Effects of Baseline Left Ventricular Hypertrophy and Decreased Renal Function on Cardiovascular and Renal Outcomes in Patients with Fabry Disease Treated with Agalsidase Alfa: A Fabry Outcome Survey Study

Abstract

Purpose: The initiation of enzyme-replacement therapy prior to the occurrence of substantial and irreversible organ damage in patients with Fabry disease is of critical importance. The Fabry Outcome Survey is an international disease registry of patients with a confirmed diagnosis of Fabry disease. In this study, data from the Fabry Outcome Survey were used for the assessment of the risks for cardiovascular and renal events in patients who received agalsidase alfa treatment.

Methods: Eligible patients were males and females aged ≥18 years with Fabry disease treated with agalsidase alfa. Cardiovascular events included myocardial infarction, left ventricular hypertrophy (LVH), heart failure, arrhythmia, conduction abnormality, and cardiac surgery. Renal events included dialysis, transplantation, and renal failure. Kaplan-Meier curves and log-rank tests were used for comparing event-free probabilities and time to first cardiovascular or renal event, from agalsidase alfa initiation to a maximum of 120 months, in patients with LVH versus normal left ventricular mass index (LVMI; ≤50 g/m2.7 in males and ≤48 g/m2.7 in females) at treatment initiation (baseline), and in patients with a low estimated glomerular filtration rate (eGFR; <90 mL/min/1.73 m2) versus normal eGFR at baseline. Multivariate Cox regression analysis was used for examining the association between key study variables and the risks for cardiovascular and renal events.

Findings: Among the 560 patients (269 males; 291 females) with available LVMI data, 306 (55%) had LVH and 254 (45%) had normal LVMI at baseline. The risk for a cardiovascular event was higher in the subgroup with LVH versus normal LVMI at baseline (hazard ratio [HR] = 1.57; 95% CI, 1.21-2.05; P < 0.001), but the risk for a renal event was similar between the 2 subgroups (HR = 1.90; 95% CI, 0.94-3.85; P = 0.074). Among the 1093 patients (551 males; 542 females) with available eGFR data, 433 (40%) had a low eGFR and 660 (60%) had a normal eGFR at baseline. The subgroup with a low eGFR at baseline had a significantly higher risk for a cardiovascular event (HR = 1.33; 95% CI, 1.04-1.70; P = 0.021) or a renal event (HR = 5.88; 95% CI, 2.73-12.68; P < 0.001) compared with patients with a normal eGFR at baseline.

Implications: In the present study, the presence of LVH and/or reduced renal function at agalsidase alfa initiation was associated with a significantly higher risk for a cardiovascular or renal event, indicating that cardiovascular and renal pathologies in Fabry disease may be inter-related. Early initiation of agalsidase alfa treatment prior to the onset of severe organ damage may improve outcomes. ClinicalTrials.gov identifier: NCT03289065.

Keywords: Fabry Outcome Survey; Fabry disease; agalsidase alfa; enzyme-replacement therapy; estimated glomerular filtration rate; left ventricular hypertrophy.

Conflict of interest statement

Disclosures Shire International GmbH, a Takeda company, funded this research, its publication, and the writing and editing of the manuscript, and was involved in the study design; the collection, analysis, and interpretation of the data; the writing of the report; and the decision to submit the article for publication. The FOS is sponsored by Shire Human Genetic Therapies Inc. a Takeda company. Dr. Feriozzi reports personal and travel fees from Takeda, personal and travel fees from Sanofi, personal and travel fees from Amicus, outside the submitted work; Dr. Linhart reports grants and personal fees from Amicus Therapeutics, grants and personal fees from Sanofi Genzyme, grants and personal fees from Takeda, outside the submitted work; Dr. Ramaswami reports grants and personal fees from Amicus, personal fees from Chiesi, personal fees from Sanofi Genzyme, grants from Takeda, outside the submitted work, and she is also a member of the Steering Committee of the Fabry Outcome Survey; Ms. Kalampoki was an employee of Takeda during the conduct of this study; Dr. Gurevich was an employee of Takeda during the conduct of this study; Dr. Hughes reports personal fees from Takeda, personal fees from Sanofi, personal fees from Amicus, personal fees from Idorsia, personal fees from Protalix, personal fees from Freeline, outside the submitted work, and she is also a member of the Steering Committee of the Fabry Outcome Survey.

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