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Trial registered on ANZCTR


Registration number
ACTRN12619000186156
Ethics application status
Approved
Date submitted
4/02/2019
Date registered
8/02/2019
Date last updated
8/02/2019
Date data sharing statement initially provided
8/02/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
The role of the brain-heart connection (autonomic nervous system) in Atrial Fibrillation; a common heart rhythm disorder
Scientific title
Characterisation of Autonomic function in Atrial Fibrillation; AF-AF Study
Secondary ID [1] 297162 0
None
Universal Trial Number (UTN)
U1111-1227-2521
Trial acronym
AF-AF
Linked study record
This is a parent study upon which this clinical cohort study is based:

Malik V, McKitrick DJ, Lau DH, Sanders P, Arnolda LF. Clinical evidence of autonomic dysfunction due to atrial fibrillation: implications for rhythm control strategy. Journal of Interventional Cardiac Electrophysiology. 2019. https://doi.org/10.1007/s10840-019-00508-z


Health condition
Health condition(s) or problem(s) studied:
Atrial Fibrillation 311212 0
Condition category
Condition code
Cardiovascular 309838 309838 0 0
Other cardiovascular diseases
Neurological 310078 310078 0 0
Studies of the normal brain and nervous system

Intervention/exposure
Study type
Observational
Patient registry
False
Target follow-up duration
Target follow-up type
Description of intervention(s) / exposure
AF-AF is an observational study designed to assess the contribution of atrial fibrillation (AF) and its risk factors (hypertension, sleep apnoea, obesity, diabetes mellitus) to dysfunction of the autonomic nervous system. We have previously performed (see listed parent study) a small study that demonstrates reflex deficits to autonomic testing in patients with paroxysmal (non permanent form of AF). Therefore we plan to perform simple (non-invasive) autonomic reflex tests such as lower body negative pressure, hand-grip testing, passively raising the legs and a valsalva (breath-holding manoeuvre) on a larger group of patients with intermittent AF, permanent AF and at any stage of their treatment (predefined by their heart team. We shall also use a non-invasive auricular vagus nerve stimulator (a clip attached to the tragus of the ear) in order to bypass the heart during reflex testing to see if suspected reflex deficits are corrected. The testing will take 2.5 hours to complete on one occasion. There will be no additional follow up tests. We plan to consecutively recruit up to 400 patients with AF at a single site to perform these autonomic tests. In some cases, where patients consent to re-enrolment after treatment of their AF (either by radio frequency catheter ablation, anti-arrhythmic medication) as well as after attempts made to manage their risk factors (also predetermined by the clinical team) we shall re-study their autonomic function to determine whether this improves as a result of elimination of either AF or its risk factors. This will be on an opt-in basis (as a re-consent) and our ethics board has approved of us re-contacting patients who demonstrate an interest at their first visit. The patients with AF will have varying burdens of their disease (and we shall aim to enrol 100 patients with the mildest form; paroxysmal AF or intermittent AF, 100 with persistent AF and then 100 patients in whom it is decided to leave them in chronic AF. Additional patients (anticipated n =100 will have repeat testing after their predetermined treatment strategy). Note we do not influence treatment decisions in our study. In detail; repeat testing will occur after electrical cardio version (to revert to normal rhythm), catheter ablation to treat AF and maintain normal rhythm, after treatment of risk factors that can maintain AF; obesity, blood pressure and diabetes, or any of these combinations. In general re-tests will occur within the study period of three years. The cardiologist running this study will be involved in patient care at the study site and therefore will determine with the patient when they have been booked in for their treatment and when they are likely to be retested. There will be no follow up as such. The responses of patients with AF will be compared to a control group (comprised of age and sex matched healthy adults, adults with risk factors for AF without the disease and finally a small cohort of patients with known autonomic disorders that affect the heart rate). These conditions are an abnormal reflex tachycardia to standing (postural tachycardia syndrome) and patients with an abnormally high resting heart rate (a condition called inappropriate sinus tachycardia). We anticipate enrolment of approximately 100 patients in this group.
Intervention code [1] 313448 0
Not applicable
Comparator / control treatment
We shall control for responses seen in patients with AF by also recruiting patients with risk factors for AF without the disease - patients referred for cardiovascular assessment as well as healthy adults without any significant diseases.
Control group
Active

Outcomes
Primary outcome [1] 318808 0
The cardiovascular reflex responses are the primary endpoint: changes in heart rate, blood pressure and derived measures of cardiac function (stroke volume, cardiac output and vascular resistance) from finger photoplethymosgraphy (finger cuff used to non-invasively measure cardiac function) as well as plethysmography (non invasive measure of vascular resistance in the forearm). Note these parameters are all components of one primary outcome (cardiovascular or haemodynamic reflex response)
Timepoint [1] 318808 0
As this study is observational - every patient will be assessed at a different timepoint in their care (at autonomic assessment session). There will be some candidates who opt-in for a repeat assessment after any treatment for their AF has been provided. This will occur at any time point after the first assessment up to the end of study enrolment - 3 years).
Primary outcome [2] 318975 0
In some cases on an opt-in basis we shall directly measure nerve firing activity (from a small needle in a nerve in the forearm - ulnar nerve).
Timepoint [2] 318975 0
As this study is observational - every patient will be assessed at a different timepoint in their care (at autonomic assessment session). There will be some candidates who opt-in for a repeat assessment after any treatment for their AF has been provided. This will be for both outcomes measured. This will occur at any time point after the first assessment up to the end of study enrolment - 3 years).
Secondary outcome [1] 366119 0
Serum inflammatory panel (C Reactive Protein, High sensitivity C reactive protein, Tumor Necrosis Alpha and cytokines such as interleukin 6 and 10). This is a composite secondary outcome.
Timepoint [1] 366119 0
As this study is observational - every patient will be assessed at a different timepoint in their care (at autonomic assessment session). There will be some candidates who opt-in for a repeat assessment after any treatment for their AF has been provided. This will be for all outcomes measured; which will occur at the same time on one visit. This will occur at any time point after the first assessment up to the end of study enrolment - 3 years).

Eligibility
Key inclusion criteria
Patients with Atrial Fibrillation (any stage of treatment or type). Control patients - healthy patients without any significant disease, patients with risk factors for AF but without disease as well as patients with other conditions which cause a high heart rate (inappropriate sinus tachycardia, postural tachycardia syndrome or supraventricular tachycardia) as well those with these conditions treated with catheter ablation in an area of the heart different to AF will be studied to compare reflex responses.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
• Hemodynamically relevant cardiac valvular disease, symptomatic coronary artery disease, peripheral artery disease
• Known autonomic disorder (including severe peripheral/autonomic neuropathy in diabetic patients).
o Diabetes itself is not an exclusion
• Significant cognitive impairment
• Parkinson’s disease
• History of stroke
• Poor mobility – unable to enter LBNP chamber
• Unable to have anti-arrhythmic drugs (AAD) and antihypertensives withheld for 5-7 days pre-autonomic testing.

Study design
Purpose
Natural history
Duration
Cross-sectional
Selection
Case control
Timing
Prospective
Statistical methods / analysis
We plan to enrol 300 participants with AF for this study (n = 100 with paroxysmal AF, n = 100 for persistent AF, n = 100 for chronic AF. We anticipate 100 patients who are retesting after treatment. Patient groups will be compared to a control group of both patients without AF, with risk factors for the disease as well healthy adults free of cardiovascular or any other disorders and not on regular medications and also patients with established cardiac autonomic disorders (n =100). These patients have inappropriate sinus tachycardia (rapid heartbeat), postural tachycardia syndrome (rapid heartbeat on standing) or vasovagal syncope; recurrent fainting spells from low heart beat and a decrease in blood pressure. There is no statistical precedent for this type of autonomic characterisation study to detect a difference related to AF. We shall therefore use a similar number of patients to a previous study we have performed; in which we analysed 355 patients with AF and despite other competing risk factors we were able to demonstrate a reduction of AF with weight directed therapy (obesity is a risk factor of AF; LEGACY Study; Journal of the American College of Cardiology, 2015). Therefore, we already have a similar cohort that we aim to use for this study. We shall perform multivariate analysis to examine the effect of covariates in this cross-sectional study design.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
SA
Recruitment hospital [1] 12986 0
The Royal Adelaide Hospital - Adelaide
Recruitment hospital [2] 12987 0
Ashford Community Hospital - Ashford
Recruitment hospital [3] 12988 0
St Andrew's Hospital Inc - Adelaide
Recruitment hospital [4] 12989 0
Calvary Wakefield Hospital - Adelaide
Recruitment postcode(s) [1] 25466 0
5000 - Adelaide
Recruitment postcode(s) [2] 25467 0
5035 - Ashford
Recruitment postcode(s) [3] 25468 0
5067 - Norwood

Funding & Sponsors
Funding source category [1] 301714 0
University
Name [1] 301714 0
Centre for Heart Rhythm Disorders, The University of Adelaide
Address [1] 301714 0
South Australian health and Medical research Institute, The University of Adelaide, North terrace, Adelaide, South Australia 5000.
Country [1] 301714 0
Australia
Primary sponsor type
University
Name
Centre for Heart Rhythm Disorders, The University of Adelaide
Address
South Australian health and Medical research Institute, The University of Adelaide, North terrace, Adelaide, South Australia 5000.
Country
Australia
Secondary sponsor category [1] 301451 0
None
Name [1] 301451 0
N/A
Address [1] 301451 0
N/A
Country [1] 301451 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 302435 0
The University of Adelaide Human Ethics Research Committee
Ethics committee address [1] 302435 0
Research services, Office of research ethics, compliance and integrity.
The University of Adelaide
Level 4, Rundle Mall Plaza
50 Rundle Mall
Adelaide SA 5000 Australia.
Ethics committee country [1] 302435 0
Australia
Date submitted for ethics approval [1] 302435 0
24/09/2018
Approval date [1] 302435 0
18/10/2018
Ethics approval number [1] 302435 0
H-2018-228

Summary
Brief summary
We are investigating how Atrial Fibrillation (AF), a common heart rhythm disorder, disrupts normal cardiovascular reflexes by affecting nerves from the heart. Whilst it is known that nerves leading to the heart can cause AF, we aim to study whether nerves arising from the heart are equally implicated, in order to provide information that can be used to offer targeted treatment using these nerves.

Hypotheses:

1. Patients with Atrial Fibrillation (AF) have abnormal cardiovascular reflexes; likely arising from dysfunction of sensory nerves arising from the heart (cardiopulmonary receptors).
2. These abnormal reflexes are more severe in patients with Permanent AF compared to paroxysmal AF and treatment of AF results in improvement of cardiac reflexes.
3. Autonomic dysfunction parallels disease progression; therefore the nerves of the heart may represent a therapeutic target in the management of AF.

We aim to characterise cardiovascular reflex function in detail of patients with AF with a minimally- invasive protocol designed to evaluate the normal function of the heart to maintain blood pressure in response to changes in blood volume (simulated by gently creating a vacuum seal around the legs; negative pressure and raising the legs passively; returning blood to the heart). We shall measure blood pressure, heart rate and do a blood test to measure hormones involved in blood pressure control. We shall also use a painless stimulator of the nerve leading from the heart (using a clip that attaches to the tragus of the ear), thereby bypassing the heart nerves on the way to the brain in order to confirm that any abnormality seen is due to the nerves within the heart rather than elsewhere). In a subset of patients, we shall insert a small needle (similar to acupuncture) to directly measure nerve activity in the forearm during reflex testing.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 90230 0
Prof Prashanthan Sanders
Address 90230 0
Centre for Heart Rhythm Disorders
University of Adelaide
South Australian Medical Medical research Institute
PO BOX 11060 Adelaide 5001 South Australia
Country 90230 0
Australia
Phone 90230 0
+61883139000
Fax 90230 0
Email 90230 0
prash.sanders@adelaide.edu.au
Contact person for public queries
Name 90231 0
Dr Varun Malik
Address 90231 0
Centre for Heart Rhythm Disorders
University of Adelaide
South Australian Medical Medical research Institute
PO BOX 11060 Adelaide 5001 South Australia
Country 90231 0
Australia
Phone 90231 0
+61 8 8313 9000
Fax 90231 0
Email 90231 0
varun.malik@adelaide.edu.au
Contact person for scientific queries
Name 90232 0
Dr Varun Malik
Address 90232 0
Centre for Heart Rhythm Disorders
University of Adelaide
South Australian Medical Medical research Institute
PO BOX 11060 Adelaide 5001 South Australia
Country 90232 0
Australia
Phone 90232 0
+61 8 8313 9000
Fax 90232 0
Email 90232 0
varun.malik@adelaide.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Individual patients' autonomic data will not be useful in a data repository. Responses (or change ) in cardiovascular measurements in response to reflex activity are more meaningful as aggregate data with appropriate confidence intervals/standard of error of measurement.
What supporting documents are/will be available?
Informed consent form
Ethical approval
Other
'Other' documents specified
Patient information sheet
How or where can supporting documents be obtained?
Type [1] 1159 0
Informed consent form
Citation [1] 1159 0
Link [1] 1159 0
Email [1] 1159 0
Other [1] 1159 0
Type [2] 1160 0
Other
Citation [2] 1160 0
Link [2] 1160 0
Email [2] 1160 0
Other [2] 1160 0
Patient information sheet
Type [3] 1161 0
Ethical approval
Citation [3] 1161 0
Link [3] 1161 0
Email [3] 1161 0
Other [3] 1161 0
Summary results
No Results