Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12621000896875
Ethics application status
Approved
Date submitted
29/05/2021
Date registered
8/07/2021
Date last updated
29/10/2021
Date data sharing statement initially provided
8/07/2021
Type of registration
Retrospectively registered

Titles & IDs
Public title
WITHDRAWal of heart failure directed therapies in recovered Atrial Fibrillation mediated cardiomyopathy- the WITHDRAW-AF study
Scientific title
WITHDRAWal of heart failure directed therapies in recovered Atrial Fibrillation mediated cardiomyopathy- investigating the impact on left ventricular ejection fraction: the WITHDRAW-AF study
Secondary ID [1] 304350 0
none
Universal Trial Number (UTN)
U1111-1268-3824
Trial acronym
WITHDRAW-AF
Linked study record

Health condition
Health condition(s) or problem(s) studied:
atrial fibrillation 322122 0
heart failure 322123 0
Condition category
Condition code
Cardiovascular 319828 319828 0 0
Other cardiovascular diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This is a randomised controlled study comparing staged withdrawal versus continuation of heart failure pharmacotherapy in patients with rhythm controlled atrial fibrillation (AF) and recovered cardiomyopathy. Patients undergoing staged withdrawal will first withdraw from a heart failure (HF) specific beta blocker with the option to replace with an antiarrhythmic agent (such as sotalol, amiodarone or flecainide) at the time of enrolment at Cardiologist discretion with an ECG performed at baseline and during initiation of antiarrhythmic therapy to monitor QTc intervals. Antiarrhythmic dose will be decided at the physician’s discretion.

At subsequent visits, mineralocorticoid receptor antagonists (MRAs) will be weaned, followed by angiotension receptor antagonists (ACE) inhibitors, angiotensin receptor blockers (ARBs) or angiotensin receptor blocker/neprilysin inhibitor (Eg. Entresto) combinations. Diuretics can be ceased if the patient is taking the equivalent or less than frusemide 40mg daily or spironolactone 25mg daily.

Participants taking 25% or less of the maximum recommended dose of ACE inhibitor or ARB can be discontinued; higher doses will be weaned by 50% every 2 weeks. The withdrawal stage involves weaning neurohormonal agents at fortnightly intervals over an 8 week period. There will be no 'wash out' period between treatment intervals. Initial withdrawal will occur at enrolment, with reduction or cessation of diuretics (depending on dose) and changing beta blocker to anti-arrhythmic agent as appropriate.

Participants will then be followed up at 3, 6, 9 and 12 months. Additional clinical reviews can be arranged based on clinical need.

This phased withdrawal method is adapted from the recent TRED-HF study. Patients in the control group (continued medical therapy) will undergo regular clinical review at 3, 6, 9 and 12 months with interval visits as clinically indicated. The total study duration is 12 months.

Participants will spend 6 months in each treatment group. Those in the initial withdrawal arm will crossover to the medical treatment arm at 6 months with a cardiac MRI prior to ensure stable left ventricular systolic function, with reinitiation of baseline or maximal tolerated neurohormonal therapy as clinically appropriate. This reinitiation will take place over the first 8 weeks after the 6 month withdrawal phase. Conversely, participants initially allocated to the continued medical therapy group will continue their baseline neurohormonal therapy until 6 months, have a repeat cardiac magnetic resonance imaging (MRI or CMR) to ensure left ventricular (LV) function remains stable, then commence staged withdrawal over 8 weeks, with a subsequent final CMR at 12 months for cardiomyopathy surveillance.

Repeat CMR at 6 and 12 months is designed as a safety mechanism for the early detection of LV dysfunction in patients during the withdrawal treatment phase. Patients with a reduction in left ventricular ejection fraction (LVEF) <45% at 6 months from weaning, in the absence of AF recurrence will be able to re-initiate anti-heart failure therapy. For the purpose of analysis of the primary end-point, the LVEF value from the 6 months scan prior to the re-introduction of neuro-hormonal blockade will be utilised.

Double crossover study design: The participants initially allocated to continuing medical therapy will continue standard care for 6 months and then crossover into the staged withdrawal group.
The participants initially allocated to staged withdrawal will undergo supervised withdrawal of heart failure therapy and remain in this allocation for 6 months and then crossover into the standard care/continued medical therapy arm after 6 months, where their usual medical therapy will be reintroduced over a 6 week period.
Intervention code [1] 320706 0
Treatment: Other
Comparator / control treatment
Patients in the ongoing medical treatment arm will continue standard care (current regime of anti-heart failure therapy) for 6 months. To avoid confounding, changes in pharmacological therapy such as further up-titration of medications, in the absence of clinical necessity will be discouraged.

Study participants will undergo baseline, 6-month and 12-month transthoracic echocardiogram and cardiac MRI surveillance. This is to ensure accurate determination of changes in LV dimensions, systolic function (including left ventricular ejection fraction and global longitudinal strain assessments), during both treatment phases (staged withdrawal and continuing medical therapy).
Control group
Active

Outcomes
Primary outcome [1] 327697 0
The primary endpoint is equivalence of phased withdrawal compared to continued medical therapy, defined as maintenance of LVEF >50% on cardiac MRI at 6 and 12 months in both study groups. This allows for inter-observer variability between imaging of <10% as recognised previously.
Timepoint [1] 327697 0
6 and 12 months post randomisation
Secondary outcome [1] 396250 0
Composite of overall mortality, cardiovascular mortality and unplanned heart failure hospitalisation ascertained from clinic reviews and electronic medical records.
Timepoint [1] 396250 0
6 and 12 months post randomisation
Secondary outcome [2] 396252 0
Change from baseline of LVEF from baseline to follow up on cardiac MRI
Timepoint [2] 396252 0
6 and 12 months post randomisation
Secondary outcome [3] 396253 0
Change from baseline of NYHA class
Timepoint [3] 396253 0
6 and 12 months post randomisation
Secondary outcome [4] 396254 0
Change in cardiac chamber dimensions as determined by cardiac MRI
Timepoint [4] 396254 0
6 and 12 months post randomisation
Secondary outcome [5] 396256 0
Change in diffuse fibrosis as determined by T1 mapping
Timepoint [5] 396256 0
6 and 12 months post randomisation
Secondary outcome [6] 396257 0
Arrhythmia recurrence (AF or AT): defined as AF or AT lasting >30 seconds as detected on Smart phone monitoring, implantable loop recorder or device interrogation.
Timepoint [6] 396257 0
12 months post randomisation
Secondary outcome [7] 397179 0
Change from baseline of heart failure / quality of life as measured by SF-36 and Minnesota Living with Heart Failure Questionnaire (MLHFQ).
Timepoint [7] 397179 0
6 and 12 months post randomisation
Secondary outcome [8] 397180 0
Change from baseline to follow up in functional capacity/exercise time (as measured by 6-minute walk test and exercise stress test)
Timepoint [8] 397180 0
6 and 12 months post randomisation
Secondary outcome [9] 397181 0
Change from baseline to follow up in cardiac biomarkers serum BNP or NTproBNP (depending on local assay)
Timepoint [9] 397181 0
6 and 12 months post randomisation
Secondary outcome [10] 397182 0
AF burden, as determined by Smart phone monitoring, implantable loop recorder or device interrogation.
Timepoint [10] 397182 0
12 months post randomisation

Eligibility
Key inclusion criteria
- Age>18 years
- AF mediated cardiomyopathy
Previous LVEF <40% in the setting of AF with recovery to >50% within 6 months after
restoration of sinus rhythm (with anti-arrhythmic medications, electrical cardioversion,
catheter ablation or any combination of these)
- NYHA class I
- Currently on pharmacological anti-heart failure therapy including at least 2 of:
- ACE inhibitor or Angiotensin receptor antagonist
- Diuretic (excluding MRA)
- Cardiac specific beta blocker
- Mineralocorticoid receptor antagonist
- Entresto (Sacubitril/Valsartan)
- No recurrence of AF with previous 6 months
- No heart failure related admissions with last 6 months
- Cardiac MRI demonstrating
- LVEF >/=50%
- The absence of ventricular late gadolinium enhancement
- Indexed LVEDV less than 10% upper limit of normal
- Able to consent
- Willing to adhere to follow up requirements
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
- Patients with unsuccessful rhythm control
- Patients with known contributing cause of LV dysfunction including
- Ischaemic cardiomyopathy
- Valvular heart disease
- Hypertrophic cardiomyopathy
- Uncontrolled current/ongoing alcohol intake
- Other cause of cardiomyopathy (eg thyroid disease)
- Significant renal impairment (eGFR<30mL/min/1.73m2)
- Contraindication to
- cardiac MRI,
- catheter ablation or
- anti-coagulation
- Any condition with expected survival < 2 years
- Patients with a clear indication for ACE/ARB therapy for reasons other than heart failure where alternative agents are contra-indicated or inappropriate
- Unable to provide informed consent

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)
Allocation concealment: clinicians referring participants for inclusion in the trial will not be aware, when this decision was made, to which group the subject will be allocated.

Study investigators involved in reporting investigation results including cardiac MRI, transthoracic echocardiography and functional testing will be blinded to treatment arm. Study investigators co-ordinating the withdrawal of therapy in the withdrawal arm, will not be involved in the reporting of investigations.

Recruitment and Randomisation: All participants will be provided with verbal and written information and informed consent will be obtained prior to enrolment.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Patient meeting eligibility following baseline screening will undergo baseline assessments and will subsequently be computer randomised in a 1:1 fashion to either initial continued HF pharmacotherapy or initial supervised phased withdrawal through simple randomisation using a randomisation table created by computer software. Study investigators reporting investigations including all cardiac imaging (MRI and echocardiography) will be blinded to randomisation status.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?


The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Crossover
Other design features
Phase
Not Applicable
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
Statistical analysis: Data will be analysed using SPSSv.26. All analyses will be conducted on an intention to treat basis using standard statistical methods for categorical and continuous data. Continuous data will be expressed as mean ± standard deviation if normally distributed (interquartile range if non-parametric data). Categorical data will be presented as numbers and percentages. Differences in variables between groups will be analysed using the chi square test for categorical data and the Student’s T-test or Mann Whitney U test for normally distributed and skewed continuous data respectively. Statistical significance is defined as a p value of <0.05.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
7/06/2021
Date of last participant enrolment
Anticipated
20/11/2023
Actual
Date of last data collection
Anticipated
22/07/2024
Actual
Sample size
Target
60
Accrual to date
7
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 19596 0
The Alfred - Melbourne
Recruitment hospital [2] 19597 0
Royal Melbourne Hospital - City campus - Parkville
Recruitment hospital [3] 19598 0
Monash Medical Centre - Clayton campus - Clayton
Recruitment hospital [4] 19599 0
Sunshine Hospital - St Albans
Recruitment postcode(s) [1] 34212 0
3004 - Melbourne
Recruitment postcode(s) [2] 34215 0
3021 - St Albans
Recruitment postcode(s) [3] 34213 0
3050 - Parkville
Recruitment postcode(s) [4] 34214 0
3168 - Clayton

Funding & Sponsors
Funding source category [1] 308721 0
Hospital
Name [1] 308721 0
Alfred Hospital
Country [1] 308721 0
Australia
Primary sponsor type
Hospital
Name
Alfred Hospital
Address
55 Commercial Road, Prahran VIC 3004
Country
Australia
Secondary sponsor category [1] 309613 0
Individual
Name [1] 309613 0
Professor Andrew Taylor
Address [1] 309613 0
Department of Cardiology
Alfred Health
55 Commercial Road, Prahran VIC 3004
Country [1] 309613 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 308644 0
Alfred Health Ethics Committee
Ethics committee address [1] 308644 0
55 Commercial Road, Prahran VIC 3004
Ethics committee country [1] 308644 0
Australia
Date submitted for ethics approval [1] 308644 0
19/03/2021
Approval date [1] 308644 0
23/04/2021
Ethics approval number [1] 308644 0
HREC/73232/Alfred-2021

Summary
Brief summary
We propose a prospective randomised clinical trial in patients with a fully recovered AF-mediated cardiomyopathy receiving ongoing heart failure therapy, given the paucity of data and the recognised reversible nature of this condition. Patients will be randomised to either staged withdrawal of neuro-hormonal therapies or their continuation and each group will crossover at 6 months for a total study duration of 12 months. Serial assessments will include cardiac imaging, exercise testing and symptom assessments throughout the study period.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 111410 0
A/Prof Sandeep Prabhu
Address 111410 0
Department of Cardiology
Alfred Hospital
55 Commercial Rd, Prahran VIC 3004
Country 111410 0
Australia
Phone 111410 0
+61 390763522
Fax 111410 0
Email 111410 0
s.prabhu@alfred.org.au
Contact person for public queries
Name 111411 0
Dr Louise Segan
Address 111411 0
Department of Cardiology
Alfred Hospital
55 Commercial Rd Prahran VIC 3004
Country 111411 0
Australia
Phone 111411 0
+61 390762000
Fax 111411 0
Email 111411 0
l.segan@alfred.org.au
Contact person for scientific queries
Name 111412 0
Dr Louise Segan
Address 111412 0
Department of Cardiology
Alfred Hospital
55 Commercial Rd Prahran VIC 3004
Country 111412 0
Australia
Phone 111412 0
+61 390762000
Fax 111412 0
Email 111412 0
l.segan@alfred.org.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Data collected will be deidentified for data analysis and aggregation purposes. This is to maintain the integrity of the data collected.


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
11818Study protocol    attachment 382088-(Uploaded-29-05-2021-12-06-21)-Study-related document.docx


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.