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

Not Applicable

Active, not recruiting

• Conditions: Fabry Disease
• Interventions: Device: Implantable Loop Recorder

• Registration Number: NCT03305250
• Lead Sponsor: University Hospital Birmingham NHS Foundation Trust

Brief Summary

Fabry disease (FD) is a genetic disorder that leads to progressive accumulation of fat or 'sphingolipid' within the tissues, including the heart muscle and conductive tissue. Improvements in the detection of FD, together with more organised clinical services for rare diseases, has led to a rapid growth in the disease prevalence. Earlier and more frequent diagnosis of asymptomatic individuals before development of the disease itself has focused attention on early detection of organ involvement and closer monitoring of disease progression. Moreover, the introduction of enzyme replacement therapy within the last two decades has changed the natural history of FD as follows: a) increased life expectancy; b) improved morbidity; c) modification of the main cause of morbidity and mortality from renal (kidney) to cardiovascular (heart) events, including heart failure, abnormal heart rhythms, stroke and sudden death. Although symptoms such as palpitations and blackouts are extremely common, information on the frequency of proven abnormal heart rhythms is limited. In addition, the rate and appropriateness of implantation of life-saving devices is very variable, including pacemakers to boost the heart when too slow and cardio-defibrillators that stop the heart when too fast. The main markers of risk in similar diseases such as hypertrophic cardiomyopathy cannot be used in FD. While patients are routinely followed up in clinic with heart tracings and echocardiography (ultrasound of the heart), a recent small study has emphasised that these tests under-estimate the burden of abnormal heart rhythms in patients with advanced FD. The use of continuous heart monitoring with an implantable loop recorder (ILR) has led to a significant change in treatment in 13 out of 15 of FD patients. The investigators believe that more frequent use of ILRs will identify a greater need for change in therapy in many more patients than currently treated, with the aim of reducing morbidity and mortality in this patient cohort. In addition this will provide valuable data to inform an estimate of future risk for these patients.

Detailed Description

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

Study Timeline

• Study First Submitted: 2017-09-21
• Study First Submitted QC: 2017-10-03
• Study First Posted: 2017-10-09
• Study Start: 2019-09-18
• Status Verified: 2024-12
• Last Update Submitted: 2025-05-11
• Last Update Posted: 2025-05-14
• Primary Completion: 2026-07
• Study Completion: 2027-07

Recruitment & Eligibility

• Status: ACTIVE_NOT_RECRUITING
• Sex: All
• Target Recruitment: 169

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)

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Interventional Arm	Implantable Loop Recorder	Using an Implantable Loop Recorder fo continuous rhythm monitoring and home follow-up. This will be combined with standard care procedure, which will include annual ECG, 24 hour Holter/5 day ECG monitoring and further investigation dependent on symptom status.

Primary Outcome Measures

Name	Time	Method
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 Outcome Measures

Name	Time	Method
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

Trial Locations

Locations (7)

University of Sydney; 🇦🇺 Sydney, Australia

University Hospitals Birmingham NHS Foundation Trust; 🇬🇧 Birmingham, West Midlands, United Kingdom

Cambridge University Hospitals NHS Foundation Trust; 🇬🇧 Cambridge, United Kingdom

Cardiff and Vale University Health Board; 🇬🇧 Cardiff, United Kingdom

Royal Free NHS Foundation Trust; 🇬🇧 London, United Kingdom

Salford Royal NHS Foundation Trust; 🇬🇧 Manchester, United Kingdom

Sheffield Teaching Hospitals NHS Foundation Trust; 🇬🇧 Sheffield, United Kingdom