Outcomes of patients treated through the Canadian Fabry disease initiative
Introduction
Fabry disease is an X-linked disorder causing progressive renal, cardiac, and neurologic disease due to deficiency of alpha galactosidase A [1]. Treatment for Fabry disease using enzyme replacement therapy (ERT) has been studied in some randomized trials [2], [3], [4], [5] and observational cohorts [6], [7] but, despite use of ERT for more than a decade, there remains uncertainty about its efficacy as published data emphasize surrogate endpoints, have small patient numbers, short trial duration [8], [9], [10], and lack documentation about use of supportive therapies which may impact outcomes such as angiotensin converting enzyme inhibitors (ACEI) [11], [12], acetylsalicylic acid (ASA), and statin agents.
The Canadian Fabry disease initiative (CFDI; clinical trials registration number NCT00455104) is a project sponsored by the Canadian Institutes of Health Research and the provincial governments of Canada in collaboration with Genzyme, a Sanofi Company, and Shire Human Genetic Therapies. We present data at 5 years of follow-up to answer two questions:
- 1.
What are the clinical outcomes of subjects with Fabry disease who receive therapy targeting cardiovascular risk factors and ERT?
- 2.
Do the Canadian evidence-based ERT guidelines exclude from therapy subjects who may derive benefit from ERT?
Section snippets
Study design
The study design has been previously reported [13]. Briefly, all Canadians between the ages of 5 and 85 years with confirmed Fabry disease are eligible for enrollment and are placed in one of three cohorts:
- Cohort 1a
Subjects receiving ERT prior to the start of the CFDI and are maintained on the ERT formulation (agalsidase alfa or agalsidase beta) at entry.
- Cohort 1b
Subjects naive to ERT who meet ERT criteria and undergo 1:1 randomization, stratified by gender, to either agalsidase alfa or agalsidase beta.
- Cohort 1c
Subjects
Comparison of ERT-treated cohorts
We report data on 362 subjects 18 years of age and over, representing 91% of known adult cases of Fabry disease in Canada. A single subject under the age of 18 met a clinical endpoint (acute hearing loss) and is not included. Fig. 1 shows the treatment allocation of subjects, crossovers of drug or cohort, and subjects lost to follow up. The allocation of subjects within Cohort 1b to the two different ERT formulations is unequal due to shortage of agalsidase beta. Table 1 shows the
Discussion
We present data from a large prospective treatment cohort which documents clinical outcomes in subjects followed using a 4 point protocol which includes use of ERT in subjects who meet evidence-based criteria, cardiovascular risk factor modification, centralization of care to experienced centers, and close follow-up of patients not on ERT to allow the early identification of disease progression which might be amenable to the use of ERT.
The indications for ERT used in the CFDI require that early
Conclusions
A protocol which includes cardiovascular risk factor modification, centralization of care, targeted use of ERT, and close follow-up of subjects not on ERT is associated with low rates of cardiovascular and renal events and death in male and female subjects with Fabry disease.
Conflict of interest
The Canadian Fabry Disease Initiative is funded jointly by the provincial governments of Canada, Genzyme, a Sanofi Company, and Shire Human Genetics Therapies. The funding bodies did not have any role in data analysis, interpretation, or manuscript preparation. SMS, DGB, RC, JTRC, KL and MLW have served on advisory boards, received fees for speaking or travel support, and participated in other clinical trials and registries sponsored by Genzyme and Shire.
Acknowledgments
CFDI Investigators: Principal Investigators: Dr. M.L. West, Dr. D. Bichet, Dr. J.T.R. Clarke, Dr. R. Casey, Dr. S.M. Sirrs.
Site investigators: Dr. A. Chan, Dr. S. Dyack, Dr. C. Greenberg, Dr. J. MacKenzie, Dr. B. Maranda, Dr. A. Mhanni, Dr. C. Morel, Dr. S. Murphy, Dr. C. Prasad, Dr. J. Raiman, and Dr. L Turner.
The investigators would like to thank the Canadian Fabry Association, subjects, and families for their support of this project.
The investigators would like to thank Dr. D. Moore, Dr. C.
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