A Randomized, Placebo-Controlled, Double-Blind Trial of the Effect of Combined Therapy With Deferoxamine and Deferiprone on Myocardial Iron in Thalassemia Major Using Cardiovascular Magnetic Resonance

Tanner, Mark; Galanello, Renzo; Dessì, Carlo; Smith, Gillian; Westwood, Mark; Agus, Annalisa; Roughton, Michael; Assomull, Ravi; Nair, SV; Walker, John M.; Pennell, Dudley J.

doi:10.1161/circulationaha.106.648790

Cited by 420 publications

(421 citation statements)

References 29 publications

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“…The changes in myocardial siderosis were quantified by myocardial T2* MRI [27,28]. The lower the T2* value in milliseconds (ms), the greater the myocardial iron load (normal value >35 ms; pathologic <25 ms, standard deviation ±20) [29,30].…”

Section: Methodsmentioning

confidence: 99%

Deferasirox in MDS patients with transfusion-caused iron overload—a phase-II study

et al. 2008

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International audienceBlood transfusions represent a main component of supportive care in myelodysplastic syndromes (MDS). To avoid organ damage caused by transfusion-dependent iron overload, an adequate iron chelation therapy is required. Recently, a new oral iron chelator deferasirox (ICL670, Exjade®) has become available. A study was conducted to demonstrate the efficacy and tolerability of deferasirox in transfusion-dependent iron-overloaded patients with MDS. The efficacy of deferasirox was monitored by changes in serum ferritin, bone marrow iron, and liver iron concentration (LIC), as determined by T2*-weighted magnetic resonance imaging. Twelve patients with MDS of different subtypes (median age 76 years, range 53–91) were enrolled. Deferasirox administered in a once-daily dose of 20–30 mg/kg for 12 months was effective in reducing median ferritin concentration from 1,515 µg/L (range 665–6,900) to 413 µg/L (range 105–3,052). Within the first 4 weeks of treatment before the continuous decline of ferritin levels, the values markedly rose in eight of 12 patients. The median LIC declined from 315 to 230 µmol/g ( = 0.02) at the end of study, accompanied by a reduction of bone marrow siderosis. The most common adverse events were mild and transient gastrointestinal disturbances, skin rash, nonprogressive transient increases in serum creatinine and urine β2-microglobulin, and a temporary reduction of the creatinine clearance. The renal parameters normalized after end of treatment. No hematologic toxicities were observed. Deferasirox proved to be effective in transfusion-dependent iron overload in MDS by mobilizing iron deposits in liver and at least stabilizing iron stores in bone marrow

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Section: Methodsmentioning

confidence: 99%

Deferasirox in MDS patients with transfusion-caused iron overload—a phase-II study

et al. 2008

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“…Pennell et al [9] suggested that, during an RCT of over 1 year, in a comparison of DFO to DFP, LVEF increased significantly in the DFP-treated group (3.1% vs. 0.3% absolute units; P 5 0.003) whilst DFP in combination with DFO raised absolute LVEF by 2.6% [10]. Moreover, Pennel et al [11] showed that these changes in LVEF (3.1% vs. 2.6%), measured by cardiac magnetic resonance (CMR) during DFP-alone or combination, were associated with risk reduction for development of heart failure over 12 months of 46.4% or 25.5%, respectively.…”

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confidence: 99%

Long‐term use of deferiprone significantly enhances left‐ventricular ejection function in thalassemia major patients

et al. 2012

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A multicenter randomized open-label long-term sequential deferiprone-deferoxamine (DFP-DFO) versus DFP alone trial (sequential DFP-DFO) performed in patients with thalassemia major (TM) was retrospectively reanalyzed to assess the variation in the left ventricular ejection fraction (LVEF) [1].Serial observations of LVEF over 3 years, in the same patient, were retrospectively assessed in 99 patients with TM during the sequential DFP-DFO multicenter randomized open-label trial [1]. A generalized estimating equation (GEE) model was used to demonstrate changes in mean LVEF over time [2].The regression coefficient of treatment suggested that the DFP-alone group showed a statistically significant increase in mean LVEF over time (coefficient 0.97, 95% CI (0.51; 1.44), P-value <0.0001).These findings suggest that long-term treatment with DFP-alone can significantly enhance LVEF over time. These findings agree with a survival analysis reporting a substantial decline in cardiac deaths during recent years, related to the switching of high-risk patients from DFO to chelation regimens that include the oral chelator DFP [3][4][5].Oral chelation treatment has improved greatly adherence and management of patients with TM [6,7].The improvement of the LVEF after 1-year DFP treatment has been reported [8][9][10][11].However, the effects of DFP on LVEF after long-term treatment have not been fully investigated.This letter reports a retrospective survey performed on patients with TM, previously enrolled in a long-term randomized open-label trial carrying ahead in Italy on the behalf of the Italian Society for the Study of Thalassaemia and Haemoglobinopathies (SoSTE) [1]. Ninety-nine out of 213 patients enrolled in the sequential DFP-DFO trial underwent longterm echocardiographic study of LVEF measured at baseline and every 12 months over three consecutive years (Fig. 1). Among these, 39 and 60 received sequential DFP (75 mg/kg for 4 days/week)-DFO (50 mg/kg for 3 days/week) or DFP-alone (75 mg/kg for 7 days/week) treatment, respectively (Table I).The hematological and clinical findings at enrollment are shown in Table I. No differences were observed at baseline between the two randomized groups. Particularly, the main findings of body iron overloading, expressed as serum ferritin at baseline, liver iron concentration (LIC), baseline LVEF <55%, and total number of blood transfusions were not statistically significantly different (Table I). Moreover, although baseline LVEF appears unlike between the two groups ( Fig. 1), this was not statistically significantly different (P-value 5 0.10, Table I).The DFP-alone group showed statistically significant increase over time in mean LVEF in comparison with sequential DFO-FP treatment (coefficient 0.97, 95% CI (0.51; 1.44), P-value <0.0001).Furthermore, the regression coefficient of treatment suggested that there was a statistically significant difference in mean LVEF between the two treated groups favoring the sequential group (coefficient 2.36, 95% CI (0.02; 4.71), P-value 5 0.047, but this ...

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“…Deferiprone has been shown to clear cardiac iron at nearly double the rate of deferoxamine, with improvement in cardiac performance 19. There appears to be a synergistic effect between deferiprone and deferoxamine: A randomized controlled trial of 65 patients over 12 months showed that defepromine reduced myocardial iron and improved ejection fraction with mild–moderate iron overload, when compared to deferoxamine alone 20. The 2013 American Heart Association (AHA) guidelines state that patients in acute heart failure should be immediately commenced on continuous (uninterrupted) intravenous iron chelation treatment with deferoxamine 50 mg/kg/day.…”

Section: Discussionmentioning

confidence: 99%

“…The 2013 American Heart Association (AHA) guidelines state that patients in acute heart failure should be immediately commenced on continuous (uninterrupted) intravenous iron chelation treatment with deferoxamine 50 mg/kg/day. Deferiprone should be introduced as soon as possible at a dose of 75 mg/kg/day (the total dose given in three divided doses) 2, 20, 21, 22. At the present time, data are lacking for the use of deferasirox in acute iron overload cardiomyopathy.…”

Section: Discussionmentioning

confidence: 99%

Acute cardiac decompensation in a patient with beta‐thalassemia and diabetes mellitus following cessation of chelation therapy

Lioudaki

Whyte

2016

Clinical Case Reports

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Key Clinical MessagePatients with higher liver iron stores are likely to have a worse cardiac outcome following noncompliance with chelation. Cardiovascular magnetic resonance identifies myocardial siderosis allowing optimization of iron chelation regimes. Diabetes puts thalassemic patients at increased risk of myocardial fibrosis. Dual chelation therapy with deferoxamine and deferiprone offers improved cardiac outcomes.

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A Randomized, Placebo-Controlled, Double-Blind Trial of the Effect of Combined Therapy With Deferoxamine and Deferiprone on Myocardial Iron in Thalassemia Major Using Cardiovascular Magnetic Resonance

Cited by 420 publications

References 29 publications

Deferasirox in MDS patients with transfusion-caused iron overload—a phase-II study

Deferasirox in MDS patients with transfusion-caused iron overload—a phase-II study

Long‐term use of deferiprone significantly enhances left‐ventricular ejection function in thalassemia major patients

Acute cardiac decompensation in a patient with beta‐thalassemia and diabetes mellitus following cessation of chelation therapy

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