Background: In thalassemia major (TM), severe cardiac siderosis can be treated by continuous parenteral deferoxamine, but poor compliance, complications and deaths occur. Combined chelation therapy with deferiprone and deferoxamine is effective for moderate myocardial siderosis, but has not been prospectively examined in severe myocardial siderosis.

Background: Heart failure secondary to myocardial iron loading remains the leading cause of death in thalassemia major (TM). We used cardiovascular magnetic resonance (CMR) to assess the prevalence of myocardial iron overload and ventricular dysfunction in a large cohort of TM patients maintained on conventional chelation treatment with deferoxamine. Methods: A mobile CMR scanner was transported from London, UK, to Sardinia, Italy where 167 TM patients were assessed for myocardial iron loading, B-natriuretic peptide (BNP), and ferritin. In patients with myocardial iron loading CMR assessments of ventricular function were also made. Results: Myocardial iron loading (T2 * < 20 ms) was present in 108 (65%) patients, which was severe (T2 * < 8 ms) in 22 (13%). Impaired (<56%) left ventricular (LV) ejection fraction (EF) was present in 5%, 20% and 62% of patients with mild, moderate or severe iron loading. Increasing myocardial iron was related to impaired LVEF (Rs = 0.57, p < 0.001), weakly related to serum ferritin (Rs = −0.34, p < 0.001), and not related to liver iron (Rs = 0.11, p = 0.26). BNP was weakly related to myocardial iron (Rs = −0.35, p < 0.001) and was abnormal in only 5 patients. Conclusions: Myocardial siderosis was found in two-thirds of thalassemia major patients on maintenance deferoxamine treatment. This was combined with a high prevalence of impaired LV function, the severity of which tracked the severity of iron deposition. BNP was not useful to assess myocardial siderosis.

Introduction: Beta thalassaemia major (TM) is a hereditary anaemia affecting 60 000 births worldwide each year. Survival is dependent upon lifelong blood transfusions with cardiac failure secondary to myocardial iron loading being the commonest cause of death. Conventional treatment with the parenteral iron chelator deferoxamine improves mortality but prognosis remains poor and it has been reported that approximately two-thirds of patients maintained on this treatment have myocardial iron loading. More recently, the oral iron chelator, deferiprone has been demonstrated to remove myocardial iron and it has been proposed that in combination with deferoxamine it may have an additive or synergistic effect. Myocardial iron can now be rapidly and reproducibly quantified using the validated cardiac magnetic resonance (CMR) T2* technique. CMR is therefore well suited to assess the efficacy of new therapies for the removal of myocardial iron in TM. Purpose: To report the primary outcome measure (heart T2*) from a randomized placebo controlled trial testing the hypothesis that the combined therapy of deferiprone and deferoxamine is superior in the removal of myocardial iron than the standard therapy of deferoxamine alone. Methods: A mobile CMR scanner (1.5T Siemens Sonata) was transported to Cagliari, Italy on 3 occasions. The myocardial T2* was assessed in 167 patients with TM. 65 patients (male 27, female 38, age 30+/−5.2years) with mild-moderate myocardial iron loading (T2* 8–20ms) were randomized to receive either deferoxamine and placebo, or deferoxamine and deferiprone. The primary outcome measure of myocardial T2* was assessed at baseline, 6 and 12 months. Normal myocardial T2* is greater than 20ms. Results: In the combined treatment group myocardial T2* improved (reducing myocardial iron) from a baseline of 11.7ms to (at 6 months) 14.6ms (+25%; CV 11.9%; p=0.007) and at 12 months 16.8ms (+40%; CV 14.2%; P&lt;0.001). In the placebo controlled group myocardial T2* improved from a baseline of 12.4ms to (at 6 months) 14.2ms (+14%; CV 14%; p=0.15) and at 12 months 15.2ms (+21%; CV 16%; p=0.02). Analysis of covariance showed a significant difference between groups (p=0.017) with the combined group showing greater effects in improving myocardial T2* (figure 1). Conclusion: In mild-moderate cardiac iron loading the combined therapy of deferiprone and deferoxamine is superior to deferoxamine alone in the removal of myocardial iron in TM. Figure 1 Figure 1.

BackgroundCombination therapy with deferoxamine and oral deferiprone is superior to deferoxamine alone in removing cardiac iron and improving left ventricular ejection fraction (LVEF). The right ventricle (RV) is also affected by the toxic effects of iron and may cause additional cardiovascular perturbation. We assessed the effects of combination therapy on the RV in thalassaemia major (TM) using cardiovascular magnetic resonance (CMR).MethodsWe retrieved imaging data from 2 treatment trials and re-analyzed the data for the RV responses: Trial 1 was a randomized controlled trial (RCT) of 65 TM patients with mild-moderate cardiac siderosis receiving combination therapy or deferoxamine with placebo; Trial 2 was an open label longitudinal trial assessing combination therapy in 15 TM patients with severe iron loading.ResultsIn the RCT, combination therapy with deferoxamine and deferiprone was superior to deferoxamine alone for improving RVEF (3.6 vs 0.7%, p = 0.02). The increase in RVEF was greater with lower baseline T2* 8-12 ms (4.7 vs 0.5%, p = 0.01) than with T2* 12-20 ms (2.2 vs 0.8%, p = 0.47). In patients with severe cardiac siderosis, substantial improvement in RVEF was seen with open-label combination therapy (10.5% ± 5.6%, p < 0.01).ConclusionsIn the RCT of mild to moderate cardiac iron loading, combination treatment improved RV function significantly more than deferoxamine alone. Combination treatment also improved RV function in severe cardiac siderosis. Therefore adding deferiprone to deferoxamine has beneficial effects on both RV and LV function in TM patients with cardiac siderosis.