TY - JOUR
TI - Relation of chelation regimes to cardiac mortality and morbidity in patients with thalassaemia major: An observational study from a large Greek Unit
AU - Ladis, V.
AU - Chouliaras, G.
AU - Berdoukas, V.
AU - Moraitis, P.
AU - Zannikos, K.
AU - Berdoussi, E.
AU - Kattamis, C.
JO - European Journal of Haematology
PY - 2010
VL - 85
TODO - 4
SP - 335-344
PB - Wiley-Blackwell Publishing Ltd
SN - 0902-4441, 1600-0609
TODO - 10.1111/j.1600-0609.2010.01491.x
TODO - deferasirox;  deferiprone;  deferoxamine;  ferritin;  hemoglobin;  iron;  benzoic acid derivative;  deferasirox;  deferiprone;  deferoxamine;  iron;  iron chelating agent;  pyridone derivative;  triazole derivative, adult;  article;  blood transfusion;  cardiovascular risk;  chelation therapy;  female;  ferritin blood level;  Greece;  heart death;  heart disease;  heart failure;  human;  iron blood level;  iron overload;  major clinical study;  male;  morbidity;  mortality;  nuclear magnetic resonance;  observational study;  priority journal;  thalassemia major;  adolescent;  age;  beta-Thalassemia;  blood;  child;  comparative study;  complication;  death;  Heart Diseases;  iron overload;  nuclear magnetic resonance spectroscopy;  pathophysiology;  treatment outcome;  young adult, Adolescent;  Adult;  Age Factors;  Benzoates;  beta-Thalassemia;  Blood Transfusion;  Child;  Death;  Deferoxamine;  Female;  Greece;  Heart Diseases;  Humans;  Iron;  Iron Chelating Agents;  Iron Overload;  Magnetic Resonance Spectroscopy;  Male;  Pyridones;  Treatment Outcome;  Triazoles;  Young Adult
TODO - Objectives: Cardiac complications because of transfusional iron overload are the main cause of death in thalassaemia major. New chelators and iron monitoring methods such as cardiac magnetic resonance (CMR) became available after the year 2000. We evaluated the impact of these new management options on cardiac mortality and morbidity. Methods: The risk of cardiac death during 1990-1999 and 2000-2008 was compared. Furthermore, after 1999, morbidity, mortality and reversal of heart failure were evaluated according to chelation regime: desferrioxamine (DFO), deferiprone (DFP) and combination therapy of DFO and DFP. We also present preliminary results for deferasirox (DFX), a new oral chelator. Results: Three hundred and fifty-four patients were included in the de novo cardiac event evaluation, while 86 were included in the improvement component. The annual risk of cardiac death in patients aged between 20-30 and 30-40 reduced from 1.52% to 0.67% and 1.87% to 0.56%, respectively, before and after the year 2000. The risk for a de novo cardiac event for DFO was 9.1 times greater than that of DFP and 23.6 than with the combination of DFP and DFO. For DFX, there was one cardiac event over 269 patient-years. The risk of cardiac death was 9.5 per 1000 patient-years for DFO, 2.5 on DFP, 1.4 on combination. In the DFX group no cardiac deaths were recorded. The odds of improvement were 8.5 times greater with DFP and 6.1 with combination therapy compared to DFO. Conclusions: The new chelation regimes, together with CMR have contributed significantly to the reduction in cardiac morbidity and mortality in patients with thalassaemia major. © 2010 John Wiley & Sons A/S.
Patients:The risk of cardiac death analysis: n=1124, 597 in 1990-1999 (only Desferal was available) and 527 in 2000-2008 (Desferal, DFP or combination of both were available). De novo cardiac event analysis: n=354; 343 were on Desferal (176 males and 167 females, mean age 21.2 years; 338 in 1999, 316 in 2000, 282 in 2001, 246 in 2002, 189 in 2003, 147 in 2004, 111 in 2005, 69 in 2006, 43 in 2007 and 33 in 2008), 97 DFP (46 males and 51 females, mean age 25.3 years; 2 in 2000, 16 in 2001, 18 in 2002, 42 in 2003, 63 in 2004, 58 in 2005, 50 in 2006, 35 in 2007 and 43 in 2008), and 166 Desferal/DFP combination (79 males and 87 females, mean age 26.7 years; 4 in 2000, 17 in 2001, 40 in 2002, 63 in 2003, 69 in 2004, 92 in 2005, 115 in 2006, 99 in 2007 and 98 in 2008). Improvement component analysis: n=86, 75 Desferal (51 males and 24 females, mean age 26.8 years; 39 in 2000, 42 in 2001, 32 in 2002, 21 in 2003, 19 in 2004, 11 in 2005, 7 in 2006, 5 in 2007 and 4 in 2008), DFP group (21 males and 14 females, mean age 31 years; 1 in 2000, 1 in 2001, 6 in 2002, 12 in 2003, 16 in 2004, 15 in 2005, 14 in 2006, 11 in 2007 and 9 in 2008) and 61 Desferal/DFP (36 males and 25 females, mean age 30.1 years; 1 in 2001, 14 in 2002, 24 in 2003, 24 in 2004, 34 in 2005, 38 in 2006, 36 in 2007 and 29 in 2008).
Indications:An unspecified number of patients with transfusional iron overload and cardiac hemosiderosis (characterized by heart failure) and for the prevention of cardiac events. Coexisting disease was thalassemia in all patients.
FreeText:All patients received blood transfusion. DFP was given at 75-100 mg/kg daily in 3 divided doses. An unspecified number of patients received DFP concomitantly. Combinations were given at similar doses as with monotherapy, 8-24 hourly infusions/3-7 times per week. Ferritin levels were evaluated. Cardiac (CMR) and hepatic magnetic resonance imaging (MRI) were used to evaluate the degree of cardiac and hepatic iron loading (liver iron concentration [LIC]). Cardiac function was assessed by symptomatology, clinical examination, chest X-rays, electrocardiograms (ECGs) and echocardiography. The risk of cardiac death between 1990-1999 and 2000-2008 was compared in all patients with thalassemia regardless of the chelation regime. The risk of cardiac death (CD) was evaluated in 2 age groups for each time period (20-30 years [yr] vs. 30-40 yr). The assessment of the incidence of de novo cardiac events (CEs) according to the chelation regime was conducted in patients with thalassemia older than 10 years. The development of a CE and the risk of CD in relation to the chelation regime were evaluated. The sum of patients in all groups was greater than the total number of patients in this study.
DosageDuration:20-40 mg/kg per infusion with at least 3 (3-5) infusions per week. Duration: not stated.
TypeofStudy:An open study evaluating the impact of chelation regimes (Desferal, deferiprone [DFP] and combination of both) on cardiac mortality and morbidity and reversal of heart failure in patients with thalassemia major from 1990-2008. An open, observational study from a large Greek Unit.
ComparativeDrug:Deferiprone was given 75-100 mg/kg daily orally in 3 divided doses. Duration: not stated.
Results:The risk of cardiac-related death during 1990-1999 vs. 2000-2008 for the 20-30 years (yr) old and 30-40 yr old were 15.2 and 18.7 vs. 6.7 and 5.6, respectively; the rate of death were 30 and 5 vs. 14 and 8, respectively. 63 de novo CEs were noted: 58 Desferal (16 in 1999, 8 in 2000, 13 in 2001, 7 in 2002, 5 in 2003, 6 in 2004, 1 in 2005, 2 in 2006, 1 in 2007 and 0 in 2008), 1 DFP (2003) and 1 Desferal/DFP (2006). Patients on DFP and Desferal/DFP had 9.1 times and 23.6 times, respectively, lower risk of de novo CE vs. Desferal. Patients on any DFP (DFP or Combination) showed 14 times lower risk vs. Desferal group. The odds ratio (OR) for the development of CEs of Desferal vs. DFP groups in patients with mild, moderate and severe hemosiderosis were 3, 3.2 and 10.3, respectively; in Desferal vs. Desferal/DFP groups, 8.9, 9.1 and 9.1, respectively. For Desferal/DFP, the effect was similar in all severities of iron load while for DFP the protective effect is more prominent in severe iron load. The rates of events were 3.3/100 person-years for Desferal (58 events median time on Desferal = 2.4 yr), 0.3/100 person-years for DFP (1 event in a patient after 4 yr on DFP), 0.6/100 person-years for Desferal/DFP (3 events in 3 patients who had been for 6 months, 73 and 35 days, respectively, on combination therapy). In all patients with cardiac improvement and those who have not been included as an improvement, the left ventricular ejection fraction normalized (>60%). Combined 9-yr data revealed that DFP patients were 8.5 times more likely to improve vs. Desferal patients, while those on combination had a 6.1 time greater likelihood. The patients on any DFP had a 6.7 times greater chance of improving vs. Desferal. Increasing level of hemosiderosis reduced the likelihood of improvement. The rates of improvement were 0.6/100 person-years for Desferal, 13.9/100 person-years for DFP, 6/100 person-years for Desferal/DFP. Overall, after 1999, 22 deaths occurred: 20 cardiac-related and 2 other causes (1 accident and 1 thromboembolic event). There were 18 CDs in the Desferal group over 1900 patient-years (risk = 9.5/1000 patients-years, median time of exposure = 2.6 yr), on the DFP group for 393 patient-years (risk = 2.5/1000 patients-years, the 1 death occurred in a patient after 1.3 yr on DFP) and 1 in the Desferal/DFP group over 709 patient-years (risk = 1.4/1000 patients-years, the 1 death occurred in a patient after 4.1 yr on combination therapy). When adjusted for sex and degree of hemosiderosis, the relative risks (RR) of experiencing CD were: Desferal 6.1 RR and 5.7 RR compared to DFP and combination, respectively (marginally non-significant). The RR for Desferal vs. DFP and Desferal/DFP was 5.2.
AdverseEffects:No adverse events were mentioned.
AuthorsConclusions:New chelation options in patients with thalassaemia have reduced cardiac morbidity and mortality. Cardiac deaths have reduced in many centres throughout the world since the year 2000. The newer chelation regimes demonstrate lower risk of cardiac events. In the past, the onset of cardiac failure in patients with thalassaemia usually progressed to death within a short period of time. This study clearly demonstrates that a significant proportion of patients who developed cardiac events, were able to regain normal cardiac function with appropriate therapy. The new regimes together with better non-invasive diagnostic facilities for identifying both hepatic and cardiac iron load are expected to improve survival even further and reduce incidence and severity of complications caused by haemosiderosis.
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