Arrhythmia Burden, Risk of Sudden Cardiac Death and Stroke in Patients With Fabry Disease

This is a 3-year open-label multicentre randomised controlled trial assessing arrhythmia burden in patients with Fabry cardiac disease. This is an observational study, but with implantable loop recorder (ILR) insertion at recruitment and removal at end of trial for the intervention arm.

Null hypothesis: There will be no difference in the identification of arrhythmia between patients following standard care compared to patients following standard care but with the addition of ILR monitoring.

Beyond the proposed hypothesis, data collected will be used to inform whether ILR in FD will:

1. Reveal a high burden of unrecognised arrhythmia
2. Lead to frequent treatment modification (anti-coagulation, pacemaker and ICD implantation, ablation)
3. Enable the development of FD specific risk prediction algorithms
4. Identify predictive power of new (Troponin, BNP, lysoGB3, T1 and T2 mapping) and traditional biomarkers

• Implantable Loop Recorder (Device): An implantable loop recorder (ILR), also known as an insertable cardiac monitor, is a small device (smaller than a AAA battery) that is inserted under the skin on the front of the chest. The ILR is inserted using local anesthetic as an out-patient procedure and lasts approximately 30 minutes. The ILR captures a continuous ECG of your heart activity, which allows doctors to detect any abnormal heart rhythms at any point. If you have the ILR, you will have the device for 3 years, after which it will be removed under local anesthetic during an out-patient procedure, again lasting approximately 30 minutes. The ILR device is completely safe and shouldn't affect your day to day living.

Primary outcomes

• First occurrence of atrial fibrillation (AF) requiring anticoagulation [Total monitoring time period in study - 3 years]: This will include all descriptions of AF, which can be defined as: 1. paroxysmal - self-terminating episodes lasting between 48 hours to 7 days 2. persistent - intermittent episodes lasting between 7 days to 1 year 3. permanent - episodes lasting longer than 1 year
• First occurrence of bradyarrhythmia requiring cardiac pacing [Total monitoring time period in study - 3 years]: This would include: 1. Symptomatic significant AV block. 2. Mobitz type 2 AV block or complete heart block irrespective of symptoms.
• First occurrence of supraventricular arrhythmia requiring drug treatment or ablation. [Total monitoring time period in study - 3 years]
• First occurrence of non-sustained ventricular tachyarrhythmia requiring drug treatment, ICD implantation or ablation [Total monitoring time period in study - 3 years]: This is classified as three or more ventricular beats at a rate >120bpm, for a duration of less than 30 seconds.

Secondary outcomes

• Frequency of arrhythmia in patients with and without late gadolinium enhancement (LGE) [3 years]: The study will aim at quantifying the extent of LGE deposited with myocardial tissue on cardiac MRI scanning. This will subsequently be correlated with the burden of arrhythmia detected to assess for potential risk factors.
• Frequency of arrhythmia according to location of myocardial fibrosis (inferolateral vs. non-inferolateral) [3 years]: The study will aim to correlate the location of myocardial fibrosis with the presence or absence of cardiac arrhythmia to define location of fibrosis as a potential risk factor for arrhythmia.
• Frequency of arrhythmia in those patients with a QRS duration greater or less than 120ms [3 years]
• Frequency of arrhythmia in those with an atrial size above or below indexed normal range for age and sex [3 years]

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* Patients with genotypically or enzymatically confirmed FD
* Adults > 18 years of age
* Evidence of cardiac involvement from FD involving either:
* Any ECG abnormality associated with FD
* Low T1 on CMR (below centre-specific normal range according to sex)
* LVH on transthoracic echo (defined as MWT >12mm)

Exclusion Criteria:

* Patient with an existing cardiac device (PPM, ICD or ILR).
* Known dual pathology:
* Known coronary artery disease (positive non-invasive imaging, confirmed myocardial infarction, percutaneous or surgical revascularisation). Patients >40 years old with symptoms that could be from coronary artery disease will have this excluded
* Known cardiomyopathy disease causing mutation (e.g. SCN5, MYBPC3)

• Results publication: Vijapurapu R, Kozor R, Hughes DA, Woolfson P, Jovanovic A, Deegan P, Rusk R, Figtree GA, Tchan M, Whalley D, Kotecha D, Leyva F, Moon J, Geberhiwot T, Steeds RP. A randomised controlled trial evaluating arrhythmia burden, risk of sudden cardiac death and stroke in patients with Fabry disease: the role of implantable loop recorders (RaILRoAD) compared with current standard practice. Trials. 2019 May 31;20(1):314. doi: 10.1186/s13063-019-3425-1. PMID 31151481

• Richard Steeds, MD, Principal investigator, University Hospital Birmingham NHS Foundation Trust