Desferrioxamine mesylate for managing transfusional iron overload in people with thalassaemia
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
The aim of this systematic review is to determine the effectiveness in terms of dose and method of administration of the iron chelating agent DFO in people with transfusion dependent thalassaemia.
Background
Thalassaemia is the most prevalent disease caused by an abnormality in a single gene (monogenic) in the world (WHO) (Chernoff 1959) and is becoming a more significant public health problem as the demographic has reduced childhood mortality from infectious diseases and malnutrition. At present it is estimated that there are over 2,000,000 transfusion‐dependant people with thalassaemia throughout the world, with the majority of cases in South‐East Asia (Weatherall 2002).
The common underlying pathology of the thalassaemias is an imbalance in the rate of synthesis of the alpha and beta globin chains of haemoglobin in red blood cells. The clinical spectrum of thalassaemia ranges from death in utero, through severe transfusion dependent anaemia to asymptomatic anaemia (Weatherall 2001; Weatherall 2002). Anaemia is a reduction in the quantity of the oxygen carrying component (haemoglobin) of the blood. The thalassaemias are diagnosed by their clinical manifestations, by morphological changes in red blood cells, by characterising haemoglobin alpha and beta chains using electrophoresis or chromatography and by molecular detection of specific genetic mutations. Children with thalassaemia major or thalassaemia intermedia usually become symptomatic between six and twelve months of age with symptoms of anaemia and enlargement of the liver and spleen due to extramedullary hematopoiesis (Olivieri 1999).
The mainstay of management of affected children with severe thalassaemia major is blood transfusion to achieve a haemoglobin concentration high enough to suppress red cell production. Without blood transfusion, people with thalassaemia may develop massive bone marrow and/ or extra‐medullary hematopoiesis resulting in severe pathology including deformities of the facial bones, spinal cord compression and pathological fractures (Olivieri 1999; Weatherall 2002).
The second major component of management is iron chelation therapy. Increased iron absorption from dietary iron in the gut in untransfused people with thalassaemia increases total body iron by between 2 and 5 grams per year (Pippard 1979; Pootrakul 1988). Regular transfusions may increase this iron load by up to 10 grams per year. Without iron chelation, iron‐mediated free radical damage may cause liver fibrosis, myocardial damage, skin pigmentation and endocrine failure including diabetes mellitus, growth failure and delayed onset of puberty (Olivieri 1999; Kushner 2001).
Iron overload may be prevented or treated with a chelating agent that complexes iron which allows excretion of chelator‐iron complexes from the body. The most widely used chelating agent is desferrioxamine mesylate (DFO) administered subcutaneously or intra‐venously (Olivieri 1997b). Oral iron chelation agents are being developed of which deferiprone (L1), is licensed in the UK, Europe and India (Olivieri 1990; Olivieri 1992; Olivieri 1995; Olivieri 1997a; Hershko 1998; Hoffbrand 1998; Mazza 1998; Olivieri 1998; Tondury 1998; Wonke 1998; Aydinok 1999; Berdoukas 2000; Cohen 2000; Del Vecchio 2000; Pippard 2000; Kushner 2001; Wanless 2002). The role of deferiprone in the management of people with iron overload remains to be established, and a separate Cochrane review is being undertaken to specifically address the use of this agent in thalassaemia.
The widespread clinical use of DFO is based on a series of well‐documented comparative studies of morbidity and survival of children with thalassaemia major born before the introduction of DFO (Barry 1974; Propper 1976; Propper 1977; Pippard 1978; Wolfe 1985; Brittenham 1988; Zurlo 1989; Aldouri 1990; Olivieri 1990; Ehlers 1991; Richardson 1993; Olivieri 1994; Gabutti 1996; BorgnaPignatti 1998a; Modell 2000). Maintaining hepatic iron stores less than 15 mg/g dry weight has been associated with reduced mortality from cardiac disease in thalassaemia (Brittenham 1994). Other studies have shown that regular chelation therapy is associated with a reduction in hepatic fibrosis, reduced prevalence of endocrine problems and a decreased risk of cardiac disease (Barry 1974; Brittenham 1994; Olivieri 1994, Gabutti 1996, Olivieri 1999).
One problem of DFO is maintaining compliance of people with thalassaemia with the injections and the demanding schedule of overnight subcutaneous or intravenous infusions (Olivieri 1997b; Weatherall 2002). Other regimens including continuous intravenous DFO in severely iron overloaded thalasseamics and intermittent subcutaneous DFO have been successful (BorgnaPignatti 1998b; Davis 2000; Franchini 2000). It has also been suggested that regimens combining DFO and vitamin C are more effective than DFO alone (Wapnick 1969; O'Brien 1974; Nienhuis 1976; Propper 1977).
A second problem concerns the toxicity of DFO, particularly at doses of greater than 40 mg/kg/day (Robins‐Browne 1985; Kushner 2001). DFO may cause retinal toxicity (optic neuropathy and retinal pigmentation and dysfunction) (Bacon 1983; Richardson 1993; De Sanctis 1996), local skin reactions (Kushner 2001) and high frequency sensorineural hearing loss (Robins‐Browne 1985; De Sanctis 1996). Other systemic side effects of DFO include growth retardation (Bousquet 1983; Koren 1989; Koren 1991; De Sanctis 1996), increased susceptibility to Yersinia infection and, less frequently renal impairment, pulmonary fibrosis and anaphylaxis (Miller 1981; Bousquet 1983; Robins‐Browne 1985; Freedman 1990; Koren 1989; Koren 1991; Tenenbein 1992).
The final problem is the cost and availability of DFO. The cost of a year's course of DFO with consumables for standard therapy is £5000 to £10,000 (BNF [45] 2003) and so the availability of this treatment is limited by cost in many countries where the disease is prevalent. There is, therefore, a pressing need to establish the most efficacious and cost effective regimens for iron chelation, although a formal health economic analysis of iron chelation is beyond the scope of this review. In spite of the importance associated with DFO, the optimal use of DFO in transfusion dependent people with thalassaemia has not been systematically reviewed.
Objectives
The aim of this systematic review is to determine the effectiveness in terms of dose and method of administration of the iron chelating agent DFO in people with transfusion dependent thalassaemia.
Methods
Criteria for considering studies for this review
Types of studies
Randomised controlled trials and quasi‐randomised controlled trials.
Types of participants
People of any age with transfusion dependent thalassaemia, from any setting worldwide.
Types of interventions
For DFO (all doses and methods of administration), the following comparisons will be considered:
(1) DFO compared with placebo;
(2) DFO compared with another iron chelating treatment schedule;
(3) DFO schedule A (either subcutaneous method of administration or dose A) compared with DFO schedule B (either intravenous method of administration or dose B).
These groups constitute three separate groups and will be analysed separately.
In a number of trials participants may have also been given Vitamin C in combination with DFO, if so a subgroup analysis will be done on these studies.
Types of outcome measures
Primary outcome
(1) Mortality
Secondary outcomes
(1) Evidence of reduced end‐organ damage
(a) cardiac failure
(b) endocrine disease
(c) surrogate markers of end‐organ damage
(d) histological evidence of hepatic fibrosis
(2) Measures of iron overload (hepatic or non‐invasive) ‐ including serum ferritin, assessment of liver and other tissue iron levels by biopsy with biochemical measurement by SQUID (superconducting quantum interference device) or by MRI (magnetic resonance imaging).
(3) Adverse events of, or toxicity due to treatment with DFO, including ocular damage, oto‐toxicity and non‐endocrine growth failure which is felt to be due to direct toxicity of DFO on vertebral height growth.
(4) Participant compliance with DFO treatment
(5) Cost of DFO
Where possible, outcome data will be grouped into those measured at six monthly intervals (i.e. six months, one year, eighteen months and so on). If outcome data are recorded at other time periods then consideration will be given to examining these as well. It is not anticipated that there will be any additional outcome measures, however data from outcomes not defined a priori but which have arisen from the review will be collected post hoc if the outcome is considered to be of relevance to the review.
Search methods for identification of studies
Relevant studies will be identified from the Group's haemoglobinopathies trials register.
The haemoglobinopathies register is compiled from electronic searches of the Cochrane Central Register of Controlled Trials (updated each new issue) and quarterly searches of MEDLINE. Unpublished work is identified by searching the abstract books of four major conferences: the European Haematology Association conference; the American Society of Hematology conference; the Caribbean Health Research Council Meetings; and the National Sickle Cell Disease Program Annual Meeting. For full details of all searching activities for the register, please see the relevant section of the Cystic Fibrosis and Genetic Disorders Group Module.
In addition to the above noted, EMBASE (1980 to 2003) will be searched to identify any other relevant studies.
Reference lists of all identified papers will additionally be screened and contact will be made with the manufacturer of desferrioxamine B (Novartis) and other iron chelators (Biomedical Frontiers, CIPLA, Lipomed, Apotex) requesting details of unpublished studies that involve desferrioxamine.
Data collection and analysis
Selection for inclusion
One reviewer (DR) will screen all titles and abstracts of papers, identified by the review search strategy, for relevancy. Only studies clearly irrelevant will be excluded at this stage. All other studies will be assessed on the basis of their full text for inclusion/exclusion using the criteria indicated above. At this stage, two reviewers (DR, SJB) will independently assess eligibility and the repeatability of decisions will be tested. If inter‐rater agreement is poor (kappa value less than or equal to 0.75), the clarity of the inclusion and exclusion criteria will be examined and improved until a better level of inter‐rater agreement is achieved (kappa value greater than 0.75) (Abramson 2001). All eligibility criteria failed by excluded studies assessed in duplicate will be recorded. Studies where important information is lacking (including foreign language studies, where a translation is awaited) will be clearly categorised and reported as studies pending an inclusion/exclusion decision.
Evaluation of methodological quality of included studies
The following criteria listed below will form the main evaluation of methodological quality (adapted from Schulz 1995).
(1) Generation of random sequence
(2) Concealment of treatment allocation schedule
(3) Blinding of clinician (person delivering treatment) to treatment allocation
(4) Blinding of patient to treatment allocation
(5) Blinding of outcome assessor to treatment allocation
(6) A minimum proportion of randomised patients included in the main analysis
(7) Equal use of co‐interventions in each study arm
Problems in respect of these issues will be recorded in full. Particular account will be taken of loss to follow‐up affecting the validity of the results for different outcomes to different degrees.
In addition methodological quality will be rated according to criteria identified in the Cochrane Handbook (Clarke 2003). This assigns ratings of A (adequate), B (unclear) or C (clearly inadequate) to each specified methodological criteria. Where information is unclear or missing, clarification will be sought from the author of the primary study. Two reviewers will undertake the evaluation of methodological quality independently (JH, DR). Methodological quality ratings, and details as to why these ratings were assigned for each criterion will be presented by individual study in tabular form in the results section of the review.
Evaluation of the methodological quality of each included study will be used in the following ways within the review:
(1) as a possible explanation for differences in results between studies;
(2) in sensitivity analyses, examining the effect on overall estimates of not considering studies of poor methodological quality.
No study will automatically be excluded from the review as a result of a rating of 'unclear' (B) or 'clearly inadequate' (C)
Data extraction
Aside from details relating to the quality of the included studies, the following two groups of data will be extracted:
(1) Study characteristics ‐ place of publication, date of publication, population characteristics, setting, detailed nature of intervention, detailed nature of comparator, detailed nature of outcomes. A key purpose of this data will be to define unexpected clinical heterogeneity in included studies independently from analysis of results.
(2) Results of included studies in respect of each of the main outcomes indicated in the review question. Reasons why an included study does not contribute data on a particular outcome will be carefully recorded and the possibility of selective reporting of results on particular outcomes considered. For dichotomous outcomes the numbers of outcomes in treatment and control groups will be recorded. For continuous outcomes, mean and standard deviation will be recorded. In both cases the "denominator" will be the numbers randomly allocated to treatment and control groups. Assumptions that the assignment of a denominator introduces with reference to missing data will be considered and discussed in full within the review. Statistical advice will be sought where included studies present results which depart from these two scenarios, especially survival analyses and randomised cross‐over studies.
The two reviewers undertaking the evaluation of the methodological quality of the included studies will do data extraction independently (JH, DR). Data will be extracted onto study specific data extraction forms that will be created, piloted and repeatability assessed. If repeatability assessment is found to be poor (kappa value less than or equal to 0.75), the forms will be re‐designed until good levels of repeatability are achieved (kappa values greater than 0.75) (Abramson 2001). Missing data will be requested from the original investigators. Disagreements will be resolved by consensus between the reviewers. Once disagreements have been resolved, the consensus data extracted will be recorded onto a third data extraction form. One reviewer (SJB) will transcribe this into the systematic review computer software RevMan 4.2 (Review Manager 2003). Another reviewer (SS) will verify all data entry for discrepancies.
Analysis of data
If the relevant data are available we will analyse the outcome of trials by genotype namely homozygous beta‐thalassaemia and HbE/beta‐thalassaemia.
Extracted data will be analysed using the most up‐to‐date version of RevMan/MetaView available at the time of analysis (Review Manager 2003).
The main method of analysis will be quantitative, but the overall interpretation will be made from a balanced assessment of the patterns of results identified across the included studies. Meta‐analysis will also be employed, but care will be taken in automatic acceptance of summary measures generated. Unexpected clinical heterogeneity will be one ground for caution. Clinical heterogeneity will be assessed by examining differences due to age of participant and age at commencement of the intervention, study quality and geographical setting of the study. Statistical heterogeneity will be the other and tested using the chi squared test and visual inspection of graphs. A significance level of less than 0.10 will be interpreted as evidence of heterogeneity. This will be discussed in the result section of the review. Even in the absence of statistical heterogeneity, the robustness of any summary measures will be explored particularly with respect to study quality. Generally the preferred form of summary result will be a summary relative risk ratio and weighted mean difference, both using a fixed effects model. The results from random effects models will also be examined, marked differences in summary measures generated being grounds for caution.
Although it is believed that every effort will have been made to identify unpublished studies, publication bias will be assessed, using funnel plots. It is acknowledged that asymmetry, of which publication bias is one cause, is difficult to detect with small numbers of studies (i.e. less than 10) often encountered in systematic reviews.
Care will be taken in translating the results of the included studies into recommendations for action. We plan to involve all reviewers in drawing conclusions and making specific recommendations for future research.
