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.

Effectiveness, safety, and cost of partial exchange transfusions in patients with sickle-cell anemia at a sickle cell disease center in sub-Saharan Africa.

The partial exchange transfusions necessary for management of some sickle-cell complications raise the issue of effectiveness in the context of limited resources and inadequate blood safety. This study evaluated the effectiveness, safety, and cost of partial exchange transfusions in 39 patients with sickle-cell anemia in Lubumbashi, looking at the patients' age and gender and the tolerability and direct cost of the transfusions. Excel and SPSS 18 were used for data entry and analysis. Chi2 and Fisher exact tests were used for comparisons. A P-value ≤ 5% was considered statistically significant. The average age of patients was 8.6 ± 6.4 years, and the majority were girls. The most frequent indications were stroke, severe infections, severe vasooclusive crises, and acute chest syndrome. Partial exchange transfusions were effective in improving hemoglobin and hematocrit as well as the percentage of HbS. No acute accident was observed during any partial exchange transfusion; one anti-Kell alloimmunization and 2 cases of iron overload were observed. The annual cost of partial exchange transfusions per patient requiring (and able to afford) regular treatment was US $ 3,345 without iron chelation and more than US $ 5000 with chelation. Partial exchange transfusions are effective and tolerated, but financially inaccessible to the majority of our sickle cell patients. Thus, an assessment is needed of the economic burden of sickle cell complications that require partial exchange transfusions in the context of countries with limited financial resources.

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.

Medical complications, resource utilization and costs in patients with myelofibrosis by frequency of blood transfusion and iron chelation therapy.

Iron chelation therapies (ICTs) can help eliminate iron surplus in erythrocyte transfusion-dependent (TD) patients with myelofibrosis (MF). The study assessed adjusted incidence rate ratios (aIRRs) of MF-related complications and resource utilization (RU) and adjusted mean monthly inpatient cost differences in patients with TD MF treated with versus without ICT (ICT+ vs. ICT-) using data from two healthcare claims databases. Patients with ≥ 2 MF International Classification of Diseases, 9th Revision (ICD-9) diagnosis codes ≥ 30 days apart were included. Among 571 patients with TD MF, 103 (18%) were ICT+ and 468 (82%) were ICT-. ICT+ patients had lower rates of thrombocytopenia (aIRR: 0.55; p < 0.001), pancytopenia (0.53; p < 0.001), emergency room visits (0.84 [95% confidence interval: 0.74-0.96]) and inpatient stays (0.75 [0.64-0.87]), but higher rates of outpatient visits (1.21 [1.18-1.23]). Adjusted mean complication-related inpatient cost difference per month was lower in ICT+ patients (-$1804 [$570]; p = 0.004). ICT+ patients had significantly lower rates of acute care, but higher rates of outpatient care.

Management of hyperphosphataemia in chronic kidney disease: summary of National Institute for Health and Clinical Excellence (NICE) guideline.

Bone disease and ectopic calcification are the two main consequences of hyperphosphataemia of chronic kidney disease (CKD). Observational studies have demonstrated that hyperphosphataemia in CKD is associated with increased mortality. Furthermore, the use of phosphate binders in dialysis patients is associated with significantly lower mortality. The UK Renal Registry data show significant underachievement of phosphate targets in dialysis patients. It is believed to be due to wide variation in how management interventions are used. The National Institute for Health and Clinical Excellence (NICE) has developed a guideline on the management of hyperphosphataemia in CKD. This is based on the evidence currently available using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology. This review outlines the recommendations including research recommendations and discusses methodology, rationale and challenges faced in developing this guideline and the health economic model used to assess the cost-effectiveness of different phosphate binders.

Predicted costs of iron-chelators in myelodysplastic syndromes: a 10-year analysis based on actual prevalence and red cell transfusion rates.

Consideration of iron-chelation (IC) in transfusion-dependent patients is recommended in most clinical-practice guidelines on myelodysplastic syndromes (MDS). The financial impact of IC on health-care systems is predicted through economic modeling, but an analysis based on actual prevalence is lacking. Here, we have investigated the potential drug-costs and need for IC in a cohort of 189 United Kingdom-based MDS patients diagnosed from 2000 to 2010. Patients with low or intermediate-1 IPSS scores were identified as eligible for IC if ≥24 red cell units (RCU) had been transfused over 12 consecutive months or the transfusion-intensity averaged ≥2 RCU per month. Drug-costs were calculated from the time patients qualified for IC until death or last follow-up. In 159 patients with low/intermediate-1 MDS, survival was superior with a low IPSS score (P = 0.014), age <70 years (P = 0.043), transfusion-independence at diagnosis (P = 0.0056) and transfusion-intensity of <2 RCU per month (P = 0.009). Reflecting the time elapsed since diagnosis, longer survival was observed with a cumulative red cell load of ≥75 U (P = 0.046). By logistic-regression analysis, transfusion-intensity independently predicted survival (P = 0.0035) in low and intermediate-1 risk MDS patients. Forty-one patients fulfilled criteria for consideration of IC. Of these, 6 patients died within 1 month; 35 patients survived for a median of 16 months (range 1-61). Had patients commenced IC, the anticipated drug-costs alone would have been ~$526,880-$2,064,800 over 10 years. The lack of association between cumulative transfusion-load and survival calls for a prospective evaluation of the cost-utility of IC in patients surviving long-term, to enable evidence-based recommendations in MDS management.

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.

Current status in iron chelation in hemoglobinopathies.

Although blood transfusions are important for patients with hemoglobinopathies, chronic transfusions inevitably lead to iron overload as humans cannot actively remove excess iron. The cumulative effects of iron overload lead to significant morbidity and mortality, if untreated. Desferrioxamine (DFO) is the reference-standard iron chelator whose safety and efficacy profile has been established through many years of clinical use. DFO side effects are acceptable and manageable however the prolonged subcutaneous infusion regimen of 5-7 days per week is very demanding and results in poor adherence to therapy. Deferiprone (Ferriprox, L1) is a bidentate molecule, orally administrable three-times/day, licensed in Europe and in other regions but in the USA and Canada, for the treatment of iron overload in patients for whom DFO therapy is contraindicated or inadequate. Preliminary evidences suggest that Deferiprone may be more effective than DFO in chelating cardiac iron. The side effects include gastrointestinal symptoms, liver dysfunction, joint pain, neutropenia and agranulocytosis. A weekly assessment of white blood cell counts is recommended because of the risk of agranulocytosis. Deferasirox is a new, convenient, once-daily oral iron chelator that has demonstrated in various clinical trials good efficacy and acceptable safety profile in adult and pediatric patients affected by transfusion-dependent thalassemia major and by different chronic anemias (SCD, BDA, MDS). The long half-life of Deferasirox (16-18 hours) provides sustained 24 hr iron chelation coverage. The efficacy and safety profile have been evaluated in more than 1000 patients in clinical trials allowing FDA registration. Patient satisfaction with Deferasirox was superior than with DFO therapy.

[Phosphorus (P) chelant in dialysis: efficacy and cost. Peritoneal dialysis solutions]. / Quelantes de fósforo (P) en diálisis: eficacia y coste. Soluciones de diálisis peritoneal.

Sevelamer use has a high prevalence, and half of patients are treated with this noncalcium binder. Two randomized studies appeared in 2007 that compared the efficacy of sevelamer over calcium salts. In the more statistically potent of the two studies, no differences were found in mortality between the sevelamer and calcium groups, except for a benefit in favor of sevelamer in patients older than 65 years. In the other less statistically potent study, lower mortality was observed in the sevelamer group. Both studies have various deficiencies and a timely meta-analysis of the two studies appearing that same year concluded that there was no significant evidence demonstrating a superior efficacy of sevelamer over calcium salts. Therefore, generalized extension of its use as a first-line binder is not recommended. However, its use can be assessed in specific clinical situations. With regard to the cost-benefit ratio, as there is no evidence that greater clinical benefits are obtained with sevelamer than with calcium salts, prudence and moderation in its use are needed because of the high cost/benefit ratio demonstrated. Otherwise, we will contribute to increasing the already very high treatment cost in these patients, with one of the highest costs per life year gained in medicine. The cost/benefit ratio of sevelamer remains unattractive from an economic point of view, even if dialysis and transplant are excluded in these patients.

Iron chelation therapy: clinical effectiveness, economic burden and quality of life in patients with iron overload.

INTRODUCTION: This study of UK patients examines clinical, health-related quality of life (HRQOL) and economic outcomes associated with iron chelation therapy (ICT). Desferrioxamine (DFO) (Desferal; Novartis, Switzerland) and Deferiprone (Ferriprox; Apotex, Canada) are ICTs used to treat iron overload. DFO requires 8-to 12-hour infusions a minimum of five times per week. Deferiprone is administered in an oral daily regimen. Although pharmacologically efficacious, clinical effectiveness of ICT within the real-world setting is yet to be fully elucidated. METHODS: A naturalistic cohort study of 60 patients (beta-thalassaemia, n=40; sickle cell disease, n=14; myelodysplastic syndromes, n=6; 63% female) receiving ICT in four UK treatment centres was conducted. Serum ferritin level data were abstracted from medical charts. Compliance, HRQOL, satisfaction and resource utilisation data were collected from interviews. Maximum ICT costs were estimated using the resource utilisation data associated with DFO. RESULTS: Mean serum ferritin levels, generally, remained elevated despite ICT. Compliance was suboptimal and HRQOL scores were lower than population norms. The total estimated mean weighted annual per-patient cost of DFO treatment was approximately pound19,000. DFO-related equipment, DFO drug, and home healthcare were estimated to account for 43%, 19% and 24% of costs, respectively. Other more minor components of total annual costs were for in-patient infusions, ICT home delivery services and monitoring costs. CONCLUSION: Generally, patients are not achieving target serum ferritin thresholds despite chronic treatment for iron overload. ICT appears to negatively impact HRQOL; compliance with ICT is poor; and, in the case of DFO, treatment costs well exceed the cost of DFO alone. These results suggest that current ICT in the real-world setting is suboptimal with respect to various clinical, HRQOL and economic outcomes.

Costs, quality of life, treatment satisfaction and compliance in patients with beta-thalassemia major undergoing iron chelation therapy: the ITHACA study.

OBJECTIVES: Iron chelation treatment (ICT) in beta-thalassemia major (beta-TM) patients undergoing blood transfusions can cause low satisfaction, low compliance, with possible negative consequences on treatment success, patients' wellbeing, and costs. The purpose was to estimate the societal burden attributable to beta-TM in terms of direct and indirect costs, health-related quality-of-life (HRQoL), satisfaction and compliance with ICT in patients undergoing transfusions and ICT. RESEARCH DESIGN AND METHODS: The naturalistic, multicenter, longitudinal Italian-THAlassemia-Cost-&-Outcomes-Assessment (ITHACA) cost-of-illness study was conducted involving patients of any age, on ICT for at least 3 years, who were enrolled at 8 Italian Thalassemia Care Centers. Costs were estimated from the societal perspective, quantified with tariffs, prices, or net earnings valid in 2006. RESULTS: One-hundred and thirty-seven patients were enrolled (median age = 28.3, 3-48 years, 49.6% male) and retrospectively observed for a median of 11.6 months. Mean direct costs were euro1242/patient/month, 55.5% attributable to ICT, 33.2% attributable to transfusions. Relevant quantity and quality of productivity was lost. Both physical and mental components of HRQoL were compromised. Little difficulties remembering to take ICT and positive satisfaction with the perceived effectiveness of therapy were declared, but not good levels of satisfaction with acceptance, perception of side effects and burden of ICT. CONCLUSIONS: The management of beta-TM patients undergoing transfusions and ICT is efficacious, although costly, but overall benefits were not always perceived as optimal by patients. Efforts must be focused to improve patients' acceptance and satisfaction with their therapy; this would contribute to a better compliance and hence an increase in treatment effectiveness and patients' overall wellbeing, with expected improved allocation of human and economic resources.

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.

Outcomes, utilization, and costs among thalassemia and sickle cell disease patients receiving deferoxamine therapy in the United States.

Deferoxamine mesylate (DFO) reduces morbidity and mortality associated with transfusional iron overload. Data on the utilization and costs of care among U.S. patients receiving DFO in typical clinical practice are limited however. This was a retrospective study using a large U.S. health insurance claims database spanning 1/97-12/04 and representing 40 million members in >70 health plans. Study subjects (n = 145 total, 106 sickle cell disease [SCD], 39 thalassemia) included members with a diagnosis of thalassemia or SCD, one or more transfusions (whole blood or red blood cells), and one or more claims for DFO. Mean transfusion episodes were 12 per year. Estimated mean DFO use was 307 g/year. Central venous access devices were required by 20% of patients. Cardiac disease was observed in 16% of patients. Mean total medical costs were $59,233 per year including $10,899 for DFO and $8,722 for administration of chelation therapy. In multivariate analyses, potential complications of iron overload were associated with significantly higher medical care costs. In typical clinical practice, use of DFO in patients with thalassemia and SCD receiving transfusions is low. Administration costs represent a large proportion of the cost of chelation therapy. Potential complications of iron overload are associated with increased costs.

Withdrawal of penicillamine from zinc sulphate-penicillamine maintenance therapy in Wilson's disease: promising, safe and cheap.

BACKGROUND: Penicillamine, once considered the cornerstone of treatment for Wilson disease (WD), is rather expensive and toxic, and often causes neurological worsening. Zinc sulphate, aiming at the treatment of free-copper toxicosis, has emerged as effective, safe and cheap alternative. AIM: To assess the effect of withdrawal of penicillamine from maintenance treatment with penicillamine and zinc sulphate. PATIENTS AND METHODS: 45 patients of WD (M:F: 28:17; age at diagnosis: 13.5+/-63 years), on both penicillamine (P) and zinc sulphate (Zn), couldn't continue penicillamine due to financial constraints. Their clinical data, disability and impairment scores (Schwab and England (S&E) score, Neurological Symptom Score (NSS), and Chu staging) and follow-up data of patients maintained only on zinc sulphate were recorded. RESULTS: Majority of patients (84.4%) had neuropsychiatric manifestations. The mean duration of treatment with penicillamine (P) and zinc sulphate (P+Zn), before stopping penicillamine, was 107.4+/-67.3 months. 40 patients improved variably, while the rest didn't. They received only zinc sulphate for 27.2+/-8.5 months (range: 12 to 34) and 44 patients (97.7%) remained status quo or improved marginally. Only one patient reported worsening in dysarthria. Their disability and impairment scores during combination (penicillamine and zinc sulphate) and Zn alone were: Chu (1.3+/-0.5 vs. 1.5+/-1.9; p=0.4), NSS (1.8+/-3.1 vs. 1.5+/-2.3; p=0.03) and S&E (96.4+/-5.6 vs. 98.6+/-3.5; p=0.03). There were no adverse effects. CONCLUSIONS: Withdrawal of penicillamine from zinc sulphate/penicillamine maintenance therapy for patients with Wilson's disease was effective, safe and economic, for almost all patients. This retrospective study reiterates that zinc sulphate may be used as a preferred mode of treatment for patients with Wilson's disease.

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.

The use of complementary and alternative medicines by surgical patients: a follow-up survey study.

UNLABELLED: In a previous study, we indicated that 42% of surgical outpatients are interested in using acupuncture as a treatment modality for preoperative anxiety. We designed this follow-up survey to assess differences in attitude toward complementary-alternative medical therapies (CAM) between patients undergoing outpatient surgeries and those undergoing inpatient surgeries. The results indicate that most surgical patients (57.4%) use some form of CAM, including self-prayer (praying for their own health; 29%), chiropractic treatment (23%), massage therapy (15%), relaxation (14%), herbs (13%), megavitamins (9%), and acupuncture (7%). Inpatient surgical respondents reported using self-prayer more than outpatient surgical respondents, but no other differences in CAM use were found between inpatient and outpatient respondents. More inpatient respondents reported disclosing their usage of CAM to perioperative physicians than did outpatient respondents. Most surgical patients were willing to accept CAM as part of their perioperative management but were not willing to pay out-of-pocket for CAM treatment. The leading CAM therapies that fewer of the respondents were willing to pay for out-of-pocket included relaxation, massage, chiropractic medicine, herbs, and acupuncture. IMPLICATIONS: Most surgical patients use some form of complementary-alternative medical therapies (CAM) and are willing to accept CAM therapy as part of their perioperative management.