Health state utilities associated with treatment for transfusion-dependent ß-thalassemia.

OBJECTIVES: Transfusion-dependent ß-thalassemia (TDT) is a genetic disease that affects production of red blood cells. Conventional treatment involves regular red blood cell transfusions and iron chelation, which has a substantial impact on quality of life. While potentially curative, allogeneic hematopoietic stem cell transplantation (allo-HSCT) is associated with risk of complications, including graft-versus-host disease (GvHD). Gene addition therapy, a novel treatment approach, involves autologous transplantation of the patient's own genetically modified hematopoietic stem cells. The purpose of this study was to estimate utilities associated with treatment approaches for TDT. METHODS: General population respondents in England valued eight health state vignettes (developed with clinician, patient, and parent input) in time trade-off interviews. RESULTS: A total of 207 participants completed interviews (49.8% female; mean age = 43.2 years). Mean (SD) utilities for the pre-transplant health states were 0.73 (0.25) with oral chelation and 0.63 (0.32) with subcutaneous chelation. Mean utilities for the transplant year were 0.62 (0.35) for gene addition therapy, 0.47 (0.39) for allo-HSCT, and 0.39 (0.39) for allo-HSCT with acute GvHD. Post-transplant utilities were 0.93 (0.15) for transfusion independent, 0.75 (0.25) for 60% transfusion reduction, and 0.51 (0.38) for chronic GvHD. Acute and chronic GvHD were associated with significant disutility (acute = - 0.09, p < 0.0001; chronic = - 0.42, p < 0.0001). CONCLUSIONS: Utilities followed expected patterns, with logical differences between treatment options for TDT and substantially greater utility for transfusion independence than for ongoing treatment involving transfusion and chelation. These utilities may be useful in cost-utility models estimating the value of treatments for TDT.

A time-driven, activity-based costing methodology for determining the costs of red blood cell transfusion in patients with beta thalassaemia major.

OBJECTIVES: To describe the methodology to estimate the total cost of administration of a single unit of red blood cells (RBC) in adults with beta thalassaemia major in an Australian specialist haemoglobinopathy centre. BACKGROUND: Beta thalassaemia major is a genetic disorder of haemoglobin associated with multiple end-organ complications and typically requiring lifelong RBC transfusion therapy. New therapeutic agents are becoming available based on advances in understanding of the disorder and its consequences. Assessment of the true total cost of transfusion, incorporating both product and activity costs, is required in order to evaluate the benefits and costs of these new therapies. METHODS: We describe the bottom-up, time-driven, activity-based costing methodology used to develop process maps to provide a step-by-step outline of the entire transfusion pathway. Detailed flowcharts for each process are described. Direct observations and timing of the process maps document all activities, resources, staff, equipment and consumables in detail. The analysis will include costs associated with performing these processes, including resources and consumables. Sensitivity analyses will be performed to determine the impact of different staffing levels, timings and probabilities associated with performing different tasks. RESULTS: Thirty-one process maps have been developed, with over 600 individual activities requiring multiple timings. These will be used for future detailed cost analyses. CONCLUSIONS: Detailed process maps using bottom-up, time-driven, activity-based costing for determining the cost of RBC transfusion in thalassaemia major have been developed. These could be adapted for wider use to understand and compare the costs and complexities of transfusion in other settings.

Cost Effectiveness of Hematopoietic Stem Cell Transplantation Compared with Transfusion Chelation for Treatment of Thalassemia Major.

Hematopoietic stem cell transplantation (HSCT) is the only cure for thalassemia major (TM), which inflicts a significant 1-time cost. Hence, it is important to explore the cost effectiveness of HSCT versus lifelong regular transfusion-chelation (TC) therapy. This study was undertaken to estimate incremental cost per quality-adjusted life-year (QALY) gained with the intervention group HSCT, and the comparator group TC, in TM patients. A combination of decision tree and Markov model was used for analysis. A hospital database, supplemented with a review of published literature, was used to derive input parameters for the model. A lifetime study horizon was used and future costs and consequences were discounted at 3%. Results are presented using societal perspective. Incremental cost per QALY gained with use of HSCT as compared with TC was 64,096 (US$986) in case of matched related donor (MRD) and 1,67,657 (US$2579) in case of a matched unrelated donor transplantation. The probability of MRD transplant to be cost effective at the willingness to pay threshold of Indian per capita gross domestic product is 94%. HSCT is a long-term value for money intervention that is highly cost effective and its long-term clinical and economic benefits outweigh those of TC.

Cost-Utility Analysis of Three Iron Chelators Used in Monotherapy for the Treatment of Chronic Iron Overload in ß-Thalassaemia Major Patients: An Italian Perspective.

PURPOSE: Deferiprone (DFP), deferasirox (DFX) and deferoxamine (DFO) are used in thalassaemia major (TM) patients to treat chronic iron overload. We evaluated the cost-effectiveness of DFP, compared with DFX and DFO monotherapy, from an Italian healthcare system perspective. METHODS: A Markov model was used over a time horizon of 5 years. Italian-specific cost data were combined with Italian efficacy data. Costs and quality-adjusted life years (QALYs) were calculated for each treatment, with cost-effectiveness expressed as cost per QALY. RESULTS: In all scenarios modelled, DFP was the dominant treatment strategy. Sensitivity analyses showed that DFP dominated the other treatments with a >99% likelihood of being cost-effective against DFX and DFO at a willingness to pay threshold of €20,000 per QALY. CONCLUSIONS: DFP was the dominant and most cost-effective treatment for managing chronic iron overload in TM patients. Its use can result in substantial cost savings for the Italian healthcare system.

Economic Burden of Thalassemia Major in Iran, 2015.

BACKGROUND: Major Thalassemia is an autosomal recessive disease with complications, mortality and serious pathology. Today, the life expectancy of patients with major thalassemia has increased along with therapeutic advances. Therefore, they need lifelong care, and caring for them would incur many costs. Being aware of the patients' costs can be effective for controlling and managing the costs and providing efficient treatments for the care of patients. Hence, this study was conducted to estimate the economic burden of the patients with major thalassemia. METHODS: Totally, 198 patients with major thalassemia were randomly selected from among the patients with major thalassemia in Tehran, Iran in 2015. The economic burden of the patients was estimated from a social perspective and through a bottom-up, prevalence-based approach. RESULTS: The average annual cost per patient was estimated $ 8321.8 regardless of the cost of lost welfare. Of this amount, $ 7286.8 was related to direct medical costs, $ 461.4 to direct non-medical costs, and $ 573.5 to indirect costs. In addition, the annual cost per patient was estimated $ 1360.5 due to the distress caused by the disease CONCLUSIONS: Considering the high costs of the treatment of patients with major thalassemia, adopting new policies to reduce the costs that patients have to pay seems necessary. In addition, making new decisions regarding thalassemia screening, even with higher costs than the usual screening costs, can be useful since the costs of treatment are high.

Healthcare costs and outcomes of managing ß-thalassemia major over 50 years in the United Kingdom.

BACKGROUND: The objective was to estimate the incidence-based costs of treating ß-thalassemia major (BTM) to the United Kingdom's National Health Service (NHS) over the first 50 years of a patient's life in terms of healthcare resource use and corresponding costs and the associated health outcomes. STUDY DESIGN AND METHODS: This was a modeling study based on information obtained from a systematic review of published literature and clinicians involved in managing BTM in the United Kingdom. A state transition model was constructed depicting the management of BTM over a period of 50 years. The model was used to estimate the incidence-based health economic impact that BTM imposes on the NHS and patients' health status in terms of the number of quality-adjusted life-years (QALYs) over 50 years. RESULTS: The expected probability of survival at 50 years is 0.63. Of patients who survive, 33% are expected to be without any complication and the other 67% are expected to experience at least one complication. Patients' health status over this period was estimated to be a mean of 11.5 discounted QALYs per patient. Total healthcare expenditure attributable to managing BTM was estimated to be £483,454 ($720,201) at 2013/14 prices over 50 years. The cost of managing BTM could be potentially reduced by up to 37% if one in two patients had a bone marrow transplant, with an ensuing improvement in health-related quality of life. CONCLUSION: This analysis provides the best estimate available of NHS resource use and costs with which to inform policy and budgetary decisions pertaining to this rare disease.

Haemoglobin disorders in Australia: where are we now and where will we be in the future?

Inherited disorders of haemoglobin (Hb), such as thalassaemia and sickle cell disease (SCD) are common and responsible for significant morbidity and mortality on a global scale. As Australia becomes increasingly ethnically diverse, their prevalence will increase. However, we lack important demographic and epidemiological data to manage these disorders and their consequences and to support affected individuals and communities. Thalassaemia and SCD are lifelong conditions. Affected individuals have reduced life expectancies, poorer quality of life and complex healthcare needs. Treatment strategies currently focus on prenatal diagnosis, red blood cell transfusion, iron chelation, management of iron-related complications, haemopoietic stem cell transplantation (HSCT) and hydroxyurea. Currently, the only curative therapy is HSCT; however, gene therapy offers the possibility of cure and trials are currently underway. These therapies are associated with significant complications and substantial costs; there is also evidence of variation in approaches to diagnosis and care. Optimal strategies for many aspects of management are not yet defined and more research is necessary to inform clinical care and health service delivery.

Molecular epidemiological characterization and health burden of thalassemia in Jiangxi Province, P. R. China.

BACKGROUND: Thalassemia is the most common inherited disease in southern China. However, this disorder is usually ignored by Jiangxi provincial health system and government due to lack of epidemiological data. MATERIALS AND METHODS: A total of 9489 samples from Hakka Han and Gan-speaking Han in three geographical areas of Jiangxi Province were analyzed for both complete blood cell (CBC) count and reverse dot blot (RDB) gene chip for thalassemia. RESULTS: 1182 cases of suspected thalassemia carriers with microcytosis (MCV<82 fL) were found by CBC count, and were tested by RDB gene chip to reveal a total of 594 mutant chromosomes, including 433 α-thalassemia mutant chromosomes and 172 ß-thalassemia mutant chromosomes. Our results indicated a higher prevalence of thalassemia with the heterozygote frequency of 9.49% in southern Jiangxi province, whereas the low frequency was found in middle (3.90%) and northern Jiangxi (2.63%). CONCLUSIONS: Based on the epidemiological data, the estimated numbers of pregnancies in Jiangxi province in which the fetus is at risk for ß-thalassemia major or intermedia, Bart's hydrops fetalis and Hb H disease are 34 (95% CI, 16 to 58), 79 (95% CI, 50 to 114) and 39 (95% CI, 27 to 58) per year, respectively. We suggested that prevention network of thalassemia should be established, especially in high prevalent southern Jiangxi (Hakka Han), including establishment of thalassemia database collection, hematological analysis laboratories, genetic counselling clinics, prenatal diagnosis centers and neonatal screening centers.

Cost-utility of chelators in transfusion-dependent ß-thalassemia major patients: a review of the pharmacoeconomic literature.

In the inherited hematologic disorder ß-thalassemia major, patients receive regular, lifelong blood transfusions, which carry excess iron that the body is unable to eliminate. Chelation therapy (deferoxamine, deferiprone, deferasirox or deferoxamine-deferiprone combination) is required to reduce iron accumulation in target organs and the associated morbidity and mortality. Each chelation regimen has a distinct safety/efficacy profile and particular costs associated with its use. This review aims to provide an overview of published cost-utility analyses of currently used chelation regimens, and to comment on the potential relevance of their findings in the USA market, where deferiprone has recently been introduced.

Predicting future blood demand from thalassemia major patients in Hong Kong.

BACKGROUND: In Hong Kong, thalassemia major (TM) patients utilized up to 9.5% of blood supply in 2009. For long-term management of blood supply, we predicted the future blood demand of TM patients for the next 10 years. METHODS AND RESULTS: Annual individual transfusion data in 2005-2009 and demographic information of 381 TM patients were obtained from the Hong Kong Red Cross Blood Transfusion Service database. A generalized estimating equation (GEE) model was fitted to establish the potential relations of blood demand with age, sex, body weight, year of transfusion and splenectomy, accounted for within-patient correlation. The fitted model was used to predict future blood demand for the existing patients by accounting for expected change in body weight and mortality rate. We also predicted the number of new cases in the future based on age- and sex-specific TM incidence and official population projections. Future blood demand was predicted by combining blood demand from the existing and new patients. Female (RR = 0.94, p = 0.006) and history of splenectomy (RR = 0.85, p<0.001) were significantly associated with lower blood demand, while age and weight had an inverted U-shape relation with maximal blood demand at around 24 years of age and 71.8 kg, respectively. We predicted that the total blood demand would increase 0.81% annually from 13,459 units in 2009 to 15,183 units in 2024, with new TM cases accounting for 31.7% of the overall blood demand in 2024. CONCLUSIONS: Our results showed that future annual blood demand from TM patients would steadily increase in the next 10 years. Reducing incidence of TM cases in the future (by improving public education, antenatal care, prenatal diagnosis) and minimizing blood use among existing TM cases (e.g. with hemopoietic stem cell transplantation) can help relieve the burden on management of future blood demand.

Cost-utility analysis of deferiprone for the treatment of ß-thalassaemia patients with chronic iron overload: a UK perspective.

BACKGROUND: Patients with ß-thalassaemia major experience chronic iron overload due to regular blood transfusions. Chronic iron overload can be treated using iron-chelating therapies such as desferrioxamine (DFO), deferiprone (DFP) and deferasirox (DFX) monotherapy, or DFO-DFP combination therapy. OBJECTIVES: This study evaluated the relative cost effectiveness of these regimens over a 5-year timeframe from a UK National Health Service (NHS) perspective, including personal and social services. METHODS: A Markov model was constructed to evaluate the cost effectiveness of the treatment regimens over 5 years. Based on published randomized controlled trial evidence, it was assumed that all four treatment regimens had a comparable effect on serum ferritin concentration (SFC) and liver iron concentration (LIC), and that DFP was more effective for reducing cardiac morbidity and mortality. Published utility scores for route of administration were used, with subcutaneously administered DFO assumed to incur a greater quality of life (QoL) burden than the oral chelators DFP and DFX. Healthcare resource use, drug costs (2010/2011 costs), and utilities associated with adverse events were also considered, with the effect of varying all parameters assessed in sensitivity analysis. Incremental costs and quality-adjusted life-years (QALYs) were calculated for each treatment, with cost effectiveness expressed as incremental cost per QALY. Assumptions that DFP conferred no cardiac morbidity, mortality, or morbidity and mortality benefit were also explored in scenario analysis. RESULTS: DFP was the dominant strategy in all scenarios modelled, providing greater QALY gains at a lower cost. Sensitivity analysis showed that DFP dominated all other treatments unless the QoL burden associated with the route of administration was greater for DFP than for DFO, which is unlikely to be the case. DFP had >99 % likelihood of being cost effective against all comparators at a willingness-to-pay threshold of £20,000 per QALY. CONCLUSIONS: In this analysis, DFP appeared to be the most cost-effective treatment available for managing chronic iron overload in ß-thalassaemia patients. Use of DFP in these patients could therefore result in substantial cost savings.

Hematopoietic cell transplantation for thalassemia: a global perspective BMT tandem meeting 2013.

Hematopoietic cell transplantation (HCT) remains the sole available curative option for patients with ß-thalassemia major. Expanded and improved supportive therapies for thalassemia now routinely extend the life span of affected individuals well into adulthood. Consequently, in regions of the world where this care is readily available, HCT has been pursued infrequently, in part owing to concerns about an expected lack of balance between risks and benefits. More recently, however, recognition of significant health problems in older patients with thalassemia, along with recognition of increased risks of graft-versus-host disease (GVHD), graft rejection, and impaired organ function leading to inferior HCT outcomes in this particular group, seem to be turning the wheels and tipping the balance again in the direction of consideration for earlier HCTs. In contrast, in countries where thalassemia is most prevalent (>100,000 new children born each year in Middle East and southeast Asia), lack of supportive care standards together with often insufficient access to dedicated health care facilities, results in the majority of these children not reaching adulthood, further supporting the need for expanded access to HCT for these patients. The cost of HCT is equivalent to that of a few years of noncurative supportive care, such that HCT in low-risk young children with a compatible sibling is justified not only medically and ethically but also financially. International cooperation can play a major role in increasing access to safe and affordable HCT in countries where there is a considerable shortage of transplantation centers. In this article, we review the current status of bone marrow transplantation for thalassemia major, with particular emphasis on a global prospective.

Cost-utility analysis of oral deferasirox versus infusional deferoxamine in transfusion-dependent ß-thalassemia patients.

BACKGROUND: Deferasirox (DFX) is a novel iron chelator that has been shown to have similar efficacy and safety compared with deferoxamine (DFO) in patients with ß-thalassemia. The aim of this study was to determine the cost utility of DFX versus DFO in ß-thalassemia major patients from Iran's society perspective. STUDY DESIGN AND METHODS: A Markov model has been developed to determine lifetime cost and quality-adjusted life-years (QALYs) of patients. To estimate the annual cost of each method, a cross-sectional study was conducted among two groups of patients who received DFO and DFX (n = 100 and n = 45, respectively). Also a time trade-off method was used to estimate the utility of two strategies. Finally a one-way and probabilistic sensitivity analysis was conducted to examine the strength of the results. RESULTS: Our base-case analysis showed that estimated total lifetime costs per patient for DFX and DFO were 47,029 international dollar ($Int) and $Int143,522, respectively, while the estimated total discounted QALYs per person were 12.28 and 7.76, respectively. Calculated incremental cost-effectiveness ratio showed that DSX is a dominant therapy and its estimated lifetime net monetary benefit was $Int273,528. CONCLUSION: We conclude that the use of DFX instead of DFO represents a cost-effective use of resources for treatment of iron overload in patients with ß-thalassemia from Iran's society perspective.

Lifetime cost-utility analyses of deferasirox in beta-thalassaemia patients with chronic iron overload: a UK perspective.

BACKGROUND AND OBJECTIVES: Regular blood transfusions for beta-thalassaemia patients lead to the accumulation of iron deposits in the body. In order to remove such deposits, iron chelation therapy is required. Subcutaneously administered deferoxamine has been the gold standard chelation therapy for over 40 years. Deferasirox is a newer chelation therapy that is taken orally once daily. The objective of this study was to estimate the long-term costs and quality-adjusted life-years (QALYs) associated with deferoxamine and deferasirox in a cohort of transfusion-dependent beta-thalassaemia patients from a UK health service perspective. METHODS: A 50-year annual cycle state transition model comprised three core health states: alive without cardiac complications, alive with cardiac complications, and dead, as well as representing other chronic complications of iron overload: diabetes, hypogonadism, hypoparathyroidism and hypothyroidism. The model was calibrated to identify sets of convergent input parameter values that predicted observed overall survival by mean lifetime compliance with chelation therapy. A pivotal non-inferiority trial informed the main estimates of the effectiveness of deferasirox, which were applied to the calibrated model. Using cost values for the year 2011, costs and utilities were summed over patients' lifetimes to estimate lifetime costs and QALY gains. RESULTS: Mean lifetime treatment costs for patients receiving deferoxamine were £70,000 higher than deferasirox. Drug acquisition costs were £100,000 higher for deferasirox, but administration costs associated with deferoxamine were £170,000 higher. Higher compliance associated with oral deferasirox administration led to fewer complications. Combined with the quality-of-life effects of an oral mode of administration, an average gain of 4.85 QALYs for deferasirox was estimated. In the base case, deferasirox dominates deferoxamine, i.e., costs less and patients gain more QALYs. The key parameter is the proportion of deferoxamine patients using balloon infusers. Sensitivity analyses showed that even when the proportion of patients using balloon infusers is decreased from 79 to 25 %, the incremental cost per QALY gained remains well under £20,000. CONCLUSION: Higher drug acquisition costs for deferasirox are offset by the avoidance of infusion-related equipment costs. Combined with health benefits derived from an oral mode of administration and improved compliance, deferasirox has a high probability of being a cost-effective intervention compared with deferoxamine.

Reproductive behaviour of mothers of children with beta-thalassaemia major.

Thalassaemia is the most common monogenic autosomal hereditary disease worldwide. This questionnaire-based cross-sectional study looked at the reproductive behaviour of 156 mothers of children affected with beta-thalassaemia major (Cooley anaemia) in Fars province, southern Islamic Republic of Iran. Regardless of the number of affected children, the parents of children with Cooley anaemia had an average of 3 unaffected children, the same as the average for the provincial population. The findings indicate that reproductive compensation occurs in families with a child with Cooley anaemia in this province. Genetic counselling, either before marriage or after the birth of the first affected child, had a significant effect on lowering the number of children born.

Iron-chelating therapies in a transfusion-dependent thalassaemia population in Thailand: a cost-effectiveness study.

BACKGROUND AND OBJECTIVE: ß-Thalassaemia is a major public health problem in Thailand. Use of appropriate iron-chelating agents could prevent thalassaemia-related complications, which are costly to the healthcare system. This study aimed to evaluate the cost effectiveness of deferoxamine (DFO), deferiprone (DFP) and deferasirox (DFX) in Thai transfusion-dependent ß-thalassaemia patients from the societal perspective. METHODS: A Markov model was used to project the life-time costs and outcomes represented as quality-adjusted life-years (QALYs). Data on the clinical efficacy and safety of all therapeutic options were obtained from a systematic review and clinical trials. Transition probabilities were derived from published studies. Costs were obtained from the Thai Drug and Medical Supply Information Center, Thai national reimbursement rate information and other Thai literature sources. A discount rate of 3% was used. Incremental cost-effectiveness ratios (ICERs) were presented as year 2009 values. A base-case analysis was performed for thalassaemia patients requiring regular blood transfusion therapy, while a separate analysis was performed for patients requiring low (i.e. symptom-dependent, less frequent) blood transfusion therapy. A series of sensitivity analysis and cost-effectiveness acceptability curves were constructed. RESULTS: Compared with DFO, using DFP was dominant with lifetime cost savings of $US91 117. Comparing DFX with DFO, the incremental cost was $US522 863 and incremental QALY was 5.77 with an ICER of $US90 648 per QALY. When compared with DFP, the ICER of DFX was $US106 445 per QALY. A cost-effectiveness analysis curve showed the probability of DFX being cost effective was 0% when compared with either DFO or DFP, based on the cost-effectiveness cut-off value of $US2902 per QALY. When compared with DFP, DFX was cost effective only if the DFX cost was as low as $US1.68 per 250 mg tablet. The results of the analysis in patients requiring low blood transfusion therapy were not different from those of the base-case analysis. CONCLUSIONS: Our findings suggest that using DFP is cost saving when compared with conventional therapy, while using DFX is not cost effective compared with either DFO or DFP in Thai patients with transfusion-dependent ß-thalassaemia. Policy-makers and clinicians may consider using such information in their decision-making process in Thailand.