Risk factors for endocrine complications in transfusion-dependent thalassemia patients on chelation therapy with deferasirox: a risk assessment study from a multi-center nation-wide cohort.

Transfusion-dependent patients typically develop iron-induced cardiomyopathy, liver disease, and endocrine complications. We aimed to estimate the incidence of endocrine disorders in transfusiondependent thalassemia (TDT) patients during long-term iron-chelation therapy with deferasirox (DFX). We developed a multi-center follow-up study of 426 TDT patients treated with once-daily DFX for a median duration of 8 years, up to 18.5 years. At baseline, 118, 121, and 187 patients had 0, 1, or ≥2 endocrine diseases respectively. 104 additional endocrine diseases were developed during the follow-up. The overall risk of developing a new endocrine complication within 5 years was 9.7% (95% Confidence Interval [CI]: 6.3-13.1). Multiple Cox regression analysis identified three key predictors: age showed a positive log-linear effect (adjusted hazard ratio [HR] for 50% increase 1.2, 95% CI: 1.1-1.3, P=0.005), the serum concentration of thyrotropin showed a positive linear effect (adjusted HR for 1 mIU/L increase 1.3, 95% CI: 1.1-1.4, P<0.001) regardless the kind of disease incident, while the number of previous endocrine diseases showed a negative linear effect: the higher the number of diseases at baseline the lower the chance of developing further diseasess (adjusted HR for unit increase 0.5, 95% CI: 0.4-0.7, P<0.001). Age and thyrotropin had similar effect sizes across the categories of baseline diseases. The administration of levothyroxine as a covariate did not change the estimates. Although in DFX-treated TDT patients the risk of developing an endocrine complication is generally lower than the previously reported risk, there is considerable risk variation and the burden of these complications remains high. We developed a simple risk score chart enabling clinicians to estimate their patients' risk. Future research will look at increasing the amount of variation explained from our model and testing further clinical and laboratory predictors, including the assessment of direct endocrine magnetic resonance imaging.

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.

Why the NIH Trial to Assess Chelation Therapy (TACT) should be abandoned.

The National Institutes of Health (NIH) Trial to Assess Chelation Therapy (TACT) was begun in 2003 and is expected to be completed in 2009. It is a trial of office-based, intravenous disodium ethylene-diamine-tetra-acetic acid (Na(2)EDTA) as a treatment for coronary artery disease (CAD). A few case series in the 1950s and early 1960s had found Na(2)EDTA to be ineffective for CAD or peripheral vascular disease (PVD). Nevertheless, a few hundred physicians, almost all of whom advocate other dubious treatments, continued to peddle chelation as an office treatment. They claim that chelation dramatically improves symptoms and prolongs life in 80% to 90% of patients. In response, academics performed 4 controlled trials during the 1990s. None favored chelation, but chelationists repudiated those findings. We have investigated the method and the trial. We present our findings in 4 parts: history, origin and nature of the TACT, state of the evidence, and risks. We present evidence that chelationists and their organization, the American College for Advancement in Medicine, used political connections to pressure the NIH to fund the TACT. The TACT protocols justified the trial by misrepresenting case series and by ignoring evidence of risks. The trial employs nearly 100 unfit co-investigators. It conflates disodium EDTA and another, somewhat safer drug. It lacks precautions necessary to minimize risks. The consent form reflects those shortcomings and fails to disclose apparent proprietary interests. The trial's outcome will be unreliable and almost certainly equivocal, thus defeating its stated purpose. We conclude that the TACT is unethical, dangerous, pointless, and wasteful. It should be abandoned.

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.

Deaths resulting from hypocalcemia after administration of edetate disodium: 2003-2005.

From 2003 to 2005, deaths of 3 individuals as a result of cardiac arrest caused by hypocalcemia during chelation therapy were reported to the Centers for Disease Control and Prevention. Two were children, both of whom were treated with edetate disodium. At the time of this writing, the adult case was still under investigation. No previous cases of death resulting from hypocalcemia during chelation have been reported. From our experience and review of the literature, we suggest that health care providers who are unfamiliar with chelation consult an expert before undertaking treatment and that hospital formularies evaluate whether stocking edetate disodium is necessary, given the risk for hypocalcemia and the availability of less toxic alternatives.

Management of childhood lead poisoning: clinical impact and cost-effectiveness.

OBJECTIVES: No consensus exists regarding the preferred treatment of childhood lead poisoning. The authors used decision analysis to compare the clinical impacts and cost-effectiveness of four management strategies for childhood lead poisoning, and to investigate how effective chelation therapy must be in reducing neuropsychologic sequelae to warrant its use. METHODS: The model was based on a 2-year-old child with moderate lead poisoning [blood lead level 1.21 to 1.88 mumol/L (25 to 39 micrograms/dL)]. The following strategies were compared: 1) no treatment; 2) EDTA provocation testing, followed by chelation if testing is positive (PROV); 3) penicillamine chelation with crossover to EDTA provocation testing if toxicity occurs (PCA); 4) EDTA provocation testing with crossover to penicillamine chelation if testing is negative (EDTA). RESULTS: The EDTA and PCA strategies prevented 22.5% of the cases of reading disability and resulted in an increase of 1.02 quality-adjusted life years compared with no treatment. When the costs of outpatient EDTA testing and chelation are considered, the EDTA strategy is more cost-effective than the PCA strategy; when inpatient costs are considered, the PCA strategy becomes more cost-effective. When costs of remedial education are considered, all strategies are cost-saving compared with no treatment if chelation reduces the risk of lead-induced reading disability by more than 20%. CONCLUSIONS: Treatment strategies for childhood lead poisoning vary in clinical impact, cost, and cost-effectiveness. Chelation of the 1.4% of United States preschoolers whose blood lead levels are 2.21 mumol/L (25 micrograms/dL) or higher could prevent more than 45,000 cases of reading disability, and save more than $900 million per year in overall costs when the costs of remedial education are considered.