Mortality analysis |
-
Only one of the four agalsidase alfa studies included mortality as an endpoint (the others noted mortality in the context of safety).
-
Although a value of n=309 is quoted by El Dib et al. (2017)El Dib R, Gomaa H, Ortiz A, Politei J, Kapoor A and Barreto F (2017) 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. PLoS One 12:e0173358. for the total mortality analysis, there were 555 patients included in the safety population alone of the Mehta et al. (2009)Mehta A, Beck M, Elliott P, Giugliani R, Linhart A, Sunder-Plassmann G, Schiffmann R, Barbey F, Ries M, Clarke JT, et al. (2009) Enzyme replacement therapy with agalsidase alfa in patients with Fabry’s disease: an analysis of registry data. Lancet 374:1986-1996. paper, which included mortality assessments.
-
There is a considerable difference in the duration of the selected studies; because the agalsidase alfa studies were generally of longer duration, more mortality events would be anticipated in this group.
-
One of the selected agalsidase alfa studies evaluated patients with end-stage renal disease (Pastores et al., 2007Pastores GM, Boyd E, Crandall K, Whelan A, Piersall L and Barnett N (2007) Safety and pharmacokinetics of agalsidase alfa in patients with Fabry disease and end-stage renal disease. Nephrol Dial Transplant 22:1920-1925.), who might be expected to have more mortality events.
-
The analysis included neither the largest (n=677) study of agalsidase alfa that specifically looked at mortality (Beck et al., 2015Beck M, Hughes D, Kampmann C, Larroque S, Mehta A, Pintos-Morell G, Ramaswami U, West M, Wijatyk A, Giugliani R, et al. (2015) Long-term effectiveness of agalsidase alfa enzyme replacement in Fabry disease: A Fabry Outcome Survey analysis. Mol Genet Metab Rep 3:21-27.), nor the mortality data from the Canadian Fabry Disease Initiative (Sirrs et al., 2014Sirrs SM, Bichet DG, Casey R, Clarke JT, Lemoine K, Doucette S, West ML and CFDI Investigators (2014) Outcomes of patients treated through the Canadian Fabry disease initiative. Mol Genet Metab 111:499-506.).
|
Renal outcomes analysis |
-
Only one agalsidase beta study was included in the renal outcomes analysis.
-
Only one of the five agalsidase alfa studies included renal events as an endpoint, and two of the studies did not include information on dialysis or transplantation.
-
The Fabry Outcome Survey study/cohort included in the El Dib analysis provided a descriptive analysis of renal events in only 78 adult patients receiving agalsidase alfa (Barba-Romero et al., 2011Barba-Romero MÁ, Rivera-Gallego A, Pintos-Morell G and Spanish FOS-Study Group (2011) Fabry disease in Spain: Description of Spanish patients and a comparison with other European countries using data from the Fabry Outcome Survey (FOS). Int J Clin Pract 65:903-910.), whereas more detailed renal endpoint data (including initiation of dialysis and renal transplantation) are available in a separate analysis of a larger population of patients from the same data source (Mehta et al., 2009Mehta A, Beck M, Elliott P, Giugliani R, Linhart A, Sunder-Plassmann G, Schiffmann R, Barbey F, Ries M, Clarke JT, et al. (2009) Enzyme replacement therapy with agalsidase alfa in patients with Fabry’s disease: an analysis of registry data. Lancet 374:1986-1996.).
|
Cardiac outcomes analysis |
-
The comparability of endpoints was not always clear (e.g., three of the cardiac “events” reported by McKechnie et al. (2015)McKechnie DGJ, Mac Lochlainn DJ, Mehta AB and Hughes DA (2015) Long term clinical outcomes in patients with Fabry disease receiving enzyme replacement therapy. Mol Genet Metab 114:S78-S79. were not specified).
-
The analysis did not take into account the different proportions of patients with left ventricular hypertrophy (LVH) at baseline, which can increase the probability of a cardiac event.
|
Cerebrovascular outcomes analysis |
-
The analysis included a study in which three of the five women who experienced a stroke had a history of stroke before initiating agalsidase alfa (Whybra et al., 2009Whybra C, Miebach E, Mengel E, Gal A, Baron K, Beck M and Kampmann C (2009) A 4-year study of the efficacy and tolerability of enzyme replacement therapy with agalsidase alfa in 36 women with Fabry disease. Genet Med 11:441-449.).
-
The analysis did not take into account the different proportions of patients with LVH at baseline, which can increase the probability of a cerebrovascular event.
|
Composite outcomes analysis |
-
The analysis included mixed patient populations, including patients with end-stage renal disease, on dialysis, with LVH etc., who might be more likely to have an event.
-
The analysis did not include the largest (n=677) study of agalsidase alfa that specifically looked at mortality (Beck et al., 2015Beck M, Hughes D, Kampmann C, Larroque S, Mehta A, Pintos-Morell G, Ramaswami U, West M, Wijatyk A, Giugliani R, et al. (2015) Long-term effectiveness of agalsidase alfa enzyme replacement in Fabry disease: A Fabry Outcome Survey analysis. Mol Genet Metab Rep 3:21-27.).
-
The longer duration of the agalsidase alfa studies (up to 15 years) means that more events might be anticipated in this group.
-
Although it was reported that the Germain et al. (2013)Germain DP, Weidemann F, Abiose A, Patel MR, Cizmarik M, Cole JA, Beitner-Johnson D, Benistan K, Cabrera G, Charrow J, et al. (2013) Analysis of left ventricular mass in untreated men and in men treated with agalsidase-beta: Data from the Fabry Registry. Genet Med 15:958-965. study had a follow-up of 9.5 years, the mean follow-up in this study was 4.8 years.
-
The graph shows that two of the agalsidase alfa studies may have disproportionately affected the composite endpoint rates.
-
One of the cited agalsidase beta studies does not appear to be included in the composite event rate graph (El Dib et al., 2017El Dib R, Gomaa H, Ortiz A, Politei J, Kapoor A and Barreto F (2017) 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. PLoS One 12:e0173358.).
|