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The Cochrane Database of Systematic... Feb 2012Thalassemia is a hereditary anaemia due to ineffective erythropoiesis. In particular, people with thalassaemia major develop secondary iron overload resulting from... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Thalassemia is a hereditary anaemia due to ineffective erythropoiesis. In particular, people with thalassaemia major develop secondary iron overload resulting from regular red blood cell transfusion. Iron chelation therapy is needed to prevent long-term complications.Both deferoxamine and deferiprone have been found to be efficacious. However, a systematic review of the effectiveness and safety of the new oral chelator deferasirox in people with thalassaemia is needed.
OBJECTIVES
To assess the effectiveness and safety of oral deferasirox in people with thalassaemia and secondary iron overload.
SEARCH METHODS
We searched the Cystic Fibrosis and Genetic Disorders Group's Haemoglobinopathies Trials Register. We also searched MEDLINE, EMBASE, EBMR, Biosis Previews, Web of Science, Derwent Drug File, XTOXLINE and three trial registries: www.controlled-trials.com; www.clinicaltrials.gov; www.who.int./ictrp/en/. Date of the most recent searches of these databases: 24 June 2010.Date of the most recent search of the Group's Haemoglobinopathies Trials Register: 03 November 2011.
SELECTION CRITERIA
Randomised controlled trials comparing deferasirox with no therapy or placebo or with another iron chelating treatment.
DATA COLLECTION AND ANALYSIS
Two authors independently assessed risk of bias and extracted data. We contacted study authors for additional information.
MAIN RESULTS
Four studies met the inclusion criteria.Two studies compared deferasirox to placebo or standard therapy of deferoxamine (n = 47). The placebo-controlled studies, a pharmacokinetic and a dose escalation study, showed that deferasirox leads to net iron excretion in transfusion-dependent thalassaemia patients. In these studies, safety was acceptable and further investigation in phase II and phase III trials was warranted.Two studies, one phase II study (n = 71) and one phase III study (n = 586) compared deferasirox to standard treatment with deferoxamine. Data suggest that a similar efficacy can be achieved depending on the ratio of doses of deferoxamine and deferasirox being compared; in the phase III trial, similar or superior efficacy for surrogate parameters of ferritin and liver iron concentration could only be achieved in the highly iron-overloaded subgroup at a mean ratio of 1 mg of deferasirox to 1.8 mg of deferoxamine corresponding to a mean dose of 28.2 mg/d and 51.6 mg/d respectively. Data on safety at the presumably required doses for effective chelation therapy are limited. Patient satisfaction was significantly better with deferasirox, while rate of discontinuations was similar for both drugs.
AUTHORS' CONCLUSIONS
Deferasirox offers an important alternative line of treatment for people with thalassaemia and secondary iron overload. Based on the available data, deferasirox does not seem to be superior to deferoxamine at the usually recommended ratio of 1 mg of deferasirox to 2 mg of deferoxamine. However, similar efficacy seems to be achievable depending on the dose and ratio of deferasirox compared to deferoxamine. Whether this will result in similar efficacy in the long run and will translate to similar benefits as has been shown for deferoxamine, needs to be confirmed. Data on safety, particularly on rare toxicities and long-term safety, are still limited.Therefore, we think that deferasirox should be offered as an alternative to all patients with thalassaemia who either show intolerance to deferoxamine or poor compliance with deferoxamine. In our opinion, data are still too limited to support the general recommendation of deferasirox as first-line treatment instead of deferoxamine. If a strong preference for deferasirox is expressed, it could be offered as first-line option to individual patients after a detailed discussion of the potential benefits and risks.
Topics: Benzoates; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Deferasirox; Deferoxamine; Erythrocyte Transfusion; Humans; Iron Chelating Agents; Iron Overload; Randomized Controlled Trials as Topic; Thalassemia; Triazoles
PubMed: 22336831
DOI: 10.1002/14651858.CD007476.pub2 -
The Cochrane Database of Systematic... Aug 2017Thalassaemia is a hereditary anaemia due to ineffective erythropoiesis. In particular, people with thalassaemia major develop secondary iron overload resulting from... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Thalassaemia is a hereditary anaemia due to ineffective erythropoiesis. In particular, people with thalassaemia major develop secondary iron overload resulting from regular red blood cell transfusions. Iron chelation therapy is needed to prevent long-term complications.Both deferoxamine and deferiprone are effective; however, a review of the effectiveness and safety of the newer oral chelator deferasirox in people with thalassaemia is needed.
OBJECTIVES
To assess the effectiveness and safety of oral deferasirox in people with thalassaemia and iron overload.
SEARCH METHODS
We searched the Cystic Fibrosis and Genetic Disorders Group's Haemoglobinopathies Trials Register: 12 August 2016.We also searched MEDLINE, Embase, the Cochrane Library, Biosis Previews, Web of Science Core Collection and three trial registries: ClinicalTrials.gov; the WHO International Clinical Trials Registry Platform; and the Internet Portal of the German Clinical Trials Register: 06 and 07 August 2015.
SELECTION CRITERIA
Randomised controlled studies comparing deferasirox with no therapy or placebo or with another iron-chelating treatment.
DATA COLLECTION AND ANALYSIS
Two authors independently assessed risk of bias and extracted data. We contacted study authors for additional information.
MAIN RESULTS
Sixteen studies involving 1807 randomised participants (range 23 to 586 participants) were included. Twelve two-arm studies compared deferasirox to placebo (two studies) or deferoxamine (seven studies) or deferiprone (one study) or the combination of deferasirox and deferoxamine to deferoxamine alone (one study). One study compared the combination of deferasirox and deferiprone to deferiprone in combination with deferoxamine. Three three-arm studies compared deferasirox to deferoxamine and deferiprone (two studies) or the combination of deferasirox and deferiprone to deferiprone and deferasirox monotherapy respectively (one study). One four-arm study compared two different doses of deferasirox to matching placebo groups.The two studies (a pharmacokinetic and a dose-escalation study) comparing deferasirox to placebo (n = 47) in people with transfusion-dependent thalassaemia showed that deferasirox leads to net iron excretion. In these studies, safety was acceptable and further investigation in phase II and phase III studies was warranted.Nine studies (1251 participants) provided data for deferasirox versus standard treatment with deferoxamine. Data suggest that a similar efficacy can be achieved depending on the ratio of doses of deferoxamine and deferasirox being compared. In the phase III study, similar or superior efficacy for the intermediate markers ferritin and liver iron concentration (LIC) could only be achieved in the highly iron-overloaded subgroup at a mean ratio of 1 mg of deferasirox to 1.8 mg of deferoxamine corresponding to a mean dose of 28.2 mg per day and 51.6 mg per day respectively. The pooled effects across the different dosing ratios are: serum ferritin, mean difference (MD) 454.42 ng/mL (95% confidence interval (CI) 337.13 to 571.71) (moderate quality evidence); LIC evaluated by biopsy or SQUID, MD 2.37 mg Fe/g dry weight (95% CI 1.68 to 3.07) (moderate quality evidence) and responder analysis, LIC 1 to < 7 mg Fe/g dry weight, risk ratio (RR) 0.80 (95% CI 0.69 to 0.92) (moderate quality evidence). The substantial heterogeneity observed could be explained by the different dosing ratios. Data on mortality (low quality evidence) and on safety at the presumably required doses for effective chelation therapy are limited. Patient satisfaction was better with deferasirox among those who had previously received deferoxamine treatment, RR 2.20 (95% CI 1.89 to 2.57) (moderate quality evidence). The rate of discontinuations was similar for both drugs (low quality evidence).For the remaining comparisons in people with transfusion-dependent thalassaemia, the quality of the evidence for outcomes assessed was low to very low, mainly due to the very small number of participants included. Four studies (205 participants) compared deferasirox to deferiprone; one of which (41 participants) revealed a higher number of participants experiencing arthralgia in the deferiprone group, but due to the large number of different types of adverse events reported and compared this result is uncertain. One study (96 participants) compared deferasirox combined with deferiprone to deferiprone with deferoxamine. Participants treated with the combination of the oral iron chelators had a higher adherence compared to those treated with deferiprone and deferoxamine, but no participants discontinued the study. In the comparisons of deferasirox versus combined deferasirox and deferiprone and that of deferiprone versus combined deferasirox and deferiprone (one study, 40 participants), and deferasirox and deferoxamine versus deferoxamine alone (one study, 94 participants), only a few patient-relevant outcomes were reported and no significant differences were observed.One study (166 participants) included people with non-transfusion dependent thalassaemia and compared two different doses of deferasirox to placebo. Deferasirox treatment reduced serum ferritin, MD -306.74 ng/mL (95% CI -398.23 to -215.24) (moderate quality evidence) and LIC, MD -3.27 mg Fe/g dry weight (95% CI -4.44 to -2.09) (moderate quality evidence), while the number of participants experiencing adverse events and rate of discontinuations (low quality evidence) was similar in both groups. No participant died, but data on mortality were limited due to a follow-up period of only one year (moderate quality evidence).
AUTHORS' CONCLUSIONS
Deferasirox offers an important treatment option for people with thalassaemia and secondary iron overload. Based on the available data, deferasirox does not seem to be superior to deferoxamine at the usually recommended ratio of 1 mg of deferasirox to 2 mg of deferoxamine. However, similar efficacy seems to be achievable depending on the dose and ratio of deferasirox compared to deferoxamine. Whether this will result in similar efficacy and will translate to similar benefits in the long term, as has been shown for deferoxamine, needs to be confirmed. Data from randomised controlled trials on rare toxicities and long-term safety are still limited. However, after a detailed discussion of the potential benefits and risks, deferasirox could be offered as the first-line option to individuals who show a strong preference for deferasirox, and may be a reasonable treatment option for people showing an intolerance or poor adherence to deferoxamine.
Topics: Administration, Oral; Benzoates; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Deferasirox; Deferiprone; Deferoxamine; Erythrocyte Transfusion; Ferritins; Humans; Iron Chelating Agents; Iron Overload; Patient Satisfaction; Pyridones; Randomized Controlled Trials as Topic; Thalassemia; Triazoles
PubMed: 28809446
DOI: 10.1002/14651858.CD007476.pub3 -
PharmacoEconomics - Open Mar 2024Hereditary hemochromatosis (HH) is an autosomal recessive disorder that leads to iron overload and multiorgan failure.
BACKGROUND
Hereditary hemochromatosis (HH) is an autosomal recessive disorder that leads to iron overload and multiorgan failure.
OBJECTIVES
The aim of this systematic review was to provide up-to-date evidence of all the current data on the costs and cost effectiveness of screening and treatment for HH.
METHODS
We searched PubMed, Cochrane Library, National Health Service Economic Evaluation Database (NHSEED), Cost-Effectiveness Analysis Registry (CEA Registry), Health Technology Assessment Database (HTAD), Centre for Reviews and Dissemination (CRD), and Econlit until April 2023 with no date restrictions. Articles that reported cost-utility, cost-description, cost-minimization, cost-effectiveness, or cost-benefit analyses for any kind of management (drugs, screening, etc.) were included in the study. Patients with HH, their siblings, or individuals suspected of having HH were included in the study. All screening and treatment strategies were included. Two authors assessed the quality of evidence related to screening (either phenotype or genotype screening) and treatment (phlebotomy and electrophoresis). Narrative synthesis was used to analyse the similarities and differences between the respective studies.
RESULTS
Thirty-nine papers were included in this study. The majority of the studies reported both the cost of phenotype screening, including transferrin saturation (TS), serum ferritin, and liver biopsy, and the cost of genotype screening (HFE screening, C282Y mutation). Few studies reported the cost for phlebotomy and erythrocytapheresis treatment. Data revealed that either phenotype or genotype screening were cost effective compared with no screening. Treatment studies concluded that erythrocytapheresis might be a cost-effective therapy compared with phlebotomy.
CONCLUSIONS
Economic studies on either the screening, or treatment strategy for HH patients should be performed in more countries. We suggest that cost-effectiveness studies on the role of deferasirox in HH should be carried out as an alternative therapy to phlebotomy.
PubMed: 38279979
DOI: 10.1007/s41669-023-00463-6 -
Health and Quality of Life Outcomes Feb 2024Understanding consequences of poor chelation compliance is crucial given the enormous burden of post-transfusional iron overload complications. We systematically... (Review)
Review
Understanding consequences of poor chelation compliance is crucial given the enormous burden of post-transfusional iron overload complications. We systematically reviewed iron-chelation therapy (ICT) compliance, and the relationship between compliance with health outcome and health-related quality of life (HRQoL) in thalassaemia patients. Several reviewers performed systematic search strategy of literature through PubMed, Scopus, and EBSCOhost. The preferred reporting items of systematic reviews and meta-analyses (PRISMA) guidelines were followed. Of 4917 studies, 20 publications were included. The ICT compliance rate ranges from 20.93 to 75.3%. It also varied per agent, ranging from 48.84 to 85.1% for desferioxamine, 87.2-92.2% for deferiprone and 90-100% for deferasirox. Majority of studies (N = 10/11, 90.91%) demonstrated significantly negative correlation between compliance and serum ferritin, while numerous studies revealed poor ICT compliance linked with increased risk of liver disease (N = 4/7, 57.14%) and cardiac disease (N = 6/8, 75%), endocrinologic morbidity (N = 4/5, 90%), and lower HRQoL (N = 4/6, 66.67%). Inadequate compliance to ICT therapy is common. Higher compliance is correlated with lower serum ferritin, lower risk of complications, and higher HRQoL. These findings should be interpreted with caution given the few numbers of evidence.
Topics: Humans; Iron Chelating Agents; Deferasirox; Deferiprone; Deferoxamine; Quality of Life; Pyridones; Benzoates; Triazoles; Thalassemia; Chelation Therapy; Ferritins; Outcome Assessment, Health Care
PubMed: 38302961
DOI: 10.1186/s12955-023-02221-y -
The Cochrane Database of Systematic... Mar 2023Regularly transfused people with sickle cell disease (SCD) and people with thalassaemia are at risk of iron overload. Iron overload can lead to iron toxicity in... (Review)
Review
BACKGROUND
Regularly transfused people with sickle cell disease (SCD) and people with thalassaemia are at risk of iron overload. Iron overload can lead to iron toxicity in vulnerable organs such as the heart, liver and endocrine glands, which can be prevented and treated with iron-chelating agents. The intensive demands and uncomfortable side effects of therapy can have a negative impact on daily activities and wellbeing, which may affect adherence.
OBJECTIVES
To identify and assess the effectiveness of different types of interventions (psychological and psychosocial, educational, medication interventions, or multi-component interventions) and interventions specific to different age groups, to improve adherence to iron chelation therapy compared to another listed intervention, or standard care in people with SCD or thalassaemia.
SEARCH METHODS
We searched CENTRAL (Cochrane Library), MEDLINE, PubMed, Embase, CINAHL, PsycINFO, ProQuest Dissertations & Global Theses, Web of Science & Social Sciences Conference Proceedings Indexes and ongoing trial databases (13 December 2021). We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Haemoglobinopathies Trials Register (1 August 2022).
SELECTION CRITERIA
For trials comparing medications or medication changes, only randomised controlled trials (RCTs) were eligible for inclusion. For studies including psychological and psychosocial interventions, educational interventions, or multi-component interventions, non-randomised studies of interventions (NRSIs), controlled before-after studies, and interrupted time series studies with adherence as a primary outcome were also eligible for inclusion.
DATA COLLECTION AND ANALYSIS
For this update, two authors independently assessed trial eligibility and risk of bias, and extracted data. We assessed the certainty of the evidence using GRADE.
MAIN RESULTS
We included 19 RCTs and one NRSI published between 1997 and 2021. One trial assessed medication management, one assessed an education intervention (NRSI) and 18 RCTs were of medication interventions. Medications assessed were subcutaneous deferoxamine, and two oral chelating agents, deferiprone and deferasirox. We rated the certainty of evidence as very low to low across all outcomes identified in this review. Four trials measured quality of life (QoL) with validated instruments, but provided no analysable data and reported no difference in QoL. We identified nine comparisons of interest. 1. Deferiprone versus deferoxamine We are uncertain whether or not deferiprone affects adherence to iron chelation therapy (four RCTs, unpooled, very low-certainty evidence), all-cause mortality (risk ratio (RR) 0.47, 95% confidence interval (CI) 0.18 to 1.21; 3 RCTs, 376 participants; very low-certainty evidence), or serious adverse events (SAEs) (RR 1.43, 95% CI 0.83 to 2.46; 1 RCT, 228 participants; very low-certainty evidence). Adherence was reported as "good", "high" or "excellent" by all seven trials, though the data could not be analysed formally: adherence ranged from 69% to 95% (deferiprone, mean 86.6%), and 71% to 93% (deferoxamine, mean 78.8%), based on five trials (474 participants) only. 2. Deferasirox versus deferoxamine We are uncertain whether or not deferasirox affects adherence to iron chelation therapy (three RCTs, unpooled, very low-certainty evidence), although medication adherence was high in all trials. We are uncertain whether or not there is any difference between the drug therapies in serious adverse events (SAEs) (SCD or thalassaemia) or all-cause mortality (thalassaemia). 3. Deferiprone versus deferasirox We are uncertain if there is a difference between oral deferiprone and deferasirox based on a single trial in children (average age 9 to 10 years) with any hereditary haemoglobinopathy in adherence, SAEs and all-cause mortality. 4. Deferasirox film-coated tablet (FCT) versus deferasirox dispersible tablet (DT) One RCT compared deferasirox in different tablet forms. There may be a preference for FCTs, shown through a trend for greater adherence (RR 1.10, 95% CI 0.99 to 1.22; 1 RCT, 88 participants), although medication adherence was high in both groups (FCT 92.9%; DT 85.3%). We are uncertain if there is a benefit in chelation-related AEs with FCTs. We are uncertain if there is a difference in the incidence of SAEs, all-cause mortality or sustained adherence. 5. Deferiprone and deferoxamine combined versus deferiprone alone We are uncertain if there is a difference in adherence, though reporting was usually narrative as triallists report it was "excellent" in both groups (three RCTs, unpooled). We are uncertain if there is a difference in the incidence of SAEs and all-cause mortality. 6. Deferiprone and deferoxamine combined versus deferoxamine alone We are uncertain if there is a difference in adherence (four RCTs), SAEs (none reported in the trial period) and all-cause mortality (no deaths reported in the trial period). There was high adherence in all trials. 7. Deferiprone and deferoxamine combined versus deferiprone and deferasirox combined There may be a difference in favour of deferiprone and deferasirox (combined) in rates of adherence (RR 0.84, 95% CI 0.72 to 0.99) (one RCT), although it was high (> 80%) in both groups. We are uncertain if there is a difference in SAEs, and no deaths were reported in the trial, so we cannot draw conclusions based on these data (one RCT). 8. Medication management versus standard care We are uncertain if there is a difference in QoL (one RCT), and we could not assess adherence due to a lack of reporting in the control group. 9. Education versus standard care One quasi-experimental (NRSI) study could not be analysed due to the severe baseline confounding.
AUTHORS' CONCLUSIONS
The medication comparisons included in this review had higher than average adherence rates not accounted for by differences in medication administration or side effects, though often follow-up was not good (high dropout over longer trials), with adherence based on a per protocol analysis. Participants may have been selected based on higher adherence to trial medications at baseline. Also, within the clinical trial context, there is increased attention and involvement of clinicians, thus high adherence rates may be an artefact of trial participation. Real-world, pragmatic trials in community and clinic settings are needed that examine both confirmed or unconfirmed adherence strategies that may increase adherence to iron chelation therapy. Due to lack of evidence this review cannot comment on intervention strategies for different age groups.
Topics: Child; Humans; Anemia, Sickle Cell; Chelating Agents; Chelation Therapy; Deferoxamine; Drug-Related Side Effects and Adverse Reactions; Iron; Thalassemia
PubMed: 36877640
DOI: 10.1002/14651858.CD012349.pub3 -
Mediterranean Journal of Hematology and... 2019Deferoxamine (DFO) or Deferiprone (DFP) or Deferasirox (DFX) monotherapy and DFO and DFP combination therapy (DFO+DFP) were four commonly implemented now chelation... (Review)
Review
BACKGROUND
Deferoxamine (DFO) or Deferiprone (DFP) or Deferasirox (DFX) monotherapy and DFO and DFP combination therapy (DFO+DFP) were four commonly implemented now chelation regimens for the iron overloaded of β-thalassemia major. This systematic review aims to determine the cost-effectiveness of four chelation regimens and provide evidence for the rational use of chelation regimens for β-thalassemia major therapy in the clinic.
METHODS
A systematic literature search in MEDLINE, EMBASE, the Cochrane Library, China Biology Medicine, China National Knowledge Infrastructure, VIP Data, and WanFang Data was conducted in April 2018. In addition, a manual search was performed. Two researchers, working independently, selected the papers, extracted the data, and assessed the methodological quality of the included documents. Each included paper was evaluated using a checklist developed by Drummond .
RESULTS
The number of records was initially 968, and eight papers met the final eligibility criteria. All the included eight papers were cost-utility analyses, and their methodological quality was fair. In these eight papers, nineteen studies were present. Nine studies of DFX versus DFO had contradictory results. Out of the nineteen studies, three studies of DFX versus DFP established that using DFP was cost-effective. Three studies of DFP versus DFO proved that using DFP was cost-effective. One survey of DFO+DFP versus DFO found that using DFO was cost-effective. One study of DFO+DFP versus DFP found that using DFP was cost-effective. Moreover, there were two studies of DFO+DFP versus DFX, but we cannot be sure which one of two chelation regimens was cost-effective.
CONCLUSION
In brief, DFP is cost-effective, followed by DFO or DFX, when an iron chelator is to be used alone for β-thalassemia iron overload treatment. All studies that compared DFO+DFP with DFO (or DFP) monotherapy established that the DFO+DFP was not cost-effective. Existing studies about DFO+DFP versus DFX could not prove which one of two chelation regimens was cost-effective. However, due to the low number of DFO+DFP versus DFO (or DFP or DFX) monotherapy studies, more extensive, high-quality research is required for further analysis and confirmation of our findings. Moreover, the cost-effectiveness is not an absolute issue when in different countries (regions) the results are opposite for other countries (regions). As a result, the local/national context had a substantial influence on the results of the pharmacoeconomic evaluation.
PubMed: 31308912
DOI: 10.4084/MJHID.2019.036 -
The Cochrane Database of Systematic... Aug 2013Thalassaemia major is a genetic disease characterised by a reduced ability to produce haemoglobin. Management of the resulting anaemia is through red blood cell... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Thalassaemia major is a genetic disease characterised by a reduced ability to produce haemoglobin. Management of the resulting anaemia is through red blood cell transfusions.Repeated transfusions result in an excessive accumulation of iron in the body (iron overload), removal of which is achieved through iron chelation therapy. Desferrioxamine mesylate (desferrioxamine) is one of the most widely used iron chelators. Substantial data have shown the beneficial effects of desferrioxamine, although adherence to desferrioxamine therapy is a challenge. Alternative oral iron chelators, deferiprone and deferasirox, are now commonly used. Important questions exist about whether desferrioxamine, as monotherapy or in combination with an oral iron chelator, is the best treatment for iron chelation therapy.
OBJECTIVES
To determine the effectiveness (dose and method of administration) of desferrioxamine in people with transfusion-dependent thalassaemia.To summarise data from trials on the clinical efficacy and safety of desferrioxamine for thalassaemia and to compare these with deferiprone and deferasirox.
SEARCH METHODS
We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Haemoglobinopathies Trials Register. We also searched MEDLINE, EMBASE, CENTRAL (The Cochrane Library), LILACS and other international medical databases, plus ongoing trials registers and the Transfusion Evidence Library (www.transfusionevidencelibrary.com). All searches were updated to 5 March 2013.
SELECTION CRITERIA
Randomised controlled trials comparing desferrioxamine with placebo, with another iron chelator, or comparing two schedules or doses of desferrioxamine, in people with transfusion-dependent thalassaemia.
DATA COLLECTION AND ANALYSIS
Six authors working independently were involved in trial quality assessment and data extraction. For one trial, investigators supplied additional data upon request.
MAIN RESULTS
A total of 22 trials involving 2187 participants (range 11 to 586 people) were included. These trials included eight comparisons between desferrioxamine alone and deferiprone alone; five comparisons between desferrioxamine combined with deferiprone and deferiprone alone; eight comparisons between desferrioxamine alone and desferrioxamine combined with deferiprone; two comparisons of desferrioxamine with deferasirox; and two comparisons of different routes of desferrioxamine administration (bolus versus continuous infusion). Overall, few trials measured the same or long-term outcomes. Seven trials reported cardiac function or liver fibrosis as measures of end organ damage; none of these included a comparison with deferasirox.Five trials reported a total of seven deaths; three in patients who received desferrioxamine alone, two in patients who received desferrioxamine and deferiprone. A further death occurred in a patient who received deferiprone in another who received deferasirox alone. One trial reported five further deaths in patients who withdrew from randomised treatment (deferiprone with or without desferrioxamine) and switched to desferrioxamine alone.One trial planned five years of follow up but was stopped early due to the beneficial effects of a reduction in serum ferritin levels in those receiving combined desferrioxamine and deferiprone treatment compared with deferiprone alone. The results of this and three other trials suggest an advantage of combined therapy with desferrioxamine and deferiprone over monotherapy to reduce iron stores as measured by serum ferritin. There is, however, no evidence for the improved efficacy of combined desferrioxamine and deferiprone therapy against monotherapy from direct or indirect measures of liver iron.Earlier trials measuring the cardiac iron load indirectly by measurement of the magnetic resonance imaging T2* signal had suggested deferiprone may reduce cardiac iron more quickly than desferrioxamine. However, meta-analysis of two trials showed a significantly lower left ventricular ejection fraction in patients who received desferrioxamine alone compared with those who received combination therapy using desferrioxamine with deferiprone.Adverse events were recorded by 18 trials. These occurred with all treatments, but were significantly less likely with desferrioxamine than deferiprone in one trial, relative risk 0.45 (95% confidence interval 0.24 to 0.84) and significantly less likely with desferrioxamine alone than desferrioxamine combined with deferiprone in two other trials, relative risk 0.33 (95% confidence interval 0.13 to 0.84). In particular, four studies reported permanent treatment withdrawal due to adverse events from deferiprone; only one of these reported permanent withdrawals associated with desferrioxamine. Adverse events also occurred at a higher frequency in patients who received deferasirox than desferrioxamine in one trial. Eight trials reported local adverse reactions at the site of desferrioxamine infusion including pain and swelling. Adverse events associated with deferiprone included joint pain, gastrointestinal disturbance, increases in liver enzymes and neutropenia; adverse events associated with deferasirox comprised increases in liver enzymes and renal impairment. Regular monitoring of white cell counts has been recommended for deferiprone and monitoring of liver and renal function for deferasirox.In summary, desferrioxamine and the oral iron chelators deferiprone and deferasirox produce significant reductions in iron stores in transfusion-dependent, iron-overloaded people. There is no evidence from randomised clinical trials to suggest that any one of these has a greater reduction of clinically significant end organ damage, although in two trials, combination therapy with desferrioxamine and deferiprone showed a greater improvement in left ventricular ejection fraction than desferrioxamine used alone.
AUTHORS' CONCLUSIONS
Desferrioxamine is the recommended first-line therapy for iron overload in people with thalassaemia major and deferiprone or deferasirox are indicated for treating iron overload when desferrioxamine is contraindicated or inadequate. Oral deferasirox has been licensed for use in children aged over six years who receive frequent blood transfusions and in children aged two to five years who receive infrequent blood transfusions. In the absence of randomised controlled trials with long-term follow up, there is no compelling evidence to change this conclusion.Worsening iron deposition in the myocardium in patients receiving desferrioxamine alone would suggest a change of therapy by intensification of desferrioxamine treatment or the use of desferrioxamine and deferiprone combination therapy.Adverse events are increased in patients treated with deferiprone compared with desferrioxamine and in patients treated with combined deferiprone and desferrioxamine compared with desferrioxamine alone. People treated with all chelators must be kept under close medical supervision and treatment with deferiprone or deferasirox requires regular monitoring of neutrophil counts or renal function respectively. There is an urgent need for adequately-powered, high-quality trials comparing the overall clinical efficacy and long-term outcomes of deferiprone, deferasirox and desferrioxamine.
Topics: Benzoates; Chelation Therapy; Deferasirox; Deferiprone; Deferoxamine; Humans; Iron Chelating Agents; Iron Overload; Pyridones; Randomized Controlled Trials as Topic; Siderophores; Thalassemia; Transfusion Reaction; Triazoles
PubMed: 23963793
DOI: 10.1002/14651858.CD004450.pub3 -
The Cochrane Database of Systematic... Nov 2010The myelodysplastic syndrome (MDS) comprises a diverse group of haematopoietic stem cell disorders. Due to symptomatic anaemia most patients require supportive therapy... (Review)
Review
BACKGROUND
The myelodysplastic syndrome (MDS) comprises a diverse group of haematopoietic stem cell disorders. Due to symptomatic anaemia most patients require supportive therapy including repeated red blood cell (RBC) transfusions. In combination with increased iron absorption, this contributes to the accumulation of iron resulting in secondary iron overload and the risk of organ dysfunction and reduced life expectancy. Since the human body has no natural means of getting rid of excess iron, iron chelation therapy is usually recommended. However, whether the new oral chelator deferasirox leads to relevant benefit is unclear.
OBJECTIVES
To assess the effectiveness and safety of oral deferasirox in people with myelodysplastic syndrome and iron overload.
SEARCH STRATEGY
We searched MEDLINE, EMBASE, The Cochrane Library, Biosis Previews, Web of Science, Derwent Drug File, XTOXLINE and three trial registries: Current Controlled Trials: www.controlled-trials.com, ClinicalTrials.gov: www.clinicaltrials.gov, ICTRP: www.who.int./ictrp/en/. Most recent searches of these databases: June 2010.
SELECTION CRITERIA
Randomised controlled trials comparing deferasirox with no therapy/placebo or with another iron chelating treatment schedule.
DATA COLLECTION AND ANALYSIS
No studies eligible for inclusion in this review were identified.
MAIN RESULTS
No studies were included in this review. However, we identified one ongoing study comparing deferasirox with deferoxamine.
AUTHORS' CONCLUSIONS
We planned to report evidence from randomised clinical trials evaluating the effectiveness of deferasirox compared to either placebo/no treatment or other chelating regimens such as deferoxamine in people with myelodysplastic syndrome. However, no completed randomised trials addressing this question could be identified.One ongoing randomised study comparing deferasirox with placebo was identified and preliminary data will hopefully be available soon. These results will be important to inform physicians and patients on the advantages and disadvantages of this treatment option.
Topics: Benzoates; Chelation Therapy; Deferasirox; Humans; Iron Chelating Agents; Iron Overload; Myelodysplastic Syndromes; Triazoles
PubMed: 21069694
DOI: 10.1002/14651858.CD007461.pub2 -
American Journal of Hematology Jul 2018Red blood cell transfusions have become standard of care for the prevention of life-threatening anemia in patients with β-thalassemia and sickle cell disease (SCD)....
Red blood cell transfusions have become standard of care for the prevention of life-threatening anemia in patients with β-thalassemia and sickle cell disease (SCD). However, frequent transfusions can lead to accumulation of iron that can result in liver cirrhosis, diabetes mellitus, arthritis, arrhythmias, cardiomyopathy, heart failure, and hypogonadotropic hypogonadism. Iron chelation therapy has been shown to reduce serum ferritin levels and liver iron content, but limitations of trial design have prevented any demonstration of improved survival. The objective of this systematic review was to investigate the impact of iron chelation therapy on overall and event-free survival in patients with β-thalassemia and SCD. Eighteen articles discussing survival in β-thalassemia and 3 in SCD were identified. Overall iron chelation therapy resulted in better overall survival, especially if it is instituted early and compliance is maintained. Comparative studies did not show any significant differences between available iron chelation agents, although there is evidence that deferiprone is better tolerated than deferoxamine and that compliance is more readily maintained with the newer oral drugs, deferiprone and deferasirox. Iron chelation therapy, particularly the second-generation oral agents, appears to be associated with improved overall and event-free survival in transfusion-dependent patients with β-thalassemia and patients with SCD.
Topics: Anemia, Sickle Cell; Blood Transfusion; Deferiprone; Deferoxamine; Humans; Iron Chelating Agents; Medication Adherence; Survival Analysis; beta-Thalassemia
PubMed: 29635754
DOI: 10.1002/ajh.25103 -
The Cochrane Database of Systematic... May 2018Regularly transfused people with sickle cell disease (SCD) and people with thalassaemia (who are transfusion-dependent or non-transfusion-dependent) are at risk of iron... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Regularly transfused people with sickle cell disease (SCD) and people with thalassaemia (who are transfusion-dependent or non-transfusion-dependent) are at risk of iron overload. Iron overload can lead to iron toxicity in vulnerable organs such as the heart, liver and endocrine glands; which can be prevented and treated with iron chelating agents. The intensive demands and uncomfortable side effects of therapy can have a negative impact on daily activities and well-being, which may affect adherence.
OBJECTIVES
To identify and assess the effectiveness of interventions (psychological and psychosocial, educational, medication interventions, or multi-component interventions) to improve adherence to iron chelation therapy in people with SCD or thalassaemia.
SEARCH METHODS
We searched CENTRAL (the Cochrane Library), MEDLINE, Embase, CINAHL, PsycINFO, Psychology and Behavioral Sciences Collection, Web of Science Science & Social Sciences Conference Proceedings Indexes and ongoing trial databases (01 February 2017). We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Haemoglobinopathies Trials Register (12 December 2017).
SELECTION CRITERIA
For trials comparing medications or medication changes, only randomised controlled trials (RCTs) were eligible for inclusion.For studies including psychological and psychosocial interventions, educational Interventions, or multi-component interventions, non-RCTs, controlled before-after studies, and interrupted time series studies with adherence as a primary outcome were also eligible for inclusion.
DATA COLLECTION AND ANALYSIS
Three authors independently assessed trial eligibility, risk of bias and extracted data. The quality of the evidence was assessed using GRADE.
MAIN RESULTS
We included 16 RCTs (1525 participants) published between 1997 and 2017. Most participants had β-thalassaemia major; 195 had SCD and 88 had β-thalassaemia intermedia. Mean age ranged from 11 to 41 years. One trial was of medication management and 15 RCTs were of medication interventions. Medications assessed were subcutaneous deferoxamine, and two oral-chelating agents, deferiprone and deferasirox.We rated the quality of evidence as low to very low across all outcomes identified in this review.Three trials measured quality of life (QoL) with validated instruments, but provided no analysable data and reported no difference in QoL.Deferiprone versus deferoxamineWe are uncertain whether deferiprone increases adherence to iron chelation therapy (four trials, very low-quality evidence). Results could not be combined due to considerable heterogeneity (participants' age and different medication regimens). Medication adherence was high (deferiprone (85% to 94.9%); deferoxamine (71.6% to 93%)).We are uncertain whether deferiprone increases the risk of agranulocytosis, risk ratio (RR) 7.88 (99% confidence interval (CI) 0.18 to 352.39); or has any effect on all-cause mortality, RR 0.44 (95% CI 0.12 to 1.63) (one trial; 88 participants; very low-quality evidence).Deferasirox versus deferoxamineWe are uncertain whether deferasirox increases adherence to iron chelation therapy, mean difference (MD) -1.40 (95% CI -3.66 to 0.86) (one trial; 197 participants; very-low quality evidence). Medication adherence was high (deferasirox (99%); deferoxamine (100%)). We are uncertain whether deferasirox decreases the risk of thalassaemia-related serious adverse events (SAEs), RR 0.95 (95% CI 0.41 to 2.17); or all-cause mortality, RR 0.96 (95% CI 0.06 to 15.06) (two trials; 240 participants; very low-quality evidence).We are uncertain whether deferasirox decreases the risk of SCD-related pain crises, RR 1.05 (95% CI 0.68 to 1.62); or other SCD-related SAEs, RR 1.08 (95% CI 0.77 to 1.51) (one trial; 195 participants; very low-quality evidence).Deferasirox film-coated tablet (FCT) versus deferasirox dispersible tablet (DT)Deferasirox FCT may make little or no difference to adherence, RR 1.10 (95% CI 0.99 to 1.22) (one trial; 173 participants; low-quality evidence). Medication adherence was high (FCT (92.9%); DT (85.3%)).We are uncertain if deferasirox FCT increases the incidence of SAEs, RR 1.22 (95% CI 0.62 to 2.37); or all-cause mortality, RR 2.97 (95% CI 0.12 to 71.81) (one trial; 173 participants; very low-quality evidence).Deferiprone and deferoxamine combined versus deferiprone alone We are uncertain if deferiprone and deferoxamine combined increases adherence to iron chelation therapy (very low-quality evidence). Medication adherence was high (deferiprone 92.7% (range 37% to 100%) to 93.6% (range 56% to 100%); deferoxamine 70.6% (range 25% to 100%).Combination therapy may make little or no difference to the risk of SAEs, RR 0.15 (95% CI 0.01 to 2.81) (one trial; 213 participants; low-quality evidence).We are uncertain if combination therapy decreases all-cause mortality, RR 0.77 (95% CI 0.18 to 3.35) (two trials; 237 participants; very low-quality evidence).Deferiprone and deferoxamine combined versus deferoxamine aloneDeferiprone and deferoxamine combined may have little or no effect on adherence to iron chelation therapy (four trials; 216 participants; low-quality evidence). Medication adherence was high (deferoxamine 91.4% to 96.1%; deferiprone: 82.4%)Deferiprone and deferoxamine combined, may have little or no difference in SAEs or mortality (low-quality evidence). No SAEs occurred in three trials and were not reported in one trial. No deaths occurred in two trials and were not reported in two trials.Deferiprone and deferoxamine combined versus deferiprone and deferasirox combinedDeferiprone and deferasirox combined may improve adherence to iron chelation therapy, RR 0.84 (95% CI 0.72 to 0.99) (one trial; 96 participants; low-quality evidence). Medication adherence was high (deferiprone and deferoxamine: 80%; deferiprone and deferasirox: 95%).We are uncertain if deferiprone and deferasirox decreases the incidence of SAEs, RR 1.00 (95% CI 0.06 to 15.53) (one trial; 96 participants; very low-quality evidence).There were no deaths in the trial (low-quality evidence).Medication management versus standard careWe are uncertain if medication management improves health-related QoL (one trial; 48 participants; very low-quality evidence). Adherence was only measured in one arm of the trial.
AUTHORS' CONCLUSIONS
The medication comparisons included in this review had higher than average adherence rates not accounted for by differences in medication administration or side effects.Participants may have been selected based on higher adherence to trial medications at baseline. Also, within the clinical trial context, there is increased attention and involvement of clinicians, thus high adherence rates may be an artefact of trial participation.Real-world, pragmatic trials in community and clinic settings are needed that examine both confirmed or unconfirmed adherence strategies that may increase adherence to iron chelation therapy.Due to lack of evidence this review cannot comment on intervention strategies for different age groups.
Topics: Adolescent; Adult; Anemia, Sickle Cell; Benzoates; Chelation Therapy; Child; Deferasirox; Deferiprone; Deferoxamine; Humans; Iron Chelating Agents; Iron Overload; Patient Compliance; Pyridones; Quality of Life; Randomized Controlled Trials as Topic; Triazoles; beta-Thalassemia
PubMed: 29737522
DOI: 10.1002/14651858.CD012349.pub2