Cardiac Involvement in Adult Patients With Fabry Disease; Relation to Enzyme Replacement Therapy

Completed

• Conditions: Fabry Disease

• Registration Number: NCT02908724
• Lead Sponsor: Ulla Feldt-Rasmussen

Brief Summary

The purpose of this study was to assess the progression of cardiac involvement in adult patients with Fabry Disease (FD), in the unique Danish Fabry cohort and comparing those FD patients receiving primary therapy vs. those that did not.

The hypothesis is, that we will not be able to see a significant positive difference in cardiac involvement in those FD patient who received FD specific therapy vs. those that did not.

Detailed Description

Enzyme replacement therapy and concomitant treatment:

FD specific treatment (ERT, enzyme replacement therapy) have been available since 2001 and patients have been treated with either agalsidase alpha (Replagal®) or agalsidase beta (Fabrazyme®) every other week at recommended doses, 0.2 mg/kg and 1.0 mg/kg, respectively.

Concomitant treatment with cardiovascular medication including angiotensin-converting-enzyme-inhibitor, angiotensin-II-receptor-blocker, acetylsalicylic acid, beta-blocker, calcium-channel-blocker, diuretics and statins, was registered for all patients.

Statistical analysis:

Primarily, we compared the progression of cardiac involvement from baseline to follow-up, according to ERT including subgroup analysis according to gender.

Secondarily, subgroup analysis of the ERT group was performed by separating patients with- and without cardiac disease at baseline, indicated by the presence of myocardial hypertrophy on transthoracic echocardiography (septal thickness or LV posterior wall thickness \>0.9 cm for females and \>1.0 for males), increased cardiac mass (Left ventricular mass index (LVMi) \>95 g/m2 for females and \>115g/m2 for males) or systolic dysfunction (ejection fraction \<55%) in accordance with the guidelines from the American Society of Echocardiography and the European Association of Echocardiography (Lang et al., 2005).

In these analyses ERT patients' baseline was defined as the last available examination prior to ERT start and follow-up as the last available examination during ERT. Inclusion in the non-ERT group required that patient had not received ERT at study end. Intra-group comparisons of progression from baseline to follow-up were made by McNemar test (categorical variables) and Wilcoxon Signed Rank Test (continuous variables).

Thirdly, for comparisons between treatment groups, linear mixed models were applied on all available data from continuous variables regarding Sokolow-Lyon voltage-, Cornell product ECG criteria and LVMi as no violations of the assumptions for linear mixed model testing were found in initial analyses. The modelling allows for individual difference at a general level (tracking) as well as individual differences in the progression over time, controlled for gender, age at baseline, treatment duration and current ERT status.

Comparisons of major organ involvement at baseline, gene mutations and alfa-galactosidase A activity between treatment groups, were performed by Chi-squared and Mann-Whitney U tests, respectively.

Data from categorical variables are presented as frequency (percentage), and continuous variables are presented as median \[range\] or estimate (±standard error). Data was analysed using SPSS (version 19.0). All tests were two-sided and a p-value \<0.05 was considered statistically significant.

Study Timeline

• Study Start: 2014-11
• Primary Completion: 2014-11
• Study Completion: 2016-02-09
• Study First Submitted: 2016-04-04
• Study First Submitted QC: 2016-09-17
• Study First Posted: 2016-09-21
• Status Verified: 2018-10
• Last Update Submitted: 2018-10-15
• Last Update Posted: 2018-10-16

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 66

Inclusion Criteria

• Genetically verified Fabry disease
• Age at baseline >18 years
• Baseline cardiac examination performed

Exclusion Criteria

• Switch from FD specific treatment (Fabrazyme or Replagal) to no FD specific treatment

Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Left Ventricular Mass Index	Up to 13 years follow-up	Measured by Transthoracic Echocardiography using a Philips IE 33. Two-dimensional parasternal images were used to determine left ventricular chamber dimensions and wall thickness; LV mass was calculated by the American Society of Echocardiography (ASE) equation and indexed to body surface area. Median \[range\] is evaluated and presented.
Left Ventricular Hypertrophy - Sokolow-Lyon voltage criteria	Up to 13 years follow-up	12-lead electrocardiography (ECG) was performed using a Schiller Cardiovit AT-2 (Schiller AG, Dietikon, Switzerland). Left ventricular hypertrophy was evaluated by Sokolow-Lyon voltage criteria (S in V1 + R in V5/V6 ≥ 35 mm). Median \[range\] and frequency (%) of hypertrophy is evaluated and presented.
Left Ventricular Hypertrophy - Cornell voltage product criteria	Up to 13 years follow-up	12-lead ECG was performed using a Schiller Cardiovit AT-2 (Schiller AG, Dietikon, Switzerland). Left ventricular hypertrophy was evaluated by Cornell product criteria (R in aVL + S in V3 (+6 mm for women) x QRS duration \> 2440 mm·ms). Median \[range\] and frequency (%) of hypertrophy is evaluated and presented.

Secondary Outcome Measures

Name	Time	Method
Clinical outcome	Up to 13 years follow-up	Cardiac interventions (medication, percutaneous coronary interventions, coronary artery bypass graft, implantation of implantable cardioverter-defibrillators or pacemakers), Cardiac symptoms (Chest pain, palpitations, edema, dyspnea, dizziness, syncope) and all-cause mortality. Frequency (%) is evaluated and presented.
Arrhythmias	Up to 13 years follow-up	Atrial fibrillation, atrial flutter, supraventricular tachycardia, non-sustained ventricular tachycardia, measured by ECG and Holter-monitoring. Frequency (%) is evaluated and presented.