European Journal of Heart Failure 2007 9(3):320-322; doi:10.1016/j.ejheart.2006.08.006
© 2007 European Society of Cardiology
Effects of combined deferiprone and desferrioxamine iron chelating therapy in β-thalassemia major end-stage heart failure
Maurizio Porcua,*,
Novella Landisb,
Stefano Salisa,
Marco Cordaa,
Pierpaolo Orrùa,
Emanuela Serraa,
Barbara Usaia,
Gildo Mattac and
Renzo Galanellod
a Division of Cardiology Azienda Ospedaliera "G. Brotzu", Via A. Ricchi 1 09134, Cagliari, Italy
b Division of Paediatrics Ospedale "Crobu", ASL 7, Carbonia, Italy
c Department of Imaging Azienda Ospedaliera "G. Brotzu", Cagliari, Italy
d Department of Biomedical Science and Biotechnologies, Ospedale Regionale per le Microcitemie ASL 8, Università degli Studi, Cagliari, Italy
* Corresponding author. Tel.: +39 070 539515; fax: +39 070 531400. E-mail address: maurizioporcu{at}aob.it
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Abstract
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Despite usual iron chelating therapy based on desferrioxamine,
patients affected by β-thalassemia major (β-TM) often
develop progressive heart failure caused by myocardial iron
overload, which is the leading cause of mortality within the
third decade of life. Heart transplantation is a limited therapeutic
option, as very often these patients have multi-organ iron deposits
and infective complications (particularly hepatitis C), secondary
to frequent blood transfusions. We report the case of a 26-year-old
male affected by β-TM with end-stage heart failure, who
showed a dramatic improvement in symptoms and myocardial function
when a new oral iron chelating agent, deferiprone, was added
to standard therapy with desferrioxamine.
Key Words: β-Thalassemia • Deferiprone • Heart failure • Heart transplantation
Received June 29, 2006; Accepted August 24, 2006
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1. Introduction
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β-Thalassemia major (β-TM) is a genetic haemoglobin
disorder which is relatively common in some geographical areas
[1,
2]. β-TM is characterized by severe anaemia, which needs
a continuous blood transfusion regimen starting from the first
months of life to prolong survival. Secondary iron overload,
which commonly involves several organs, is the major negative
prognostic factor in these patients. Despite a consistent improvement
in prognosis and quality of life in patients treated early with
regular blood transfusions and iron-chelation with desferrioxamine,
life expectancy is still significantly reduced
[2,
3]. Heart
failure secondary to extensive myocardial iron overload is the
leading cause of mortality, representing more than 50% of all
deaths in thalassemia patients
[2,
3]. Although severe heart
failure usually develops in the second and third decades of
life, these patients are generally not considered as candidates
for heart transplantation, as multi-organ iron overload and
frequent transfusion-related infections
[1] may reduce early
post-transplant survival. Heart transplantation has been performed
only in very selected patients affected by this haematological
disorder characterized by iron overload
[4-6], but extensive
data on long-term results are still not available. Despite controversial
preliminary results
[7], more recent laboratory and clinical
data based on a new iron chelating agent, deferiprone, has shown
satisfying outcome in reversal of iron overload in β-TM
patients, with an acceptable profile of safety
[8-12]. We describe
the case of a young β-TM patient with end-stage heart failure,
listed for heart transplantation, who presented an unexpected
and sustained improvement of his cardiac condition after combining
baseline subcutaneous desferrioxamine iron chelating treatment
with oral deferiprone.
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2. Case report
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A 26-year-old β-TM male, who had been treated since the
age of 14 months with appropriate blood transfusions and subcutaneous
infusion of desferrioxamine adjusted according to serum ferritin
level (mean daily dose 2500 mg), was admitted with end-stage
heart failure. In the previous few months, despite optimal medical
treatment with enalapril, carvedilol and furosemide, the patient
had experienced progressive severe dyspnoea, with symptoms caused
by minimal activities (NYHA Class IV) and several episodes of
persistent atrial fibrillation, which needed acute i.v. infusion
and long-term prophylaxis with amiodarone. Some weeks before
he had been admitted for acute decompensation, which had responded
to short-term i.v. enoximone infusion. A very enlarged left
ventricle was detected, with a severe reduction in contractility
(
Table 1). Magnetic resonance imaging (MRI) of the heart showed
a very low T2-star value, consistent with a relevant myocardial
iron overload
[13]. For this reason, the patient underwent the
usual pre-operative assessment for heart transplantation. Mild
liver dysfunction secondary to iron deposits and hepatitis C-related
infection, with very low viral replication, was detected, but
they were not considered absolute contraindications. Right heart
catheterization showed baseline pulmonary vascular resistance
within normal values (120 dyne/sec/cm
–5). No other significant
organ deteriorations were detected and the patient was included
on the waiting list for heart transplantation. Fourteen months
later, in accordance with new literature reports, the iron chelating
treatment was modified and deferiprone 25 mg/kg three times
a day was added to the baseline therapy. Subcutaneous desferrioxamine
was reduced to a mean daily dose of 500 mg according to the
new serum ferritin level. Over a 5-month period the patient
reported a progressive significant reduction in dyspnoea. About
8 months after the beginning of the new iron chelating regimen
the patient was completely free from shortness of breath (NYHA
Class I), even during strenuous physical activities. Echocardiography
showed a marked improvement in ventricular dimension, with a
normalized systolic function (
Table 1). The patient did not
experience any other episode of palpitations and no arrhythmias
were detected on repeated 24-h Holter monitoring. Listing for
heart transplantation was suspended. Diuretic therapy was successfully
tapered off over a short time, while enalapril, carvedilol and
amiodarone were maintained. Mean serum ferritin decreased from
1400 µg/l to 378 µg/l and cardiac MRI showed a significant
increase in T2-star, compatible with a reduction in myocardial
iron. Benefits have been sustained over 19 months. No relevant
side effects related to deferiprone have been reported.
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Table 1 Laboratory parameters on listing for heart transplantation (baseline) and 8 months after initiation of combined (desferrioxamine and deferiprone) iron chelating therapy
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3. Discussion
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In β-TM iron overload due to long-term blood transfusions
and excessive gastrointestinal iron absorption is a frequent
cause of myocardial dysfunction and progressive heart failure.
β-TM patients respond poorly to the usual pharmacological
treatment with ACE-inhibitors, beta-blockers and diuretics.
Despite their young age, heart transplantation cannot be considered
as a routine therapeutic option in thalassemia patients. This
is because iron overload generally leads to relevant and irreversible
alterations of the function of several organs, such as the liver,
thyroid, parathyroid, gonads and pancreas, which may limit post-transplant
prognosis
[1]. Moreover, repeated blood transfusions starting
from the first months of life have been associated with a high
risk of haematological viral transmission, such as HIV, HCV
and HBV infections, which are normally not compatible with the
long-term post-transplant immunosuppression regimen. Bearing
in mind these major limitations, since this haemoglobin disorder
is endemic in our region, we decided to open our heart transplant
program to very selected end-stage heart failure β-TM patients.
Since the beginning of our program in 1989, four young β-TM
patients have undergone orthotopic heart transplantation
[14].
All of these patients were treated while awaiting heart transplant
with iron chelation therapy based on subcutaneous desferrioxamine,
and showed an inexorable progression of their heart failure.
Two patients, who were both transplanted in severe haemodynamic
deterioration, presented major complications in the early post-operative
period (multiorgan failure and sepsis) and died within 2 months.
The other two patients, who were both treated with optimal post-operative
subcutaneous desferrioxamine infusion, are still alive 10 and
7 years after transplantation, respectively, with an excellent
quality of life and a normal systolic function. However, endomyocardial
biopsies performed up to the second post-transplant year showed
mild iron deposits in the right ventricle, suggesting a slow
process of graft siderosis, which is consistent with the rate
of myocardial iron deposits of non-transplanted patients treated
with conventional iron chelation. Since recent preliminary results
have suggested beneficial effects of a new iron chelating agent,
deferiprone, used in combination with the usual therapy with
desferrioxamine, we decided to modify the chelating regimen
in our fifth β-TM candidate for heart transplantation.
An unexpected improvement in symptoms and systolic function
was detected only a few months after the introduction of the
new combined chelating protocol. The patient returned to a normal
daily life, with no shortness of breath even during sports activities
such as mountain biking or wave surfing. The persistent stability
in his cardiological condition allowed us to remove him from
the waiting list for heart transplantation and to discontinue
all diuretic therapy. Recent sporadic reports seem to confirm
the great efficacy of the combination of deferiprone with desferrioxamine
in the reversal of severe heart failure in β-TM. Wu et
al. described two young β-TM females with end-stage heart
failure and systolic dysfunction who had normalized LVEF and
functional capacity a few months after initiation of treatment
with the combination of deferiprone and desferrioxamine
[15].
Similar results were found by Tsironi et al. in a 28-year-old
man, with a severe reduction of contractility and congestive
heart failure, who showed a relevant clinical and echocardiographic
improvement 18 months after starting deferiprone
[16]. A recent
prospective controlled trial which enrolled 61 asymptomatic
patients with evidence of myocardial siderosis, previously treated
with subcutaneous desferrioxamine, showed a significant reduction
of cardiac iron deposits and an improvement in contractility
in those patients who were randomly switched to deferiprone
iron chelating monotherapy
[17]. Cardiac benefits were also
observed in 20 β-TM patients with mildly reduced ventricular
function, who had a significant improvement in contractility
after combining deferiprone with desferrioxamine
[18]. Previous
observations and our report strongly support the opportunity
to use deferiprone added to desferrioxamine in β-TM patients
with severe heart failure, even in end-stage conditions. However,
randomised clinical trials are needed in larger populations
to define the long-term efficacy and the safety of this combined
iron chelating treatment in very compromised β-TM heart
failure patients.
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Abstract
1. Introduction