ALBERT

Description: Background. Transfusion-dependent thalassemic patients require chelation therapy to treat iron overload and prevent its complications. Deferoxamine (DFO) is an effective iron chelator, but must be administered as an 8–12 hour infusion 5–7 times per week, leading to poor compliance and/or reduced quality of life. Deferasirox (DSX) is an investigational once-daily oral chelator that has been shown to produce reductions in liver iron concentrations and serum ferritin similar to those obtained with DFO. Cost-effectiveness analysis is a technique used to determine whether the benefits of new therapies are worth their additional costs. The objective of this analysis was to evaluate from a US perspective the cost-effectiveness (CE) of DSX vs DFO in patients with transfusion-dependent thalassemia. Methods. A decision-analysis model was used to estimate the total additional lifetime costs and quality-adjusted life year (QALY) gained with DSX versus DFO in patients with transfusion-dependent thalassemia (≥8 transfusions per year). Compliant patients were assumed to receive dosages of DSX and DFO that have been shown to be similarly effective in such patients. Probabilities of complications of iron overload and death by average compliance with chelation were estimated using data from published studies. Compliance with DFO and costs of complications of iron overload and DFO administration were based on analyses of health insurance claims data of transfusion-dependent thalassemic patients. Because data on compliance with DSX in typical clinical practice are unavailable, to be conservative, we used published data on compliance with the three-times-daily oral chelator deferiprone vs DFO. Utilities (weights representing patient quality of life) were obtained from a study that used time-trade-off techniques to measure patient preferences for oral vs infusional chelation therapy, as well as published literature and assumption. Analyses were based on the wholesale acquisition cost of generic DFO and the anticipated cost of DSX in the US. Results were generated alternatively for DFO-naïve patients (age 5 years, no prior DFO therapy) and DFO-experienced patients (age 17 years [mean of thalassemia patients in DSX trials] and 12 years of prior DFO therapy). Costs and QALYs were discounted at 3% annually. Results. In DFO-naïve patients, DSX results in a gain of 4.4 QALYs per patient. These benefits are obtained at an additional expected lifetime cost of $165,207 per patient. CE is $37,516 per QALY gained. In DFO-experienced patients, the benefits of DSX are attenuated by prior inadequate chelation with DFO, with DSX resulting in a gain of 2.7 QALYs per patient at an additional expected lifetime cost of $143,832 per patient. CE in DFO-experienced patients is $53,239 per QALY. Conclusion: The CE of DSX vs DFO in patients with transfusion-dependent thalassemia is favorable compared with other generally-accepted treatments for patients with hematologic/oncologic disorders (e.g., rHuEPO for chemotherapy-induced anemia). Results were most favorable for DSX in DFO-naïve patients, suggesting that earlier initiation of DSX may be more cost-effective.

Description: Background. Patients with thalassemia receiving chronic transfusions require chelation therapy to prevent complications from iron overload. Although deferoxamine (DFO) is an effective iron chelator, its poor bioavailability and short plasma half-life require that it be administered as a slow continuous subcutaneous or intravenous infusion over an 8–12 hour period 5–7 times per week. This burdensome regimen leads to poor compliance and/or quality of life in many patients. The objective of this study was to document the lifetime clinical and economic consequences of inadequate compliance with DFO in patients with transfusion-dependent thalassemia. Methods. We used data from published studies to estimate the lifetime incidence of complications of iron overload that are attributable to inadequate compliance with DFO therapy in patients with transfusion-dependent thalassemia. Complications considered included cardiac disease, diabetes, hypothyroidism, hypogonadism, hypoparathyroidism, and death due to cardiac disease. Current compliance with DFO therapy as well as costs of complications were obtained from an analysis of health insurance claims data of patients with transfusion-dependent thalassemia. Adequate compliance was defined as 260 infusions per year (i.e., five per week). Costs were discounted at 3% annually. Results. Current DFO use was estimated to be 169 infusions per year on average (3.25 per week). Based on this level of DFO use, 95% of patients with transfusion-dependent thalassemia are projected to experience cardiac disease during their lifetime. Diabetes is projected to be experienced by 28%, hypothyroidism by 25%, hypogonadism by 63%, and hypoparathyroidism by 22%. Cardiac-disease-free life expectancy is projected to be 22 years; overall life expectancy, 28 years. The discounted expected lifetime cost of complications of iron overload is projected to be $51,956 per patient. If use of DFO therapy were to increase to 260 infusions per year on average, the lifetime risk of cardiac disease would decline to 61%. The lifetime risks of diabetes, hypothyroidism, and hypoparathyroidism would to decline to 23%, 15%, and 9% respectively. Cardiac-disease-free life expectancy would improve to 44 years. Overall life expectancy would improve to 47 years. The lifetime risk of hypogonadism would increase to 72% as a consequence of longer life expectancy. The discounted expected lifetime medical care costs of complications of iron overload would be reduced to $35,875. Life expectancy lost as a consequence of inadequate compliance is estimated to be approximately 18 years. Conclusions. Inadequate compliance with DFO therapy in patients with transfusion-dependent thalassemia results in substantial morbidity and mortality, as well as increased medical care costs associated with complications of iron overload. Our estimates of the economic consequences of inadequate compliance are conservative, as they do not include other direct non-medical care costs (e.g., caregiver costs), or the costs of lost productivity associated with morbidity and premature mortality. An effective iron chelator that is less burdensome to administer than DFO may result in substantial clinical and economic benefits.

Description: Traditionally, statistical procedures have been derived via analytic calculations whose validity often relies on sample size growing to infinity. We use tools from deep learning to develop a new approach, adversarial Monte Carlo meta-learning, for constructing optimal statistical procedures. Statistical problems are framed as two-player games in which Nature adversarially selects a distribution that makes it difficult for a statistician to answer the scientific question using data drawn from this distribution. The players’ strategies are parameterized via neural networks, and optimal play is learned by modifying the network weights over many repetitions of the game. Given sufficient computing time, the statistician’s strategy is (nearly) optimal at the finite observed sample size, rather than in the hypothetical scenario where sample size grows to infinity. In numerical experiments and data examples, this approach performs favorably compared to standard practice in point estimation, individual-level predictions, and interval estimation.