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

<div><p>Background</p><p>Anderson-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.</p><p>Objectives</p><p>To evaluate the efficacy and safety of ERT for AFD.</p><p>Materials and methods</p><p>For 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.</p><p>Results</p><p>77 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.</p><p>Conclusions</p><p>Agalsidase 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.</p></div

Progression of composite endpoints, according to ERT regimens throughout the years.

<p>Progression of composite endpoints, according to ERT regimens throughout the years.</p

Comparison of the plotted proportional meta-analysis, according to ERT regimens, for cardiovascular complications.

<p>Effect differences were seen due to the non-overlap of the 95% confidence intervals favoring the use of agalsidase beta compared to untreated patients, as their CIs did not overlap. There was no statistically significance difference between agalsidase alfa and both untreated patients and agalsidase beta, as their CIs overlapped.</p

Comparison of the plotted proportional meta-analysis, according to ERT regimens, for cerebrovascular complications.

<p>Effect differences were seen due to the non-overlap of the 95% confidence intervals favoring the use of agalsidase beta compared to both untreated patients and agalsidase alfa, as their CIs did not overlap. There was no statistically significance difference between agalsidase alfa and untreated patients, as their CIs overlapped.</p

Comparison of the plotted proportional meta-analysis, according to ERT regimens, for renal complications.

<p>Effect differences were seen due to the non-overlap of the 95% confidence intervals favoring the use of agalsidase beta compared to untreated patients, as their CIs did not overlap. There was no statistically significance difference between agalsidase alfa and both untreated patients and agalsidase beta, as their CIs overlapped.</p

Characteristics of patients undergoing ERT: Comparison among different regimens for AFD patients.

<p>Characteristics of patients undergoing ERT: Comparison among different regimens for AFD patients.</p

Flowchart of the review.

<p>Flowchart of the review.</p

Pooled analysis of proportions from cohort studies for all-cause mortality.

<p>Panel A: agalsidase alfa (primary analysis). Panel B: agalsidase alfa (sensitivity analysis excluding children). Panel C: agalsidase beta. Panel D: untreated patients.</p

MRI of the female patient 54, showing the typical pattern of white matter abnormality found in X-ALD.

<p>MRI of the female patient 54, showing the typical pattern of white matter abnormality found in X-ALD.</p

Kaplan–Meier survival curves.

<p>(A) Overall disease onset of the main phenotypes Addison-only, cerebral (CALD) and adrenomyeloneuropathy (AMN). Disease onset were significantly different (log rank test, p<0.001). (B) Disease onset of CALD, according to latitude of origin of the patient (ns). (C) CALD survival until death.</p