Enzyme replacement therapy with agalsidase alfa in patients with Fabry's disease: an analysis of registry data

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Enzyme replacement therapy with agalsidase alfa in patients with Fabry’s disease: an analysis of registry data A Mehta, M Beck, P Elliott, R Giugliani, A Linhart, G Sunder-Plassmann, R Schiffmann, F Barbey, M Ries, J T R Clarke, on behalf of the Fabry Outcome Survey investigators*

Summary Lancet 2009; 374: 1986–96 Published Online December 2, 2009 DOI:10.1016/S01406736(09)61493-8 See Comment page 1950 *Listed at end of paper University College London, London, UK (A Mehta FRCP, P Elliott FRCP); University of Mainz, Mainz, Germany (Prof M Beck MD); Medical Genetics Service/HCPA and Department of Genetics/ UFRGS, Porto Alegre, Brazil (Prof R Giugliani MD); Charles University, Prague, Czech Republic (Prof A Linhart MD); Division of Nephrology and Dialysis, Department of Medicine III, Medical University Vienna, Vienna, Austria (Prof G Sunder-Plassmann MD); Institute of Metabolic Disease, Baylor Research Institute, Dallas, TX, USA (Prof R Schiffmann MD); University Hospital of Lausanne, Lausanne, Switzerland (F Barbey MD); Shire Human Genetic Therapies Inc, Cambridge, MA, USA (M Ries MD); Hospital for Sick Children, Toronto, ON, Canada (Prof J T R Clarke MD); and Centre Hospitalier Universitaire, Sherbrooke, QC, Canada (Prof J T R Clarke MD) Correspondence to: Dr A Mehta, Department of Haematology, Royal Free Hospital, London NW3 2QG, UK [email protected]

Background We analysed 5-year treatment with agalsidase alfa enzyme replacement therapy in patients with Fabry’s disease who were enrolled in the Fabry Outcome Survey observational database (FOS). Methods Baseline and 5-year data were available for up to 181 adults (126 men) in FOS. Serial data for cardiac mass and function, renal function, pain, and quality of life were assessed. Safety and sensitivity analyses were done in patients with baseline and at least one relevant follow-up measurement during the 5 years (n=555 and n=475, respectively). Findings In patients with baseline cardiac hypertrophy, treatment resulted in a sustained reduction in left ventricular mass (LVM) index after 5 years (from 71·4 [SD 22·5] g/m²·⁷ to 64·1 [18·7] g/m²·⁷, p=0·0111) and a significant increase in midwall fractional shortening (MFS) from 14·3% (2·3) to 16·0% (3·8) after 3 years (p=0·02). In patients without baseline hypertrophy, LVM index and MFS remained stable. Mean yearly fall in estimated glomerular filtration rate versus baseline after 5 years of enzyme replacement therapy was –3·17 mL/min per 1·73 m² for men and –0·89 mL/min per 1·73 m² for women. Average pain, measured by Brief Pain Inventory score, improved significantly, from 3·7 (2·3) at baseline to 2·5 (2·4) after 5 years (p=0·0023). Quality of life, measured by deviation scores from normal EuroQol values, improved significantly, from –0·24 (0·3) at baseline to –0·17 (0·3) after 5 years (p=0·0483). Findings were confirmed by sensitivity analysis. No unexpected safety concerns were identified. Interpretation By comparison with historical natural history data for patients with Fabry’s disease who were not treated with enzyme replacement therapy, long-term treatment with agalsidase alfa leads to substantial and sustained clinical benefits. Funding Shire Human Genetic Therapies AB.

Introduction Fabry’s disease is a rare progressive multisystem disorder resulting from deficiency of the lysosomal enzyme α-galactosidase A. Renal failure, cardiomyopathy, and cerebrovascular disease are the main causes of morbidity and premature death.1 During the past 8 years, results of randomised controlled trials and clinical studies of the two preparations of enzyme replacement therapy, agalsidase alfa (Shire Human Genetic Therapies [HGT]) and agalsidase beta (Genzyme Corporation), have shown the safety and efficacy of treatment in small groups of adults and children with Fabry’s disease.2–7 Two observational databases, the Fabry Outcome Survey (FOS) and the Fabry Registry, follow the treatment of patients receiving agalsidase alfa and agalsidase beta, respectively. Data from these registries extend our knowledge of the natural history of the disease and its response to enzyme replacement therapy.1,8–11 We report FOS data for the effects of 5 years of treatment with agalsidase alfa on cardiac mass and function, renal function, pain, and quality of life.

Methods Patients FOS was approved by ethics institution review boards of participating centres. Patients gave written informed 1986

consent and were either receiving or not receiving enzyme replacement therapy with agalsidase alfa. No patient received agalsidase beta during the study. Every patient’s medical history was documented by a physician or nurse specialist, including year of diagnosis, signs and symptoms, treatment, demographic details, and family history. Results of routine clinical assessments or diagnostic procedures were obtained and submitted electronically to the central FOS database.

Procedures Treatment outcome was assessed longitudinally as changes from baseline in four clinical domains: cardiac mass and function, renal function, pain, and quality of life. Baseline values were obtained 12 months or less before and 14 days or less after start of treatment. We defined time intervals from baseline as: year 1, 1 year within 3 months; year 2, 2 years within 6 months; year 3, 3 years within 6 months; and year 5, 5 years within 12 months. Data for years 4 and 5 were combined because of low patient numbers. When several values were within a particular interval, the last recorded value was used. Left ventricular mass (LVM) was determined by standard echocardiography and was adjusted for height with the Devereux formula.12 Left ventricular hypertrophy (LVH) www.thelancet.com Vol 374 December 12, 2009

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was predefined as an LVM index higher than the upper normal limit (men, >51 g/m²·⁷; women, >48 g/m²·⁷). Midwall fractional shortening (MFS [%]) was determined by echocardiography as a measure of left ventricular contractility.13 Impaired MFS is an independent predictor of adverse clinical outcome in patients with arterial hypertension.14 MFS was considered normal if greater than 15%.13 Estimated glomerular filtration rate (GFR) was calculated from serum creatinine measurements with the abbreviated Modification of Diet in Renal Disease formula.15 Estimated GFRs calculated with the abbreviated Modification of Diet in Renal Disease formula were lower than were those calculated with the Cockcroft-Gault formula; however, there was a strong correlation between estimates from these two formulae at baseline (R=0·85, p<0·0001) and after 5 years of treatment (R=0·89, p<0·0001). Data for estimated GFR were analysed overall and separately for men and women because of differences in progression of renal dysfunction between sexes.16 The Brief Pain Inventory questionnaire was used for subjective assessment of pain.17 This questionnaire assesses present pain levels and retrospective reports of pain during the previous week, scoring pain at its worst, at its least, and on average on the basis of a visual analogue scale from 0 (no pain) to 10 (worst pain imaginable). The EuroQol questionnaire is a validated generic measure of health-related quality of life covering five dimensions.18 A score of 1 indicates full health and 0 is equivalent to death. Scores were compared with those for the general population and reported as deviation from normal values.

Criteria

Year 1

Year 2

Year 3

Year 5

Stabilisation

85·0% No deterioration from baseline (ie, LVM remained constant or decreased), or normal at baseline with no increase higher than sex-specific normal values for LVM (women, <48 g/m²·⁷; men, <51 g/m²·⁷)

88·1%

88·7%

80·7%

10% reversibility

Reduction of LVM by 10% or more

52·5%

69·0%

52·8%

35·1%

20% reversibility

Reduction of LVM by 20% or more

37·5%

52·4%

32·1%

22·8%

Stabilisation or improvement

MFS remained constant or increased, or MFS of 15% or greater at baseline that did not fall below the lower limit of normal (15%)

89·5%

80·0%

85·7%

76·9%

Reversibility

Patients with MFS less than 15% at baseline who had values of 15% or greater during treatment

31·6%

25·0%

26·5%

15·4%

Estimated GFR of 130 mL/min per 1·73 m² or higher at baseline with reduction to no less than 90 mL/min per 1·73 m²

81·8%

75·0%

92·3%

85·7%

Decelerated decline Estimated GFR less than 130 mL/min per (Schiffmann criteria)20 1·73 m² at baseline and reduction by less than 5 mL/min per 1·73 m² per year

62·7%

65·6%

70·2%

81·6%

Renal stability or improvement (Germain criteria)21

Change in estimated GFR of less than 20% from baseline at 5 years, or estimated GFR increase of 20% or more from baseline

93·6%

80·9%

74·2%

69·1%

Stabilisation

No worsening in quality of life on the basis of deviance of quality of life score

75·6%

77·1%

72·7%

74·5%

Improvement

Quality of life score (deviance) less than UK normal at baseline, with improvement during 5 years of treatment

63·4%

64·6%

63·6%

60·8%

Normalisation

Quality of life score (deviance) less than UK normal at baseline, with improvement increasing to normal during 5 years of treatment

9·8%

12·5%

6·8%

7·8%

Stabilisation

BPI score remained stable or improved by one point

60·6%

72·1%

68·3%

69·4%

Reversibility

BPI score improved by more than one point 39·4%

60·5%

48·8%

53·1%

Cardiac LVM

MFS

Renal Estimated GFR Patients with hyperfiltration or improvement19

Quality of life EuroQol

Statistical analysis The effectiveness analysis population included patients in FOS (aged >18 years at baseline) with baseline and 5-year follow-up data for any one of these variables. Availability of intermediate data was not a requirement. Differences in individual responsiveness to enzyme replacement therapy were assessed in all four clinical domains. Table 1 shows criteria used to determine response to treatment.19–21 The relation between changes in LVM during treatment and first sentinel cardiac, renal, and cerebrovascular events (panel) that occurred during this period were assessed. For this analysis, patients were divided into two groups based on the presence or absence of LVH after 5 years of treatment (LVH, either LVH at baseline and last follow-up or developed LVH during therapy; no LVH, either never had LVH or LVM index returned to normal levels during therapy). Patients who had previous events or for whom LVM data were missing were excluded. The first occurrence of any of these events, irrespective of organ system, was also analysed and defined as a composite event. Safety analyses included all patients aged 18 years or older at baseline who were exposed to at least one dose of agalsidase alfa (0·2 mg/kg every other week) on or before www.thelancet.com Vol 374 December 12, 2009

Proportion of responders (%)

Worst pain BPI

Patients were classed as responders or non-responders to enzyme replacement therapy at each analysis timepoint on the basis of defined criteria within the four clinical domains. More than one level of response was identified to assess stability and reversibility of disease progression. Patients for whom data did not meet these criteria were classed as non-responders. LVM=left ventricular mass. MFS=midwall fractional shortening. GFR=glomerular filtration rate. EuroQol=European quality of life questionnaire. BPI=Brief Pain Inventory.

Table 1: Criteria defining patients with Fabry’s disease who responded to treatment and the proportion of patients who met these criteria during 5 years of treatment with agalsidase alfa

June 30, 2006. All patients had at least one baseline creatinine measurement. At every visit, adverse events since the previous infusion were recorded, including potential adverse events occurring within 24 h of infusion. The sensitivity analysis included all patients in the safety analysis 1987

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Panel: Sentinel clinical events reported between baseline and last recorded left ventricular mass measurement Cardiac • Anginal chest pain syndrome • Acute myocardial infarction • Development of symptomatic heart failure • Insertion of a permanent pacemaker for symptomatic bradycardia–arrhythmia Cerebrovascular • Transient ischaemic attack • Prolonged reversible ischaemic neurological deficit • Stroke Renal • Initiation of dialysis • Renal transplantation Composite event • First occurrence of any event, irrespective of affected organ system

population for whom baseline and one follow-up measurement were available for any of the variables of interest (LVM, MFS, estimated GFR, Brief Pain Inventory score, or deviation score from EuroQol values). Paired t tests were used for statistical analyses at a significance level of p<0·05. Data analysis was done with SAS (version 9.1).

Role of the funding source Data collection and analysis in FOS were supported by the funding source. Data were obtained and entered by staff of participating institutions. Data analysis, interpretation, and writing of the report was coordinated and supervised by the authors. Funding for editorial assistance was provided by the funder. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.

Results At the time of analysis (database locked October, 2007), FOS contained data for 1428 patients from 19 countries, of whom 692 (607 adults) were receiving agalsidase alfa. 5-year longitudinal data were not available for most patients because therapy was continuing. Baseline and 5-year follow-up data were available for 181 adults (mean age 39·2 [12·3] years; 126 men; 176 (97·2%) Caucasian). Mutation data were available for 152 patients (102 men): 75 missense mutations (52 men), 35 non-sense mutations (22 men), 26 deletions (17 men), nine splice-site mutations (six men), and seven insertions (five men). Patients came from 27 treatment centres in Europe (n=149), North America (n=27), and Australia (n=5). Three centres contributed more than 15 patients: University Hospital, Mainz, Germany (n=51), Royal Free Hospital, London, UK (n=29), and the National Institutes 1988

of Health, Bethesda, MD, USA (n=16). Data for use of concomitant drugs were scarce. Use of angiotensinconverting enzyme inhibitors was reported in 80 patients, and of angiotensin II receptor blockers in 34 patients. Mean systolic and diastolic blood pressures were normal at baseline: 127·6 (15·6) mm Hg (n=166) and 74·2 (11·4) mm Hg (n=167), respectively. They remained within the normal range during the course of the study; however, there were significant reductions in systolic blood pressure relative to baseline after 1, 2, 3, and 5 years (changes after: year 1, –4·4 mm Hg, n=113, p=0·0013; year 2, –4·6 mm Hg, n=134, p=0·0006; year 3, –4·0 mm Hg, n=136, p=0·0138; year 5, –5·8 mm Hg, n=153, p<0·0001) and significant reductions in diastolic blood pressure relative to baseline after 1 and 2 years of treatment (changes after: year 1, –2·8 mm Hg, n=113, p=0·008; year 2, –2·4 mm Hg, n=135, p=0·0185). Hypertension (defined as systolic blood pressure ≥140 mm Hg or diastolic blood pressure ≥90 mm Hg) was reported in 44 patients (31 men) at baseline.22 There were small but significant reductions in systolic and diastolic blood pressure relative to baseline in patients with pre-existing hypertension after 1, 2, 3, and 5 years of treatment (all p<0·05) (figures 1A and 1B). Blood pressure remained normal in patients in whom it was normal at baseline. Mean LVM index at baseline was 58·3 (27·2) g/m²·⁷. Overall prevalence of LVH was 30·4% (24 women, 31 men). Mean systolic and diastolic blood pressures were normal at baseline in patients with pre-existing LVH (systolic 130·7 [16·9] mm Hg and diastolic 74·5 [11·2] mm Hg) and without LVH (systolic 124·5 [15·2] mm Hg and diastolic 72·1 [12·0] mm Hg). Hypertension was present in 15 patients with LVH at baseline, and in seven patients without. Mean MFS was 15·0% at baseline. MFS was lower than the normal range in 40 of the 87 patients for whom data were available (24 men, 16 women). In patients with baseline LVH, there was a sustained and significant improvement in mean LVM index during treatment (p=0·0111) (table 2, figure 2A). MFS was mildly abnormal in these patients at baseline and improved significantly after 1, 2, and 3 years of treatment (p=0·001, 0·0176, and 0·02, respectively) (table 3, figure 2B). Systolic but not diastolic blood pressure fell significantly after 1, 2, and 5 years of treatment in patients with baseline LVH (all p<0·05) (figures 1C and 1D). In patients without LVH at baseline, LVM index and MFS remained normal during the 5 years of observation, although significant increases in MFS were recorded after 1 and 2 years (table 3). Overall, patients had a significant decrease in mean LVM after 1, 2, and 3 years of treatment with agalsidase alfa relative to baseline (changes after: year 1, –7·3 g/m²·⁷, p<0·0001; year 2, –9·0 g/m²·⁷, p=0·0004; year 3, –6·3 g/m²·⁷, p=0·0085) and a corresponding significant increase in mean MFS (changes after: year 1, 2·5%, p<0·0001; year 2, 2·3%, p=0·0004; year 3, 1·3%, p=0·0085). No significant www.thelancet.com Vol 374 December 12, 2009

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A

C Baseline hypertension No Yes

Change in SBP from baseline (mm Hg)

10 5

5

0 (96)

(80)

(29)

0

(100)

(33)

–5

(38)

(33)

(112) –5

(47)

(43)

(38) –10

–10 (38)

–20

–15

(41)

(36)

*

(50)

*

*

(33)

–15

*

*

–20

*

*

–25

Change in DBP from baseline (mm Hg)

LVH at baseline No LVH LVH

10

–25

B

D

10

10

5 5 (101)

(114)

(97)

0

(80)

(33) 0

(32)

(28)

–5

(38)

(33)

(41)

* *

*

–15 0

1

(52)

(48)

–5

(38)

–10

(45)

(39)

(36)

* 3

2

4

–10

5

0

1

2

3

4

5

Year

Year

Figure 1: Changes in systolic and diastolic blood pressure relative to baseline in patients with Fabry’s disease during 5 years of treatment with agalsidase alfa According to (A, B) presence of hypertension at baseline, and (C, D) presence of left ventricular hypertrophy at baseline. Patient numbers are shown in parentheses. Horizontal lines represent baseline. SBP=systolic blood pressure. LVH=left ventricular hypertrophy. DBP=diastolic blood pressure. *p<0·05 versus baseline.

LVH at baseline

No LVH at baseline

n

Mean baseline LVM index (g/m²·⁷)

Mean LVM index at year end (g/m²·⁷)

Mean change from baseline (g/m²·⁷)

p value*

n

Mean baseline LVM index (g/m²·⁷)

Mean LVM index at year end (g/m²·⁷)

Mean change from baseline (g/m²·⁷)

Year 1

23

68·5 (20·0)

58·4 (19·6)

–10·1 (12·0)

0·0006

17

38·5 (6·5)

35·0 (5·7)

–3·5 (6·8)

NS

Year 2

24

70·1 (19·7)

56·9 (16·7)

–13·3 (17·2)

0·001

18

38·9 (6·5)

35·6 (7·4)

–3·4 (9·2)

NS

Year 3

29

70·1 (21·2)

59·8 (18·0)

–10·3 (20·8)

0·0121

24

38·4 (6·2)

36·9 (6·9)

–1·5 (8·5)

NS

Year 5

32

71·4 (22·5)

64·1 (18·7)

–7·3 (15·3)

0·0111

25

38·7 (6·3)

40·5 (10·0)

1·8 (10·1)

p value*

NS

Data are mean (SD, where applicable). Baseline values for each comparison are different because data were not available for all patients at every time point. LVH=left ventricular hypertrophy. LVM=left ventricular mass. NS=not significant. *Paired t test, significance at p<0·05.

Table 2: Change in mean left ventricular mass index during 5 years of treatment with agalsidase alfa in patients with Fabry’s disease with and without left ventricular hypertrophy at baseline

changes in mean systolic or diastolic blood pressure were noted in patients without LVH at baseline. Stabilisation or improvement in LVM index was reported in 46 (80·7%) patients after 5 years of enzyme replacement therapy (table 1). LVM index remained stable or improved in 23 (71·9%) patients with baseline LVH (figure 3), and in 23 (92%) patients without LVH at baseline. Stabilisation or improvement in MFS was www.thelancet.com Vol 374 December 12, 2009

reported in 40 (76·9%) patients after 5 years of treatment (table 1). MFS stabilised or improved in 20 (95·2%) patients without baseline LVH, and in 18 (62·1%) of those with baseline LVH. Table 4 shows the mean change in estimated GFR during treatment for patients who had not undergone renal transplant (figure 2C, figure 4). After 5 years of treatment, patients with chronic kidney disease stages 1– 1989

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A

D LVH at baseline No Yes

Change in LVM index from baseline (g/m2·7)

5 0

1·0 0·5

(25) (18)

(17)

(24)

–5

(32)

–10

(29)

(23)

*

(24)

–15

*

Change in average pain from baseline (BPI score)

10

*

–20

0 (33)

–0·5

–25

(53)

–1·5

*

*

–2·0

*

(44)

(45)

–1·0

*

–2·5

B

E

7·5

1·0

Change in worst pain from baseline (BPI score)

Change in MFS index from baseline (%)

0·5

*

5·0

** *

(22) (16) 2·5

*

(15)

(26) (23)

(21) (21)

0

(29)

0 (33)

–0·5

(41) (43)

–1·0

(49)

–1·5 –2·0

*

–2·5

–2·5

C

F

5

0·25

*

(41)

(80)

–10

*

–15

(99)*

(103)

*

–20

*

–25 –30

Women Men

–35

*

* *

* (92)

*

0·20

(47)

(45)

(44)

–5

Change in QoL deviation score from baseline

Change in eGFR from baseline (mL/min per 1·73 m2)

0

0·15 (41)

0·10

*

(48) (51)

(44) 0·05 0 –0·05 –0·10

–40 0

1

2

3

4

5

Year

0

1

2

3

4

5

Year

Figure 2: Changes in four clinical domains relative to baseline in patients with Fabry’s disease during 5 years of treatment with agalsidase alfa (A) Left ventricular mass (LVM) index in patients with and without baseline left ventricular hypertrophy (LVH). (B) Midwall fractional shortening (MFS) in patients with and without baseline LVH. (C) Estimated glomerular filtration rate (eGFR) in men and women. (D) Average pain measured by Brief Pain Inventory (BPI) score. (E) Worst pain measured by BPI score. (F) Quality of life (QoL) deviation score. Patient numbers are shown in parentheses. Horizontal lines represent baseline. Data for renal function include all patients (including hyperfiltrators) without end-stage renal disease. *p<0·05 versus baseline.

3 showed yearly decreases of between –1·53 and –2·63 mL/min per 1·73 m² (table 5). Mean yearly fall in estimated GFR after 5 years of treatment was –2·83 mL/min per 1·73 m² for men (p=0·0001) and –0·87 mL/min per 1·73 m² for women (not significant) with stage 1 disease at baseline. Corresponding values for men and women with stage 2 disease at baseline were –2·17 and –0·85 mL/min per 1·73 m² (p=0·0004 1990

and p=0·01), respectively. In patients with stage 3 disease at baseline, the mean yearly fall in estimated GFR after 5 years was –3·0 mL/min per 1·73 m² in men (p=0·006) and –1·01 ml/min per 1·73 m² in women (p=0·02). In patients with hyperfitration (estimated GFR ≥130 mL/min per 1·73 m²), estimated GFR tended to decrease to within the normal range during treatment. www.thelancet.com Vol 374 December 12, 2009

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LVH at baseline n

No LVH at baseline

Mean baseline Mean MFS at MFS (%) year end (%)

Mean change from p value* baseline (%)

n

Mean baseline Mean MFS at Mean change MFS (%) year end (%) from baseline (%)

p value*

Year 1

22

13·7% (2·3)

16·3% (3·0)

2·6% (3·2)

0·001

15

16·4% (2·0)

18·6% (2·4)

2·2% (3·3)

0·02

Year 2

23

13·8% (2·2)

15·7% (4·0)

1·9% (3·5)

0·0176

16

16·5% (2·4)

19·5% (3·6)

2·9% (4·0)

0·0107

Year 3

26

14·3% (2·3)

16·0% (3·8)

1·7% (3·6)

0·02

21

17·0% (2·4)

17·5% (2·5)

0·4% (2·9)

NS

Year 5

29

14·1% (2·3)

14·6% (2·9)

0·5% (3·4)

NS

21

17·0% (2·4)

17·9% (2·4)

0·8% (3·3)

NS

Data are mean (SD, where applicable). Baseline values for each comparison are different because data were not available for all patients at every timepoint. LVH=left ventricular hypertrophy. MFS=midwall fractional shortening. NS=not significant. *Paired t test, significance at p<0·05.

Table 3: Change in mean midwall fractional shortening during 5 years of treatment with agalsidase alfa in patients with Fabry’s disease with and without left ventricular hypertrophy at baseline

Non-responders Stabilisation or improvement

10% improvement 20% improvement

Proportion of patients (%)

100

80

60

40

20

0 Year 1 (n=23)

Year 2 (n=24)

Year 3 (n=29)

Year 5 (n=32)

Figure 3: Proportion of patients with Fabry’s disease with left ventricular hypertrophy at baseline who showed sustained improvement in left ventricular mass index during 5 years of treatment with agalsidase alfa Table 1 shows definitions of response levels.

n

Mean baseline eGFR (mL/min per 1·73 m²)

Mean eGFR at year end (mL/min per 1·73 m²)

After 5 years of enzyme replacement therapy, the responder analysis showed that estimated GFR reached the normal range in 12 patients (roughly 86%) with baseline hyperfiltration (table 1). At 5 years, response rates for patients with chronic kidney disease stages 1–3 at baseline were between 68·8% and 89·1% based on decelerated decline criteria: corresponding response rates for renal stabilisation or improvement were between 56·5% and 75·0%. The sole patient who had stage 4 chronic kidney disease at baseline responded in terms of both applicable criteria. A further 12 patients had undergone renal transplant at baseline and their data were excluded from this analysis; no patient needed renal transplantation during the treatment period. Hypertension was present at baseline in 38 of the 140 patients in the renal analysis for whom bloodpressure data were available. Table 6 shows bloodpressure measurements for all subgroups defined by baseline stage of chronic kidney disease. Mean systolic Mean change in eGFR to year end (mL/min per 1·73 m²)

Mean yearly change in eGFR (mL/min per 1·73 m²)

p value*

All patients Year 1

121

85·46 (29·21)

82·31 (29·12)

–3·15 (13·01)

–3·15

Year 2

143

86·17 (27·65)

79·03 (29·47)

–7·14 (16·82)

–3·57

0·01 0·001

Year 3

137

87·51 (28·63)

76·77 (27·01)

–10·74 (14·91)

–3·58

0·001

Year 5

150

87·04 (28·80)

74·75 (28·65)

–12·29 (18·40)

–2·46

0·001

Year 1

80

94·02 (30·56)

90·30 (31·02)

–3·72 (14·84)

–3·72

0·028

Year 2

99

93·23 (28·37)

85·58 (31·60)

–7·65 (19·05)

–3·83

0·0001

Year 3

92

96·26 (29·01)

82·65 (27·91)

–13·61 (14·66)

–4·54

<0·0001

Year 5

103

94·71 (29·77)

78·84 (31·08)

–15·87 (20·04)

–3·17

<0·0001

Year 1

41

68·76 (16·81)

66·71 (16·33)

–2·05 (8·45)

–2·05

NS

Year 2

44

70·28 (17·81)

64·30 (16·46)

–5·98 (10·27)

–2·99

0·0004

Year 3

45

69·61 (17·49)

64·74 (20·59)

–4·87 (13·80)

–1·62

0·02

Year 5

47

70·23 (17·37)

65·80 (19·96)

–4·44 (10·72)

–0·89

0·007

Men

Women

Data are mean (SD, where applicable). Values are given overall and according to sex of patients. Baseline values for each comparison are different because data were not available at every time point for all patients. eGFR=estimated glomerular filtration rate. NS=not significant. *Paired t test, significance at p<0·05.

Table 4: Change in mean estimated glomerular filtration rate during 5 years of treatment with agalsidase alfa in all patients with Fabry’s disease (including hyperfiltrators) without end-stage renal disease

www.thelancet.com Vol 374 December 12, 2009

1991

Articles

2

(1)

Women Men

1

Mean annualised change in eGFR (mL/min per 1·73 m2)

0 –1

(31)

(11)

(51)

(5)

–2 (33) –3

(58)

–4

(4) (17)

(128)

(12)

(43)

Normal reduction†

–5 –6

Inclusion criterion for intensified ERT trial*

–7 –8 (20) –9 –10 –11 –12 (14)

na

ry

Fa b

Fa b

ry

na

tu

ra

ld ec lin e|| Fa t ur br al yn d ec at lin ur Ag al e¶ als re id du as ct eb io nd et a§ ev Fa elo br yn pe dE at ur SR al D‡ re du ct io nn oE SR D‡ FO SC KD sta ge 4 FO SC KD sta ge 3 FO SC KD sta ge 2 FO SC KD sta ge 1

–13

Figure 4: Mean yearly fall in estimated glomerular filtration rate according to stage of chronic kidney disease at baseline in male and female patients with Fabry’s disease during 5 years of treatment with agalsidase alfa Data are plotted according to baseline stage of chronic kidney disease. Patient numbers are shown in parentheses. Data from previous studies for the expected natural fall in renal function in patients with Fabry’s disease and the effects of agalsidase beta are plotted for reference and comparison. ERT=enzyme replacement therapy. FOS=Fabry Outcome Survey. CKD=chronic kidney disease. ESRD=end-stage renal disease. eGFR=estimated glomerular filtration rate. *Schiffmann et al.20 †Lindeman et al.23 ‡Schiffmann et al.16 §Germain et al.21 ¶Schwarting et al.9 ||Branton et al.24 See Online for webappendix

1992

and diastolic blood pressures were normal at baseline and reduced slightly during the study in all patient subgroups. Mean average pain fell from baseline after 1, 2, 3, and 5 years of treatment (from 3·7 [2·3] at baseline to 2·5 [2·4] after 5 years) (tables 1 and 7, figures 2D and 2E). Reductions were significant at years 2, 3, and 5 (p=0·0015, p=0·0128, and p=0·0023, respectively). Severity of worst pain also decreased at all timepoints, with significant reductions at 2 years (p=0·0076) and 5 years (p=0·0137). After 5 years of treatment, a clinically significant reduction of pain (defined as improvement of >1 point on the Brief Pain Inventory) was recorded for average and worst pain (32 patients [60·4%] and 26 patients [53·1%], respectively). Before initiation of enzyme replacement therapy, quality of life was worse in patients with Fabry’s disease than in the general population (tables 1 and 8, figure 2F). Mean deviation score from normal EuroQol values improved significantly compared with baseline after 5 years of treatment (from –0·24 [0·30] to 0·07 [0·25];

p=0·0483). Significant reductions in the mean deviation scores were also reported after 1 and 2 years of treatment (p=0·0247 and p=0·0026). Six (20·0%) of 30 patients with LVH at the last assessment had first sentinel cardiac events compared with four (8·9%) of 45 patients with normal LVM. Cerebrovascular events were also most frequent in patients with LVH, occurring in eight (22·9%) of 35 patients with LVH and three (6·7%) of 45 patients with normal LVM. No renal events occurred. For the composite event, seven (33·3%) of 21 patients who had an event had LVH compared with six (14·6%) of 41 patients with normal LVM at study end. The sensitivity analysis (n=475) showed that overall the changes in all parameters were in the same direction as those in patients with 5-year longitudinal data (webappendix). 555 patients met criteria for the safety analysis. Mean duration of treatment was 3·1 (2·1) years. In this group, 188 patients had 826 adverse events during 5 years of observation. The most frequently reported adverse events, occurring in four or more patients, were: infusion-related reactions (n=35 patients); cerebrovascular accident and pyrexia (n=12 each); dizziness and transient ischaemic attack (n=11 each); headache and nausea (n=10 each); fatigue (n=9); abdominal pain, dyspnoea, chest pain, and diarrhoea (n=8 each); vomiting and chronic renal failure (n=6 each); back pain, oedema, and neuralgia (n=5 each); and cellulitis, anxiety, depression, insomnia, paraesthesia, impaired hearing, atrial fibrillation, bradycardia, flushing, dysphagia, rash, proteinuria, renal impairment, and chills (n=4 each). 209 events (ten serious) in 70 patients were reported as at least possibly related to treatment, of which 156 (five serious) in 56 patients were infusion-related reactions. 32 deaths (26 men) were reported; none were deemed to be related to treatment. 29 patients who died had a history of severe cardiac, renal, or cerebrovascular involvement. Therapy had been withdrawn before death in five cases. No new safety concerns were identified.

Discussion We report long-term data for the effects of enzyme replacement therapy with agalsidase alfa on cardiac mass and function, renal function, pain, and quality of life in a large group of patients enrolled in FOS. Our results show sustained benefits of agalsidase alfa during 5 years of treatment. Patients with LVH at baseline had a clinically significant reduction in LVH during the 5 years and an improvement in myocardial contractility during the first 3 years of treatment. In patients with normal LVM at baseline, cardiac mass remained stable, with LVM index within normal limits in more than 90% of patients. These results were accompanied by an improvement in MFS, which was significant during the first 2 years. On the basis of the natural history of Fabry’s disease, one might have expected a progressive increase in LVM in affected patients with time.25 Sentinel clinical events occurred in a www.thelancet.com Vol 374 December 12, 2009

Articles

n

Mean baseline eGFR (mL/min per 1·73 m²)

Mean eGFR at year end (mL/min per 1·73 m²)

Mean change in eGFR to year end (mL/min per 1·73 m²)

Mean yearly change in p value* eGFR (mL/min per 1·73 m²)

Hyperfiltrators (≥130 mL/min per 1·73 m²) Year 1

11

144·49 (13·40)

131·13 (21·61)

–13·35

–13·35

0·05

Year 2

12

139·64 (8·75)

118·04 (43·46)

–21·60

–10·80

NS

Year 3

13

142·47 (13·19)

114·36 (16·56)

–28·11

–9·37

0·001

Year 5

14

143·50 (13·25)

108·07 (20·26)

–35·43

–7·09

0·001

CKD stage 1 (90–129 mL/min per 1·73 m²) Year 1

35

107·06 (11·15)

103·94 (18·37)

–3·12

–3·12

NS

Year 2

47

106·89 (10·34)

99·06 (19·38)

–7·83

–3·91

0·01

Year 3

45

107·63 (10·34)

95·37 (19·49)

–12·26

–4·09

0·001

Year 5

48

107·06 (10·30)

93·93 (23·48)

–13·13

–2·63

0·001 NS

CKD stage 2 (60–89 mL/min per 1·73 m²) Year 1

55

73·61 (8·59)

72·21 (12·32)

–1·39

–1·39

Year 2

60

74·16 (8·73)

69·33 (14·03)

–4·83

–2·41

0·001

Year 3

58

73·25 (8·54)

66·84 (13·71)

–6·40

–2·13

0·001

Year 5

64

73·98 (8·74)

66·33 (17·26)

–7·64

–1·53

0·001

CKD stage 3 (30–59 mL/min per 1·73 m²) Year 1

19

48·78 (8·23)

45·92 (9·88)

–2·87

–2·87

0·05

Year 2

23

49·76 (7·93)

45·23 (9·82)

–4·54

–2·27

0·01

Year 3

21

49·77 (8·31)

41·07 (10·19)

–8·70

–2·90

0·001

Year 5

23

49·76 (7·93)

39·53 (14·50)

–10·23

–2·05

0·001

CKD stage 4 (15–29 mL/min per 1·73 m²) Year 1

1

28·78

34·60

5·81

5·81

NA

Year 2

1

28·78

29·29

0·50

0·25

NA

Year 3

0

Year 5

1

·· 28·78

·· 37·05

··

··

NA

8·27

1·65

NA

Data are mean (SD, where applicable). Values are relative to chronic kidney disease (CKD) stage at baseline. Baseline values for each comparison are different because data were not available at every timepoint for all patients. eGFR=estimated glomerular filtration rate. NS=not significant. NA=not applicable. *Paired t test, significance at p<0·05.

Table 5: Change in mean estimated glomerular filtration rate during 5 years of treatment with agalsidase alfa in patients with Fabry’s disease without end-stage renal disease

greater proportion of patients with LVH than without LVH after 5 years of treatment, drawing attention to the importance of LVH in progression of Fabry’s disease. These data show that LVH is associated with clinical events. They also support and extend previous findings from FOS and are consistent with the results of a randomised clinical trial showing that enzyme replacement therapy with agalsidase alfa reduced LVM in men with Fabry’s disease.4,26 Data for renal function show that, during 5 years of treatment, the rate of fall of estimated GFR is substantially slower than are those reported in most studies of historical controls with Fabry’s disease.9,16,21,24,27 The mean yearly decreases in estimated GFR in patients with stage 3 chronic kidney disease receiving enzyme replacement therapy for 5 years seem to be less pronounced than are those reported for patients not receiving this therapy with estimated GFR lower than 60 mL/min per 1·73 m² (men, –3·0 vs –6·8 mL/min per 1·73m²; women, –1·0 vs –2·1 mL/min per 1·73 m², respectively).16 Overall, the reduction of estimated GFR in female patients given enzyme replacement therapy was similar to the normal rate expected with age, www.thelancet.com Vol 374 December 12, 2009

whereas the rate of decrease in male patients was roughly two to three times greater than normal expected rates.23,27 Responder analysis provided evidence of stabilisation or improvement in measures of renal function in more than half of patients with chronic kidney diseases stages 1–3. Comparisons with historical controls should, however, be made with caution because previous and present methods or calculations used to measure renal function differ. Additionally, data from most previous studies include only male patients. There have also been improvements in supportive care in recent years (eg, improved management of blood pressure) that might have contributed to stabilisation of renal and cardiac function.19,28 Since few data for the use of angiotensinconverting enzyme inhibitors and angiotensin II receptor blockers were available in our study, the contribution of these drugs to stabilisation of renal function cannot be excluded. Nevertheless, the reported stabilisation of renal function lends support to and extends previous data.19,21 The sustained improvements in pain and quality of life that we report also corroborate previous results.2,10 No new safety concerns were identified. 1993

Articles

n Mean baseline blood presure (mm Hg)

Mean blood pressure at year end (mm Hg)

p value* Mean change in blood pressure to year end (mm Hg)

Hyperfiltrators (≥130 mL/min per 1·73 m²) 9

128·11 (11·84)

123·11 (11·71)

–5·0

NS

Diastolic

9

76·11 (10·83)

68·33 (8·09)

–7·78

0·038

Year 2 10

126·30 (12·54)

121·20 (10·13)

–5·10

NS

Diastolic 10

75·40 (10·46)

68·10 (7·88)

–7·30

NS

Year 3 Systolic

11

127·36 (12·41)

Diastolic

11

74·45 (10·41)

121·82 (14·18) –5·55

NS

68·18 (7·57)

NS

–6·27

Year 5

Year 1 Systolic

16

129·75 (17·95)

127·38 (17·73)

–2·38

NS

Diastolic 16

72·56 (11·37)

67·69 (8·62)

–4·88

NS

125·16 (16·42) –3·42

NS

Year 2 Systolic

19

128·58 (18·58)

Diastolic 19

74·16 (13·21)

12

Diastolic

12

128·0 (12·04) 75·83 (11·01)

124·58 (9·76)

–3·42

NS

75·17 (9·16)

–0·67

NS

CKD stage 1 (90–129 mL/min per 1·73 m²)

Systolic

18

–0·47

NS

128·22 (18·94) 129·11 (14·77)

0·89

NS

72·33 (10·76) –0·39

NS

72·72 (12·55)

Year 5 Systolic

20

Diastolic 20

Year 1

73·68 (9·60)

Year 3 Diastolic 18

Systolic

129·0 (18·18) 74·30 (12·88)

123·60 (20·14)

–5·40

NS

72·80 (8·24)

–1·50

NS

CKD stage 4 (15–29 mL/min per 1·73 m²) 25

124·68 (15·38)

121·20 (18·03) –3·48

NS

Year 1

Diastolic 25

71·36 (10·71)

68·92 (11·09) –2·44

NS

Year 2

Year 2 Systolic

p value* Mean change in blood pressure to year end (mm Hg)

CKD stage 3 (30–59 mL/min per 1·73 m²)

Systolic

Systolic

Mean blood pressure at year end (mm Hg)

(Continued from previous column)

Year 1

Systolic

n Mean baseline blood pressure (mm Hg)

36

125·06 (13·46)

121·11 (13·91)

–3·94

NS

Diastolic 36

71·14 (11·38)

70·75 (9·61)

–0·39

NS

Year 3

··

··

··

Systolic

1

120·0

Diastolic

1

70·0

··

Year 3

··

NA

132·0

12·0

NA

54·0

–16·0

NA

··

··

··

NA

Year 5

Systolic

37

125·16 (13·59)

124·35 (17·87)

–0·81

NS

Systolic

1

120·0

116·0

–4·0

NA

Diastolic

37

71·84 (11·03)

72·08 (10·02)

0·24

NS

Diastolic

1

70·0

64·0

–6·0

NA

41

124·37 (13·39)

121·78 (12·32)

–2·59

NS

Diastolic 41

70·73 (11·15)

71·73 (9·45)

1·0

NS

Year 5 Systolic

CKD stage 2 (60–89 mL/min per 1·73 m²) Year 1 Systolic

47

129·30 (17·28)

123·19 (12·22)

–6·11

0·0096

Diastolic 46

73·26 (11·19)

71·83 (11·03)

–1·43

NS

49 129·65 (17·52)

122·51 (15·70)

–7·14

0·005

Data are mean (SD, where applicable). Values are relative to chronic kidney disease (CKD) at baseline. Baseline values for each comparison are different because data were not available at every timepoint for all patients. NS=not significant. NA=not applicable. *Paired t test, significance at p<0·05.

Table 6: Change in mean systolic and diastolic blood pressures during 5 years of treatment with agalsidase alfa in patients with Fabry’s disease without end-stage renal disease

Year 2 Systolic

Diastolic 49

74·04 (12·13)

70·65 (10·43) –3·39

0·0375

50

130·46 (16·38)

122·34 (14·10) –8·12

0·0011

Diastolic 50

73·14 (11·59)

Year 3 Systolic

73·24 (11·17)

0·10

NS

Year 5 Systolic

56

129·39 (16·59)

Diastolic

57

73·86 (11·74)

119·68 (16·58) –9·71 72·67 (9·64)

–1·19

0·0002 NS

(Continues in next column)

The limitations of this study warrant further consideration. A major limitation is that no data are available from a comparable control group not receiving enzyme replacement therapy. In FOS, the population of patients not receiving this therapy is generally less severely affected than are the population receiving enzyme replacement therapy, and includes a higher proportion of women. Furthermore, few follow-up assessments are done on patients who are not severely affected, resulting 1994

in scarce available data. Thus, changes in clinical variables in response to treatment can only be assessed relative to previous data for progression of untreated disease. Comprehensive baseline and 5-year treatment data were available from a relatively small proportion of the patients receiving treatment. Our results for this group of patients are substantiated, however, by the sensitivity analysis that was done for a much larger cohort. Patients who withdrew from treatment or died during the course of the study were excluded. One should note, however, that the number of patients who have died since the initiation of FOS is small.29 Other inherent limitations of multinational observational databases include variations between treatment centres in the range of investigations done, follow-up treatment protocol (including supportive care), and rigour with which data were entered. Additionally, inclusion of patients could be affected by differences in practice and access to treatment between countries. www.thelancet.com Vol 374 December 12, 2009

Articles

n

Mean baseline BPI score

Mean BPI score at year end

Mean change in BPI score

p value*

Average pain Year 1

33

3·6 (2·3)

3·1 (2·7)

–0·5 (2·1)

NS

Year 2

45

3·7 (2·4)

2·6 (2·3)

–1·1 (2·2)

0·0015

Year 3

44

3·8 (2·4)

2·9 (2·5)

–0·9 (2·3)

0·0128

Year 5

53

3·7 (2·3)

2·5 (2·4)

–1·2 (2·7)

0·0023

Worst pain Year 1

33

5·2 (1·9)

4·7 (2·9)

–0·5 (2·4)

NS

Year 2

43

5·0 (2·1)

3·8 (2·6)

–1·3 (2·9)

0·0076

Year 3

41

5·0 (2·1)

4·3 (2·7)

–0·7 (2·7)

NS

Year 5

49

5·0 (2·2)

3·7 (3·0)

–1·3 (3·5)

0·0137

Data are mean (SD). Brief Pain Inventory (BPI) scores of 1–4 show mild, 5–6, moderate, and 7–10, severe pain. Baseline values for each comparison are different because data were not available at every timepoint for all patients. NS=not significant. *Paired t test, significance at p<0·05.

Table 7: Change in mean average and worst pain scores in patients with Fabry’s disease during 5 years of treatment with agalsidase alfa

n

Mean baseline QoL deviation score

p Mean change Mean QoL value* deviation score in QoL deviation score at year end

Year 1 41 –0·24 (0·29)

–0·15 (0·26)

0·09 (0·25)

0·0247

Year 2 48 –0·24 (0·30)

–0·13 (0·23)

0·11 (0·23)

0·0026

Year 3 44 –0·25 (0·29)

–0·19 (0·25)

0·06 (0·24)

NS

Year 5 51 –0·24 (0·30)

–0·17 (0·28)

0·07 (0·25)

0·0483

Data are mean (SD) and are mean deviation scores from EuroQol values for the general population. Baseline values for each comparison are different because data were not available at every timepoint for all patients. QoL=quality of life. NS=not significant. *Paired t test, significance at p<0·05.

Table 8: Mean change in quality of life relative to baseline and to control levels in patients with Fabry’s disease during 5 years of treatment with agalsidase alfa

High-quality, multidisciplinary supportive care is needed to achieve optimum results with enzyme replacement therapy. Some case selection also results from the predominant inclusion of the most severely affected patients when the database was initiated because of a perceived need for urgent therapy. More women and patients with mild manifestations were included in subsequent years. Despite these limitations, data from observational studies are valuable, because large-scale controlled clinical trials in patients with such rare diseases are very difficult to conduct. Our results suggest long-term benefits of enzyme replacement therapy with agalsidase alfa in adults with Fabry’s disease. These results extend findings from previous studies and clinical trials that have shown enzyme replacement therapy to be a well tolerated and effective treatment for many disease-related manifestations. However, advanced cardiac and renal disease cannot be reversed in all patients, and our knowledge of replacement therapy suggests little success in treatment of pre-existing cerebrovascular disease.21,30,31 Looking to www.thelancet.com Vol 374 December 12, 2009

the future, controlled clinical trials to assess whether early initiation of enzyme replacement therapy will achieve improved results are very important, and, consequently, early diagnosis is crucial. Contributors AM participated in database design, data collection, analysis, and discussion, drafted the report, and coordinated revision by coauthors. MB obtained data and participated in the literature search and data analysis and interpretation. PE was involved in data analysis, interpretation, and writing of the report. GS-P was involved in data interpretation and writing of the report. RS revised the manuscript, requested and obtained additional data, and modified data analysis. MR participated in database design, data analysis and interpretation, writing, creation of figures, and study design. JTRC partipated in study design and data collection and interpretation. FB participated in data collection and interpretation and revision of the manuscript. AL participated in database and analysis design, data collection, and revision of the manuscript. RG participated in data collection and interpretation and revision of the manuscript. The FOS investigators Argentina P Rozenfeld (La Plata). Australia K Nicholls (Melbourne). Austria B Plecko, P Kotanko, C Binder, M Brunner-Krainz (Graz); G Sunder-Plassmann, J Kleinert, W Kristoferitsch, W Schreiber (Vienna). Belgium F Eyskens (Antwerp); M C Nassogne, Y Pirson, P Goyens, M Libert (Brussels); C Verellen-Dumoulin, F Dehout, D Roland, L Van Maldergem (Charleroi); N Mazoin (Verviers). Brazil R Giugliani (Porto Alegre). Canada R Casey (Calgary); A Chan (Edmonton); M West (Halifax); D Bichet (Montreal); R Drouin (Sherbrooke); J Clarke (Toronto). Czech Republic A Linhart, G Dostalova (Prague). France G Choukroun (Amiens); M-C Drobacheff (Besançon); C Goizet (Bordeaux); P Bataille (Boulogne); L Aaron (Bourges); R Boudet (Brive La Gaillarde); S Benzaine (Cambrai); F Vuillemet (Colmar); B Lorcerie (Dijon); C Thevenot (Laon); E Hachulla (Lille); A Fouilhoux (Lyon); B Dussol (Marseille); R Reade (Maubeuge); P Kaminsky (Nancy); A Kuster, M Lino (Nantes); T Ghafari (Nice); O Lidove, D P Germain, N Ouali (Paris); V Gaborieau (Pau); R Jaussaud (Reims); P Hardy (Rouvroy); B Richalet (Saint Lô); V Klotz (Selestrat); E Andres (Strasbourg); F Labarthe (Tours); R Perrichot (Vannes). Germany A von Armin-Baas, J Hennermann (Berlin); S Stolz (Cottbus); B Hoffmann (Düsseldorf); H P H Neumann (Freiberg); A Gal, N Muschol (Hamburg); A Das, S Illsinger (Hanover); C Haase (Jena); M Beck (Mainz); R Schueuermann (Mannheim); B Koletzko (Munich); A Rolfs, F Rimmele, S Weis (Rostock); R Wössner, C Wanner (Würzburg). Hungary L Maródi (Debrecen). Israel G Altarescu (Jerusalem). Italy O Gabrielli (Ancona); D Concolino (Catanzaro); G Zoli (Cento); R Parini (Monza); R Di Vito (Ortona); A Burlina (Padova); G Perticoni (Perugia); C Feliciani (Rome); S Feriozzi (Viterbo). Japan A Komatsuda (Akita); I Yabe (Hokkaido); F Furusyo (Korume City); R Katafuchi (Koga City); S Maruyama (Nagoya); T Sato (Matsue City); Y Kai (Miyazaki); M Furujyo (Okayama); S Okada, T Mori (Osaka); Y Sugi, A Ootake (Saitama); K Satou (Sendai); K Komamura (Suita); T Mori (Takatsuki); F Furusyo (Tokushima); Y Eto (Tokyo); Y Ueno (Wakayama). Netherlands C Hollak, F Wijburg (Amsterdam). Norway G Houge (Bergen). Slovenia B Vujkovac (Slovenj Gradec); M Zerjav-Tansek (Ljubjana). Spain M A Barba (Albacete); A Franco, V Climent, M Arenas (Alicante); M D Del Pino (Almeria); J Herrera, E Gómez Huertas (Asturias); G Pintos, M Ibernon (Badalona); R Torra, V Torregrosa (Barcelona); J González (Cádiz); A Mora (Elche); V Valverde, J Martin, E Del Bosque (Elda); M Pineda (Esplugues); M D Prados (Granada); J Torras (Hospitalet); I Martin (Huelva); S Hernández (Linares); F J Barbado, M Lopez Rodriguez (Madrid); T Bosch, M A Ruiz (Mallorca); J M de Toro (Ourense); J Paniagua (Ponferrada); L M Tamargo (Ronda); V Fernández (Santiago); A Perez García, M I Febrer (Valencia); A Rivera (Vigo); F Cabadés (Vinaroz). Switzerland P Ferrari, O Bonny, J Theytaz, Y Huynh-Do (Bern); F Barbey, J Theytaz, D Teta (Lausanne); F Ruggieri, S Magage, J-C Lubanda (Zurich). UK C Hendriksz (Birmingham); P Deegan, U Ramaswami (Cambridge); A Mehta, D Hughes (London). USA R Schiffmann (Texas); G Pastores (New York).

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Articles

Conflicts of interest AM has received speaker fees, research support, and funding for symposium attendance from Shire HGT, Genzyme, and Actelion. MB has received speaker fees, funding for symposium attendance, and unrestricted scientific grants from Shire HGT, Genzyme, Actelion, and Biomarin. PE has received speaker fees, funding for symposium attendance, and unrestricted educational grants from Shire HGT and Genzyme. RG has received speaker fees and funding for symposium attendance from Shire HGT. AL and GS-P have received speaker fees, travel grants, and research support from both Shire HGT and Genzyme. MR was an employee of Shire HGT. RS has received honoraria and research support from Shire HGT and Amicus Therapeutics. The practical work for this study was supported in part by the Intramural Program of the National Institutes of Health (NINDS). FB has received speaker fees, research support, and funding for symposium attendance from Shire HGT and Genzyme. JTRC has received speaker fees, honoraria, and travel and research grants from Shire HGT and Genzyme. Honoraria were not paid in relation to FOS data entry or the writing of this report. Acknowledgments This study was funded by Shire HGT. The FOS database is under the independent control of the FOS International Board. Editorial assistance was provided by Harriet Crofts (Oxford PharmaGenesis Ltd, Oxford, UK). References 1 Mehta A, Ricci R, Widmer U, et al. Fabry disease defined: baseline clinical manifestations of 366 patients in the Fabry Outcome Survey. Eur J Clin Invest 2004; 34: 236−42. 2 Schiffmann R, Kopp JB, Austin HA 3rd, et al. Enzyme replacement therapy in Fabry disease: a randomized controlled trial. JAMA 2001; 285: 2743−49. 3 Eng CM, Guffon N, Wilcox WR, et al. Safety and efficacy of recombinant human alpha-galactosidase A-replacement therapy in Fabry’s disease. N Engl J Med 2001; 345: 9−16. 4 Hughes DA, Elliott PM, Shah J, et al. Effects of enzyme replacement therapy on the cardiomyopathy of Anderson−Fabry disease: a randomised, double-blind, placebo-controlled clinical trial of agalsidase alfa. Heart 2008; 94: 153−58. 5 Banikazemi M, Bultas J, Waldek S, et al. Agalsidase-beta therapy for advanced Fabry disease: a randomized trial. Ann Intern Med 2007; 146: 77−86. 6 Ramaswami U, Wendt S, Pintos-Morell G, et al. Enzyme replacement therapy with agalsidase alfa in children with Fabry disease. Acta Paediatr 2007; 96: 122–27. 7 Wraith JE, Tylki-Szymanska A, Guffon N, et al. Safety and efficacy of enzyme replacement therapy with agalsidase beta: an international, open-label study in pediatric patients with Fabry disease. J Pediatr 2008; 152: 563–70, 570 e1. 8 Eng CM, Fletcher J, Wilcox WR, et al. Fabry disease: baseline medical characteristics of a cohort of 1765 males and females in the Fabry Registry. J Inherit Metab Dis 2007; 30: 184−92. 9 Schwarting A, Dehout F, Feriozzi S, Beck M, Mehta A, Sunder-Plassmann G. Enzyme replacement therapy and renal function in 201 patients with Fabry disease. Clin Nephrol 2006; 66: 77−84. 10 Hoffmann B, Garcia de Lorenzo A, Mehta A, Beck M, Widmer U, Ricci R. Effects of enzyme replacement therapy on pain and health related quality of life in patients with Fabry disease: data from FOS (Fabry Outcome Survey). J Med Genet 2005; 42: 247−52. 11 Feriozzi S, Schwarting A, Sunder-Plassmann G, West M, Cybulla M. Agalsidase alfa slows the decline in renal function in patients with Fabry disease. Am J Nephrol 2009; 29: 353−61. 12 Devereux RB, Alonso DR, Lutas EM, et al. Echocardiographic assessment of left ventricular hypertrophy: comparison to necropsy findings. Am J Cardiol 1986; 57: 450−58. 13 Lang RM, Bierig M, Devereux RB, et al. Recommendations for chamber quantification: a report from the American Society of Echocardiography’s Guidelines and Standards Committee and the Chamber Quantification Writing Group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardiology. J Am Soc Echocardiogr 2005; 18: 1440−63.

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