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Enzyme replacement therapy for Anderson-Fabry disease

  1. Regina P El Dib1,*,
  2. Paulo Nascimento2,
  3. Gregory M Pastores3

Editorial Group: Cochrane Cystic Fibrosis and Genetic Disorders Group

Published Online: 28 FEB 2013

Assessed as up-to-date: 12 DEC 2012

DOI: 10.1002/14651858.CD006663.pub3

How to Cite

El Dib RP, Nascimento P, Pastores GM. Enzyme replacement therapy for Anderson-Fabry disease. Cochrane Database of Systematic Reviews 2013, Issue 2. Art. No.: CD006663. DOI: 10.1002/14651858.CD006663.pub3.

Author Information

  1. 1

    Botucatu Medical School, Universidade Estadual Paulista (UNESP), Botucatu, São Paulo, Brazil

  2. 2

    UNESP - Univ Estadual Paulista, Botucatu, São Paulo, Brazil

  3. 3

    New York University School of Medicine, Neurogenetics Laboratory, New York, New York, USA

*Regina P El Dib, Botucatu Medical School, Universidade Estadual Paulista (UNESP), Distrito de Rubião Júnior, s/n, Botucatu, São Paulo, 18603-970, Brazil. eldib@fmb.unesp.br. re.lucci@terra.com.br.

Publication History

  1. Publication Status: New search for studies and content updated (no change to conclusions)
  2. Published Online: 28 FEB 2013

SEARCH

 

Background

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Feedback
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Notes
  19. Index terms

Please see glossary in the appendicies for definition of terms used throughout the review (Appendix 1).

 

Description of the condition

Anderson-Fabry disease (AFD) is an X-linked recessive multi-systemic disorder caused by a deficiency of the lysosomal enzyme alpha–galactosidase A (AGAL). The incidence of AFD is estimated at 1 in 117,000 live births for males (Meikle 1999); although recent newborn screening surveys suggest that the incidence may be much higher, up to 1 in 3100 (Spada 2006). Although the vast majority of reports have focused on the symptomatic male patients, females with AFD can develop disease-related problems. However, clinical expression among females tends to be more variable and onset of symptoms tends to occur at a later age (Wilcox 2008).

Clinically, AFD is characterized by major renal, cardiac and cerebrovascular complications; consequent to the progressive deposition of an incompletely metabolized substrate (Gb3) in multiple cell types, and attendant mechanisms of tissue injury that remain to be more fully defined. Alterations in vascular reactivity and a propensity for thrombo-embolic disease are believed to play a role in the increased risk for particular problems, such as stroke. Recently studies have shown that a deacylated form of Gb3 (globotriaosylsphingosine, lyso-Gb3 ) is elevated in plasma obtained from individuals with AFD. Lyso-Gb3 is a potent inhibitor of AGAL and alpha–galactosidase B (N-acetylgalactosaminidase), and it has been found to promote smooth muscle cell proliferation in vitro (Aerts 2008).

Renal and cardiac failure represent major sources of morbidity, and likely account for the reduced survival among affected males and females (wherein median age of death is 50 to 57 years and 70 to 72 years, respectively). In conjunction, pain crises, acroparaesthesia, hearing loss and gastrointestinal problems lead to significant reduction in patients’ health-related quality of life. Although the vast majority of reports have focused on the symptomatic male patients, females with AFD can develop disease-related problems. However, clinical expression among females tends to be more variable and onset of symptoms tends to occur at a later age. The expression of the disease in females appears to be influenced by the particular AGAL mutation and the pattern of X chromosome inactivation in each organ (Wang 2007).

 

Description of the intervention

Enzyme replacement therapy (ERT) for AFD represents the first specific treatment. It consists of the regular intravenous infusion of a recombinant enzyme formulation. Two forms of recombinant AGAL exist; specifically, agalsidase alfa (Replagal, Shire Human Genetic Therapies, Cambridge, MA) and agalsidase beta (Fabrazyme, Genzyme Corporation, Cambridge, MA). Agalsidase alfa is generated by the activation of the AGAL gene in a continuous human cell line; whereas agalsidase beta is produced in a Chinese hamster ovary (CHO) mammalian cell expression system, transduced with the human AGAL sequence. Both enzyme preparations are approved in Europe and many other countries, but in the United States the Federal Drug Administration approved only agalsidase beta (Eng 2001; Schiffmann 2001). Administration of ERT is usually once every two weeks, using a dose of 0.2 mg/kg body weight when using agalsidase alfa or 1 mg/kg for agalsidase beta.

 

How the intervention might work

Intravenous enzyme infusions appear to be reasonably well tolerated, with reported infusion reaction of about 10%; mostly consisting of fever and transient rigors of mild to moderate intensity. A proportion of people with AFD receiving ERT have sero-converted (i.e. developed antibodies); the frequency of antibodies against agalsidase alfa and agalsidase beta has been reported at 55% and 83% of individuals treated respectively (Eng 2001; Schiffmann 2001). Antibody formation did not influence clinical efficacy or outcomes in either of the initial clinical studies undertaken, and antibody titres usually decreased over time. In a few cases, IgE antibodies have been reported after infusion of agalsidase beta (Eng 2001). Recent studies have shown the presence of antibodies may influence the Gb3 storage in skin capillaries and Gb3 excretion in urine, although no relation between antibody formation and plasma Gb3 levels or clinical outcome has been established thus far (Hollack 2009).

 

Why it is important to do this review

A systematic review is needed to establish the evidence base for the effectiveness and safety of ERT for treating AFD.

 

Objectives

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Feedback
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Notes
  19. Index terms

To evaluate the effectiveness and safety of ERT compared to other interventions, placebo or no interventions, for treating AFD.

 

Methods

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Feedback
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Notes
  19. Index terms
 

Criteria for considering studies for this review

 

Types of studies

Randomized and quasi-randomized controlled clinical trials.

 

Types of participants

Individuals with AFD of any age and any degree of disease severity. Diagnosis should be established either by accepted criteria based on concentration of enzyme activity or by mutation analysis.

 

Types of interventions

Enzyme replacement therapy (agalsidase beta or agalsidase alfa) in any amount given for a period of at least one month compared to: each other; another intervention (fat-restricted diet, drugs, exercises, etc); no intervention; or to placebo.

 

Types of outcome measures

 

Primary outcomes

  1. Changes in globotriaosylceramide (Gb3) concentration in plasma and tissue (i.e. endothelial cells)
  2. Death
  3. Pain (measured by the McGill Pain Questionnaire*)
    1. Acroparaesthesia (measured by the intensity and duration of acroparaesthesia as reported by the individual)
    2. Fabry crises

*Post hoc change: we will also consider other validated pain questionnaires.

 

Secondary outcomes

  1. Effect of therapy on renal function (e.g. increase in serum creatinine and proteinuria; creatinine and insulin clearance)
  2. Symptoms and complications of disease (such as occurrence of renal failure, skin, cerebrovascular and cardiac complications) based on the following observations: serum creatinine level, proteinuria (ratio of urinary protein to urinary creatinine in mg/dL), ratio of urinary albumin to urinary creatinine (in mg/dL), 12-lead electrocardiography, echocardiography, neurologic examination, head magnetic resonance imaging, exercise tolerance, and AFD symptom assessment
  3. Parameters: echocardiographic (such as thickness of cardiac structures, left ventricular volume, measures of systolic and diastolic function, heart rate)
  4. Histologic analysis of microvascular capillary endothelial deposits of Gb3 in biopsy specimens; glomeruli and mesangial widening
  5. Adverse effects of treatment (including severe adverse effects such as dyspnoea, malaise, hypertension and gastrointestinal symptoms, and antibody formation), based on the type and frequency of adverse events in treated patients and those on placebo. It should be noted that certain adverse events may represent AFD complications, and thus may not necessarily be related to the recombinant enzyme formulation
  6. Quality of life (as determined by the Short Form 36 (SF-36) and the impact of clinical variables on domain scores within the SF-36 (Smith 2000)
  7. Costs

 

Search methods for identification of studies

There were no language restriction and the trials were identified from the sources listed below.

 

Electronic searches

Relevant trials were identified from the Cystic Fibrosis and Genetic Disorders Group's Inborn Errors of Metabolism Trials Register using the term: FABRY.

The Register is compiled from electronic searches of the Cochrane Central Register of Controlled Trials (CENTRAL) (updated with each new issue of The Cochrane Library), quarterly searches of MEDLINE and the prospective handsearching of one journal - Journal of Inherited Metabolic Disease. Unpublished work were identified by searching through the abstract books of the Society for the Study of Inborn Errors of Metabolism conference and the SHS Inborn Error Review Series. For full details of all searching activities for the register, please see the relevant section of the Cystic Fibrosis and Genetic Disorders Group Module.

Date of the most recent search of the Cystic Fibrosis and Genetic Disorders Group's Inborn Errors of Metabolism Trials Register: 11 September 2012.

We also searched Cochrane Central Register of Controlled Trials (Clinical Trials) (Issue 9, 2012) Ovid EMBASE (1980 to September 2012), PubMed (1980 to September 2012) and the Literature Latino-Americana e do Caribe em Ciências da Saúde - LILACS (1982 to September 2012). These search strategies are listed in the Appendices (Appendix 2; Appendix 3; Appendix 4; Appendix 5).

In order to maximise sensitivity, the search strategies included terms for enzyme replacement therapy for AFD or Fabry disease. We searched with both subject headings and free text words, and we expected to identify all trials of enzyme replacement therapy for AFD or Fabry disease. The following exhaustive list of synonyms for enzyme replacement therapy for AFD or Fabry disease were used:

((Fabry Disease) OR (Disease, Fabry) OR (Angiokeratoma Corporis Diffusum) OR (Anderson-Fabry Disease) OR (Anderson Fabry Disease) OR (Disease, Anderson-Fabry) OR (Fabry's Disease) OR (Disease, Fabry's) OR (Fabrys Disease)) AND ((agalsidase beta) OR (Fabrazyme) OR (Genzyme brand of AGAL) OR (Agalsidase alfa) OR (Replagal) OR (Shire HGT brand of AGAL)).

 

Searching other resources

Reference lists of the identified relevant trials were scrutinized for additional citations.

Specialists in the field and authors of the included trials were contacted for any possible unpublished data.

 

Data collection and analysis

 

Selection of studies

Two authors (RED and GMP) independently screened the trials identified by the literature search. We resolved discrepancies in results by discussion.

 

Data extraction and management

Two authors (RED and GMP) independently extracted data. We resolved discrepancies in results by discussion. We used a standard form to extract the following information: characteristics of the trial (design, methods of randomisation); participants; interventions; outcomes (types of outcome measures, timing of outcomes, adverse events).

We presented different enzyme therapies (alfa and beta) as separate interventions as we did not judge these sufficiently comparable to combine.

When possible, outcome data were grouped into those measured at up to one month, over one month and up to three months, over three months and up to six months and over six months and up to 12 months and annually thereafter. In a post hoc change, we also considered other time-points such as 'over five months and up to six months' where multiple data sets from an individual trial were available for a single planned time-point.

 

Assessment of risk of bias in included studies

We assessed every trial using a simple form and followed the domain-based evaluation as described in the Cochrane Handbook for Systematic Reviews of Interventions 5.1 (Higgins 2011).

We assessed the following domains as having either low, unclear or high risk of bias:

  1. randomisation
  2. concealment of allocation
  3. blinding (of participants, caregivers and outcome assessors)
  4. incomplete outcome data
  5. selective reporting
  6. other potential sources of bias

 

1. Randomisation

Low risk: adequate generation of allocation
Unclear risk: not described in the paper or by contacting authors
High risk: inadequate generation of allocation

 

2. Concealment of allocation

Low risk: adequate allocation concealment
Unclear risk: not described in the paper or by contacting authors
High risk: inadequate allocation concealment

 

3. Blinding (of participants, caregivers and outcome assessors)

Low risk: adequately described
Unclear risk: described as blinded, but no information provided
High risk: not blinded

 

4. Incomplete outcome data

We recorded the rates of withdrawal for each outcome as follows:
Low risk: less than 20% and equal for both groups;
Unclear risk: not reported in paper or by authors;
High risk: greater than 20% or not equal for any comparison groups or both.

 

5. Selective reporting

We considered the possibility of selective reporting of outcomes when data were not available in the 'Results' section of the published paper, but according to the 'Methods' section these outcome data were collected.

 

6. Other potential sources of bias

We recorded any other factors we felt might cause bias.

 

Measures of treatment effect

For dichotomous data (such as death, presence or absence of Fabry crises and adverse effects), we used the risk ratio (RR), with 95% confidence intervals (95% CIs) as the effect measure.

For continuous data (such as changes in Gb3 concentration, echocardiographic parameters, pain and quality of life scores) we used the mean difference (MD) (in which the effect estimates of individual trials are weighted by dispersion measures), with 95% CIs. When standard errors were reported within the trial reports, we converted these to standard deviations (SD = SE x  square root of n).

For time-to-event data (such as effects on renal function) we planned to consider a joint model for longitudinal and discrete time-to-event data in which the discrete event time distribution is modelled as a linear function of the slope of an individual's longitudinal process on the probit scale (Jones 2009). Effect of therapy on renal function (e.g. increase in serum creatinine and proteinuria; creatinine and insulin clearance) would be measured as time-to-event-data or number of events. However, the only trial reporting on this outcome only reported on one time-point, which has been presented as continuous data (Schiffmann 2001).

For other outcomes such as cost, or outcomes where there were insufficient data to enter into the meta-analysis, we planned to present the information narratively.

 

Unit of analysis issues

We planned to include in the review data from any eligible cross-over trials; we planned to analyse these using a method recommended by Elbourne (Elbourne 2002).

 

Dealing with missing data

For any new trial which may be included in a future update of this review, we will contact authors to clarify methodological issues (such as generation and allocation concealment, blind method and withdrawals) as well as for any missing outcome data.

 

Assessment of heterogeneity

We planned to qualify inconsistency among the pooled estimates using the I2 statistic. This illustrates the percentage of the variability in effect estimates resulting from heterogeneity rather than sampling error (Higgins 2003; Higgins 2011). We considered there to be a low degree of heterogeneity if I2 was below 25%, a moderate degree if I2 between 25% and 50%, and a high degree if I2 was over 50%.

 

Assessment of reporting biases

We planned to assess publication bias by drawing a funnel plot (trial effect versus trial size), but there were not sufficient trials included in the review. In future analysis, funnel plots will be used in an exploratory data analysis to assess for the potential existence of small trial bias. There are a number of explanations for the asymmetry of a funnel plot, including true heterogeneity of effect with respect to trial size, poor methodological design of small trials (Sterne 2001) and publication bias and selective reporting of outcomes. Thus, this exploratory data tool may be misleading (Tang 2000; Thornton 2000) and we will not place undue emphasis on this tool.

 

Data synthesis

We used the fixed-effect model to analyse data, if in future updates, significant heterogeneity (e.g. I2 higher than 50%) is identified, we will compute pooled estimates of the treatment effect for each outcome under a random-effects model (with two or more trials).

 

Subgroup analysis and investigation of heterogeneity

For future reviews we plan to investigate heterogeneity by conducting meta-analyses by subgroups as described below.

  1. Types of dosage. We plan to sub-divide dosage in lower dose (less than 2 mg/kg) and higher dose (more than 2 mg/kg). These cut off dosages were chosen arbitrarily.
  2. Duration of intervention. We also plan to sub-divide duration of intervention up to one year and more than one year.These time divisions were chosen arbitrarily.
  3. Age at commencement of treatment, for example, up to the age of 18 years and over age 18 years.
  4. Severity of disease, by less severe and more severe disease (as reported within the trials).

 

Sensitivity analysis

If we had included an adequate number of trials, we planned to perform a sensitivity analysis to test the robustness of analyses to certain assumptions in the results. In future analysis, we will include the following factors in the sensitivity analysis, separating trials according to:

  1. allocation concealment quality (low risk, high risk or unclear risk);
  2. blinding of participants, caregiver and outcome assessment (low risk, high risk or unclear risk);
  3. rates of withdrawal for each outcome.

 

Results

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Feedback
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Notes
  19. Index terms
 

Description of studies

See: Characteristics of included studies; Characteristics of excluded studies.

 

Results of the search

For the original review, we identified 273 references from the electronic searches (El Dib 2010). After initial assessment of these references, 54 were looked at in more detail as being potentially eligible for inclusion. Following the whole verification of the 54 articles, 31 of them were excluded from the review (Excluded studies) Thus, five trials (represented by 23 individual references), which enrolled 187 participants were included in this review (Included studies).

For the first update of the review in 2012, 368 references were identified by the searches. After an initial shift for relevance, we selected seven references for careful consideration and obtained them in full text, when available. Following assessment of the full articles, we included one new trial (five references) (Vedder 2007) and excluded two further trials (Fernhoff 2011; West 2011).

 

Included studies

 

Agalsidase alfa versus placebo

Two trials were included in this comparison and are described in detail below (Hughes 2008; Schiffmann 2001).

 
Trial design

Both trials were described as randomized double-blind placebo-controlled clinical trials (Hughes 2008; Schiffmann 2001). Both trials were for six months (Hughes 2008; Schiffmann 2001), but one had an additional 36 months follow up (Hughes 2008).

Both trials recruited only males and included 15 and 26 participants respectively (Hughes 2008; Schiffmann 2001). The ratio of participants in the treatment and placebo groups varied; one trial achieved an almost equal split, randomising 14 participants to treatment and 12 to placebo (Schiffmann 2001); and the other trial did not state how many participants were in each group (Hughes 2008).

 
Types of interventions

Both trials compared enzyme replacement therapy (ERT) to placebo. One trial administered agalsidase alfa (Replagal™) every two weeks (dose not given); the other trial used a regimen of 0.2 mg/kg (administered over 40 minutes) every two weeks with an additional follow-up report of more 36 months (Hughes 2008).

 
Types of outcomes measured

Moore evaluated transversal doppler measurements, left ventricular volume, heart rate and stroke volume. The following Doppler parameters were obtained: peak flow velocity, mean flow velocity, end-diastolic velocity, pulsatility index, and resistance index (Schiffmann 2001).

At baseline and six months, Hughes measured left ventricular mass, QRS duration and levels of Gb3 in cardiac tissue, urine sediment and plasma and adverse effects (Hughes 2008).

 

Agalsidase beta versus placebo

Three trials were included in this comparison and are described in detail below (Banikazemi 2007; Bierer 2006; Eng 2001).

 
Trial design

All three trials were described as randomized placebo-controlled clinical trials (Banikazemi 2007; Bierer 2006; Eng 2001); and two of these were described as double-blind (Banikazemi 2007; Eng 2001). Trial duration ranged from five months (Eng 2001) to 35 months (Banikazemi 2007).

The number of participants included in each trial ranged from six (Bierer 2006) to 82 (Banikazemi 2007) and the three trials randomized mostly males (Banikazemi 2007; Bierer 2006; Eng 2001). The ratio of participants in the treatment and placebo groups varied across trials; two had a ratio of 2:1 treatment-to-placebo (Banikazemi 2007; Bierer 2006); and one had an even split of 29 participants in each group (Eng 2001).

In one trial, the investigators were part of the Genzyme Corporation in Cambridge, Massachussetts (Eng 2001). Only one trial was described as multicenter; there were 26 referral centers in six countries of North America and Europe (Banikazemi 2007).

 
Types of interventions

All three trials compared enzyme replacement therapy (ERT) to placebo. Each trial compared agalsidase beta (recombinant human alfa-galactosidase A) to placebo (Banikazemi 2007; Bierer 2006; Eng 2001). Two trials used the same dose (1mg/kg intravenously every two weeks), but one gave this dose for 20 weeks (Eng 2001) and the other for up to 35 months (median 18.5 months) (Banikazemi 2007). The final trial gave a dose of 1 mg/kg every other week for 18 months (Bierer 2006).

 
Types of outcomes measured

Thurberg evaluated urinary creatinine, urinary protein excretion, renal function and dermatologic characteristics of glycolipid accumulation in the dermis (Eng 2001). Measurements were taken at baseline and after infusion 11 at five months.

Banikazemi measured the time to first clinical event (renal, cardiac, or cerebrovascular event or death) (Banikazemi 2007). The following measures were taken: serum creatinine level; proteinuria; ratio of urinary albumin to urinary creatinine; 12-lead electrocardiography; echocardiography; neurologic examination; head magnetic resonance imaging; Brief Pain Inventory; exercise tolerance; plasma globotriaosylceramide level; Fabry symptom assessment; physical examination; blood chemistries; urinalysis; IgG antibody titers to agalsidase beta; and optional skin biopsy. All measurements were taken at baseline; serum creatinine levels were measured every four weeks, and all other baseline measures were repeated every 12 weeks, except for echocardiography, head magnetic resonance imaging, and exercise tolerance, which were repeated every 24 weeks. The estimated glomerular filtration rate (GFR) was determined by using the 4-variable Modification of Diet in Renal Disease formula.

Bierer measured cardiopulmonary exercise performance, forced expiratory volume and forced vital capacity every three months over an 18-month period (Bierer 2006).

 

Agalsidase alfa versus agalsidase beta

One trial was included in this comparison and is described in detail below (Vedder 2007).

Trial design

The trial was described as a randomized clinical trial, with patients being treated for a period of at least 12 months. A total of 36 patients (18 males and 18 females) were included in the trial. A total of 34 patients had at least 12 months of follow-up and a sub-group of patients (25 out of 34) was followed for more than 24 months of treatment. Two female patients withdrew after six months of agalsidase treatment.

Types of interventions

Patients were treated with either agalsidase alfa or agalsidase beta at an equal dose of 0.2 mg/kg bi-weekly.

Types of outcomes measured

Reduction in left ventricular mass after 12 and 24 months of treatment was considered the primary outcome. The authors also evaluated the occurrence of treatment failure (defined as progression of cardiac, renal or cerebral disease), glomerular filtration rate, pain, anti-agalsidase antibodies, and globotriaosylceramide levels in plasma and urine.

 

Excluded studies

Following the whole verification of the 56 articles, 33 of them were excluded from the review (Alamartine 2005; Banikasemi 2005; Beck 2004; Beer 2006; Breunig 2006; Cartwright 2004; Elliott 2006; Eto 2005; Fernhoff 2011; Germain 2007; Guffon 2002; Guffon 2004; Hajioff 2006; Hilz 2004; Jardim 2006; Jardim 2006b; Kalliokoshi 2006; Kampmann 2002; Kobayashi 2005; Kosch 2004; Linthorst 2004; Linthorst 2006; Mignani 2004; Mills 2004; Pisani 2005; Ramaswami 2007; Ries 2006; Schiffmann 2003; Schiffmann 2006; Spinelli 2004; Utsumi 2005; Weidemann 2003; West 2011). The main reasons for exclusion being that these were case series, cohort studies, or retrospective studies.

 

Risk of bias in included studies

 

Agalsidase alfa versus placebo

 

Generation of randomisation sequence

Hughes did not give a description regarding the generation of allocation; thus, this trial was classified as having an unclear risk of bias. (Hughes 2008).

For the Moore trial, it was stated that a randomization schedule was prepared prior to the start of the trial. Randomization was blocked to minimize imbalances between groups, however the authors did not report the method used for this, therefore we also classified it as unclear (Schiffmann 2001).

 

Allocation concealment

For the Hughes trial there was no description regarding the concealment of allocation; thus, this was judged to have an unclear risk of bias (Hughes 2008).

The other trial was classified as having a low risk of bias (Schiffmann 2001). The randomization schedule was prepared prior to the start of the trial and was provided to an unblinded pharmacist in the research pharmacy; no medical or sponsor personnel had access to the randomization code until the trial was completed (Schiffmann 2001).

 

Blinding

The Hughes trial was stated as being double-blind (Hughes 2008). All data were independently analysed by Royal Free Hospital investigators; the data remained blinded until the database was unlocked and the statistical analyses performed (Hughes 2008). We therefore judge this to be at a low risk of bias regarding this domain.

Moore did not describe any blinding process, therefore it was classified as having an unclear risk of bias (Schiffmann 2001).

 

Incomplete outcome data

There was no mention of withdrawals, drop outs or ITT in the Hughes trial, therefore we judged this to have an unclear risk of bias (Hughes 2008).

Moore describes four withdrawals and gives reasons for these; one participant, randomized to the placebo trial arm, withdrew from the trial for personal reasons and three further participants (one from the ERT group and two from the placebo group) declined the follow-up acetazolamide challenge arm of the trial at completion of the trial (Schiffmann 2001). However, ITT was not described in this trial. Overall, we have assessed this domain as having a low risk of bias (Schiffmann 2001).

 

Selective reporting

We judged both included trials to be free of selective reporting and having a low risk of bias (Hughes 2008; Schiffmann 2001).

 

Other potential sources of bias

We did not identify any other potential sources of bias (Hughes 2008; Schiffmann 2001).

 

Agalsidase beta versus placebo

 

Generation of randomisation sequence

The generation of allocation from the Banikazemi trial presented a low risk of bias as the randomisation codes were described as being computer-generated (Banikazemi 2007). The other two trials were described as randomized, but no details were given of how the sequences were generated; therefore these trials presented an unclear risk of bias (Bierer 2006; Eng 2001).

 

Allocation concealment

One trial was classified as having a low risk of bias since the randomization codes were maintained centrally at a secure location (Banikazemi 2007).

For the trials by Bierer and Thurberg there was no description regarding the concealment of allocation; thus, these trials were classified as having an unclear risk of bias (Bierer 2006; Eng 2001).

 

Blinding

In the Banikazemi trial, materials were packaged identically, and the sponsor staff, investigators, and participants were blinded to treatment allocation leading to a low risk of bias (Banikazemi 2007). The trial by Thurberg was described as double blind, however, information was only provided in relation to two outcomes. It was stated that each renal biopsy was reviewed under light microscopy by three independent renal pathologists who were blinded to treatment status of the patient at the time of biopsy; immunofluorescence trials were scored blinded (Eng 2001). Bierer reported that this trial was double blind, but provided no further details (Bierer 2006). We therefore judge both of these trials to have an unclear risk of bias (Bierer 2006; Eng 2001).

 

Incomplete outcome data

Withdrawals and drop outs, were noted by Banikazemi to be less than 20% (Banikazemi 2007). The Banikazemi trial used intention-to-treat analysis only in the primary outcome of their trial (time to first clinical event - renal, cardiac, or cerebrovascular event or death). We therefore assessed this as having an unclear risk of bias (Banikazemi 2007).

There was no description regarding withdrawals, drop outs and ITT in either the Bierer or Thurberg trials (Bierer 2006; Eng 2001).

 

Selective reporting

We judged all three included trials to be free of selective reporting (Banikazemi 2007; Bierer 2006; Eng 2001). The trials reported all the significant and non-significant results. We therefore judge all three trials to have a low risk of bias (Banikazemi 2007; Bierer 2006; Eng 2001).

 

Other potential sources of bias

While in the Thurberg trial, the investigators were part of the Genzyme Corporation in Cambridge, Massachussetts, we judge this trial to have an unclear risk of bias (Eng 2001).

 

Agalsidase alfa versus agalsidase beta

 

Generation of randomisation sequence

Different sets of randomization blocks were applied to both groups in the trial (Vedder 2007). Each block consisted of four envelopes that contained a paper stating agalsidase alfa or beta (i.e., manual randomization); the envelopes were generated by people not involved in obtaining informed consent. Therefore, we classified this trial as having a low risk of bias.

 

Allocation concealment

The envelopes were checked by two people not involved in obtaining informed consent, thus we classified the trial as having a low risk of bias for this domain (Vedder 2007).

 

Blinding

This trial was not blinded. The authors stated that "blinding of the enzyme products was not feasible, since the quality and storage life after rebottling could not be guaranteed". Furthermore, the authors reported that envelopes were opened by the investigator in the presence of the patient. Therefore we classified the risk of bias as high (Vedder 2007).

 

Incomplete outcome data

In the overall analysis, in the agalsidase alfa group 10% of patients withdrew, whereas there were no withdrawals in the agalsidase beta group (Vedder 2007). However, in the LVMass analysis there were withdrawal rates of 50% and 62.5% in the agalsidase alfa and beta groups, respectively. Therefore we classified this trial as having a high risk of bias.

 

Selective reporting

We judged the trial to be free of selective reporting and therefore classified this domain as having a low risk of bias (Vedder 2007).

 

Other potential sources of bias

We did not identify any other potential sources of bias (Vedder 2007).

 

Effects of interventions

We present the data from agalsidase alfa and agalsidase beta separately because of differences in trial design and treatment dose.

 

Agalsidase alfa versus placebo

Two trials were included in this comparison with a total of 41 participants: Hughes enrolled 15 participants; and Moore enrolled 26 participants (Hughes 2008; Schiffmann 2001).

 

Primary outcomes

 
1. Changes in globotriaosylceramide (Gb3) concentration in plasma and tissue

Two trials reported on this outcome at six months (end of treatment) (Hughes 2008; Schiffmann 2001).There was no statistically significant difference between treatment groups in the plasma Gb3 concentration, MD -2.07 (95% CI -6.64 to 2.50) (Hughes 2008; Schiffmann 2001) ( Analysis 1.1). There were also no statistically significant differences between treatment groups regarding the subcategories: urine sediment Gb3, MD -812.00 (95% CI -1897.83 to 273.83); and kidney, MD -2.50 (95% CI -9.47 to -4.47) (Schiffmann 2001) ( Analysis 1.2;  Analysis 1.3). Hughes did not report a statistically significant difference between the participants receiving agalsidase alfa and those receiving placebo for myocardial Gb3 levels at over three months and up to six months, MD 0.07 (95% CI -0.35 to 0.49) (Hughes 2008) ( Analysis 1.4).

 
2. Death

Neither of the included trials reported on this outcome (Hughes 2008; Schiffmann 2001).

 
3. Pain (measured by the McGill Pain Questionnaire)
 
a. Acroparaesthesia

We intended to measure this outcome by the intensity and duration of acroparaesthesia as reported by the individual; however none of the included trials reported on this outcome (Hughes 2008; Schiffmann 2001).

 
b. Fabry crises

We planned to present whether the participants had reported the presence or absence of crises as a binary outcome, but none of the included trials reported on this outcome (Hughes 2008; Schiffmann 2001).

 
c. The Brief Pain Inventory severity

One trial reported on this outcome (Schiffmann 2001). There was a statistically significant difference favoring the participants receiving agalsidase alfa versus placebo in all the subcategories studied: at over one month and up to three months, MD -2.10 (95% CI -3.79 to -0.41); at over three months and up to five months, MD -1.90 (95% CI -3.65 to -0.15); and at over five months and up to six months, MD -2.00 (95% CI -3.66 to -0.34) (Schiffmann 2001) ( Analysis 1.5).

 
d. The Brief Pain Inventory pain-related quality of life

One trial reported on this outcome (Schiffmann 2001). There was no statistically significant difference between groups in the subcategories studied at over one month and up to three months, MD -0.90 (95% CI -2.73 to 0.93) and at over three months and up to five months, MD -1.80 (95% CI -3.77 to 0.17). However, at over five months and up to six months a significant difference favoring agalsidase alfa was noted, MD -2.10 (95% CI -3.92 to -0.28) (Schiffmann 2001) ( Analysis 1.6).

 

Secondary outcomes

 
1. Effect of therapy on renal function

One trial reported on this outcome (Schiffmann 2001). Creatinine clearance and inulin clearance were used to estimate glomerular filtration rate. There were no statistically significant difference between both groups in the subcategories creatinine clearance at end of treatment (up to six months), and insulin clearance (up to six months) respectively, MD 10.30 (95% CI -15.37 to 35.97) and MD -0.50 (95% CI -21.36 to 20.36) (Schiffmann 2001) ( Analysis 1.7;  Analysis 1.8).

There was also no statistically significant difference between groups in the subcategories: glomeruli with mesangial widening at up to six months, MD -14.70 (95% CI -36.72 to 7.32); glomeruli with segmental sclerosis at up to six months and obsolescent glomeruli at up to six months; MD 3.80 (95% CI -2.35 to 9.95) and MD 6.50 (95% CI -8.93 to 21.93) (Schiffmann 2001) ( Analysis 1.9;  Analysis 1.10;  Analysis 1.11).

 
2. Symptoms and complications of disease (such as renal failure, skin, cerebrovascular and cardiac complications)

Neither of the included trials reported on this outcome (Hughes 2008; Schiffmann 2001).

 
3. Parameters: echocardiographic

There was no statistically significant difference between groups for mean left ventricular wall thickness, MD -0.79 (95% CI -3.62 to 2.04); left ventricular internal diameter (diastolic), MD -3.70 (95% CI -11.73 to 4.33); left ventricular internal diameter (systolic), MD -2.70 (95%CI -9.91 to 4.51); and left ventricular ejection fraction, MD 1.88 (95%CI -4.68 to 8.44) (Hughes 2008) ( Analysis 1.12).

 
4. Histologic analysis of microvascular capillary endothelial deposits of Gb3 in biopsy specimens

Neither of the included trials reported on this outcome (Hughes 2008; Schiffmann 2001).

 
5. Adverse effects of treatment

Neither of the included trials reported on this outcome (Hughes 2008; Schiffmann 2001).

 
6. Quality of life (as determined by the Short Form 36 (SF-36) and the impact of clinical variables on domain scores within the SF-36 (Smith 2000))

Neither of the included trials reported on this outcome (Hughes 2008; Schiffmann 2001).

 
7. Costs

Neither of the included trials reported on this outcome (Hughes 2008; Schiffmann 2001).

 

Agalsidase beta versus placebo

Three trials were included in this comparison with a total of 146 participants: Banikazemi enrolled 82 participants; Bierer enrolled 6 participants; and Thurberg enrolled 58 participants (Banikazemi 2007; Bierer 2006; Eng 2001).

 

Primary outcomes

 
1. Changes in globotriaosylceramide (Gb3) concentration in plasma and tissue

One of the included trials reported on this outcome in tissue (Eng 2001). There was a statistically significant difference favoring the participants receiving agalsidase beta versus placebo in three subcategories: kidney, MD -1.70 (95% CI -2.09 to -1.31); heart, MD -0.90 (95% CI -1.18 to -0.62); and composite, MD -4.80 (95% CI -5.45 to -4.15) (Eng 2001) ( Analysis 2.1).

None of the included trials reported the effect on plasma concentrations (Banikazemi 2007; Bierer 2006; Eng 2001).

 
2. Death

There was no statistically significant difference in death as reported in one trial, RR 1.85 (95% CI 0.08 to 43.96) ( Analysis 2.2). There was one death from a total of 51 participants in agalsidase beta and no deaths in the placebo group (n = 31) (Banikazemi 2007).

 
3. Pain (measured by the McGill Pain Questionnaire)
 
a. Acroparaesthesia

We intended to measure this outcome by the intensity and duration of acroparaesthesia as reported by the individual; however none of the included trials reported this outcome (Banikazemi 2007; Bierer 2006; Eng 2001).

 
b. Fabry crises

We planned to present whether the participants had reported the presence or absence of crises as a binary outcome, but none of the included trials reported this outcome (Banikazemi 2007; Bierer 2006; Eng 2001).

 

Secondary outcomes

 
1. Effect of therapy on renal function

The number of renal events (33% increase in serum creatinine level; end-stage renal disease) were reported by Banikazemi; there was no statistically significant difference in the number of events between groups, RR 0.87 (95% CI 0.37 to 2.04) (Banikazemi 2007) ( Analysis 2.3).

 
2. Symptoms and complications of disease (such as renal failure, skin, cerebrovascular and cardiac complications)
 
a. Cardiac events

Cardiopulmonary exercise test was reported by Bierer (Bierer 2006). There were no significant differences between groups in any of the subcategories evaluated (average heart rate reserve, MD 21.30 (95% CI -1.28 to 43.88); average maximum oxygen uptake measured at peak exercise, MD 0.22 (95% CI -0.94 to 1.38); maximum oxygen uptake measured at peak exercise, MD 2.60 (95% CI -13.16 to 18.36); and oxygen pulse average at peak exercise, MD 2.10 (95% CI -3.67 to 7.87)) ( Analysis 2.4).

There were no significant differences in decrease in diastolic blood pressure in the Bierer trial, RR 1.50 (95% CI 0.34 to 6.70) (Bierer 2006) ( Analysis 2.5).

Banikazemi reported cardiac events and there was also no significant differences between studied groups RR 0.46 (95% CI 0.11 to 1.90) (Banikazemi 2007) ( Analysis 2.6).

 
b. Cerebrovascular events

There was no significant difference in the number of cerebrovascular events between groups in the Banikazemi trial, RR 0.12 (95% CI 0.01 to 2.48) (Banikazemi 2007) ( Analysis 2.7).

 
c. Percentage of participants achieving zero scores in skin

For participants achieving zero scores in skin at five months, there was a statistically significant difference in the Thurberg trial favoring the participants receiving agalsidase beta versus placebo in two subcategories: superficial endothelial cells, RR 19.67 (95% CI 4.13 to 93.63) and deep endothelial cells, RR 11.00 (95% CI 2.88 to 42.08) (Eng 2001). There was no significant difference between groups in two further sub-categories: smooth muscle cells, RR 1.50 (95% CI 0.10 to 22.62); or in perineurium cells, RR 1.04 (95% CI 0.07 to 15.72) ( Analysis 2.8) (Eng 2001).

Thurberg also reported data for participants achieving a zero score or a reduction in skin ( Analysis 2.9); there was a statistically significant difference favoring the participants receiving agalsidase beta versus placebo in two subcategories: superficial endothelial cells, RR 2.81 (95% CI 1.72 to 4.59) and deep endothelial cells, RR 2.79 (95% CI 1.67 to 4.67) (Eng 2001). There was no significant difference between groups in two further sub-categories: smooth muscle cells, RR 1.50 (95% CI 0.10 to 22.62); or in perineurium cells, RR 1.49 (95% CI 0.68 to 3.25).

 
3. Parameters echocardiographic

None of the included trials reported this outcome (Banikazemi 2007; Bierer 2006; Eng 2001).

 
4. Histologic analysis of microvascular capillary endothelial deposits of Gb3 in biopsy specimens

None of the included trials reported this outcome (Banikazemi 2007; Bierer 2006; Eng 2001).

 
5. Adverse effects of treatment
 
a. Any adverse event

Two trials reported adverse events; one at over three month and up to six months (Eng 2001) and one at 24 months (Banikazemi 2007).

There were statistically significant differences in favor of placebo regarding rigors at both time-points and combined, RR 16.12 (95% CI 3.35 to 77.58) ( Analysis 2.10). Likewise, occurrence of fever at both time-points and combined was statistically significant in favor of placebo, RR 7.84 (95% CI 1.88 to 32.68) ( Analysis 2.11). Only Banikazemi reported temperature changed sensation, at 24 months there was no statistically significant difference, RR 3.04 (95% CI 0.37 to 24.82) (Banikazemi 2007) ( Analysis 2.12). Likewise only one trial reported chills; there was no statistically significant difference at over three months and up to six months, RR 9.00 (95% CI 0.51 to 159.94) (Eng 2001) ( Analysis 2.13). Both trials reported hypertension; there was no statistically significant difference at either time-point or combined, RR 2.94 (95% CI 0.80 to 10.86) (Banikazemi 2007; Eng 2001) ( Analysis 2.14). Only one trial reported vomiting, chest pain and fatigue; there was no statistically significant difference for any of these at 24 months, vomiting RR 8.00 (95% CI 0.47 to 137.27), chest pain RR 6.77 (95% CI 0.39 to 118.36) and fatigue RR 6.77 (95% CI 0.39 to 118.36) (Banikazemi 2007) ( Analysis 2.15;  Analysis 2.16;  Analysis 2.17). Thurberg reported on headache and pain related to Fabry disease at over three months and up to six months (Eng 2001) ( Analysis 2.18;  Analysis 2.19). Neither outcome showed a statistically significant difference; headache, RR 2.50 (95% CI 0.53 to 11.86); and pain related to Fabry disease, RR 3.00 (95% CI 0.33 to 27.18) (Eng 2001).

 
b. Any serious adverse events

None of the included trials reported this outcome (Banikazemi 2007; Bierer 2006; Eng 2001).

 
6. Quality of life (as determined by the Short Form 36 (SF-36) and the impact of clinical variables on domain scores within the SF-36 (Smith 2000))

None of the included trials reported this outcome (Banikazemi 2007; Bierer 2006; Eng 2001).

 
7. Costs (presented narratively)

None of the included trials reported this outcome (Banikazemi 2007; Bierer 2006; Eng 2001).

 

Agalsidase alfa versus agalsidase beta

One trial was included in this comparison with a total of 34 participants (Vedder 2007).

 

Primary outcomes

 
1. Changes in globotriaosylceramide (Gb3) concentration in plasma and tissue

Vedder reported a median (range) of 3.3 umol/l (1.45 to 6.42) and 3 umol/l (1.89 to 7.85) for 12 and 24 months of treatment, respectively in agalsidade alfa arm, while there was a median (range) of 2.48 umol/l (1.40 to 3.93) and 2.23 umol/l (0.92 to 4.3) for 12 and 24 months of treatment, respectively in agalsidade beta arm.

 
2. Death

There was a death from multiple cerebral infarctions after 20 months in the agalsidase alfa treatment group, RR 3.00 (95% CI 0.13 to 69.09) (Vedder 2007) ( Analysis 3.1).

 
3. Pain (measured by BPI-3)
 
a. Acroparaesthesia and Fabry crises

The trial described no significant reduction of pain score (BPI-3) after 12 months of treatment in either of the studied groups: alfa 0 (range 25 to 1); and beta 21.5 (range 24 to 3). The values did not change for analysis at the 24 month time-point (Vedder 2007).

 

Secondary outcomes

 
1. Effect of therapy on renal function

The trial reported that renal insufficiency, defined as an increase of serum creatinine greater than 33%, progressed in two patients treated with agalsidase alfa, who had baseline GFR measurements of 22 and 30 ml/min (within 24 months). Furthermore, also in the agalsidase alfa group, progression of renal insufficiency was seen in one other patient after 30 months of treatment (Vedder 2007).

 
2. Symptoms and complications of disease (such as renal failure, skin, cerebrovascular and cardiac complications)
 
a. Cardiac events

Two patients suffered from atrial fibrillation after 42 and 36 months of agalsidase beta treatment (Vedder 2007). Furthermore, atrial fibrillation also occurred in a male patient treated with agalsidase alfa for 30 months. There was no statistically significant difference for cardiac events, RR 0.47 (95% CI 0.05 to 4.60) (Vedder 2007) ( Analysis 3.2).

 
b. Cerebrovascular events

The included trial did not report this outcome (Vedder 2007).

 
c. Percentage of participants achieving zero scores in skin

The included trial did not report this outcome (Vedder 2007).

 
3. Parameters echocardiographic

The trial reported LVMass (g). There was a median (range) of 244 g (157 to 424) and 294 g (196 to 502) for 12 and 24 months of treatment, respectively in the agalsidase alfa arm, while there was a median (range) of 296 g (169 to 401) and 308 g (196 to 471) for 12 and 24 months of treatment, respectively in the agalsidase beta arm (Vedder 2007).

 
4. Histologic analysis of microvascular capillary endothelial deposits of Gb3 in biopsy specimens

The included trial did not report this outcome (Vedder 2007).

 
5. Adverse effects of treatment
 
a. Any adverse event

There was no significant difference in the number of any adverse events between groups in the Vedder trial, RR 0.36 (95% CI 0.08 to 1.59) (Vedder 2007) ( Analysis 3.3).

 
b. Any serious adverse events

There was no significant difference in the number of any serious adverse events between groups in the Vedder trial, RR 0.30 (95% CI 0.03 to 2.57) (Vedder 2007) ( Analysis 3.4).

 
6. Quality of life (as determined by the Short Form 36 (SF-36) and the impact of clinical variables on domain scores within the SF-36 (Smith 2000))

The included trial did not report on this outcome, but it is included as an outcome in the protocol (Vedder 2007). We contacted the main author for further clarification and hope these data can be included in a future update of this review.

 
7. Costs (presented narratively)

The included trial did not report this outcome (Vedder 2007).

 

Discussion

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Feedback
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Notes
  19. Index terms

The effectiveness of therapy in reducing the incidence and severity or delaying the onset of AFD-related complications, and its impact on long-term survival is not known at this time. Heterogeneity in clinical expression requires long-term studies in a large cohort of patients, which is being undertaken through observational surveys or patient registries.

It has been shown that ERT for AFD can modify the course of disease in treated patients. Compared with the group of participants receiving placebo, those treated with either agalsidase alfa or agalsidase beta experienced a reduction in Gb3 concentration in plasma and tissues. Although this finding is indicative of ‘proof of concept’, its clinical significance is uncertain as the trials examined did not provide specific information on correlation with clinical events or survival. Trial results indicated an effect of ERT on neuropathic pain, cardiac morphology and renal function, and a positive influence on health-related quality of life. However, additional information from trials including a greater number of participants is required. It is likely that advanced disease stage prior to the start of treatment influenced outcome. Trials in asymptomatic or oligo-symptomatic individuals may provide information on the effectiveness of therapy in preventing or delaying the onset of symptoms or disease-related complications (Ramaswami 2007; Ries 2006; Ries 2007; Wraith 2008).

Treatment with ERT appears to be relatively well-tolerated. Antibody formation has been reported in a significant proportion of treated individuals. Although trials indicate that the presence of neutralizing antibodies may potentially influence therapeutic outcome, in the absence of controlled trials no definitive conclusions can be provided at this time. Infusion-related adverse events may be controlled by the use of pre-medication and the administration of the enzymes at a slower rate. Treatment is widely available, based on the country of origin for patients in the registry programs.

In the agalsidase alfa comparison, even though we used a random-effects model (to better deal with heterogeneity), we found a high level of heterogeneity (I2 = 91%) in the outcome plasma Gb3 at up to six months. This method assumes that the effects being estimated in the different trials are not identical, but follow some distribution. In this case the effect may have varied due to different population or intervention characteristics (such the dose, duration and regimen).

We included six trials in this systematic review, that were of low methodological quality; mainly, providing results that were presented in a manner that made statistical analysis difficult. For future updates of this review, we will contact authors to clarify the methodological issues.

 

Authors' conclusions

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Feedback
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Notes
  19. Index terms

 

Implications for practice

Limited evidence from five small poor quality randomised controlled trials shows no robust evidence for use of either agalsidase alfa or beta to treat AFD. The long-term influence of ERT on risk of morbidity and mortality related to AFD remains to be established. Careful evaluation is needed to ascertain the possible benefit of using concomitant medications (such as angiotension converting enzyme inhibitors for their reno-protective properties or antiplatelet aggregating agents for primary and secondary stroke prevention) in affected individuals whether receiving ERT or not. There is also a need to understand prognostic determinants and therapeutic outcome, which may allow stratification of patients and identification of the subset of patients most likely to achieve the best results with treatment.

 
Implications for research

This review highlights the need for continued research into the use of ERT for AFD. Currently, there are investigations into other therapeutic approaches, such as substrate reduction therapy and enzyme enhancement with pharmacologic chaperones, which might have therapeutic value. Subsequent trials should help define the use of ERT and other options (as these become available and considered either in combination or as monotherapy) in the management of people with AFD. Given the rarity of AFD and evidence of an ERT-treatment effect, it is not deemed ethical to proceed with new trials including a placebo group. Data on outcomes are being prospectively collected through surveillance or registry-based programs, as post-marketing commitments made by the sponsors.

 

Acknowledgements

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Feedback
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Notes
  19. Index terms

We would like to thank Tracey Remmington and Nikki Jahnke from the Cystic Fibrosis & Genetics Disorders Group for their outstanding help and Julia Mortimer from the Heart Group for her help during the preparation of this review.

 

Data and analyses

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Feedback
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Notes
  19. Index terms
Download statistical data

 
Comparison 1. Agalsidase alfa versus placebo

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Plasma Gb32Mean Difference (IV, Random, 95% CI)Subtotals only

    1.1 At up to 6 months
239Mean Difference (IV, Random, 95% CI)-2.07 [-6.64, 2.50]

 2 Urine sediment Gb31Mean Difference (IV, Fixed, 95% CI)Totals not selected

    2.1 At up to 6 months
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

 3 Kidney Gb31Mean Difference (IV, Fixed, 95% CI)Totals not selected

    3.1 At up to 6 months
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

 4 Myocardial globotriaosylceramide levels1Mean Difference (IV, Fixed, 95% CI)Totals not selected

    4.1 Over 3 months and up to 6 months
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

 5 The Brief Pain Inventory Severity1Mean Difference (IV, Fixed, 95% CI)Totals not selected

    5.1 Over one month and up to three months
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

    5.2 Over three months and up to five months
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

    5.3 Over five months and up to six months
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

 6 The Brief Pain Inventory pain-related quality of life1Mean Difference (IV, Fixed, 95% CI)Totals not selected

    6.1 Over one month and up to three months
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

    6.2 Over three months and up to five months
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

    6.3 Over five months and up to six months
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

 7 Creatinine clearance1Mean Difference (IV, Fixed, 95% CI)Totals not selected

    7.1 At up to 6 months
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

 8 Insulin clearance1Mean Difference (IV, Fixed, 95% CI)Totals not selected

    8.1 At up to 6 months
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

 9 Glomeruli with mesangial widening1Mean Difference (IV, Fixed, 95% CI)Totals not selected

    9.1 At up to 6 months
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

 10 Glomeruli with segmental sclerosis1Mean Difference (IV, Fixed, 95% CI)Totals not selected

    10.1 At up to 6 months
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

 11 Obsolescent glomeruli1Mean Difference (IV, Fixed, 95% CI)Totals not selected

    11.1 At up to 6 months
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

 12 Echocardiographic data on left ventricular structure and function over three months and up to six months1Mean Difference (IV, Fixed, 95% CI)Totals not selected

    12.1 Mean left ventricular wall thickness (mm)
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

    12.2 Left ventricular internal diameter (mm) (diastolic)
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

    12.3 Left ventricular internal diameter (mm) (systolic)
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

    12.4 Left ventricular ejection fraction
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

 
Comparison 2. Agalsidase beta versus placebo

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Microvascular endothelial deposits of globotriaosylceramide1Mean Difference (IV, Fixed, 95% CI)Totals not selected

    1.1 Kidney - over three months and up to six months
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

    1.2 Heart - over three months and up to six months
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

    1.3 Composite - over three months and up to six months
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

 2 Death (intention-to-treat population)1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

 3 Renal events (intention-to-treat population)1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

 4 Cardiopulmonary exercise test1Mean Difference (IV, Fixed, 95% CI)Totals not selected

    4.1 Average heart rate reserve
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

    4.2 Average maximum oxygen uptake measured at peak exercise (L/minutes)
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

    4.3 Maximum oxygen uptake measured at peak exercise (ml/kg/mins)
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

    4.4 Oxygen pulse average at peak exercise
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

 5 Cardiopulmonary exercise test1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    5.1 Decrease in diastolic blood pressure
16Risk Ratio (M-H, Fixed, 95% CI)1.5 [0.34, 6.70]

 6 Cardiac events182Risk Ratio (M-H, Fixed, 95% CI)0.46 [0.11, 1.90]

 7 Cerebrovascular events (intention-to-treat population)1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

 8 Participants achieving zero scores in skin over three months and up to six months1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

    8.1 Superficial endothelial cells
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    8.2 Deep endothelial cells
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    8.3 Smooth muscle cells
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    8.4 Perineurium
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 9 Participants achieving zero score or reduction in skin over three months and up to six months1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

    9.1 Superficial endothelial cells
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    9.2 Deep endothelial cells
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    9.3 Smooth muscle cells
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    9.4 Perineurium
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 10 Adverse event: Rigors2140Risk Ratio (M-H, Fixed, 95% CI)16.12 [3.35, 77.58]

    10.1 Over three and up to six months
158Risk Ratio (M-H, Fixed, 95% CI)29.0 [1.81, 464.38]

    10.2 At 24 months
182Risk Ratio (M-H, Fixed, 95% CI)10.94 [1.54, 77.95]

 11 Adverse event: Fever2140Risk Ratio (M-H, Fixed, 95% CI)7.84 [1.88, 32.68]

    11.1 Over three and up to six months
158Risk Ratio (M-H, Fixed, 95% CI)7.0 [0.92, 53.36]

    11.2 At 24 months
182Risk Ratio (M-H, Fixed, 95% CI)8.51 [1.18, 61.58]

 12 Adverse event: Temperature changed sensation1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

    12.1 At 24 months
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 13 Adverse event: Chills1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

    13.1 Over three and up to six months
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 14 Adverse event: Hypertension2140Risk Ratio (M-H, Fixed, 95% CI)2.94 [0.80, 10.86]

    14.1 Over three and up to six months
158Risk Ratio (M-H, Fixed, 95% CI)7.0 [0.38, 129.74]

    14.2 At 24 months
182Risk Ratio (M-H, Fixed, 95% CI)2.13 [0.47, 9.60]

 15 Adverse event: Vomiting1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

    15.1 At 24 months
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 16 Adverse event: Chest pain1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

    16.1 At 24 months
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 17 Adverse event: Fatigue1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

    17.1 At 24 months
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 18 Adverse event: Headache1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

    18.1 Over three and up to six months
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 19 Adverse event: Pain related to Fabry Disease1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

    19.1 Over three and up to six months
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 
Comparison 3. Agalsidase alfa versus agalsidase beta

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Death1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

 2 Cardiac events1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

 3 Any adverse event1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

 4 Any serious adverse events1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

 

Appendices

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Feedback
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Notes
  19. Index terms
 

Appendix 1. Glossary


TermExplanation

AcroparaesthesiaPain, tingling and numbness of the hands and forearms

AngiokeratomaSkin condition characterized by intradermal hemangioma over which there is thickening of the epidermis

Angiokeratoma corporis diffusumX-linked disorder caused by a deficiency of the lysosomal enzyme alpha-galactosidase A, also known as Anderson-Fabry disease

CardiacRelating to the the heart

Cerebro-vascular diseaseGroup of brain dysfunctions related to disease, usually an obstruction, of the blood vessels supplying the brain

DeacylatedDescribing a compound from which one or more acyl groups (an organic radical derived from an organic acid by the removal of the carboxylic hydroxyl group) has been removed

DermatologicRelating to the skin

DyspnoeaDebilitating symptom or experience of unpleasant or uncomfortable respiratory (breathing) sensations

EchocardiographyStandard ultrasound techniques imaging two-dimensional slices of the heart to diagnose cardiovascular disease

ElectrocardiographyTransthoracic interpretation of the electrical activity of the heart captured and externally recorded by skin electrodes

EndothelialThin layer of cells that line the interior surface of blood vessels

GastrointestinalRelating to the digestive system

GlobotriaosylceramideType of glycolipid compound which accumulates in the blood vessel walls of people with Fabry disease as a result of a deficiency in alpha-galactosidase A, a lysosomal enzyme

Glomerular filtration rateVolume of fluid filtered from the renal (kidney) glomerular capillaries into the Bowman´s capsule (a cup-like sac at the beginning of the tubular component of a nephron in the mammalian kidney) per unit time

Glomeruli Capillary tuft surrounded by Bowman's capsule in nephrons of the vertebrate kidney

GlycosphingolipidItSubtype of glycolipids containing the amino alcohol sphingosine; a ceramide (a sphingolipid) linked to one or more sugars via the terminal hydroxyl group

IgE antibodiesType of immunoglobulin made by the body which are implicated in allergic reactions

IgG antibodiesType of immunoglobulin involved in fighting foreign bodies, bacterial and viral infections

Left ventricular ejection fractionFraction of blood pumped out of the left ventricle with each heart beat

LyonizationPhenomenon wherein one of the two copies of the X chromosome present in female mammals is inactivated

Lysosomal hydrolase alpha-galactosidaseEnzyme involved in glycolipid catabolism, which requires an acidic environment as maintained in the lysosome

Lysosomal inclusionsStorage bodies associated with lysosomal dysfunction, usually a deficiency of an enzyme involved in catabolism

Mammalian cell expression systemElements involved in the translation of genetic information to form a particular protein

Mesangial wideningThickening of the mesangium, a part of the renal glomerulus between capillaries

Microvascular diseaseAngiopathy or condition affecting small blood vessels in the body

Myocardial infarctionCommonly known as a heart attack, resulting from an interruption of blood supply to part of the heart

Neurologic diseaseDisorder of the brain, spinal cord and nerves

NeuropathicReferring to disorders of the peripheral nervous system

Parametric dataParametric statistical tests assume that the data are 'normally distributed', that is, when graphed, the data follow a 'bell shaped curve'

Perineurium cellsCells from the perineurium, the middle layer of the protective perineural sheath surrounding peripheral nerves

ProteinuriaPresence of an excess of serum proteins in the urine

RenalRelating to the kidneys

Segmental sclerosisScarring or degeneration, often used in relation to disease of a kidney section

Sero-convertedDevelopment of antibodies in the blood as a result of the introduction of a foreign body, infection or immunization

Serum creatinineBy-product of metabolism that is measured in serum as a indicator of kidney function

SubstrateMolecule that is acted upon by an enzyme

Thrombo-embolicBlocking of a blood vessel by a blood clot dislodged from its site of origin

TransducedConversion of one type of energy or signal into another; in genetics the introduction of DNA into a different cell type, to induce the formation of the corresponding gene product

Urinary albuminPresence of albumin, a protein, in the urine

X-linkedRelating to genes or characteristics or conditions carried on the X chromosome



 

Appendix 2. Search strategy - Clincal Trials (The Cochrane Library, Issue 1, 2008)


Search Strategy

((Fabry Disease) OR (Disease, Fabry ) OR (Angiokeratoma Corporis Diffusum) OR (Anderson-Fabry Disease) OR (Anderson Fabry Disease) OR (Disease, Anderson-Fabry) OR (Fabry's Disease) OR (Disease, Fabry's) OR (Fabrys Disease)) AND ((agalsidase beta) OR (Fabrazyme) OR (Genzyme brand of agalsidase beta))



 

Appendix 3. Search strategy - EMBASE (1980 - September 2008)


Search Strategy

1. Randomized controlled trial/

2. Controlled study/

3. Randomization/

4. Double blind procedure/

5. Single blind procedure/

6. Clinical trial/

7. (clinical adj5 trial$).ti,ab,hw.

8. ((doubl$ or singl$ or tripl$ or trebl$) adj5 (blind$ or mask$)).ti,ab,hw.

9. Placebo/

10. Placebo$.ti,ab,hw.

11. Random$.ti,ab,hw.

12. Methodology.sh.

13. latin square.ti,ab,hw.

14. crossover.ti,ab,hw.

15. cross-over.ti,ab,hw.

16. Crossover Procedure/

17. Drug comparison/

18. Comparative study/

19. (comparative adj5 trial$).ti,ab,hw.

20. (control$ or prospectiv$ or volunteer$).ti,ab,hw.

21. exp "Evaluation and Follow Up"/

22. Prospective study/

23. or/1-22

24. animal/ not (human/ and animal/)

25. 23 not 24



 

Appendix 4. Search strategy - PubMed (1966 - September 2008)


Search Strategy

randomized controlled trial [Publication Type] OR controlled clinical trial [Publication Type] OR randomized controlled trials [MeSH Terms] OR random allocation [MeSH Terms] OR double blind method [MeSH Terms] OR single blind method [MeSH Terms] OR clinical trial [Publication Type] OR clinical trials [MeSH Terms] OR (clinical* [Text Word] AND trial* [Text Word]) OR single* [Text Word] OR double* [Text Word] OR treble* [Text Word] OR triple* [Text Word] OR placebos [MeSH Terms] OR placebo* [Text Word] OR random* [Text Word] OR research design [MeSH Terms] OR comparative study [MeSH Terms] OR evaluation studies [MeSH Terms] OR follow-up studies [MeSH Terms] OR prospective studies [MeSH Terms] OR control* [Text Word] OR prospectiv* [Text Word] OR volunteer* [Text Word]



 

Appendix 5. Search strategy - LILACS (1982 - September 2008)


Search Strategy

(Pt randomized controlled trial) OR (Pt controlled clinical trial) OR (Mh randomized controlled trials) OR (Mh random allocation) OR (Mh double blind method) OR (Mh single blind method) AND NOT (Ct animal) AND NOT (Ct human and Ct animal) OR (Pt clinical trial) OR (Ex E05.318.760.535$) OR (Tw clin$) AND (Tw trial$) OR (Tw ensa$) OR (Tw estud$) OR (Tw experim$) OR (Tw investiga$) OR (Tw singl$) OR (Tw simple$) OR (Tw doubl$) OR (Tw doble$) OR (Tw duplo$) OR (Tw trebl$) OR (Tw trip$) AND (Tw blind$) OR (Tw cego$) OR (Tw ciego$) OR (Tw mask$) OR (Tw mascar$) OR (Mh placebos) OR (Tw placebo$) OR (Tw random$) OR (Tw randon$) OR (Tw casual$) OR (Tw acaso$) OR (Tw azar) OR (Tw aleator$) OR (Mh research design) AND NOT (Ct animal) AND NOT (Ct human and Ct animal) OR (Ct comparative study) OR (Ex E05.337$) OR (Mh follow-up studies) OR (Mh prospective studies) OR (Tw control$) OR (Tw prospectiv$) OR (Tw volunt$) OR (Tw volunteer$) AND NOT ((Ct animal) AND NOT (Ct human and Ct animal))



 

Feedback

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Feedback
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Notes
  19. Index terms
 

Comment on use of Cochrane methodology for rare, chronic, progressive diseases, 28 July 2010

 

Summary

 

Comment 1

In the Cochrane review of enzyme replacement therapies (ERT) for Fabry disease, you conclude that the randomized controlled trials with agalsidase alfa and agalsidase beta did not provide robust evidence for the use of either product. In the same review, it is acknowledged that ERT can have a positive effect on, among others, renal function and cardiac morphology. Health care providers may have great difficulty in putting this combination of contradictory statements in the right context. In our opinion, this confusion may result from the Cochrane review methodology itself which is based on the assessment of randomized, placebo-controlled studies1.  This has limitations in very rare, chronic, progressive diseases where patient numbers are very low and long-term administration of placebo may be considered unethical.

Fabry disease is a rare, inherited, lifelong, progressive disorder of metabolism. Conventional proof of treatment efficacy in more common diseases requires adequately powered long-term, placebo-controlled studies of clinical outcome; however, these are simply not possible in Fabry disease. Short-term trials, mostly of 6-months duration, have explored initial effects of ERT on existing symptoms and/or GL-3 storage2, 3. Collection of longitudinal data for analysis of changes in renal function and left ventricular hypertrophy, however, typically requires multiple years of follow-up that is only possible in an open-label study setting where patients are receiving active treatment as intravenous infusions every two weeks4-6. The Cochrane review methodology, unfortunately, systematically excludes such important open-label studies. There is a risk that the positive effects of ERT on major causes of morbidity and mortality in Fabry disease are not taken into account when making therapeutic decisions based on your review.

The main conclusion is that the current studies were too small but, as acknowledged by the authors, the Fabry population is extremely small and heterogeneous which makes it extraordinarily difficult to conduct additional larger-scale, placebo-controlled or open-label clinical trials. Pooling of data from the small studies performed in this orphan population and analyzing outcome measures individually lacks adequate statistical power to draw conclusions. Using an aggregate definition of a clinical event as in the Phase 4 study of agalsidase beta7, was a creative response to these difficulties and did increase statistical power; a similar approach may be applicable to a meta-analysis.  These challenges will remain the same for any new therapy developed for this rare disease and others, and appropriate understanding of this situation is necessary to make advances in the treatment of ultra-orphan diseases.

A recent systematic review performed by experts in the field of Fabry disease8 did include both randomized controlled trials and open-label studies and provides caregivers with a different view of the overall outcomes with ERT.

 

Comment 2

We noted a few inaccuracies in the text that we want to bring to the authors’ attention. We wonder why the authors have chosen to refer to the Phase 3 studies by Thurberg et al and Moore et al9,10.  These are sub-studies specifically investigating histology and regional cerebral blood flow, respectively, in the Phase 3 agalsidase beta and alfa study cohorts. The correct references for the publications of the full sets of data are Eng et al 2001 and Schiffmann et al 2001.2, 3

 

Comment 3

Moreover, auditory loss is mentioned as the outcome measure of the study by Hughes et al (page 19). Perhaps the authors can explain why this outcome measure was selected for this cardiac study.

 

Comment 4

The conflict of interest section does not mention the author’s involvement in the algasidase studies.

 

Conflict of Interests

Vinciane Pirard, MD, is an employee of Genzyme Europe BV, a subsidiary of Genzyme Corporation, the manufacturer of agalsidase beta.

 

References

1.    Elphick HE, Tan A, Ashby D, Smyth RL. Systematic reviews and lifelong diseases. BMJ 2002;325:381-4.

2.    Eng CM, Guffon N, Wilcox WR, et al. Safety and efficacy of recombinant human alpha-galactosidase A--replacement therapy in Fabry's disease. New England Journal of Medicine 2001;345:9-16.

3.    Schiffmann R, Kopp JB, Austin HA, 3rd, et al. Enzyme replacement therapy in Fabry disease: a randomized controlled trial. JAMA 2001;285:2743-9.

4.    Germain DP, Waldek S, Banikazemi M, et al. Sustained, long-term renal stabilization after 54 months of agalsidase beta therapy in patients with Fabry disease. Journal of the American Society of Nephrology 2007;18:1547-57.

5.    Schiffmann R, Ries M, Timmons M, Flaherty JT, Brady RO. Long-term therapy with agalsidase alfa for Fabry disease: safety and effects on renal function in a home infusion setting. Nephrology Dialysis Transplantation 2006;21:345-54.

6.    Weidemann F, Niemann M, Breunig F, et al. Long-term effects of enzyme replacement therapy on fabry cardiomyopathy: evidence for a better outcome with early treatment. Circulation 2009;119:524-9.

7.    Banikazemi M, Bultas J, Waldek S, Wilcox WR, Whitley CB, McDonald M, et al. Agalsidase-beta therapy for advanced Fabry disease: a randomized trial. Annals of Internal Medicine 2007;146:77-86.

8.    Schaefer RM, Tylki-Szymanska A, Hilz MJ. Enzyme replacement therapy for Fabry disease: a systematic review of available evidence. Drugs 2009;69:2179-205.

9.    Thurberg BL, Randolph Byers H, Granter SR, Phelps RG, Gordon RE, O'Callaghan M. Monitoring the 3-year efficacy of enzyme replacement therapy in fabry disease by repeated skin biopsies. Journal of Investigative Dermatology 2004;122:900-8

10.  Moore DF, Altarescu G, Herscovitch P, Schiffmann R. Enzyme replacement reverses abnormal cerebrovascular responses in Fabry disease. BMC Neurology 2002;2:4.

 

Reply

 

Response 1

The practice of evidence-based medicine should be a systematic process, which includes: the formulation of a relevant clinical question based on the patient’s clinical status; literature search(es) for relevant clinical articles; critical analysis of evidence regarding their validity and applicability; and, lastly, transfer of the important findings to clinical practice1. When researching information on interventions or prevention, we seek studies that best fit this mould, which means that the systematic reviews offer level 1 evidence responses for health-care decision making1. The systematic reviews include primary studies (clinical trials) which are methodologically appropriate and stringent, and are potentially bias-free. Therefore, our Cochrane review aimed to evaluate the effectiveness and safety of enzyme replacement therapy compared to other interventions, placebo or no interventions, for treating Anderson-Fabry disease through a systematic review of randomized controlled trials.

Systematic reviews, however, are criticized for frequently offering inconsistent evidence and an absence of straightforward recommendations2. Their value seems to be depreciated when the conclusions are uncertain or based on less than the highest grading of evidence3. A study has found that the majority of Cochrane reviews highlight the poor evidence, or absence of evidence, for the healthcare questions covered4.  The study found that Cochrane systematic reviews were about evenly split between those in which the authors concluded that the intervention was beneficial and those in which the evidence neither supported nor refuted the intervention tested4. Around half of the reviews analysed in this study (47.83%) did not offer enough evidence for clinical practice, and the authors asked for further research4. In only 0.98% of the 1016 reviews did the authors not consider it necessary to undertake further investigation, despite not finding sufficient evidence to support or refute the intervention4. Even when the reviews found evidence to support the intervention for use in clinical practice, a large percentage of authors considered this evidence was limited, and suggested that further research would be worthwhile (43.01%)4. Although systematic reviews are regarded as level 1 evidence for decision-making with regard to healthcare therapies, it was observed that most systematic review authors concluded that there was insufficient evidence to answer the questions around therapeutic strategies for treatment and prevention of diseases4.

In very rare, chronic, progressive diseases the same should apply. In other words, if the purpose is to assess effectiveness and safety of an intervention on rare disease we should map the knowledge through a systematic review of randomized controlled trials. The limitation here would not be the design of the study, but it would be the sample size evaluated by the included studies. Therefore, a systematic review could bring together the small clinical trials and when appropriate plot their results into a meta-analysis. One of the aims of a meta-analysis is to more powerfully estimate the true "effect size" as opposed to a smaller "effect size" derived in a single study under a given single set of assumptions and conditions.

In addition, the use of placebo is fully justified as to its non-malfeasance or methodology requirement: “The benefits, risks, burdens and effectiveness of a new method should be tested against those of the best current prophylactic, diagnostic, and therapeutic methods. This does not exclude the use of placebo, or no treatment, in studies where no proven prophylactic, diagnostic or therapeutic method exists”5 and “However, a placebo-controlled trial may be ethically acceptable, even if proven therapy is available, under the following circumstances:

  • where for compelling and scientifically sound methodological reasons its use is necessary to determine the efficacy or safety of a prophylactic, diagnostic or therapeutic method; or
  • where a prophylactic, diagnostic or therapeutic method is being investigated for a minor condition and the patients who receive placebo will not be subject to any additional risk of serious or irreversible harm.” 5

The systematic review cited above (Schaefer RM et al 2009), examined a total of 9 RCTs and 23 open-label studies, noting that in the majority endpoints represented subclinical parameters rather than clinical outcomes. As acknowledged by the authors, writing and editorial support in preparation of the article was received from Genzyme Europe BV and Hester van Lier of Excerpta Medica.

 

Response 2

Regarding the Phase 3 studies by Thurberg et al and Moore et al. These are sub-studies specifically investigating histology and regional cerebral blood flow, respectively, in the Phase 3 agalsidase beta and alfa study cohorts. We have therefore amended the study IDs in the review and the main reference for the previously listed Thurberg 2004 study will now be Eng 2001, and for Moore 2002 this will be Schiffmann 2001 as suggested.

 

Response 3

When we performed the systematic review we also aimed to map the outcomes that the primary studies evaluated. Therefore, we decided to cite all the outcomes reported within primary studies, even those not listed as outcomes of interest within our review. Besides all other inclusion criteria, we required that there had to be at least one of our pre-defined outcomes reported within a study in order for it to be eligible for inclusion. With regards to auditory loss in the table for Hughes 2008 (Characteristics of included studies), this was not a primary outcome. We note, however, that not all outcomes were fully listed within the ‘Characteristics of included studies’ table for the Hughes 2008 study and we have amended this within the review. The relevant section within the table now lists all reported outcomes and is as follows: 

The primary efficacy endpoint was myocardial Gb3 content; the secondary efficacy endpoint was reduction of the left ventricular mass by MRI assessment. In addition, QRS duration and levels of Gb3 in cardiac tissue, urine sediment and plasma, echocardiography, electrocardiography, pure-tone audiometry, impedance audiometry and otoacoustic emission testing were also performed. Adverse events were computed.

When we state positive effect on, among others, renal function and cardiac morphology, we believe our interpretation of the data suggested treatment appears to modify disease course, with outcome influenced by disease stage, and perhaps better in those who initiated treatment at an earlier disease stage. But the responses reported are often focused on single organ/system function, and the extent to which treatment impacts survival and quality of life approximating normal or that of the general population remains to be demonstrated.

 

Response 4

This has been updated to correctly reflect the authors’ conflicts of interest. Thank you for highlighting this omission. The text inserted is as follows:

El Dib R has no conflict of interest to declare. Pastores GM  is the recipient of research grants from Actelion, Amicus, Biomarin, Genzyme, Protalix and Shire HGT (pharmaceutical and biotechnology companies engaged in drug development programs for lysosomal storage disorders).

 

References

  1. Mulrow CD, Cook DJ, Davidoff F. Systematic Reviews: critical links in the great chain of evidence. Annals of Internal Medicine. 1997; 126: 389-391.
  2. Browman GP. Essence of evidence-based medicine: a case report. Journal of Clinical Oncology. 1999(7); 17:1969.
  3. Egger M, Smith GD, Phillips NA. Meta-analysis: principles and procedures. BMJ. 1997; 315.
  4. El Dib RP, Atallah NA, Andriolo RB. Mapping the Cochrane evidence for decision-making in health care. Journal of Evaluation in Clinical Practice 2007; 13(4):689-92.
  5. WMA Declaration of Helsinki - Ethical Principles for Medical Research Involving Human Subjects 2000.

 

Contributors

All comments made by: Vinciane Pirard, MD, Genzyme, The Netherlands.

Response from review authors: Regina P El Dib and Gregory M Pastores.

Feedback Editor: John Walter.

Managing Editor: Tracey Remmington.

Co-ordinating Editor: Alan Smyth

 

What's new

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Feedback
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Notes
  19. Index terms

Last assessed as up-to-date: 12 December 2012.


DateEventDescription

12 December 2012New citation required but conclusions have not changedDespite the addition of one new included trial, the conclusions remain the same as those in the original review (El Dib 2010).

12 December 2012New search has been performedOne new trial has been included in the review (Vedder 2007). Two trials have been added to the excluded studies (Fernhoff 2011; West 2011).

Data and information have been included for a 'Agalsidase alfa versus agalsidase beta' comparison group (Vedder 2007).



 

History

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Feedback
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Notes
  19. Index terms

Protocol first published: Issue 3, 2007
Review first published: Issue 5, 2010


DateEventDescription

15 February 2012AmendedContact details updated.

15 February 2011Feedback has been incorporatedFeedback, along with a response has been added to this review.

In the Included studies section, the study IDs previously listed as Thurberg 2004 and Moore 2002 have been changed to Eng 2001 and Schiffmann 2001, to more accurately reflect the primary study reports. Furthermore, all outcomes reported by Hughes are now listed in full in the tables (Characteristics of included studies) (Hughes 2008).

The Declarations of interest section has been updated.

20 September 2008New citation required and conclusions have changedSubstantive amendment



 

Contributions of authors

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Feedback
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Notes
  19. Index terms

Regina P El Dib (RED) was responsible for the conception of this review and also for the design and overall co-ordination of the protocol. RED is the guarantor of the review.

RED was responsible for developing the search strategy, undertaking searches, screening search results, organising retrieval of papers. Both RED and Gregory M Pastores (GMP) were responsible for screening retrieved papers against the inclusion criteria, appraising quality of papers and extracting data. RED wrote to authors of papers for additional information and located potentially relevant unpublished or ongoing trials. RED provided additional data about papers and obtained and screened data on unpublished trials. RED was responsible for data management for the review and entering data into RevMan. RED and GMP analysed and interpreted the data and wrote up the results. RED provided a methodological perspective; and GMP provided a clinical perspective.

 

Declarations of interest

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Feedback
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Notes
  19. Index terms

R El Dib and P Nascimento have no conflict of interest to declare. GM Pastores is the recipient of research grants and support from Actelion, Amicus, Biomarin, Genzyme/Sanofi, Protalix/Pfizer, and Shire HGT; pharmaceutical and biotechnology companies engaged in drug development programs for lysosomal storage disorders.

 

Sources of support

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Feedback
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Notes
  19. Index terms
 

Internal sources

  • No sources of support supplied

 

External sources

  • Provided by CAPES, Brazil.

 

Differences between protocol and review

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Feedback
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Notes
  19. Index terms

The Assessment of risk of bias in included studies section was updated from the protocol given the new guidelines published in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).

We decided for our secondary outcome 'Pain' we would also consider other validated pain questionnaires as well as the previously stated McGill Pain Questionnaire.

While analysing available data we agreed to also considered other time-points as well as those originally stated where multiple data sets from an individual trial were available for a single a priori planned time-point.

 

Notes

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Feedback
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Notes
  19. Index terms

Post hoc change: we will also consider other validated pain questionnaires.

* Indicates the major publication for the study

References

References to studies included in this review

  1. Top of page
  2. AbstractRésumé
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Feedback
  13. What's new
  14. History
  15. Contributions of authors
  16. Declarations of interest
  17. Sources of support
  18. Differences between protocol and review
  19. Notes
  20. Characteristics of studies
  21. References to studies included in this review
  22. References to studies excluded from this review
  23. Additional references
  24. References to other published versions of this review
Banikazemi 2007 {published data only}
  • Banikazemi M, Bultas J, Waldek S, Wilcox WR, Whitley CB, McDonald M, et al. Agalsidase-beta therapy for advanced Fabry disease: a randomized trial. Annals of Internal Medicine 2007;146(2):77-86.
Bierer 2006 {published data only}
  • Bierer G, Balfe D, Wilcox WR, Mosenifar Z. Improvement in serial cardiopulmonary exercise testing following enzyme replacement therapy in Fabry disease. Journal of Inherited Metabolic Disease 2006;29(4):572-9.
  • Bierer G, Wilcox WR, Balfe D, Mosenifar Z. Improvement in cardiopulmonary exercise testing during enzyme replacement therapy in fabry disease [Abstract]. American Thoracic Society International Conference; 2005. 2005:[B65] [Poster: A45].
Eng 2001 {published data only}
  • Desnick RJ. International Fabry Disease Study Group. Enzyme therapy for Fabry disease [abstract]. Journal of Inherited Metabolic Disease 2001;24:774.
  • Desnick RJ, International Fabry Study Group. Fabry disease enzyme therapy: phase 3 and extension results [abstract]. Journal of Inherited Metabolic Disease 2001;24(Suppl 1):98.
  • Eng CM, Guffon N, Wilcox WR, Germain DP, Lee P, Waldek S, International Collaborative Fabry Disease Study Group, et al. Safety and efficacy of recombinant human alpha-galactosidase A - replacement therapy in Fabry's disease. New England Journal of Medicine 2001;345(1):9-16.
  • Lee P, Banikazemi M, Guffon N, Wilcox WR, Waldek S, Germain DP, et al. Severe glomerulosclerosis and proteinuria may influence response to therapy in fabry disease [abstract]. Journal of Inherited Metabolic Disease 2003;26 Suppl 2:158.
  • Linthorst GE, Aerts JMFG, Bosman DK, Heymans HSA, Hollack CEM. Aenzyme-supplementation therapy for Fabry disease: first possible treatment [abstract]. The Netherlands Journal of Medicine 2001;58:A22.
  • Thurberg BL, Byers RH, Granter SR, Phelps RG, Gordon RE, O'Callaghan M. Monitoring the 3-year efficacy of enzyme replacement therapy in fabry disease by repeated skin biopsies. Journal of Investigative Dermatology 2004;122(4):900-8.
  • Thurberg BL, Phelps R, Granter S, Byers R, Gordon RE, O'Callaghan M. Fabrazyme clears globotriaosylceramide from the skin of fabry patients [abstract]. Journal of Inherited Metabolic Disease 2003;26 Suppl 2:174.
  • Thurberg BL, Rennke H, Colvin RB, Dikman S, Gordon RE, Collins AB, et al. Globotriaosylceramide accumulation in the Fabry kidney is cleared from multiple cell types after enzyme replacement therapy. Kidney International 2002;62(6):1933-46.
  • Waldek S, Germain D P, Banikazemi M, Guffon N, Lee P, Linthorst G, et al. Stabilization of renal function after enzyme replacement therapy in Fabry Disease [abstract]. Nephrology Dialysis Transplantation 2003;18 Suppl 4:630.
  • Wilcox WR, Banikazemi M, Guffon N, Waldek S, Lee P, Linthorst GE, et al. Long-term safety and efficacy of enzyme replacement therapy for Fabry disease. American Journal of Human Genetics 2004;75(1):65-74.
Hughes 2008 {published data only}
  • Hajioff D, Enever Y, Quiney R, Zuckerman J, Mackermot K, Mehta A. Hearing loss in Fabry disease: the effect of agalsidase alfa replacement therapy. Journal of Inherited Metabolic Disease 2003;26(8):787-94.
  • Hajioff D, Goodwin S, Quiney R, Zuckerman J, MacDermot KD, Mehta A. Hearing improvement in patients with Fabry disease treated with agalsidase alfa. Acta Paediatrica 2003;92(443):28-30.
  • Hajioff D, Quiney RE, Zuckerman J, McDermott K Mehta A. Hearing loss in Fabry's disease: the effect of alpha-galactosidase A replacement therapy [abstract]. Annals of Neurology 2003;54 Suppl 7:S26.
  • Hughes DA, Elliott PM, Shah J, Zuckerman J, Coghlan G, Brookes 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(2):153-8.
Schiffmann 2001 {published data only}
  • Moore DF, Altarescu G, Herscovitch P, Schiffmann R. Enzyme replacement reverses abnormal cerebrovascular responses in Fabry disease. BMC Neurology 2002;2:4.
  • Moore DF, Altarescu G, Ling GS, Jeffries N, Frei KP, Weibel T, et al. Elevated cerebral blood flow velocities in Fabry disease with reversal after enzyme replacement. Stroke 2002;33(2):525-31.
  • Moore DF, Scott LTC, Gladwin MT, Altarescu G, Kaneski C, Suzuki K, et al. Regional cerebral hyperperfusion and nitric oxide pathway dysregulation in Fabry disease: reversal by enzyme replacement therapy. Circulation 2001;104(13):1506-12.
  • Schiffmann R, Hauer P, Freeman B, Ries M, Scott LJ, Polydefkis M, et al. Enzyme replacement therapy and intraepidermal innervation density in Fabry disease. Muscle Nerve 2006;34(1):53-6.
  • Schiffmann R, Kopp JB, Austin HA, Sabnis S, Moore DF, Weibel T, et al. Clinical effect of enzyme replacement in Fabry disease [abstract]. Journal of Inherited Metabolic Disease 2001;24(7):775.
  • Schiffmann R, Kopp JB, Austin HA, Sabnis S, Moore DF, Weibel T, et al. Enzyme replacement therapy in Fabry disease: a randomized controlled trial. JAMA 2001;285(21):2743-9.
Vedder 2007 {published data only}
  • Vedder AC, Linthorst GE, Houge G, Groener JE, Ormel EE, Bouma BJ, et al. Online CONSORT checklist S1 to 'Treatment of Fabry disease: outcome of a comparative trial with agalsidase alfa or beta at a dose of 0.2 mg/kg' [online]. PLoS One 2007; Vol. 2, issue 7:e598.
  • Vedder AC, Linthorst GE, Houge G, Groener JE, Ormel EE, Bouma BJ, et al. Online supporting information to 'Treatment of Fabry disease: outcome of a comparative trial with agalsidase alfa or beta at a dose of 0.2 mg/kg' [online]. PLoS One 2007; Vol. 2, issue 7:e598.
  • Vedder AC, Linthorst GE, Houge G, Groener JE, Ormel EE, Bouma BJ, et al. Online trial treatment protocol S1 to 'Treatment of Fabry disease: outcome of a comparative trial with agalsidase alfa or beta at a dose of 0.2 mg/kg' [online]. PLoS One 2007; Vol. 2, issue 7:e598.
  • Vedder AC, Linthorst GE, Houge G, Groener JE, Ormel EE, Bouma BJ, et al. Online trial treatment protocol S2 to 'Treatment of Fabry disease: outcome of a comparative trial with agalsidase alfa or beta at a dose of 0.2 mg/kg' [online]. PLoS One 2007; Vol. 2, issue 7:e598.
  • Vedder AC, Linthorst GE, Houge G, Groener JE, Ormel EE, Bouma BJ, et al. Treatment of Fabry disease: outcome of a comparative trial with agalsidase alfa or beta at a dose of 0.2 mg/kg. PLoS One 2007;2(7):e598.

References to studies excluded from this review

  1. Top of page
  2. AbstractRésumé
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Feedback
  13. What's new
  14. History
  15. Contributions of authors
  16. Declarations of interest
  17. Sources of support
  18. Differences between protocol and review
  19. Notes
  20. Characteristics of studies
  21. References to studies included in this review
  22. References to studies excluded from this review
  23. Additional references
  24. References to other published versions of this review
Alamartine 2005 {published data only}
Banikasemi 2005 {published data only}
Beck 2004 {published data only}
Beer 2006 {published data only}
  • Beer M, Weidemann F, Breunig F, Knoll A, Koeppe S, Machann W, et al. Impact of enzyme replacement therapy on cardiac morphology and function and late enhancement in Fabry's cardiomyopathy. American Journal of Cardiology 2006;97(10):1515-8.
Breunig 2006 {published data only}
Cartwright 2004 {published data only}
Elliott 2006 {published data only}
  • Elliott PM, Kindler H, Shah JS, Sachdev B, Rimoldi OE, Thaman R, et al. Coronary microvascular dysfunction in male patients with Anderson-Fabry disease and the effect of treatment with alpha galactosidase A. Heart 2006;92(3):357-60.
Eto 2005 {published data only}
  • Eto Y, Ohashi T, Utsunomiya Y, Fujiwara M, Mizuno A, Inui K, et al. Enzyme replacement therapy in Japanese Fabry disease patients: the results of a phase 2 bridging study. Journal of Inherited Metabolic Disease 2005;28(4):575-83.
Fernhoff 2011 {published data only}
  • Fernhoff P, Goker-Alpan O, Holida M, Nedd K, Barshop BA, Mardach R, et al. Safety and tolerability of agalsidase alfa in patients with Fabry disease formerly treated with agalsidase beta. Journal of Inherited Metabolic Disease 2011;34(Suppl 3):S227.
Germain 2007 {published data only}
  • Germain DP, Waldek S, Banikazemi M, Bushinsky DA, Charrow J, Desnick RJ, et al. Sustained, long-term renal stabilization after 54 months of agalsidase beta therapy in patients with Fabry disease. Journal of the American Society of Nephrology 2007;18(5):1547-57.
Guffon 2002 {published data only}
  • Guffon N. The clinical benefit of Fabrazyme treatment [abstract]. Journal of Inherited Metabolic Disease 2002;25 Suppl 1:116.
Guffon 2004 {published data only}
Hajioff 2006 {published data only}
Hilz 2004 {published data only}
  • Hilz MJ, Brys M, Marthol H, Stemper B, Dütsch M. Enzyme replacement therapy improves function of C-, Adelta-, and Abeta-nerve fibers in Fabry neuropathy. Neurology 2004;62(7):1066-72.
Jardim 2006 {published data only}
  • Jardim LB, Gomes I, Netto CB, Nora DB, Matte US, Pereira F, et al. Improvement of sympathetic skin responses under enzyme replacement therapy in Fabry disease. Journal of Inherited Metabolic Disease 2006;29(5):653-9.
Jardim 2006b {published data only}
  • Jardim LB, Aesse F, Vedolin LM, Pitta-Pinheiro C, Marconato J, Burin MG, et al. White matter lesions in Fabry disease before and after enzyme replacement therapy: a 2-year follow-up. Arquivos de Neuro-Psiquiatria 2006;64(3B):711-7.
Kalliokoshi 2006 {published data only}
  • Kalliokoshi RJ, Kantola I, Kalliokoshi KK, Engblom E, Sundell J, Hannujainen JC, et al. The effect os 12-month enzyme replacement therapy on myocardial perfusion in patients with Fabry disease. Journal of Inherited Metabolic Disease 2006;29:112-8.
Kampmann 2002 {published data only}
  • Kampmann C, Ries M, Bahner F, Kim KS, Bajbouj M, Beck M. Influence of enzyme replacement therapy (ERT) on Anderson Fabry disease associated hypertrophic infiltrative cardiomyopathy (HIC). European Journal of Pediatrics 2002;161(2):R5.
Kobayashi 2005 {published data only}
  • Kobayashi M, Ida H, Ohashi T, Eto Y. Safety of enzyme replacement therapy among 20 Japanese patients with classical type of Fabry disease [abstract]. Journal of Inherited Metabolic Disease 2005;28 Suppl 1:166.
Kosch 2004 {published data only}
  • Kosch M, Koch H-G, Oliveira JP, Soares C, Bianco F, Breuning F, et al. Enzyme replacement therapy administered during hemodialysis in patients with Fabry disease. Kidney International 2004;66(3):1279-82.
Linthorst 2004 {published data only}
  • Linthorst GE, Hollak CE, Donker-Koopman WE, Strijland A, Aerts JM. Enzyme therapy for Fabry disease: neutralizing antibodies toward agalsidase alpha and beta. Kidney International 2004;66(4):1589-95.
Linthorst 2006 {published data only}
  • Linthorst Ge, Vedder AC, Ormel EE, Johannes AMFG, Hollak CEM. Home treatment for Fabry disease: practice guidelines based on 3 years experience in The Netherlands. Nephrology, Dialysis, Transplantation 2006;21:355-360.
Mignani 2004 {published data only}
  • Mignani R, Panichi V, Giudicissi A, Taccola D, Boscaro F, Feletti C, et al. Enzyme replacement therapy with agalsidase beta in kidney transplant patients with Fabry disease: a pilot study. Kidney International 2004;65(4):1381-85.
Mills 2004 {published data only}
  • Mills K, Vellodi A, Morris P, Cooper D, Morris M, Young E, et al. Monitoring the clinical and biochemical response to enzyme replacement therapy in three children with Fabry disease. European Journal of Pediatrics 2004;163:163.
Pisani 2005 {published data only}
  • Pisani A, Spinelli L, Sabbatini M, Andreucci MV, Procaccini D, Abbaterusso C, et al. Enzyme replacement therapy in Fabry disease patients undergoing dialysis: effects on quality of life and organ involvement. American Journal of Kidney Diseases 2005;46(1):120-7.
Ramaswami 2007 {published data only}
Ries 2006 {published data only}
  • Ries M, Clarke JT, Whybra C, Timmons M, Robinson C, Schlaggar BL, et al. Enzyme-replacement therapy with agalsidase alfa in children with Fabry disease. Pediatrics 2006;118(3):924-32.
Schiffmann 2003 {published data only}
Schiffmann 2006 {published data only}
  • Schiffmann R, Ries M, Timmons M, Flaherty JT, Brady RO. Long-term therapy with agalsidase alfa for Fabry disease: safety and effects on renal function in a home infusion setting. Nephrology, Dialysis, Transplantation 2006;21(2):345-54.
Spinelli 2004 {published data only}
Utsumi 2005 {published data only}
  • Utsumi K, Mitsuhashi F, Asahi K, Sakurazawa M, Arii K, Komaba Y, et al. Enzyme replacement therapy for Fabry disease: morphologic and histochemical changes in the urinary sediments. Clinica Chimica Acta 2005;360(1-2):103-7.
Weidemann 2003 {published data only}
  • Weidemann F, Breunig F, Beer M, Sandstede J, Turschner O, Voelker W, et al. Improvement of cardiac function during enzyme replacement therapy in patients with Fabry disease: a prospective strain rate imaging study. Circulation 2003;108(11):1299-301.
West 2011 {published data only}
  • West M, Bichet D, Casey R, Clarked J, Sirrs S, LeMoine K, et al. Agalsidase alfa and agalsidase beta have similar effects on outcomes in Fabry disease – results from the Canadian Fabry disease initiative. Molecular Genetics and Metabolism 2011;102:S3–S47.

Additional references

  1. Top of page
  2. AbstractRésumé
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Feedback
  13. What's new
  14. History
  15. Contributions of authors
  16. Declarations of interest
  17. Sources of support
  18. Differences between protocol and review
  19. Notes
  20. Characteristics of studies
  21. References to studies included in this review
  22. References to studies excluded from this review
  23. Additional references
  24. References to other published versions of this review
Aerts 2008
  • Aerts JM, Groener JE, Kuiper S, Donker-Koopman WE, Strijland A, Ottenhoff R, et al. Elevated globotriaosylsphingosine is a hallmark of Fabry disease. Proceedings of the National Academy of Sciences of the United States of America 2008;105(8):2812-7.
Elbourne 2002
  • Elbourne DR, Altman DG, Higgins JPT, Curtin F, Worthington HV, Vail A. Meta-analyses involving cross-over trials: methodological issues. International Journal of Epidemiology 2002;31(1):140-9.
Higgins 2003
Higgins 2011
  • Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.0.1 (updated March 2011). The Cochrane Collaboration, 2011. Available from www.cochrane-handbook.org 20011.
Hollack 2009
Jones 2009
Meikle 1999
Ries 2007
Smith 2000
Spada 2006
  • Spada M, Pagliardini S, Yasuda M, Tukel T, Thiagarajan G, Sakuraba H, et al. High incidence of later-onset Fabry disease revealed by newborn screening. American Journal of Human Genetics 2006;79(1):31-40.
Sterne 2001
  • Sterne JAC, Egger M, Davey Smith G. Investigating and dealing with publication and other biases. In: Egger M, Davey Smith G, Altman DG editor(s). Systematic Reviews in Health Care. London: BMJ Publishing Group, 2001:189-208.
Tang 2000
Thornton 2000
Wang 2007
  • Wang RY, Lelis A, Mirocha J, Wilcox WR. Heterozygous Fabry women are not just carriers, but have a significant burden of disease and impaired quality of life. Genetics in Medicine 2007;9(1):34-45.
Wilcox 2008
  • Wilcox WR, Oliveira JP, Hopkin RJ, Ortiz A, Banikazemi M, Feldt-Rasmussen U, et al. Females with Fabry disease frequently have major organ involvement: lessons from the Fabry Registry. Molecular Genetics and Metabolism 2008;93(2):112-28.
Wraith 2008
  • Wraith JE, Tylki-Szymanska A, Guffon N, Lien YH, Tsimaratos M, Vellodi A, et al. Safety and efficacy of enzyme replacement therapy with agalsidase beta: an international, open-label study in pediatric patients with Fabry disease. Journal of Pediatrics 2008;152(4):563-70.