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

Abstract

Background: Fabry disease (FD) is a genetic disorder caused by a deficiency in the enzyme alpha-galactosidase A, leading to an accumulation of glycosphingolipids in tissues across the body. Cardiac disease is the leading cause of morbidity and mortality. Advanced disease, characterised by extensive left ventricular hypertrophy, ventricular dysfunction and fibrosis, is known to be associated with an increase in arrhythmia. Data identifying risk factors for arrhythmia are limited, and no Fabry-specific risk stratification tool is available to select those who may benefit from initiation of medical or device therapy (implantable cardiac defibrillators). Current monitoring strategies have a limited diagnostic yield, and implantable loop recorders (ILRs) have the potential to change treatment and clinical outcomes.

Aim: The aim of this study is to determine whether ILRs can (1) improve arrhythmia detection in FD and (2) identify risk predictors of arrhythmia.

Methods: A prospective, 5-year, open-label, international, multi-centre randomised controlled trial of a minimum of 164 participants with genetically or enzymatically confirmed FD (or both) who have evidence of cardiac disease will be recruited from five centres: Queen Elizabeth Hospital, Birmingham, UK; Salford Royal Hospital, Salford, UK; Royal Free Hospital, London, UK; Addenbrookes Hospital, Cambridge, UK; and Westmead Hospital, Sydney, Australia. Participants will be block-randomised (1:1) to two study arms for cardiac monitoring (i) control arm: standard of care with annual 24 h or 5-day Holter monitor or (ii) treatment arm: continuous cardiac monitoring with ILR implantation plus standard of care. Participants will undergo multiple investigations-blood/urine biomarkers, 12-lead and advanced electrocardiogram (ECG) recording, echocardiography and cardiovascular magnetic resonance (CMR) imaging-at baseline and 6-12 monthly follow-up visits. The primary endpoint is identification of arrhythmia requiring initiation or alteration in therapy. Secondary outcome measures include characterising the risk factors associated with arrhythmia and outcome data in the form of imaging, ECG and blood biomarkers.

Discussion: This is the first study evaluating arrhythmia burden and the use of ILR across the spectrum of risk profiles in Fabry cardiomyopathy. This will enable detailed characterisation of arrhythmic risk predictors in FD and ultimately support formulation of Fabry-specific guidance in this high-risk population.

Trial registration: ClinicalTrials.gov ( NCT03305250 ). Registered on 9 October 2017.

Keywords: Arrhythmia; Cardiomyopathy; Fabry; ILR.

Conflict of interest statement

RK has received honoraria from Sanofi-Genzyme. DH has received honoraria from Shire, Sanofi-Genzyme and Amicus. The other authors declare that they have no competing interests.

Figures

Fig. 1

Study timeline. A minimum of 164 participants will undergo baseline investigation and randomisation to standard care with annual Holter monitoring or to intervention with an implantable loop recorder device for continued electrocardiogram (ECG) monitoring. All participants will be followed up at 12 monthly intervals (centre-dependent) for the entire 36-month study period, with investigations repeated at each time-point.

Fig. 2

Block randomisation process. The high-risk features include LVH (MWT > 12 mm or elevated LVMi greater than two SD), LA dilatation (M-mode measurement > 40 mm or biplane volume > 34 mL on echo), elevated troponin (above centre specific reference ranges), prolonged QRS duration > 120 ms, presence of LGE on CMR imaging, a MSSI greater than 20. *There will be a variable number of patients from each high-risk feature group to ensure a variable risk profile within the study cohort (zero risk factors – 20 participants, one risk factor – 40 participants, two risk factors – 40 participants, three risk factors – 40 participants, four or five risk factors – 24 participants. Abbreviations: CMR cardiac magnetic resonance imaging, ECG electrocardiogram, ILR implantable loop recorder, LA left atrium, LGE late gadolinium enhancement, LVH left ventricular hypertrophy, LVMi indexed left ventricular mass, MSSI Mainz severity score index; MWT maximum wall thickness, SD standard deviation, TTE transthoracic echocardiography.

Fig. 3

Summary demonstrating participant activity for the duration of the study. All study visits will occur during routine clinical follow-up visits for Fabry disease surveillance, with only two extra hospital visits for screening and implantable loop recorder (ILR) insertion. The shaded columns represent optional monitoring visits that will be centre-dependent. Adapted from SPIRIT (Standard Protocol Items Recommendations for Interventional Trials) figure (2013). Abbreviations: CMR cardiac magnetic resonance, ECG electrocardiogram, QOL quality of life.