Introduction
Globally, there are at least 60,000 individuals born with thalassemia major (TM) each year [
1]. Regular blood transfusions are mandatory for long term survival, but over a period of years these cause a secondary state of tissue iron overload. Myocardial iron deposition can result in cardiomyopathy, and heart failure remains the leading cause of death [
2‐
4]. The introduction of the iron chelator deferoxamine greatly ameliorates the effects of iron toxicity, but long-term cardiac mortality has been very disappointing [
3,
5]. The ongoing deaths from cardiac iron loading may relate to inadequate compliance or genetic factors related to metal transporters not yet fully elucidated [
6‐
8], but whatever the cause, there is strong evidence that long-term deferoxamine chelation does not effectively prevent myocardial siderosis in a majority of patients [
9,
10]. Deferiprone, the first approved oral chelator, has been shown in randomized controlled trials to be effective monotherapy at 100 mg/kg/day in treating mild to moderately severe myocardial iron loading (myocardial T2* 8–20 ms), significantly improving both myocardial iron and ejection fraction [
11], and the combination of deferiprone at 75 mg/kg/day with deferoxamine is likewise effective [
12]. However greater total iron clearance is seen with combined treatment [
13‐
15], which suggests that it might be useful for severe myocardial siderosis (T2* < 10 ms).
The conventional treatment at many centers for severe myocardial siderosis with heart failure is long-term, continuous, high-dose intravenous deferoxamine. Several small studies have confirmed that this approach is effective, and reversal of cardiomyopathy is possible [
16,
17]. However, deaths still occur, complications such as infection and thrombosis are common, and poor compliance with these demanding regimes is problematic [
16]. Combined chelation therapy in this situation might be effective, yet prospective trials examining the treatment of severe cardiac siderosis are lacking. Cardiovascular magnetic resonance (CMR) permits highly reproducible measurements of myocardial iron loading (T2*) [
18,
19], and ventricular function [
20,
21], making this modality ideally suited to assessing cardiovascular response to chelation treatments in TM [
9‐
12]. Therefore, we prospectively examined the effects of combination therapy in TM patients with severe myocardial siderosis.
Discussion
Heart failure secondary to myocardial iron loading remains the single most important cause of death in patients with TM [
2,
3]. It is well recognized that LV dysfunction and symptomatic heart failure occur at an advanced stage of cardiac siderosis, at which point treatment can be difficult and there is a poor prognosis [
27,
28]. Non-continuous deferoxamine monotherapy appears to be inadequate in such patients [
29,
30]. Intensive, continuous intravenous deferoxamine is probably more effective, and reverses cardiomyopathy in many, but not all cases [
16,
17], and many centers consider this (or continuous subcutaneous infusion [
31]) to be the standard of care. Combined therapy with deferoxamine and deferiprone has been demonstrated to be of clear benefit in the treatment of cardiac siderosis in TM [
12,
13,
32,
33], but the role of combined therapy in the management of severe cardiac siderosis has not been specifically addressed beyond a few case reports [
34‐
36] yet it has potential advantages over standard intensive intravenous chelation. Firstly, the presence of a long-term intravenous central catheter is not required which obviates the attendant risks (including infection and thrombosis). Secondly, the risk of deferoxamine toxicity might be reduced through the lower doses used in combined therapy. Thirdly, the use of intermittent subcutaneous deferoxamine therapy is less disruptive to patients and could confer improved compliance, which is considered a key factor in improving mortality in TM [
16,
37]. Finally, there is substantial evidence to suggest that deferiprone has superior cardioprotective effects [
4,
11,
38,
39], which remain to be fully explained, but anti-oxidant effects and influence on iron transport mechanisms are possibilities [
6‐
8].
This study demonstrates that combined therapy in patients with severe cardiac siderosis results in large and significant improvements in myocardial iron loading and ventricular function. In all cases bar one, an improvement in myocardial T2* was coupled with an improvement in ejection fraction. In this one case, the apparent lack of improvement in cardiac function might reflect unknown biological factors, or measurement error. Despite comparable chelation regimes, some subjects showed far greater improvements in myocardial iron clearance and cardiac function compared to others. Although not formally assessed in this study, the degree of compliance to the prescribed chelation dose is likely to account for the majority of these observed differences. Other factors that might play a role in determining response to therapy include individual variation in chelation metabolism, or genetic factors involved in the regulation of myocardial iron metabolism. Clearance of iron from the heart is slow with all treatments in severe cardiac siderosis however, and treatment for 12 months is clearly inadequate to clear the cardiac iron, indicating that changes in chelation tailored to the cardiac siderosis must be guided by repeated cardiac T2* measurements. It would appear from the current trial that treatment of these patients would be necessary at the same chelation intensity for approximately 3–4 years to raise the T2* above 20 ms (assuming that the rate of clearance is constant). During this period the liver iron and ferritin will become low, and one clear advantage of the combination regime is that the likelihood of adverse effects of deferoxamine in these circumstances can be ameliorated through appropriate dose reduction (20.3 mg/kg for 4.5 days per week at the end of 12 months treatment in this study).
The rate of clearance of myocardial iron in the current trial of combination therapy (5.7 to 7.9 ms) was similar to that reported in a previous prospective study by Anderson who reported the changes in myocardial T2* in patients presenting with heart failure due to cardiac siderosis in response to high dose 24 hour per day intravenous deferoxamine for 12 months (5.1 to 8.1 ms) [
17]. In both these studies, there were impressive improvements in ejection fraction (current study +14.4%; Anderson's study +11%) from a similar baseline (current study 51.2%; Anderson's study 52.0%). This emphasizes the relatively high value of ejection fraction at which patients with TM develop heart failure compared to patients with coronary disease and cardiomyopathy. Recently, the normal reference range for LV volumes and function in TM
without myocardial iron have been determined by CMR [
22]. An adaptive response to their chronic anemic state and other factors produces a hyperdynamic circulation, resulting in significantly different LV parameters as compared with normal controls. The mean LV ejection fraction is therefore significantly increased in TM patients, with the mean measured by CMR for women being 75.1 ± 5.9%, and men 71.0% ± 6.1%. These are 6–8% absolute units higher than normal subjects and indicate that TM patients have impaired LV function at higher values of LV ejection fraction than previously thought. Improvements in ejection fraction were mediated via a reduction in end systolic volume, with end diastolic volume not being significantly changed. This reflects no change in volume loading, but an improvement in contractility.
These results also demonstrate that following the addition of deferiprone, the total weekly deferoxamine dose and infusion frequency can be significantly reduced without compromising myocardial iron loading and function. The incidence of adverse effects was low and consistent with prior studies of these chelators. A recent prospective study has demonstrated that twice weekly deferoxamine infusions in conjunction with deferiprone five times per week, shows similar efficacy to standard deferoxamine monotherapy in removing iron [
40]. A reduction in intensity of deferoxamine chelation is likely to confer considerable benefits to the patient. In Anderson's study, where much higher doses of continuous deferoxamine were used (mean dose 46 mg/kg/day, 7 days/week), neuro-toxicity was documented in two-thirds of patients. No cases of deferoxamine toxicity were reported in this study. The reduced dose frequency seen in the current study (4.5 days/week at 12 months) is likely to be more convenient to patients and potentially improve compliance.
This study addresses a number of other issues regarding the management of cardiac siderosis in TM. CMR techniques have recently illuminated the weak relation between liver iron/ferritin, and myocardial siderosis [
10,
41,
42]. This has challenged existing opinion that survival without cardiac disease is good where serum ferritin levels and liver iron remain below 2500 μg/l and 15 mg/g/dry weight, respectively [
2,
43‐
45]. The 3-year mean ferritin levels, and baseline liver iron concentrations of this cohort are given in table
3. The vast majority of these patients with severe cardiac siderosis would have been considered at low risk of cardiac complications on the basis of traditional static ferritin and liver iron concentration based thresholds. Yet all these subjects demonstrated LV dysfunction at baseline. Both subjects with decompensated heart failure had 3 year mean ferritin levels <2500 μg/L, and baseline liver iron concentration <15 mg/g/dry weight. These findings highlight the difficulties in using such surrogate parameters to guide cardiac management.
1
| 2297 | 1.5 | 9.3 |
2
| 1135 | 3.0 | 4.4 |
3
| 1273 | 1.9 | 7.1 |
4
| 1211 | 8.4 | 1.5 |
5
| 2342 | 1.9 | 7.1 |
6
| 1400 | 1.7 | 8.2 |
7
| 3667 | 0.95 | 15.2 |
8
| 2442 | 1.2 | 11.8 |
9
| 1867 | 4.1 | 3.2 |
10
| 1957 | 3.9 | 3.4 |
11
| 500 | 1.6 | 8.6 |
12
| 967 | 11.2 | 1.1 |
13
| 2835 | 3.2 | 4.2 |
14
| 1250 | 5.0 | 2.6 |
15
| 1536 | 5.9 | 2.2 |
BNP has been found to have diagnostic and prognostic use in non-siderotic heart failure [
46,
47], but data regarding its application in thalassemia is sparse [
10]. In this cohort, only the 2 subjects in overt cardiac failure had abnormal BNP levels. This suggests that BNP levels become raised only at a very advanced stage, and are therefore unlikely to contribute significantly to the pre-clinical identification of siderotic cardiomyopathy. The lack of significant change in BNP over 12 months (in the whole group) despite considerable improvements in cardiac function and cardiac siderosis also suggests little role for serial BNP measurements in these patients. It is possible that an explanation for this finding is that BNP secretion is impaired in cardiac siderosis (cardiac endocrinopathy).
Acknowledgements
Regione Sardegna (L.R. 11, 1990). Ithanet project (Electronic Infrastructure for Thalassemia Research Network). Funding was received from CORDA, Royal Brompton and Harefield Hospital Charitable Funds, The Cooley's Anemia Foundation, Apotex, the UK Thalassemia Society and the University College London Special Trustees Charity. The funding sources played no role in the study design, in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.
Competing interests
Professor Pennell had full access to all the data in the study and had final responsibility for the decision to submit for publication. The authors are solely responsible for the conduct, data storage, data analysis and reporting of this trial. Professor Pennell is a consultant to, has received speaker's honoraria and research support from, and has participated in chelation drug research with Apotex. He is also a consultant to, and is participating in, chelation drug research with Novartis. He is a consultant to Siemens Medical Solutions, and a director of Cardiovascular Imaging Solutions. Professor Galanello has received speaker's honoraria and research support from Apotex and Novartis. Ms Smith is a consultant to, and is participating in chelation drug research with Novartis. Dr Walker has received research support from Novartis and speaker's honoraria from Apotex. Dr Westwood has received speaker's honoraria from Apotex. Dr Nair was supported by the British Heart Foundation. The other authors have no interests to declare.
Authors' contributions
All authors have seen and approved the final version of the manuscript. DP co-designed and coordinated the study, managed the research, and co-wrote the manuscript. RG co-designed and coordinated the study, and managed the trial patients. MT coordinated the study, acquired and analyzed the CMR data, and co-wrote the manuscript. CD, MP, and AA were involved in the management of the trial patients. GS acquired and analyzed the CMR data. MW was involved in the study design and data acquisition. SN was involved in data acquisition and analysis. MW was involved in the study design, data acquisition and analysis.