Comparison of Yearly Cost Related to Complications Between Deferasirox and Deferiprone Monotherapy in Thalassemia.

BACKGROUND: Hemoglobin disorders such as thalassemia major have created an economic burden on the health care system. Iron chelation therapy (ICT) is the most expensive cost component in patients with thalassemia. ICT was administered to reduce the toxic effects of iron overload. This study aims to compare the costs of iron chelators as monotherapy in patients with thalassemia major in Indonesia, specifically in Cipto Faculty of Medicine, Universit. METHODS: This is a retrospective analytical observational study. Data were collected from the thalassemia registry from 2016 to 2019. Patients' age, gender, type of thalassemia, and type of iron chelation were recorded. Complications and total annual costs were evaluated. All thalassemia patients aged ≥2 years who were only receiving monotherapy ICT and had no history of therapy switching were eligible. We excluded subjects who moved out to other facilities or lost to follow-up. RESULTS: From a total of 256 subjects, 249 subjects were included. The median age is 28 years old. Both sexes were represented equally. As many as 96.8% of subjects have thalassemia beta. Deferiprone was the most common iron chelator used (86.7%). Complications were observed in the subjects based on 4-year data collection; most of them were cardiomyopathy, diabetes mellitus, delayed puberty, and malnutrition ( P =0.422; P =0.867; P =0.004; and P =0.125, respectively). Deferiprone had a lower mean annual cost of USD 3581 than deferasirox, which had a cost of USD 6004. CONCLUSIONS: Cardiomyopathy, diabetes mellitus, delayed puberty, and malnutrition were the most common complications found in the study. This study showed that deferiprone should be taken as consideration as a drug of choice to treat iron overload in thalassemia provided by Indonesian national health insurance which is less costly despite the probability of complications found after the treatment was given. Further investigations are required to evaluate contributing factors of complications in thalassemia.

Differences in medical costs between TCM users and TCM nonusers in inpatients with thalassemia.

BACKGROUND: Thalassemia has brought serious health threats and economic burdens to patients worldwide. There is no sovereign remedy for thalassemia, both conventional and Traditional Medicine (TM) methods have certain effects on this disease. As typical of TM, Traditional Chinese Medicine (TCM) has been widely used in the treatment of thalassemia. Previous studies mainly focused on conventional treatments for thalassemia and patients' medical burden, but no research has examined the effects of TCM use on the economic burdens for thalassemia inpatients in mainland China. The main objective of this study is to compare the medical cost differences between TCM users and TCM nonusers, furtherly, we will discuss the role of TCM use in the treatment of thalassemia. METHODS: We employed the 2010-2016 Medicare claims database provided by the China Health Insurance Research Association (CHIRA). Chi-square and Mann-Whitney tests were used to analyze the differences between TCM users and TCM nonusers. Multiple regression analysis was performed using the ordinary least squares method to compare the TCM users' inpatient medical cost with TCM nonusers', and to further examine the correlation between TCM cost, conventional medication cost and nonpharmacy cost for TCM users. RESULTS: A total of 588 urban thalassemia inpatients were identified, including 222 TCM users and 366 TCM nonusers. The inpatient medical cost of TCM users was RMB10,048 (USD1,513), which was significantly higher than TCM nonusers (RMB1,816 (USD273)). Total inpatient cost for TCM users was 67.4% higher than those of TCM nonusers (P < 0.001). With confounding factors fixed, we found that the conventional medication cost and nonpharmacy cost were positively correlated with TCM cost. CONCLUSION: Total hospitalization expenses for TCM users were higher than TCM nonusers. Both the conventional medication cost and nonpharmacy cost of TCM users were all higher than TCM nonusers. We infer TCM plays a complementary role, rather than an alternative, in the treatment of thalassemia due to the lack of cooperative treatment guidelines. It is recommended that a cooperative diagnosis and treatment guidelines should be generated to balance the use of TCM and conventional medicine for treating thalassemia, so as to reduce the economic burdens on patients.

Adherence to iron chelation therapy and associated healthcare resource utilization and costs in Medicaid patients with sickle cell disease and thalassemia.

BACKGROUND: Sub-optimal patient adherence to iron chelation therapy (ICT) may impact patient outcomes and increase cost of care. This study evaluated the economic burden of ICT non-adherence in patients with sickle cell disease (SCD) or thalassemia. METHODS: Patients with SCD or thalassemia were identified from six state Medicaid programs (1997-2013). Adherence was estimated using the medication possession ratio (MPR) of ≥0.80. All-cause and disease-specific resource utilization per-patient-per-month (PPPM) was assessed and compared between adherent and non-adherent patients using adjusted incidence rate ratios (aIRR). All-cause and disease-specific healthcare costs were computed using mean cost PPPM. Regression models adjusting for baseline characteristics were used to compare adherent and non-adherent patients. RESULTS: A total of 728 eligible patients treated with ICT in the SCD cohort, 461 (63%) adherent, and 218 in the thalassemia cohort, 137 (63%) adherent, were included in this study. In SCD patients, the adjusted rate of all-cause outpatient visits PPPM was higher in adherent patients vs non-adherent patients (aIRR [95% CI]: 1.05 [1.01-1.08], p < 0.0001). Conversely, adherent patients incurred fewer all-cause inpatients visits (0.87 [0.81-0.94], p < 0.001) and ER visits (0.86 [0.78-0.93], p < 0.001). Similar trends were observed in SCD-related resource utilization rates and in thalassemia patients. Total all-cause costs were similar between adherent and non-adherent patients, but inpatient costs (adjusted cost difference = -$1530 PPPM, p = 0.0360) were lower in adherent patients. CONCLUSION: Patients adherent to ICT had less acute care need and lower inpatient costs than non-adherent patients, although they had more outpatient visits. Improved adherence may be linked to better disease monitoring and has the potential to avoid important downstream costs associated with acute care visits and reduce the financial burden on health programs and managed care plans treating SCD and thalassemia patients.

The effects of economic sanctions on disease specific clinical outcomes of patients with thalassemia and hemophilia in Iran.

BACKGROUND: The sanctions applied by both the USA and the EU against Iran do not formally ban the exports of medicines; in practice, however, patients are experiencing great difficulty in securing the treatment. This article documents the impact of international sanctions on patients with thalassemia and hemophilia in southern Iran. METHODS: This survey examined the specific effects of external sanctions on the access of patients to their treatment between 2009 and 2012 from the point of view of patients with thalassemia (n=69) and congenital coagulation disorders (n=40) as well as related physicians (n=20). Also, clinical manifestation and laboratory data of patients were compared in the same period. RESULTS: Access to deferoxamine and Exjade as iron chelators in patients with thalasseamia, respectively, declined by almost 70% and half over this period. In addition, access to lyophilized coagulation factor VIII concentrate in hemophilia A dramatically dropped from 96.7% in 2009 to 3.3% in 2012. The clinical results showed a significant deterioration of arthropathy (P<0.001) in hemophiliac patients and a significant increase in serum ferritin levels in thalassemia patients (P=0.036). CONCLUSION: Sanctions had significant effect on public health on patients with thalassemia and hemophilia.

Iron overload in thalassemia and related conditions: therapeutic goals and assessment of response to chelation therapies.

Transfusional iron loading inevitably results in hepatic iron accumulation, with variable extrahepatic distribution that is typically less pronounced in sickle cell disease than in thalassemia disorders. Iron chelation therapy has the goal of preventing iron-mediated tissue damage through controlling tissue iron levels, without incurring chelator-mediated toxicity. Historically, target levels for tissue iron control have been limited by the increased frequency of deferoxamine-mediated toxicity and low levels of iron loading. With newer chelation regimes, these limitations are less evident. The reporting of responses to chelation therapies has typically focused on average changes in serum ferritin in patient populations. This approach has three limitations. First, changes in serum ferritin may not reflect trends in iron balance equally in all patients or for all chelation regimens. Second, this provides no information about the proportion of patients likely respond. Third, this gives insufficient information about iron trends in tissues such as the heart. Monitoring of iron overload has advanced with the increasing use of MRI techniques to estimate iron balance (changes in liver iron concentration) and extrahepatic iron distribution (myocardial T2*). The term nonresponder has been increasingly used to describe individuals who fail to show a downward trend in one or more of these variables. Lack of a response of an individual may result from inadequate dosing, high transfusion requirement, poor treatment adherence, or unfavorable pharmacology of the chelation regime. This article scrutinizes evidence for response rates to deferoxamine, deferiprone (and combinations), and deferasirox.

Update on iron chelators in thalassemia.

Over the past four decades, there have been dramatic improvements in survival for patients with thalassemia major due in large measure to improved iron chelators. Two chelators are approved for use in the United States and Canada, parenteral deferoxamine and oral deferasirox. Three are available in much of the rest of the world, where oral deferiprone is also approved (in the United States, deferiprone is only available in studies, for emergency use, or on a "compassionate-use" basis). Many trials and worldwide clinical experience demonstrate that each of the three drugs can chelate and remove iron, and thereby prevent or improve transfusional hemosiderosis in thalassemia patients. However, the chelators differ strikingly in side-effect profile, cost, tolerability and ease of adherence, and (to some degree) efficacy for any specific patient. The entire field of chelator clinical trials suffers from the fact that each drug (as monotherapy or in combination) has not been tested directly against all of the other possibilities. Acknowledging the challenges of assessing chelators with diverse properties and imperfect comparative data, the purpose of this review is to summarize the last 4 years of studies that have improved our understanding of the applications and limitations of iron chelators in various settings for thalassemia patients, and to point out areas for much-needed future research.

The proceedings of the 17th International Conference on Chelation: application of effective chelation therapies in iron loading and non iron loading conditions, and the gap in the prevention and treatment policies on thalassemia between developed and developing countries.

Substantial progress in the use of chelating drugs for the treatment of iron overload and of non iron loading conditions has been presented during the 17th International Conference on Chelation (ICOC) held in November 2007 at Shenzhen, China. Major challenges lie ahead for the prevention and treatment of thalassemia in China, India, Thailand, Indonesia and many other developing countries where millions of heterozygote thalassemia carriers live and thousands of homozygote thalassemia patients are born annually. The progressive improvement of the economic climate in developing countries will increase the demand and resources for more prenatal and antenatal diagnoses, transfusions and chelation therapy in forthcoming years. Despite the major advances in diagnosis and treatment in developed countries, the vast majority of thalassemia patients in developing countries die untreated because they cannot afford the cost of transfusions and chelation therapy. New approaches and infrastructures and more efforts are needed to overcome the difficulties of supplying new techniques and treatments to patients in developing countries. International and local organizations need to be persuaded to act collectively and effectively to improve chelation and related treatments for thalassemia and other conditions, especially at this time that universally effective and inexpensive chelation therapies can be applied.

Risk/benefit assessment, advantages over other drugs and targeting methods in the use of deferiprone as a pharmaceutical antioxidant in iron loading and non iron loading conditions.

Tissue damage caused by oxidative stress is a common characteristic of many conditions involving different major organs such as the brain, heart, liver and kidneys. The treatment of such conditions using classical antioxidants is not in most cases sufficient or effective because it lacks specificity and has a low therapeutic index. Increased evidence from in vitro, in vivo and clinical studies suggest that deferiprone (L1) can be used as a potent pharmaceutical antioxidant by mobilizing labile iron and copper and/or inhibiting their catalytic activity in the formation of free radicals and oxidative stress in tissue damage. The high therapeutic index, tissue penetration, rapid iron binding and clearance of the iron complex, and the low toxicity of L1, support its application as an antioxidant pharmaceutical for adjuvant, alternative or main therapy, especially in conditions where other treatments have failed. Substantial clinical improvement and reversal in most cases of the tissue damage has been observed in cardiomyopathy in thalassemia, diabetic nephropathy and glomerulonephritis in kidney disease, Friedreich's Ataxia and Fanconi Anemia patients. In contrast to L1, both deferoxamine (DFO) and deferasirox (DFRA) have major disadvantages in their use in non iron loading conditions due to toxicity implications. Further studies in the above and other conditions and optimization of the L1 therapy in each individual will increase the prospects of the application and role of L1 as a universal antioxidant pharmaceutical.

Ethical issues and risk/benefit assessment of iron chelation therapy: advances with deferiprone/deferoxamine combinations and concerns about the safety, efficacy and costs of deferasirox.

New developments in the area of iron and other metal metabolism and toxicity and the effects and uses of chelators have been presented at the 16th International Conference on Chelation (ICOC), Limassol, Cyprus in October 2006. Marketing practices by pharmaceutical companies, contradictory policies by regulatory authorities and ineffective policies by health authorities deprive thousands of thalassemia and other transfused patients of life saving iron chelating drugs and of efficacious chelation treatments. Thousands of patients were using deferasirox (DFRA) worldwide a few months after the European Union (EU) authorities, and about 1 year after the Food and Drugs Administration (FDA), proceeded to its accelerated approval with no sufficient evidence that the drug was efficacious, especially for clearing excess cardiac iron, and also safe. Cases of fatal, acute, irreversible renal and liver failure, fatal agranulocytosis and other toxicities have recently been reported with DFRA. The FDA has not yet approved deferiprone (L1) depriving thousands of patients of potentially life saving treatment. The high cost of DFRA at 60 euros/g, L1 at 5.5 euros/g and deferoxamine (DFO) at 8.3 euros/g, diminishes the prospects of universal chelation therapy, especially for patients in developing countries. The safety and efficacy record of L1, DFO, and their combination in particular, appear to provide universal solutions in the treatment of transfusional iron overload, and also in reducing mortality because of their ability to clear rapidly and effectively excess cardiac iron.

Consequences and costs of noncompliance with iron chelation therapy in patients with transfusion-dependent thalassemia: a literature review.

BACKGROUND: Patients with thalassemia major require iron chelation therapy (ICT) to prevent complications from transfusional iron overload. Deferoxamine is effective, but requires administration as a slow continuous subcutaneous or intravenous infusion five to seven times per week. Deferiprone is a three-times-daily oral iron chelator, but has limited availability in the United States. Deferasirox is a once-daily oral iron chelator that was approved in the United States in 2005 for patients older than 2 years of age with transfusional iron overload. STUDY DESIGN AND METHODS: Published evidence on rates of compliance with ICT and the association between compliance, and the incidence and costs of complications of iron overload, in patients with thalassemia major was reviewed. RESULTS: A total of 18 studies were identified reporting data on compliance with ICT, including 7 that examined deferoxamine only, 6 that examined deferiprone only, and 5 that compared deferoxamine and deferiprone; no studies reporting compliance with deferasirox were identified. In studies of deferoxamine only, estimated mean compliance ranged from 59 to 78 percent. Studies of deferiprone generally reported better compliance, ranging from 79 to 98 percent. Results of comparative studies of deferoxamine and deferiprone suggest that compliance may be better with oral therapy. Numerous studies demonstrate that that poor compliance with ICT results in increased risk of cardiac disease and endocrinopathies, as well as lower survival. Although data on the costs of noncompliance are limited, a recent model-based study estimated the lifetime costs of inadequate compliance with deferoxamine to be $33,142. CONCLUSIONS: Inadequate compliance with ICT in thalassemia major is common and results in substantial morbidity and mortality, as well as increased costs.

Future chelation monotherapy and combination therapy strategies in thalassemia and other conditions. comparison of deferiprone, deferoxamine, ICL670, GT56-252, L1NAll and starch deferoxamine polymers.

Deferiprone (L1), and appropriate combinations with deferoxamine (DFO), can be used effectively for the treatment of thalassemia and other transfusional iron loading conditions. A number of experimental iron chelators such as deferasirox or ICL670 or Exjade (4-(3,5-bis (2-hydroxyphenyl)-1,2,4-triazol-1-yl)-benzoic acid), deferitrin (4,5-dihydro-2-(2,4-dihydroxyphenyl)-4-methylthiazole-4 (S)-carboxylic acid) or GT56-252, 1-allyl-2-methyl-3-hydroxypyrid-4-one or L1NAll and starch DFO polymers, are under clinical evaluation. ICL670 is the most advanced in development and appears to be effective in reducing liver iron in some patients but is overall ineffective in causing negative iron balance. It is also suspected that it is not effective in cardiac iron removal. Combination therapies using L1, DFO and new iron chelating drugs may cause higher efficacy and lower toxicity by comparison to monotherapies. However, several limitations including the high cost of the new chelating drugs may not facilitate the availability of these new treatments to the vast majority of thalassemia patients, most of whom live in developing countries.

Comparison of subcutaneous infusion needles for transfusion-dependent thalassemia patients by the intrapersonal cross-over assessment model.

Needle-induced trauma is one of the major contributing factors for poor compliance in patients with thalassaemia major on iron chelation therapy. A new generation of needles is currently available on the market, but their theoretical advantages have not been tested clinically. We performed a study to compare the pros and cons of the representative prototypes from each of the new (Thalaset needle) and old (butterfly scalp vein needle) generations of needles. Patients with thalassemia major who had been receiving subcutaneous iron chelation therapy for at least 2 years were recruited. Patients using butterfly needles were instructed to switch to the newer form of needle (Thalaset) for 2.5 months and then to change back to butterfly needles for another 2.5 months. Comparison was done by the intrapersonal cross-over model using three identical sets of questionnaires collected at the beginning of the study and after the use of Thalaset and butterfly needles, respectively. Fifty-four (22 females; 32 males) patients were included in the statistical analysis. The median age was 24.1 years (range = 7.6-47.2 years). Local reactions such as pain, itchiness, tenderness, and swelling were significantly different among the three evaluation periods and were all in favor of the Thalaset needle (all with P < 0.001), even after adjusting for the intention-to-treat calculation. The Thalaset needle is significantly better than the butterfly needle in reducing needle-related trauma. It induced fewer local skin reactions such as pain, itchiness, tenderness, and swelling. However, recommendations for its routine clinical use require further cost-effectiveness analysis.

Clinical research: a tale of two studies.

Threats to the status of clinical research have been well documented in the past three decades, and the National Institutes of Health and the Congress have done much to alleviate them. But the relationships of academic investigators and pharmaceutical companies remain a treacherous area. This vital nexus, on which so much progress depends, must be carefully maintained. In this paper I present two examples of academic/pharmaceutical company collaborations, both in search of a similar drug. The cases illustrate both some important hazards and accomplishments of clinical research.

Patients' health or company profits? The commercialisation of academic research.

This paper is a personal account of the events associated with the author's work at the University of Toronto's Hospital for Sick Children on a drug, deferiprone, for the treatment of thalassaemia. Trials of the drug were sponsored by the Canadian Medical Research Council and a drug company which would have been able, had the trials been successful, to seek regulatory approval to market the drug. When evidence emerged that deferiprone might be inadequately effective in a substantial proportion of patients, the drug company issued legal threats when the author proposed informing her patients and the scientific community. Until protests were made by international authorities in her field of research, the hospital and university did not adequately support the author's academic freedom and responsibilities as a medical practitioner. It is argued that underlying cause of this, and of other similar cases, is the political philosophy which is driving the commercialisation of universities and bringing about the deregulation of drug approval procedures. Together these changes constitute a serious threat to the public good.

Synthesis and physicochemical assessment of novel 2-substituted 3-hydroxypyridin-4-ones, novel iron chelators.

Novel 3-hydroxypyridin-4-one containing tridentate ligands were synthesised and their physicochemical properties characterised, including ionisation constants and stoichiometric titration with Fe(III). There is an urgent demand for orally active iron chelators with potential for the treatment of thalassaemia. In principle, tridentate ligands are likely to be more kinetically stable than bidentate molecules, but to date no satisfactory molecules have been identified. Fe(III) stability constants were assessed by competition with the hexadentate ligand EDTA. In all cases no evidence was found for a tridentate mode of iron chelation; instead the ligands behaved as bidentate hydroxypyridinones. As a consequence they provide no advantage over the more simple alkyl hydroxypyridinones.