©Ferrata Storti Foundation
Total Page：16
File Type：pdf, Size：1020Kb
Transfusion Iron Overload research paper Comparative effects of deferiprone and deferoxamine on survival and cardiac disease in patients with thalassemia major: a retrospective analysis ANTONIO PIGA, CARMEN GAGLIOTI, EUGENIA FOGLIACCO, FERNANDO TRICTA Background and Objectives. Iron-induced cardiac dis- he iron chelator deferoxamine has been available ease remains the main cause of death in patients with for the treatment of iron overload for more than 3 thalassemia major, despite chelation therapy with defer- decades. Deferoxamine use can prolong survival oxamine. Deferiprone is an iron chelator that has the T potential to be more effective than deferoxamine in remov- and has been shown to ameliorate hepatic, endocrine and cardiac dysfunction in iron-overloaded patients ing intracellular iron from the heart. However, to date, no 1-6 study has been designed to examine the frequency of car- with thalassemia major. However, cardiac disease diac complications and survival as the primary outcomes remains a frequent cause of morbidity among tha- of a comparative study between these two chelators. This lassemia patients1,7 and is still responsible for 70% of retrospective study assessed the survival and the occur- deaths.8 Compliance with regular chelation therapy, as rence of cardiac disease in all patients with thalassemia determined by the ability to perform more than 265 major treated for at least 4 years with deferiprone or defer- deferoxamine infusions per year1 or maintenance of oxamine at a single center. most serum ferritin values below 2500 µg/L, has been Design and Methods. The patients were, on average, identified as an important factor in limiting the inci- 18.4 years old at the start of the review period and were dence of cardiac disease and prolonging the survival followed up, on average, for 6 years. At baseline there was among patients with thalassemia major.7,9 The age at no significant difference in the percentage of patients the start of chelation therapy and the hepatic iron con- with cardiac disease in the two therapy groups. centration have also been suggested as factors which Results. At the end of the study, cardiac dysfunction, could affect the development of cardiac disease.4,8 expressed as worsening of pre-existing cardiac abnor- Although optimization of subcutaneous deferoxamine mality or development of new cardiac disease, was diag- infusions (needle, pump, adjustment of daily life) has nosed in 2 (4%) of the 54 deferiprone-treated patients been achieved in many centers, the cumbersome nature and in 15 (20%) of the 75 deferoxamine-treated patients, of slow daily subcutaneous infusions of deferoxamine, from the first to the last measurement (p = 0.007). The and the resulting discomfort and adverse effects, have Kaplan Meier analysis of cardiac disease-free survival prevented optimal compliance in approximately 50% over the 5-year period was significantly more favorable in 1,10 the deferiprone group (p = 0.003). of patients. Interpretation and Conclusions. None of the patients Deferiprone (L1, 1,2-dimethyl-3-hydroxypyrid-4-one) treated with deferiprone died, while 3 of the patients treat- is an orally active chelator, which has been recently ed with deferoxamine died because of irreversible wors- approved in Europe for the treatment of iron overload. ening of their cardiac condition during the study period. As a small, lipophilic bidentate molecule, deferiprone Findings from this study suggest that long-term therapy would theoretically have the potential to be more effec- with deferiprone provides a greater cardio-protective effect tive than deferoxamine in removing intracellular iron against the toxicity of iron overload than does subcuta- from some tissues, as has been demonstrated in the neous deferoxamine. Formal prospective studies are war- case of red cell membranes.11,12 Link et al. reported that ranted to confirm this effect. deferiprone, at concentrations achieved in humans with standard doses, was more effective than deferoxamine Key words: thalassemia, chelation, iron, deferiprone, in removal of iron from iron-loaded neonatal rat myo- deferoxamine. cytes.13 These data from in vitro and animal studies are con- Haematologica 2003; 88:489-496 sistent with those from clinical studies that report a http://www.haematologica.org/2003_05/489.htm low rate of iron-induced clinical complications during deferiprone therapy.11-19 However, to date, no study has ©2003, Ferrata Storti Foundation been designed to examine the frequency of cardiac complications and survival as the primary outcomes of a comparative study of deferoxamine and deferiprone. From the Department of Pediatric Hematology, University of Turin, Italy These observations constituted the rationale for (AP, CG, EF), Apotex Research Inc, Canada (FT). designing a study to compare mortality and cardiac Correspondence: Antonio Piga, MD, Department of Pediatric Hematology, morbidity in patients with thalassemia treated long- University of Turin, Italy. E-mail: [email protected] term with either deferoxamine or deferiprone. haematologica/journal of hematology vol. 88(05):may 2003 489 A. Piga et al. Design and Methods 12-hour subcutaneous infusion, 4-7 days a week. Three patients in the deferoxamine group had their Study design chelation intensified with intravenous chelation A retrospective analysis was conducted on sur- during the study period. Despite the intensive vival and occurrence of cardiac disease in all chelation with deferoxamine they were not exclud- patients with thalassemia major treated for at least ed from the analysis. Compliance with subcuta- 4 years with deferiprone or deferoxamine at a sin- neous deferoxamine therapy was assessed at each gle center between 31 January 1995 and 29 March transfusional event by the following: 2001. The medical records of patients aged ≥ 5 • comparison of number of infusions reported by years at the time of the start of the review period, the patient with the number prescribed; with a diagnosis of thalassemia major confirmed by • examination of infusion sites; laboratory tests (electrophoresis and/or DNA analy- • number of completed infusions recorded by a sis) and appropriate clinical enrollment criteria special electronic pump (Crono®, Canè S.r.l, (hemoglobin and transfusion dependency) were Italy); evaluated. Patients with congenital anemias other • pharmacy records of syringes and needles dis- than thalassemia major, who were HIV-positive, pensed. who had a history of malignancy or who required Deferiprone (Ferriprox®, Apotex Inc.) was pre- radiation or chemotherapy were not included in scribed at the dose of 25-100 mg/kg/day, divided the analysis. in three doses. Compliance was assessed at each Patients were excluded from the data analysis transfusional event by the electronic MEMS® cap for the following reasons: chelation therapy with (Medication Event Monitoring System, Ardex Ltd, one of the chelators for less than 4 years during the Switzerland), which records the time and date of review period; no information available on chela- each opening of the deferiprone container. Com- tion therapy or cardiac status; only 1 cardiac pliance for patients participating in clinical trials assessment; age <5 years at the start of the review was also measured by monthly counts of the num- period (6 patients); HIV-positive status. ber of deferiprone tablets dispensed and returned. The Regional Ethical Review Board approved the Regular determinations of serum ferritin level study. All eligible patients or their guardians gave were used to monitor basic iron overload in all authorization for the review of their medical patients. The treating hematologist used all the records. above information during regular interviews with each patient as part of the clinical management of Patients thalassemia and to promote compliance. All patients received the same transfusion regi- men, aimed at maintaining pre-transfusion hemo- Cardiac assessments globin levels at 9.5 -10.0 g/dL and the mean hemo- A single cardiologist, experienced in hemoglo- globin at 12.0 g/dL. A software program, previous- binopathies but blind to the therapy that the ly designed for thalassemia-oriented clinical patients were receiving, assessed the cardiac sta- records, calculated the annual transfusional iron tus of all patients. The standard assessment includ- input on the basis of the net weight and hematocrit ed physical examination, ECG, echocardiogram, and of the blood transfused.20 cardiac status based on the criteria of the New York All patients were treated with deferoxamine Heart Association (NYHA).21 When indicated, a 24- until January 1995, when some were switched to hour electrocardiographic Holter and/or stress test deferiprone because they were enrolled in clinical were also performed. The treating physician sys- trials, or their clinical condition required the drug. tematically screened the clinical records of each For those patients who were treated with patient followed at the center. All patients who deferiprone as part of clinical studies, the major had had at least two cardiac assessments were criteria of their inclusion into the studies were age evaluated, even if their first assessment was com- (10 years of age or older), the severity of the body pleted after the initiation of the study period. The iron load (serum ferritin level >2000 ng/µL or liv- first assessment was considered as the baseline er iron concentration >4 mg/g dry weight) and value for each patient. The records of patients with inability to use deferoxamine