Outcomes of patients treated through the Canadian Fabry disease initiative

https://doi.org/10.1016/j.ymgme.2014.01.014Get rights and content

Highlights

  • Risk factor modification, close follow-up, and targeted use of ERT can reduce Fabry-related events.

  • ERT and risk factor modification does not reduce the risk of stroke in Fabry disease.

  • Use of evidence-based ERT guidelines did not result in an excess of ERT-responsive complications.

Abstract

Background

The Canadian Fabry disease initiative (CFDI) tracks outcomes of subjects with Fabry disease treated enzyme replacement therapy (ERT) given to subjects who meet evidence-based treatment guidelines and cardiovascular risk factor modification.

Methods

We report 5 year follow-up data on 362 subjects for a composite endpoint (death, neurologic or cardiovascular events, development of end-stage renal disease or sustained increase in serum creatinine of 50% from baseline).

Results

At enrollment, 86 subjects had previously received ERT (Cohort 1a) and 67 subjects were newly started (Cohort 1b) and randomized to agalsidase alfa or agalsidase beta. 209 subjects did not initially meet ERT criteria (Cohort 1c), 25 of whom met ERT criteria in follow-up and were moved to Cohort 1b (total N = 178 ERT treated subjects). Use of supportive therapies such as aspirin (78%), renin-angiotensin blockade (59%), and statins (55%) was common in ERT treated subjects. In Cohort 1a, 32 subjects met the composite endpoint with 8 deaths. In Cohort 1b, 16 subjects met the composite endpoint with 1 death. Cohort 1b had fewer clinical events than Cohort 1a (p = 0.039) suggesting that the treatment protocol was effective in targeting subjects at an earlier stage. 19.4% of Cohort 1b subjects on agalsidase alfa and 13.3% on agalsidase beta had a clinical event (p = 0.57). 10 Cohort 1c subjects had clinical events, none of which would have been prevented by earlier use of ERT.

Conclusions

Cardiovascular risk factor modification and targeted use of ERT reduce the risk of adverse outcomes related to Fabry disease.

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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