ethics application status
Not yet submitted
Date submitted
2/08/2023
Date registered
4/09/2023
Date last updated
4/09/2023
Date data sharing statement initially provided
4/09/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
The feasibility of oral anticoagulant drug adjustments based on brain imaging evaluation in patients with atrial fibrillation
Scientific title
Evaluating Covert cerebrovascular cHanges to Optimise anticoagulant therapy Efficacy and Safety in Atrial Fibrillation Pilot
Secondary ID [1] 310268 0
Nil known
Universal Trial Number (UTN)
U1111-1295-9976
Trial acronym
ECHOES-AF
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Atrial fibrillation (AF) 330956 0
Anticoagulant therapy 330957 0
Silent brain infarct (SBI) 330958 0
Cerebral microbleed (CMB) 330959 0
Cerebral small vessel disease (CSVD) 330960 0
Condition category
Condition code
Cardiovascular 327759 327759 0 0
Diseases of the vasculature and circulation including the lymphatic system
Stroke 327760 327760 0 0
Haemorrhagic
Stroke 327761 327761 0 0
Ischaemic

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Participants assigned to the interventional group will receive a non-contrast brain magnetic resonance imaging (MRI) examination (no gadolinium injection), followed by anticoagulation management adjustment recommendations to the participants and their general practitioners (GP) or specialist for consideration based on the brain MRI evaluation. Recommendations include:
1. Intensive anticoagulant therapy by taking oral anticoagulant (OAC) for 1 year (150 mg/oral tablet/ twice daily for Dabigatran, or 20 mg/oral tablet/once daily for Rivaroxaban, or 5 mg/oral tablet/twice daily for Apixaban) if detecting silent brain infarct (SBI) of presumed cardiogenic cause (>15 mm in long diameter regardless of location, or at the cortical area irrespective of size, or two or more lesions) or a high burden of cerebral small vessel disease (CSVD) (summary CSVD score >2) even though there is a low-to-medium stroke risk estimated from the CHA2DS2-VASc score (less than or equal to 1 for men or less than or equal to 2 for women).
2. Conservative anticoagulant therapy by switching from warfarin to non-Vitamin K-dependent oral anticoagulant (NOAC) and NOAC dose lowering for 1 year (110 mg/oral tablet/twice daily for Dabigatran, or 15 mg/oral tablet/once daily for Rivaroxaban, or 2.5 mg/oral tablet/twice daily for Apixaban) if there are 2 or more cerebral microbleeds (CMBs).
The brain MRI scan, performed by the MRI radiographer at one designated medical imaging provider, will take approximately 20 minutes. It is only required once after randomisation. A radiology report of the MRI examination made by the radiologist will be provided to the participants and their GP/specialist after the examination. One of the study researchers will audit the radiology report to ensure the participant’s completion of the brain MRI examination.
The participant shall record the daily use of OAC in a dedicated form provided by the study team. At each clinic visit during follow-up, the GP/specialist will collect the form and give it to the research team.
Intervention code [1] 326649 0
Prevention
Intervention code [2] 326650 0
Treatment: Other
Intervention code [3] 326806 0
Treatment: Drugs
Comparator / control treatment
Participants assigned to the control group will not have brain MRI performance. Whether OAC applies to them depends on the participant’s stroke risk estimated by the CHA2DS2-VASc score. It follows the latest European Society of Cardiology (ESC) guidelines for the management of atrial fibrillation (Hindricks G, et al. Eur Heart J. 2021):
1. Take OAC for 1 year if the CHA2DS2-VASc score >1 for men or >2 for women (a flexible dosage of 0-6 mg according to the international normalised ratio [INR] value/oral tablet/once daily for warfarin, 150 mg/oral tablet/ twice daily for Dabigatran, or 20 mg/oral tablet/once daily for Rivaroxaban, or 5 mg/oral tablet/twice daily for Apixaban).
2. Decide OAC use according to the participant's preference if the CHA2DS2-VASc score =1 for men or =2 for women (same as in scenario 1 in terms of medication usage if OAC applies).
3. No OAC use if the CHA2DS2-VASc score =0 for men or =1 for women.
The participant shall record the daily use of OAC in a dedicated form provided by the study team. At each clinic visit during follow-up, the GP/specialist will collect the form and give it to the research team.
Control group
Active

Outcomes
Primary outcome [1] 335563 0
The percentage of enrolled participants (eligible and consented) from those screened (an audit of study enrolment/withdrawal logs)
Timepoint [1] 335563 0
One year after randomisation
Primary outcome [2] 335800 0
The number of site activation over time (an audit of study enrolment/withdrawal logs)
Timepoint [2] 335800 0
One year after randomisation
Primary outcome [3] 335801 0
The number of enrolled participants over time (an audit of study enrolment/withdrawal logs)
Timepoint [3] 335801 0
One year after randomisation
Secondary outcome [1] 424962 0
The proportion of the participants with OAC management changes after brain MRI evaluation (a review of medical records)
Timepoint [1] 424962 0
One year after randomisation
Secondary outcome [2] 424963 0
OAC adherence (a review of the participant’s medication diary)
Timepoint [2] 424963 0
One year after randomisation
Secondary outcome [3] 425676 0
All-cause death during follow-up (an audit of medical records)
Timepoint [3] 425676 0
One year after randomisation
Secondary outcome [4] 425677 0
A composite of stroke, transient ischemic attack (TIA), or systemic embolism (an adjudication of medical records)
Timepoint [4] 425677 0
One year after randomisation
Secondary outcome [5] 425678 0
Intracranial hemorrhage (ICH) (an adjudication of medical records)
Timepoint [5] 425678 0
One year after randomisation
Secondary outcome [6] 425679 0
Major bleeding (an adjudication of medical records)
Timepoint [6] 425679 0
One year after randomisation
Secondary outcome [7] 425680 0
Non-major clinically relevant bleeding (an adjudication of medical records)
Timepoint [7] 425680 0
One year after randomisation
Secondary outcome [8] 425681 0
Any bleeding (a review of self-report from the participants)
Timepoint [8] 425681 0
One year after randomisation
Secondary outcome [9] 425682 0
A composite of major adverse cardiac and cerebrovascular events (MACCE), including death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, and nonfatal hospitalisation for heart failure (an adjudication of medical records)
Timepoint [9] 425682 0
One year after randomisation
Secondary outcome [10] 425683 0
A composite of any bleeding or thromboembolism events (a review of self-report from the participants)
Timepoint [10] 425683 0
One year after randomisation
Secondary outcome [11] 425684 0
Change in cognitive function (Telephone Interview of Cognitive Status [TICS] and Telephone Montreal Cognitive Assessment [tMOCA] tests at baseline and one year after randomisation)
Timepoint [11] 425684 0
Baseline and one year after randomisation
Secondary outcome [12] 425685 0
Change in depression level (assessed by patient Health Questionnaire-9 [depression module] at baseline and one year after randomisation)
Timepoint [12] 425685 0
Baseline and one year after randomisation
Secondary outcome [13] 425686 0
Change in subject frailty level (assessed by a dedicated frailty screening scale at baseline and one year after randomisation)
Timepoint [13] 425686 0
Baseline and one year after randomisation
Secondary outcome [14] 425687 0
Change in health-related quality of life (HRQoL) (assessed by the EuroQol 5 Dimension 5 Level [EQ-5D-5L] instrument at baseline and one year after randomisation)
Timepoint [14] 425687 0
Baseline and one year after randomisation
Secondary outcome [15] 425688 0
Change in disability or dependence in the daily activities (assessed by the modified Rankin Scale at baseline and one year after randomisation)
Timepoint [15] 425688 0
Baseline and one year after randomisation
Secondary outcome [16] 425689 0
A composite prevalence of the participants with SBI of presumed cardiogenic cause, having a high burden of CSVD, or with two or more CMBs by review of the radiological report and a central adjudication of brain MRI images
Timepoint [16] 425689 0
Two weeks after randomisation
Secondary outcome [17] 425690 0
Quality-adjusted life-years (a review of participant’s EQ-5D-5L and an audit of health care costs, including brain MRI costs)
Timepoint [17] 425690 0
One year after randomisation

Eligibility
Key inclusion criteria
1. Adults (age >=18 years).
2. Have non-valvular atrial fibrillation (AF) or atrial flutter (AFL) as documented by electrocardiography (ECG) (12-lead ECG, rhythm strip, or Holeter) in the past 6 months before enrolment, regardless of AF clinical patterns.
3. Take OAC at study entry or willing to receive OAC for thromboprophylaxis without any contradiction, and standard-dose OAC is appliable.
4. Willing to undergo brain MRI.
5. Willing to participate after being told the trial information (purpose and procedures) and provide written informed consent by the participant or an appropriate legal surrogate.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. History of heart valve disease (i.e., prosthetic valve or hemodynamically relevant valve disease).
2. AF or AFL due to reverse causes of cardiac surgery, pulmonary embolism, and untreated hyperthyroidism.
3. Known presence of atrial myxoma, left ventricular thrombus, or active endocarditis.
4. Severe, disabling stroke (modified Rankin scale [mRS] score of 4 to 5) within the past 3 months, or any stroke within the past 14 days, or TIA within 3 days before enrolment.
5. An obvious impairment of renal function (serum creatine >=1.5 mg/dL [133 µmol/L] or creatinine clearance [CrCL, Cockcroft-Gault Equation] <= 50 mL/min) or hepatic function (persistent alanine transaminase [ALT], aspartate transaminase [AST], or alkaline phosphatase [ALP] >3x upper limit of the normal range [ULN], acute clinical hepatitis, chronic active hepatitis, or cirrhosis).
6. Any other conditions associated with increased bleeding risk including:
a. Major surgery within the past 2 months or planned surgery or intervention within the next 3 months.
b. Anemia (hemoglobin level <100 g/L) or thrombocytopenia (platelet count <100/µL).
c. Gastrointestinal (GI) hemorrhage within the past 6 months or symptomatic gastroduodenal ulcer disease documented by endoscopy in the previous 30 days.
d. Sustained uncontrolled hypertension (systolic blood pressure [SBP] >180 mmHg and/or diastolic blood pressure [DBP] >100 mmHg).
e. Needs anticoagulant therapy for disorders other than AF.
f. Known intracranial neoplasm, arteriovenous malformation (AVM), or aneurysm before randomisation.
7. Not eligible for MRI examination, such as decompensated heart failure that hinders flat lying during MRI scanning, claustrophobia, and metallic foreign body or iatrogenic implantable device contradicted to MRI.
8. Have malignancy or other serious concomitant diseases with a life expectancy of <2 years.
9. Women who are pregnant or of childbearing potential who refuse to use medically acceptable contraception throughout the trial.
10. Participating in another trial of anticoagulant therapy that conflicts with the ECHOES-AF Pilot.
11. Any other condition, in the opinion of investigators, that renders the patient unsuitable for the trial and would compromise adherence and safe participation (e.g. drug addiction, alcohol abuse, etc.).

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Central randomisation by phone/fax/computer
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Stratified allocation with stratifications by age, sex, and the clinical pattern of atrial fibrillation.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?


The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint/s
Safety
Statistical methods / analysis
Simple descriptive statistics and tests (proportions, means, chi-squared, t-tests) will be used to describe recruitment rates and differences in the characteristics of the participants between two randomised groups. The number of site activation and enrolled participants over time will be plotted. Statistical models will be used to estimate the likely outcome rates (all-cause death, any stroke/TIA or systemic embolism, ICH, major bleeding, clinically relevant non-major bleeding, any bleeding, MACCE, and any bleeding or thromboembolism events.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
1/01/2024
Actual
Date of last participant enrolment
Anticipated
30/06/2025
Actual
Date of last data collection
Anticipated
30/06/2026
Actual
Sample size
Target
300
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW

Funding & Sponsors
Funding source category [1] 314475 0
Government body
Name [1] 314475 0
The NSW Cardiovascular Elite Postdoctoral Researcher Grant
Country [1] 314475 0
Australia
Funding source category [2] 314618 0
Other Collaborative groups
Name [2] 314618 0
The George Institute for Global Health
Country [2] 314618 0
Australia
Primary sponsor type
Other Collaborative groups
Name
The George Institute for Global Health
Address
Level 5, 1 King St, Newtown, NSW 2042
Country
Australia
Secondary sponsor category [1] 316580 0
None
Name [1] 316580 0
Address [1] 316580 0
Country [1] 316580 0
Other collaborator category [1] 282773 0
University
Name [1] 282773 0
University of Edinburgh
Address [1] 282773 0
5 Forrest Hill, Edinburgh EH1 2LX, UK
Country [1] 282773 0
United Kingdom
Other collaborator category [2] 282774 0
Hospital
Name [2] 282774 0
Shanghai Ren Ji Hospital
Address [2] 282774 0
No. 160 Pujian Road, Pudong New District, Shanghai, 200127
Country [2] 282774 0
China
Other collaborator category [3] 282775 0
Hospital
Name [3] 282775 0
Beijing Anzhen Hospital
Address [3] 282775 0
No. 2 Anding Road, Chaoyang District, Beijing, 100029
Country [3] 282775 0
China

Ethics approval
Ethics application status
Not yet submitted
Ethics committee name [1] 313526 0
Human Research Ethics & Clinical Trials Governance, UNSW Sydney
Ethics committee address [1] 313526 0
High Street, Kensington, UNSW Sydney 2052
Ethics committee country [1] 313526 0
Australia
Date submitted for ethics approval [1] 313526 0
15/09/2023
Approval date [1] 313526 0
Ethics approval number [1] 313526 0

Summary
Brief summary
ECHOES-AF Pilot is a prospective, randomised, open-label, blinded endpoint (PROBE) pilot-phase trial. It aims to investigate the feasibility of a future phase III trial that OAC management adjustments based on brain imaging evaluation may optimise anticoagulant therapy efficacy and safety in patients with AF compared with current standard management that depends on a stroke risk estimation by the CHA2DS2-VASc score. Prior large-scale observational studies confirmed that patients with AF have a high prevalence of covert cerebrovascular changes. Furthermore, some of these subclinical changes were associated with an increased risk of brain infarction if not taking OAC (like SBI) or associated with more ICH while taking OAC (like CMB). Therefore, our proposed brain imaging-based strategy includes i) considering intensive OAC use if detecting silent brain infarct (SBI) of presumed cardiogenic cause (>15 mm, located at the cortical area, or two or more lesions) or a high CSVD burden (CSVD burden score >2) on brain MRI in the participants with low-to-medium stroke risk (CHA2DS2-VASc less than or equal to 1 for men or less than or equal to 2 for women), and ii) considering conservative OAC use by switching from warfarin to NOAC and NOAC dose lowering in those with two or more CMBs. All participants will be followed for 12 months with a recording of MRI cost, the presence of imaging signs of interest, changes in cognitive function, depression, disability or dependence in daily activities, HRQoL and subject frailty levels, OAC management changes after brain MRI involvement, OAC adherence, and clinical outcomes of all-cause death, stroke/TIA or systemic embolism, any bleeding, and MACCE during follow-up. In the ECHOES-AF Pilot, the medical intervention of brain imaging-based OAC management adjustments will only be recommended to the participants and their GP/specialist rather than a mandatory acceptance.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 128450 0
Dr Zien Zhou
Address 128450 0
The George Institute for Global Health (Level 5, 1 King St, Newtown, NSW 2042)
Country 128450 0
Australia
Phone 128450 0
+61 434432202
Fax 128450 0
Email 128450 0
[email protected]
Contact person for public queries
Name 128451 0
Craig Anderson
Address 128451 0
The George Institute for Global Health (Level 5, 1 King St, Newtown, NSW 2042)
Country 128451 0
Australia
Phone 128451 0
+61280524521
Fax 128451 0
+61280524502
Email 128451 0
[email protected]
Contact person for scientific queries
Name 128452 0
Zien Zhou
Address 128452 0
The George Institute for Global Health (Level 5, 1 King St, Newtown, NSW 2042)
Country 128452 0
Australia
Phone 128452 0
+61 434432202
Fax 128452 0
Email 128452 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
Individual participant data underlying published results after deidentification (text, tables, figures, and appendices).
When will data be available (start and end dates)?
Beginning 3 months following main results publication with no end date determined.
Available to whom?
Researchers who provide a methodologically sound proposal and whose proposed use of the data has been approved by the study office identified for this purpose.
Available for what types of analyses?
To achieve aims in the approved proposal or for individual participant data meta-analysis..
How or where can data be obtained?
Access subject to approvals by Principal Investigator ([email protected]). To gain access, data requestors will need to sign a data access agreement.


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.