Deferasirox for managing transfusional iron overload in people with sickle cell disease
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To evaluate the effectiveness and safety of oral deferasirox for management of transfusional iron overload in people with SCD.
Background
Description of the condition
Sickle cell disease (SCD) is an autosomal recessive genetic disorder caused by a single nucleotide mutation of the haemoglobin ß‐chain. The worldwide birth rate of people who are homozygous or compound heterozygous for symptomatic SCD is about 2.2 per 1000 births (Angastiniotis 1998; Modell 2008). However, the incidence of this disease varies widely according to ethnic group (Modell 2008). Populations originating from sub‐Saharan Africa, the Middle East and parts of the Mediterranean are predominantly affected, but population movement has made SCD a worldwide problem.
The inheritance of one mutated gene (substitution of valine for glutamic acid in the sixth position of the beta chain of the haemoglobin molecule) together with the normal gene for adult haemoglobin (HbA) results in a mutant protein giving rise to a defective variant of haemoglobin. People with the heterozygous state (HbAS or sickle cell trait) are called sickle cell carriers. They are asymptomatic and need neither treatment nor occupational restrictions. The heterozygous state gives some advantage to carriers against malaria infection and has therefore persisted (Weatherall 1998; Richer 2005).
The homozygous state (HbSS) results from inheriting the mutation from both parents. SCD can also occur when people are compound heterozygous by inheriting the sickle cell gene from one parent and another variant haemoglobin gene, such as haemoglobin C, D, OArab or E, or a β‐thalassaemia gene from the second parent. This gives rise to HbSC, HbSD, HbSOArab, HbSE or HbSβ+ or HbSβ0. All of these genotypes cause clinically significant SCD with chronic haemolytic anaemia and a predisposition to blockage of small blood vessels resulting in painful crises, acute chest syndrome, cerebral infarction and other complications due to the sickling of the red blood cells. However, the overall severity and patterns of organ damage vary widely depending upon genotype (Platt 1991; Miller 2000; Powars 2005).
Unlike people with β‐thalassaemia major, who require regular blood transfusions throughout life from soon after birth, the majority of people with SCD require red cell transfusions only occasionally and intermittently. These are required for indications such as the management of acute severe anaemia in children e.g. due to splenic sequestration or transient Parvovirus B19 induced aplastic crisis, acute chest syndrome, acute stroke or as a prophylactic measure before operations. Red cell transfusions are not usually required for the management of the chronic anemia, or acute painful episodes (Josephson 2007). At adulthood the majority of people with SCD have received several red blood cell transfusions for various reasons.
A small but increasing number of people with SCD are on long‐term transfusions, most commonly for secondary stroke prevention, but also for primary stroke prevention, or for recurrent pulmonary complications in people who have not responded to hydroxycarbamide. Over the last decade trials have evaluated the effect of regular prophylactic transfusions for the primary prevention of stroke in children with SCD (Adams 1998; Adams 2005). Trans‐cranial doppler (TCD) screening is now recommended as routine care. High‐risk children are identified by high‐flow velocities on TCDs and should be offered long‐term transfusion therapy.
Since the body has no physiological mechanism to actively excrete excess iron, repeated blood transfusions lead to an increased body iron burden including iron deposition into the liver, heart, pancreas and other endocrine organs. This mechanism is well known for people with thalassaemia on regular transfusion programs. As studies have shown, people with SCD with repeated blood transfusions can be affected by the same long‐term problems due to iron overload (Vichinsky 2005). Even if there is no solid evidence showing that iron chelation improves clinical outcome in SCD, iron chelation therapy is generally offered to iron‐overloaded people with SCD.
Description of the intervention
Deferoxamine (DFO, Desferal®), reviewed in detail in a Cochrane Review (Roberts 2005), has been the treatment of choice for iron overload for the last 40 years. As it has been available for a long time it is the only chelating agent for which profound effect on the long‐term survival of a large cohort of patients with thalassaemia has been shown (Borgna‐Pignatti 2004; Brittenham 1994; Gabutti 1996; Zurlo 1989). To be clinically effective DFO has to be administered as a subcutaneous infusion over 8 to 12 hours, five to seven days per week. This regimen has been demonstrated to reduce the body iron load, prevent the onset of iron‐induced complications and even reverse some of the organ‐damage due to iron (Olivieri 1994). But the arduous schedule of overnight subcutaneous infusions often leads to reduced compliance (Olivieri 1997; Modell 2000; Cappellini 2005). Another problem concerns the toxicity of DFO, particularly at higher doses. Toxicities beside local skin reactions also include ophthalmologic (optic neuropathy, retinal pigmentation) and hearing problems (high frequency sensorineural hearing loss). Rare adverse effects like growth retardation, renal impairment (Koren 1991), anaphylactic reactions and pulmonary fibrosis (Freedman 1990) have been reported. The high cost (about $US 10,000 a year) of DFO (Delea 2008) and the consumables required as well as its complicated mode of administration limit its use in developing countries.
Oral preparations have been highly sought after for many years. In 1987 two studies showed that the orally active iron chelator deferiprone (1,2 dimethyl‐3‐hydroxypyrid‐4‐1, also known as L1, CP20, Ferriprox® or Kelfer) could achieve effective short‐term iron chelation (Kontoghiorghes 1987a; Kontoghiorghes 1987b). Doubts on the efficacy to reduce liver iron and prevent liver damage arose due to individuals with progression to overt liver fibrosis (Olivieri 1998). The hypothesis of direct liver toxicity of deferiprone could not been confirmed though (Wanless 2002; Wu 2006). Several studies have shown in the meantime the efficacy of deferiprone for iron chelation (Ceci 2002; Maggio 2002) and in particular its benefit on cardiac iron and cardiac morbidity (Peng 2008). However, it's use has been quite limited, mainly as second‐line therapy, due to its range of adverse effects (Hoffbrand 2003). These include gastrointestinal disturbances, arthropathy, neutropenia and agranulocytosis (Hoffbrand 1989). Recently studies on combination therapy with synergistic effects of DFO and deferiprone have been performed (Kattamis 2003; Origa 2005; Farmaki 2006; Galanello 2006; Tanner 2007; Kolnagou 2008). An excellent Cochrane Review on the effectiveness of deferiprone in people with thalassemia has recently been published (Roberts 2007).
How the intervention might work
Deferasirox (4‐[3,5‐bis(2‐hydroxyphenyl)‐1H‐1,2,4‐triazol‐1‐yl]‐benzoic acid) also known as CGP 72670, ICL670 or Exjade® is a new oral chelator available for routine use. It is approved for the treatment of secondary iron overload by the US Food and Drug Administration (FDA) (FDA 2005) and the European Medicines Agency (EMEA) (EMEA 2007). It is rapidly absorbed after administration and has a bioavailability of about 70%. Safety and tolerability was shown in a randomised dose escalation trial in people with β‐thalassaemia in 2003 (Nisbet‐Brown 2003). The elimination half‐life of 8 to 16 hours allows a once‐daily administration after the tablets have been added to water or juice. Being a tridentate chelator two molecules of deferasirox are needed to bind one molecule of iron. The excretion of the bound iron is mainly via faeces.
Adverse effects known from experiences in people with thalassaemia include gastrointestinal disturbances (nausea, stomach pain or diarrhoea) that are generally mild and a diffuse rash being more common at higher doses (Cappellini 2006). More rarely, fever, headache and cough are encountered. The main adverse effect with the use of deferasirox seems to be a mild to moderate elevation of the creatinine level in about a third of patients. Elevations of liver enzyme levels have also been described with a lower incidence (5.6%) (Cappellini 2006). As with standard therapy (DFO), hearing loss and ocular disturbances including cataracts and retinal disorders have been reported with a very low incidence (< 1%).
Why it is important to do this review
Deferoxamine necessitates a serious commitment from the user and due to its adverse effects, deferiprone is only approved as second line therapy in some countries. Thus, much hope is being placed in the new oral chelator deferasirox which apparently offers a promising line of treatment due to its iron chelation properties and safety and tolerability profile (Cappellini 2007). To adequately manage the increasing number of people with SCD being regularly transfused due to TCD screening results, a systematic review of the effectiveness and safety of deferasirox looking at people with SCD according to Cochrane standards is urgently needed.
Objectives
To evaluate the effectiveness and safety of oral deferasirox for management of transfusional iron overload in people with SCD.
Methods
Criteria for considering studies for this review
Types of studies
Randomised controlled trials (RCTs), published and unpublished, will be considered for this review.
Types of participants
People with SCD (irrespective of genotype, age and from any setting worldwide), who have received repeated red blood cell transfusions in the past or who are receiving regular red blood cell transfusions currently which have resulted in iron overload (defined as ferritin levels of over 1000 ng/ml on at least two occasions).
Types of interventions
For oral deferasirox (all schedules and doses), the following comparisons will be considered:
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deferasirox compared with no therapy or placebo;
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deferasirox compared with another iron chelating treatment schedule (i.e. deferoxamine or deferiprone or any combination thereof).
These comparisons constitute two separate groups and will be analysed separately.
Types of outcome measures
Primary outcomes
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Overall mortality measured at any point in time
Secondary outcomes
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Reduced end‐organ damage due to iron deposition
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cardiac failure (necessitating medical treatment)
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endocrine disease (necessitating substitution hormone therapy or treatment of diabetes)
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histological evidence of hepatic fibrosis
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pathological surrogate markers of end‐organ damage (i.e. elevated liver enzymes, elevated fasting glucose or pathological oral glucose tolerance test (OGTT), pathological measures (e.g. ejection fraction) in echocardiography)
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Measures of iron overload
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serum ferritin (ng/ml)
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iron levels in biopsies of liver and other tissue (mg/g liver dry weight)
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tissue iron assessment by SQUID (superconducting quantum interference device) (mg/g liver wet weight)
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tissue iron assessment by MRI (magnetic resonance imaging) (ms)
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Measures of iron excretion (urine and faeces) over 24 hours (mg/kg/d)
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Any adverse events
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raised levels of creatinine or kidney failure (above upper normal limit or rise of more than 20% above baseline level)
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skin rash
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gastrointestinal disturbances
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neutropenia or agranulocytosis (absolute neutrophil count (ANC) less than 1000/µl or less than 500/µl)
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raised levels of liver enzymes (above upper normal limit or raise of more than 20% above baseline level) or progression to liver fibrosis
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hearing loss
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eye problems (e.g. retinal toxicity)
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unanticipated adverse events as reported in the primary studies
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Participant satisfaction (measured e.g. by questionnaire) and compliance with chelation treatment (measured by the number of people in each arm that show adequate level of adherence to treatment (intake or application of iron chelator on five or more days per week)).
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Cost of intervention per year.
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, if the outcome is considered to be of clinical relevance.
Search methods for identification of studies
No language restriction will be applied.
Electronic searches
We will identify relevant studies from the Cystic Fibrosis and Genetic Disorders Group's Haemoglobinopathies Trials Register using the term ICL670.
The Haemoglobinopathies Trials Register is compiled from electronic searches of the Cochrane Central Register of Controlled Trials (Clinical Trials) (updated each new issue of The Cochrane Library) and quarterly searches of MEDLINE. Unpublished work is identified by searching the abstract books of five major conferences: the European Haematology Association conference; the American Society of Haematology conference; the British Society for Haematology Annual Scientific Meeting; 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 Cochrane Cystic Fibrosis and Genetic Disorders Group Module.
In addition Medline (1950 to 07/2008), EMBASE (1980 to 07/2008), EBMR Evidence Based Medicine Reviews (1991 to 07/2008), Biosis Previews (1969 to 07/2008), ISI Web of Science (1945 to 07/2008), Derwent Drug File (1983 to 07/2008) and XTOXLINE (1965 to 07/2008) will be searched to identify any other relevant studies. The search strategy will include the following keyword terms (for details see Appendix 1; Appendix 2; Appendix 3; Appendix 4; Appendix 5):
deferasirox*
ICL670*
ICL 670*
CGP72670*
CGP 72670*
Exjade*
The chemical substance name "4‐(3,5‐bis(2‐hydroxyphenyl)‐(1,2,4)‐triazol‐1‐yl) benzoic acid" will be searched by splitting it up in searchable terms (2‐hydroxyphenyl, triazol‐1‐yl, benzoic acid) and combining those by AND.
Since deferasirox treatment is an intervention where there is a lot of current research going on, the following three trial registries will be searched in all possible fields using keyword terms as previously described.
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Current Controlled Trials Register: www.controlled‐trials.com
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ClinicalTrials.gov: www.clincialtrials.gov
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ICTRP: www.who.int./ictrp/en/
Current studies will be listed and trigger the next update of this review if completed.
Searching other resources
Reference lists of all identified papers will be screened additionally to identify other potentially relevant citations.
Contact will be made with the manufacturer of deferasirox (Novartis) as well as with selected experts in the field to request information on unpublished studies that involved deferasirox.
Data collection and analysis
Selection of studies
One author (JM) will screen all titles and abstracts of papers identified by the search strategies for relevance. We will only exclude citations which are clearly irrelevant at this stage. We will obtain full copies of all potentially relevant papers. At this stage two review authors (JM and DB) will independently screen the full papers, identify relevant studies and assess eligibility of studies for inclusion. We will resolve any disagreement on the eligibility of studies through discussion and consensus, or if necessary through a third party (GA). We will excluded all irrelevant records and record details of the studies and the reasons for their exclusion. We will clearly categorise studies where important information is lacking (including foreign language studies awaiting translation) and report these as studies pending inclusion or exclusion.
Data extraction and management
Aside from details relating to the quality of the included studies, we will extract two groups of data.
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Study characteristics: place of publication; date of publication; population characteristics; setting; detailed nature of intervention; detailed nature of comparator; and detailed nature of outcomes. A key purpose of this data will be to define unexpected clinical heterogeneity in included studies independently from the analysis of the results.
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Results of included studies with respect to each of the main outcomes indicated in the review question. We will carefully record reasons why an included study does not contribute data on a particular outcome and consider the possibility of selective reporting of results on particular outcomes.
Two review authors (JM, DB) will independently undertake data extraction using a data extraction form developed by the authors. The review authors will resolve any disagreements by consensus or through discussion with a third author (GA). Once disagreements have been resolved, we will record the extracted data extracted on the final data extraction form. One review author (JM) will transcribe these into RevMan 5.0 (Review Manager 2008). Another review author (DB) will verify all data entry for discrepancies.
Assessment of risk of bias in included studies
Two review authors (JM, DB) will assess every study using a simple form and will follow the domain‐based evaluation as described in the Cochrane Handbook for Systematic Reviews of Interventions 5.0.0 (Higgins 2008).
We will assess the following domains as 'Yes' (i.e. low risk of bias), 'Unclear' (uncertain risk of bias) or 'No' (i.e. high risk of bias):
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Randomisation
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Concealment of allocation
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Blinding (of participants, personnel and outcome assessors)
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Incomplete outcome data
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Selective outcome reporting
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Other sources of bias
We will compare the assessments and discuss any inconsistencies between the review authors in the interpretation of inclusion criteria and their significance to the selected studies. We will resolve any disagreements through discussion with a third author (GA). We will not automatically exclude any study as a result of a rating of 'Unclear' or 'No'. We will present the evaluation of the risk of bias in included studies in tabular form in the 'Results' section of the review.
Measures of treatment effect
We will analyse extracted data using the most up‐to‐date version of RevMan available at the time of analysis (Review Manager 2008).
Ideally, we plan to extract hazard ratios with their 95% confidence intervals for the time‐to‐event outcomes mortality and end‐organ damage. If hazard ratios are not given, we will use indirect estimation methods described by Parmar (Parmar 1998) and Williamson (Williamson 2002) to calculate them.
If we are unable to either extract these data from the study reports or receive the necessary information from the primary investigators, we will, as an alternative, use the proportions of participants with the respective outcomes measured at three months, six months, then six‐monthly intervals (i.e. twelve months, eighteen months, etc.) to be able to calculate risk ratios (RR). If outcome data are recorded at other time periods, then we will give consideration to examining these as well.
We will express any results for binary outcomes as RR with 95% confidence intervals as measures of uncertainty. We will express continuous outcomes will be expressed as mean differences (MD) with 95% confidence intervals as measures of uncertainty.
Unit of analysis issues
When conducting a meta‐analysis combining results from cross‐over studies, we plan to use the methods recommended by Elbourne (Elbourne 2002). For combining parallel and cross‐over studies, we will use the methods described by Curtin (Curtin 2002a; Curtin 2002b; Curtin 2002c).
For some outcomes, a possible perception of the comparison might be whether deferasirox is not inferior to standard treatment with deferoxamine. Therefore, a per‐protocol analysis is of interest, as is often used for non‐inferiority studies, for our primary outcome as well as for the groups one to five of our secondary outcomes.
Studies included in the review may report information concerning the intention‐to‐treat (ITT) or per protocol (PP) population or both. Witte lists several proposals for analysing these, depending on the data available (Witte 2004).
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If all studies report only an ITT analysis (or all studies report only a PP analysis), we will perform a non‐inferiority meta‐analysis based on Witte's `perfect case' proposal.
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If some studies report only an ITT analysis and others only a PP analysis (exclusively), we will perform meta‐regression with analysis type as a covariate.
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If some studies report only an ITT analysis and others only a PP analysis, whilst others report both, we will undertake a sensitivity analysis.
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If all studies give enough information to do both analyses, we will analyse a bivariate model.
For time‐to‐event data, we will state non‐inferiority if the relative difference in hazard ratios is less than 10%. For RRs, we will define non‐inferiority as a RR difference of less than 10% in treatment failures compared to standard therapy. For the continuous outcomes of "measures of iron overload and iron excretion" as well as "costs" we will also consider a relative difference of 10% as equivalent.
Dealing with missing data
We will request any missing data from the original investigators.
Assessment of heterogeneity
We will assess clinical heterogeneity by examining differences between groups as detailed below. We will assess statistical heterogeneity in the results of studies using the I2 statistic (Higgins 2002; Higgins 2003).
Assessment of reporting biases
We make a great effort to minimise the likelihood of publication bias by the use of a comprehensive search strategy and contacting the manufacturer of deferasirox. We do not plan to use funnel plots to assess publication bias, since asymmetry is difficult to detect with a small number of studies (i.e. less than 10) and we do not expect this many studies to be included in the initial version of this review. If in future we include more than 10 studies in the review, we will use funnel plots to graphically assess the likelihood of publication bias. We will take care in translating the results of the included studies into recommendations for action by involving all review authors in drawing conclusions.
Data synthesis
If appropriate, we will conduct meta‐analyses of pooled data from all contributing studies using a fixed‐effect model as primary analysis. However, if we find marked clinical or statistical heterogeneity (I2 more than 50%) we will also use a random‐effects model. We will report results from both models.
Subgroup analysis and investigation of heterogeneity
We will assess clinical heterogeneity by examining differences due to
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age of participants
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age at commencement of the intervention
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baseline measures of iron overload
We plan subgroup analyses for different
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doses of intervention (≤ 10mg/kg; > 10 to ≤ 20mg/kg; > 20 to ≤ 30mg/kg; > 30mg/kg)
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genotypes of SCD (e.g. HbSS, HbS/β‐Thal or HbSC)
Sensitivity analysis
We will perform sensitivity analyses based on assessment of risk of bias and publication status (unpublished and published studies).
