# Prevention of Cardiomyopathy in Transfusion-Dependent Homozygous Thalassaemia Today and the Role of Cardiac Magnetic Resonance Imaging

Authors: Athanassios Aessopos; Vasilios Berdoukas; Maria Tsironi
Journal: Advances in Hematology
 (2009)

---

## Abstract

Transfusion and iron chelation therapy revolutionised survival and reduced morbidity in patients with transfusion-dependent beta thalassaemia major. Despite these improvements, cardiac disease remained the most common cause of death in those patients. Recently the ability to determine the degree of cardiac iron overload, through cardiac magnetic resonance imaging (CMR) has allowed more logical approaches to iron removal, particularly from the heart. The availability of two oral chelators, deferiprone and deferasirox has reduced the need for the injectable chelator deferrioxamine and an additional benefit has been that deferiprone has been shown to be more cardioprotective than deferrioxamine. This review on the prevention of cardiac disease makes recommendations on the chelation regime that would be desirable for patients according to their cardiac iron status as determined by CMR determined by CMR.  It also discusses approaches to chelation management should CMR not be available.


---

## Body

## 1. Introduction

In beta thalassaemia major, transfusion and iron chelation therapy have significantly improved survival and reduced morbidity [1, 2]. However, heart complications still
represent significant morbidity and remain the leading cause of mortality in
transfusion-dependent thalassaemia (TM) patients [2]. In some cases this was because of the
difficulty in accepting the chelation treatment, which was cumbersome [3],
and also occurred even in some patients who accepted the chelation therapy well [4, 5].Today,
three chelators are available for body iron reduction in transfusion-dependent
anaemias.  Deferrioxamine, the injectable
form, has been available for almost 40 years, deferiprone, the first oral iron
chelator, was licensed in Europe since 1999 and recently deferasirox has been
licensed in many countries.Knowledge derived by recent
MRI (CMR) studies which also assessed cardiac function showed that all
patients with reduced LV function had cardiac iron overload and in many cases
this was severe [6–9].  Therefore, the
ability to assess cardiac iron by MRI and greater choices in iron chelation
have revolutionised the approach to management of transfusion iron overload
with the ability to appropriately tailor iron chelation therapy and promises
improved survival.The suggested
iron chelation regimes available till recently, that is, with desferrioxamine at
30–40 mg/kg body weight per infusion, 8–10 hours per infusion 5–7 days per
week, improved survival and reduced morbidity [10].  However, varying compliance and other factors
resulted in continuing presentation of cardiac dysfunction and premature
cardiac deaths.


## 2. Iron Load and Predictive Factors of Heart Injury from Iron

For many years, prediction
of potential heart iron injury in TM patient was considered necessary in order
to assess the efficacy of the treatment regimes, particularly the chelation
therapy and to propose any modification.
Ferritin levels, and liver iron concentrations (LICs) were the standard
surrogate markers used.  Assessment of
cardiac function particularly by echocardiography is certainly
important but of limited value, because, usually, once changes are seen, the
patients already have established cardiomyopathy though, in some circumstances, there
are some parameters that can be determined with echocardiography that can
predict that the patient is iron overloaded such as the total diameter index. The
latter is calculated by adding the ASE end-diastolic measurements of the RV
diameter, the intraventricular septum thickness, the LV diameter, and the
posterior wall thickness divided by BSA. A total
diameter index (Tdi) >5.57 cms/m2 is highly specific for
predicting cardiac iron (91.4%) but only had a low sensitivity (31.8%) [11].In two recent studies, one of which assessed most recent [9] and one of which assessed highest, lowest, mean
5 year, and most recent ferritin [8], there was a statistically significant
relationship of ferritin to MRI-assessed cardiac iron but no predictive value
between the two indices.Until recently, the LIC was
given great significance with respect to the risk of cardiac disease and it was
recommended that levels >12 mg/gm dry weight were associated with cardiac
death [12].
However, in one study on 58 transfusion-dependent patients, aged between 10–45
years, the majority of whom had thalassaemia major and who were on regular
chelation therapy with desferrioxamine, it was demonstrated that LIC (by
biopsy) was not related to cardiac dysfunction as assessed by stress MUGA, [13]
in that both the resting LVEF and the increase in LVEF after exercise stress
showed no statistical relationship to the LIC.
In another large study from Torino, 652 patients with thalassaemia major
aged between 1–27 years, the LIC, as
estimated by SQUID   and echocardiography findings, showed similar lack of relationship [14].  These findings have been elucidated by recent
MRI studies.  One did not show
statistical significance between LIC and cardiac iron and the others did, while
there was no predictive value between them [6–9].  Therefore,
using LIC as a predictor of cardiac mortality can be misleading. Caution should
be exercised, particularly in patients with satisfactory ferritin levels and LIC
as if they are low, both the patients and their physician may believe
that the patient is protected from heart disease and it is not realised that
patients with such levels may have excessive cardiac iron and need intensification of chelation therapy [8].   Irrespective
of this, major efforts should be made to maintain low LICs because high levels
are potentially dangerous and are associated with other morbidities such as
increased risk of siderophore bacterial infections, cirrhosis, and hepatoma.As there was no particular
examination giving a real indication of cardiac risk, the ability to
determine cardiac iron, was therefore, crucial.
Cardiac biopsy is invasive and inaccurate [15, 16],
therefore, the ability to assess cardiac iron noninvasively, reproducibly, and
accurately  was imperative. Cardiac
magnetic resonance imaging (CMR) has offered
that capability.  A number of studies have
demonstrated the value of  CMR  in indirect
assessment of cardiac iron overload (T2*) and function parameters [17–21]. Many other centres are instituting either the
same or similar MRI techniques. The results appear to be comparable using
different machines and in different countries [22].
They are reproducible and robust, provided that the T2* method is used and
the area measured is the intraventricular septum [23].
The classification of patients is that those with T2*>20 msecs are
regarded as not having cardiac iron [6, 8, 9].  Those
with T2* between 10–20 msec have mild-to-moderate cardiac iron load and those
<10 msecs are considered to have heavy cardiac iron load.


## 3. Chelation Treatment for Prevention of Iron Induced Heart Disease

Chelation treatment today should be guided by MRI
findings  if the technique is available.
In the presence of excess cardiac and/or hepatic iron, treatment strategies include
increase of the dose and/or frequency of desferrioxamine, switch to oral chelators in maximal permissible doses (deferiprone or deferasirox) depending on the degree of cardiac iron load or to the combination of deferiprone
with desferrioxamine, provided there are no contraindications to their use [24]. With respect to hepatic iron
removal, the efficacy of the two oral chelators is at least equal to the
standard doses of desferrioxamine [25–27].
Recent and ongoing studies have demonstrated that deferiprone, which is a small
molecule that permeates all tissues, is more efficient in removing cardiac iron
and improving cardiac function than
desferrioxamine [25, 26].  Clinical studies with deferasirox
are currently ongoing with respect to removal of cardiac iron.  As yet, there are no studies with
combinations of deferasirox and desferrioxamine so this therapeutic regime
cannot be recommended at this stage.According to the
current knowledge and based on
the CMR findings, the suggested
chelation regimes are as follows.


### 3.1. Acceptable Cardiac Iron

For patients with T2* greater than 20 msec, the
therapeutic strategy should be continuation of
monotherapy with either desferrioxamine or either of the available oral
chelators (deferiprone and desferasirox)
with regular followup. For
patients convenience, desferrioxamine administration may be converted to either
of the two oral chelators.


### 3.2. Mild-to-Moderate Cardiac Iron Loading

T2* values between 10–20 msec are considered to reflect a
mild-to-moderately iron-loaded myocardium. Bearing in mind that the patients
may be at risk of developing cardiac problems under stress such as infections,
clearing myocardial tissue from iron seems to be a rational target. Therefore,
combined treatment for these patients should not be a priori excluded. Patients
have presented with LV dysfunction at levels of T2* of 15 msec, without any
precipitating factors [8].
Therefore, if T2* is ≤15 msec, combination chelation therapy is
recommended [24]. However, questions still exist, regarding the
frequency and the amount of desferrioxamine administration that is appropriate
in a combined regimen. A dose of 35–40 mg/kg/day three-four times weekly
combined with deferiprone at a dose of 75 mg/kg/day seems to be reasonable.  In patients with T2* 15–20 msec, monotherapy
with either deferiprone or deferasirox together with careful followup are
available options [25, 26].  As
there are no published trials, at present available, on the efficacy of
deferasirox in removing cardiac iron, if it is to be prescribed, it is
advisable that MRI followup be more frequent than if deferrioxamine and
deferiprone are prescribed.  Patients
treated up to the time of the MRI with desferrioxamine in this category and who
availed themselves of that treatment satisfactorily  should not be on
monotherapy with that compound, as deferrioxamine was inadequate at preventing the iron
accumulation in the heart and may indicate some type of resistance to its
efficacy in the heart within that patient.


### 3.3. Heavy Cardiac Iron Load

Patients with T2*<10 msec are considered to have
severe iron overload and this category includes most patients with reduced left
ventricular (LV) function. Even those patients with normal ejection fraction in
this category are considered to be at a great risk of developing cardiac
dysfunction. Thus, all patients in this category have a strong indication for
combined chelation treatment.  The doses
of deferrioxamine should be approximately 50 mg/kg/subcutaneous infusion up to
7 days per week if tolerated and the deferiprone should be given at doses
between 75–100 mg/kg/day in three divided doses. If the use of deferiprone is
contraindicated, then the patients should be treated with intensive
desferrioxamine therapy, either through continuous infusions through an
indwelling catheter or by subcutaneous continuous infusions [28].Any treatment modification
should be followed by close monitoring. Should any serious adverse effect
present as a consequence of the administration of a particular chelator, appropriate guidelines as to its continued use should be followed.If treatment has ultimately
modified the CMR patient’s classification, then  it may be adjusted as discussed
earlier according to the changes in CMR values.


### 3.4. Guidelines If MRI Is Not Available

In countries where
MRI is not available, then all the patients’ traditional parameters need
to be analysed, (ferritins, liver iron concentrations) as well as ECG and
echocardiogram, taking into account the above-discussed limitations. These may
serve as a guide to treatment. In
general, iron-related cardiomyopathy rarely appears before the age of about 14
years.  Therefore, until that age, the
choice of chelator that should be recommended depends on those parameters and
which of the three chelators will be more acceptable and tolerable for the
patient and his/her family.A recent study from
Italy has shown that patients who continued treatment with
deferrioxamine had a greater incidence of cardiomyopathy with greater cardiac-related mortality than patients who were changed to deferiprone [29].  This difference should be considered in
patients who do not have access to CMR in determining which chelator would be
most suitable for patients.Furthermore, according to the knowledge from MRI studies in
countries where followup of patients occurs, up to 65% of patients have
cardiac iron load. In Sardinia, 13% had severe cardiac iron overload [9].  In our
study, 48% of patients have T2*<15 msecs [8]. In countries where patients compliance to
treatment is inadequate, there was poor availability of chelation and/or the
followup was not well organized, the percentage of cardiac iron-loaded
patients is likely to be higher.  Therefore, for patients who have never had
optimal care, it is very likely the patients will have cardiac iron load
and intensive chelation as the treatment
of choice.  In patients who have been poorly
chelated, the risk of chelation toxicity is minimal and would only be likely to
occur after prolonged therapy, however, it is important to be vigilant for such
complications. MRI is more necessary for those patients who have had good chelation therapy but who
are at risk of chelation inadequacy with respect to the heart and for those who have had treatment modification in order to follow
the efficacy of the changed chelation regime.


## 3.1. Acceptable Cardiac Iron

For patients with T2* greater than 20 msec, the
therapeutic strategy should be continuation of
monotherapy with either desferrioxamine or either of the available oral
chelators (deferiprone and desferasirox)
with regular followup. For
patients convenience, desferrioxamine administration may be converted to either
of the two oral chelators.


## 3.2. Mild-to-Moderate Cardiac Iron Loading

T2* values between 10–20 msec are considered to reflect a
mild-to-moderately iron-loaded myocardium. Bearing in mind that the patients
may be at risk of developing cardiac problems under stress such as infections,
clearing myocardial tissue from iron seems to be a rational target. Therefore,
combined treatment for these patients should not be a priori excluded. Patients
have presented with LV dysfunction at levels of T2* of 15 msec, without any
precipitating factors [8].
Therefore, if T2* is ≤15 msec, combination chelation therapy is
recommended [24]. However, questions still exist, regarding the
frequency and the amount of desferrioxamine administration that is appropriate
in a combined regimen. A dose of 35–40 mg/kg/day three-four times weekly
combined with deferiprone at a dose of 75 mg/kg/day seems to be reasonable.  In patients with T2* 15–20 msec, monotherapy
with either deferiprone or deferasirox together with careful followup are
available options [25, 26].  As
there are no published trials, at present available, on the efficacy of
deferasirox in removing cardiac iron, if it is to be prescribed, it is
advisable that MRI followup be more frequent than if deferrioxamine and
deferiprone are prescribed.  Patients
treated up to the time of the MRI with desferrioxamine in this category and who
availed themselves of that treatment satisfactorily  should not be on
monotherapy with that compound, as deferrioxamine was inadequate at preventing the iron
accumulation in the heart and may indicate some type of resistance to its
efficacy in the heart within that patient.


## 3.3. Heavy Cardiac Iron Load

Patients with T2*<10 msec are considered to have
severe iron overload and this category includes most patients with reduced left
ventricular (LV) function. Even those patients with normal ejection fraction in
this category are considered to be at a great risk of developing cardiac
dysfunction. Thus, all patients in this category have a strong indication for
combined chelation treatment.  The doses
of deferrioxamine should be approximately 50 mg/kg/subcutaneous infusion up to
7 days per week if tolerated and the deferiprone should be given at doses
between 75–100 mg/kg/day in three divided doses. If the use of deferiprone is
contraindicated, then the patients should be treated with intensive
desferrioxamine therapy, either through continuous infusions through an
indwelling catheter or by subcutaneous continuous infusions [28].Any treatment modification
should be followed by close monitoring. Should any serious adverse effect
present as a consequence of the administration of a particular chelator, appropriate guidelines as to its continued use should be followed.If treatment has ultimately
modified the CMR patient’s classification, then  it may be adjusted as discussed
earlier according to the changes in CMR values.


## 3.4. Guidelines If MRI Is Not Available

In countries where
MRI is not available, then all the patients’ traditional parameters need
to be analysed, (ferritins, liver iron concentrations) as well as ECG and
echocardiogram, taking into account the above-discussed limitations. These may
serve as a guide to treatment. In
general, iron-related cardiomyopathy rarely appears before the age of about 14
years.  Therefore, until that age, the
choice of chelator that should be recommended depends on those parameters and
which of the three chelators will be more acceptable and tolerable for the
patient and his/her family.A recent study from
Italy has shown that patients who continued treatment with
deferrioxamine had a greater incidence of cardiomyopathy with greater cardiac-related mortality than patients who were changed to deferiprone [29].  This difference should be considered in
patients who do not have access to CMR in determining which chelator would be
most suitable for patients.Furthermore, according to the knowledge from MRI studies in
countries where followup of patients occurs, up to 65% of patients have
cardiac iron load. In Sardinia, 13% had severe cardiac iron overload [9].  In our
study, 48% of patients have T2*<15 msecs [8]. In countries where patients compliance to
treatment is inadequate, there was poor availability of chelation and/or the
followup was not well organized, the percentage of cardiac iron-loaded
patients is likely to be higher.  Therefore, for patients who have never had
optimal care, it is very likely the patients will have cardiac iron load
and intensive chelation as the treatment
of choice.  In patients who have been poorly
chelated, the risk of chelation toxicity is minimal and would only be likely to
occur after prolonged therapy, however, it is important to be vigilant for such
complications. MRI is more necessary for those patients who have had good chelation therapy but who
are at risk of chelation inadequacy with respect to the heart and for those who have had treatment modification in order to follow
the efficacy of the changed chelation regime.


## 4. Conclusions on Prevention of Heart Disease

This genetic
defect that was formerly almost universally fatal has been revolutionised with
the availability of adequate chelation therapy and more recently with other
important advances.It remains important,
practically, to aim to maintain low LICs and ferritin levels, particularly as
the latter are easily accessible and assessable. Similarly, echocardiography should remain a routine tool as it
does have some predictive value and can also be used to monitor patients in
whom intensification of chelation therapy has been instituted.CMR can be particularly
helpful in identifying all TM patients at risk of developing heart disease by
assessing the cardiac iron load. Chelation therapy can be tailored to remove
the excess heart iron. Attention to patient’s continuous compliance with
adequate chelation is mandatory.The definite ability to know and reduce cardiac iron as
well as improvement in cardiac function that has been reported  should
certainly lead to even further significant reduction in cardiac mortality and
morbidity.  In situations in which CMR is
not available, data available from other centres can help the clinicians with
their decision as to which iron chelator to recommend for each individual
patient.



---

*Source: 964897-2009-04-29.xml*