Enzyme replacement therapy for Anderson-Fabry disease: A complementary overview of a Cochrane publication through a linear regression and a pooled analysis of proportions from cohort studies

Abstract

BackgroundAnderson-Fabry disease (AFD) is an X-linked recessive inborn error of glycosphingolipid metabolism caused by a deficiency of alpha-galactosidase A. Renal failure, heart and cerebrovascular involvement reduce survival. A Cochrane review provided little evidence on the use of enzyme replacement therapy (ERT). We now complement this review through a linear regression and a pooled analysis of proportions from cohort studies.ObjectivesTo evaluate the efficacy and safety of ERT for AFD.Materials and methodsFor the systematic review, a literature search was performed, from inception to March 2016, using Medline, EMBASE and LILACS. Inclusion criteria were cohort studies, patients with AFD on ERT or natural history, and at least one patient-important outcome (all-cause mortality, renal, cardiovascular or cerebrovascular events, and adverse events) reported. The pooled proportion and the confidence interval (CI) are shown for each outcome. Simple linear regressions for composite endpoints were performed.Results77 cohort studies involving 15,305 participants proved eligible. The pooled proportions were as follows: a) for renal complications, agalsidase alfa 15.3% [95% CI 0.048, 0.303; I2 = 77.2%, p = 0.0005]; agalsidase beta 6% [95% CI 0.04, 0.07; I2 = not applicable]; and untreated patients 21.4% [95% CI 0.1522, 0.2835; I2 = 89.6%, p<0.0001]. Effect differences favored agalsidase beta compared to untreated patients; b) for cardiovascular complications, agalsidase alfa 28% [95% CI 0.07, 0.55; I2 = 96.7%, p<0.0001]; agalsidase beta 7% [95% CI 0.05, 0.08; I2 = not applicable]; and untreated patients 26.2% [95% CI 0.149, 0.394; I2 = 98.8%, p<0.0001]. Effect differences favored agalsidase beta compared to untreated patients; and c) for cerebrovascular complications, agalsidase alfa 11.1% [95% CI 0.058, 0.179; I2 = 70.5%, p = 0.0024]; agalsidase beta 3.5% [95% CI 0.024, 0.046; I2 = 0%, p = 0.4209]; and untreated patients 18.3% [95% CI 0.129, 0.245; I2 = 95% p < 0.0001]. Effect differences favored agalsidase beta over agalsidase alfa or untreated patients. A linear regression showed that Fabry patients receiving agalsidase alfa are more likely to have higher rates of composite endpoints compared to those receiving agalsidase beta.ConclusionsAgalsidase beta is associated to a significantly lower incidence of renal, cardiovascular and cerebrovascular events than no ERT, and to a significantly lower incidence of cerebrovascular events than agalsidase alfa. In view of these results, the use of agalsidase beta for preventing major organ complications related to AFD can be recommended.

Enzyme replacement therapy in Fabry disease in Poland – position statement

“…38,39 In addition, ERT (agalsidase beta) led to significant reductions in the clinically significant composite renal, cardiac, and neurologic endpoint (-61%, P = 0.034, for the "per--protocol" population). 40,41 Numerous clinical observations also indicated that the clinical effects depend on the stage of the disease in which ERT was initiated. The use of ERT in patients at a younger age, with less severe organ damage, without irreversible complications, or without previous serious cardiovascular events, resulted in more beneficial clinical effects.…”

“…Special indications for diagnostic testing for Fabry disease Chronic kidney disease, proteinuria, or albuminuria of unknown origin Unexplained left ventricular hypertrophic cardiomyopathy Transient ischemic attack or stroke in young people White matter lesions with an unclear cause Unexplained neuropathy of thin nerve fibers Angiokeratoma or cornea verticillataFamily history of Fabry disease (indication for active family screening of patients with diagnosed disease; inheritance related to the X chromosome) Effect of enzyme replacement therapy on clinical parameters in patients with Fabry disease (based on Germain et al,38 Germain et al,39 Banikazemi et al,40 and El Dib et al)41 …”

Effects of Enzyme Replacement Therapy and Antidrug Antibodies in Patients with Fabry Disease

“…53 However, recent reviews reported only a small benefit of the use of ERT. 66,80 One mechanism suspected to play a role in curbing ERT efficacy is the formation of ADAs against infused enzymes, which is a major focus of this review.…”

Strong increase of leukocyte apha‐galactosidase A activity in two male patients with Fabry disease following oral chaperone therapy

“…Left ventricular (LV) myocardial hypertrophy (LVMH) and cardiac fibrosis have been suggested as risk factors for arrhythmias and sudden death (Krämer et al, ). Currently, it is widely accepted that enzyme replacement therapy (ERT) provides benefits in terms of cardiac hypertrophy and renal disease, at least when initiated in the early stage of the disease (El Dib et al, ). Migalastat (or 1‐deoxygalactonojirimycin hydrochloride) has first been described as a competitive inhibitor of the α‐Gal A.…”