Hindawi Publishing Corporation
`Advances in Hematology
`Volume 2009, Article ID 964897, 4 pages
`doi:10.1155/2009/964897
`
`Review Article
`Prevention of Cardiomyopathy in
`Transfusion-Dependent Homozygous Thalassaemia Today and
`the Role of Cardiac Magnetic Resonance Imaging
`
`Athanassios Aessopos, Vasilios Berdoukas, and Maria Tsironi
`
`First Department of Medicine, University of Athens, “Laiko” Hospital, Goudi, Athens 11527, Greece
`
`Correspondence should be addressed to Athanassios Aessopos, aaisopos@med.uoa.gr
`
`Received 12 September 2008; Accepted 5 March 2009
`
`Recommended by Paolo Rebulla
`
`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.
`
`Copyright © 2009 Athanassios Aessopos et al. This is an open access article distributed under the Creative Commons Attribution
`License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly
`cited.
`
`1. Introduction
`
`In beta thalassaemia major, transfusion and iron chelation
`therapy have significantly improved survival and reduced
`morbidity [1, 2]. However, heart complications still rep-
`resent 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 reduc-
`tion 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 trans-
`fusion 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 prema-
`ture 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
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`echocardiography is certainly important but of limited value,
`because, usually, once changes are seen, the patients already
`have established cardiomyopathy though, in some circum-
`stances, 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 relation-
`ship [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,
`∗
`method is used and the area measured
`provided that the T2
`
`is the intraventricular septum [23]. The classification of
`∗ > 20 msecs are regarded as
`patients is that those with T2
`∗
`between 10–
`not having cardiac iron [6, 8, 9]. Those with T2
`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 desfer-
`rioxamine [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.
`
`∗
`greater
`3.1. Acceptable Cardiac Iron. For patients with T2
`than 20 msec, the therapeutic strategy should be continua-
`tion of monotherapy with either desferrioxamine or either
`of the available oral chelators (deferiprone and desferasirox)
`with regular followup. For patients convenience, desferriox-
`amine 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, com-
`bined treatment for these patients should not be a priori
`excluded. Patients have presented with LV dysfunction at
`∗
`of 15 msec, without any precipitating factors
`levels of T2
`is ≤15 msec, combination chelation
`∗
`[8]. Therefore, if T2
`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
`∗
`15–20 msec, monotherapy
`reasonable. In patients with T2
`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
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`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.
`
`∗ < 10 msec
`3.3. Heavy Cardiac Iron Load . Patients with T2
`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 approx-
`imately 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 con-
`centrations) 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,
`∗ < 15 msecs [8]. In countries
`48% of patients have T2
`
`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 continu-
`ous 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.
`
`References
`
`inβ -
`[1] B. Modell, M. Khan, and M. Darlison, “Survival
`thalassaemia major in the UK: data from the UK thalassaemia
`register,” The Lancet, vol. 355, no. 9220, pp. 2051–2052, 2000.
`[2] C. Borgna-Pignatti, S. Rigolotto, P. De Stefano, et al., “Survival
`and complications in patients with thalassemia major treated
`with transfusion and deferoxamine,” Haematologica, vol. 89,
`no. 10, pp. 1187–1193, 2004.
`[3] J. J. Caro, A. Ward, T. C. Green, et al., “Impact of thalassemia
`major on patients and their families,” Acta Haematologica, vol.
`107, no. 3, pp. 150–157, 2002.
`[4] A. Aessopos, D. Farmakis, A. Hatziliami, et al., “Cardiac status
`in well-treated patients with thalassemia major,” European
`Journal of Haematology, vol. 73, no. 5, pp. 359–366, 2004.
`[5] N. F. Olivieri, D. G. Nathan, J. H. Macmillan, et al., “Survival
`in medically treated patients with homozygous β-thalassemia,”
`The New England Journal of Medicine, vol. 331, no. 9, pp. 574–
`578, 1994.
`
`Apotex Tech.
`Ex. 2029
`
`

`

`4
`
`Advances in Hematology
`
`of myocardial iron in thalassaemia,” International Journal of
`Cardiovascular Imaging, vol. 21, no. 5, pp. 531–538, 2005.
`[23] N. R. Ghugre, C. M. Enriquez, T. D. Coates, M. D. Nelson Jr.,
`∗
`and J. C. Wood, “Improved R2
`measurement in myocardial
`iron overload,” Journal of Magnetic Resonance Imaging, vol. 23,
`no. 1, pp. 9–16, 2006.
`[24] M. A. Tanner, R. Galanello, C. Dessi, et al., “A random-
`ized, 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,” Circulation, vol. 115, no. 14, pp. 1876–
`1884, 2007.
`[25] D. J. Pennell, V. Berdoukas, M. Karagiorga, et al., “Random-
`ized controlled trial of deferiprone or deferoxamine in beta-
`thalassemia major patients with asymptomatic myocardial
`siderosis,” Blood, vol. 107, no. 9, pp. 3738–3744, 2006.
`[26] C.-T. Peng, K.-C. Chow, J.-H. Chen, Y.-P. Chiang, T.-Y. Lin,
`and C.-H. Tsai, “Safety monitoring of cardiac and hepatic
`systems in β-thalassemia patients with chelating treatment in
`Taiwan,” European Journal of Haematology, vol. 70, no. 6, pp.
`392–397, 2003.
`[27] M. D. Cappellini, A. Cohen, A. Piga, et al., “A phase 3 study
`of deferasirox (ICL670), a once-daily oral iron chelator, in
`patients with β-thalassemia,” Blood, vol. 107, no. 9, pp. 3455–
`3462, 2006.
`[28] L. J. Anderson, M. A. Westwood, S. Holden, et al., “Myocardial
`iron clearance during reversal of siderotic cardiomyopathy
`with intravenous desferrioxamine: a prospective study using
`∗
`T2
`cardiovascular magnetic resonance,” British Journal of
`Haematology, vol. 127, no. 3, pp. 348–355, 2004.
`[29] C. Borgna-Pignatti, M. D. Cappellini, P. De Stefano, et
`al., “Cardiac morbidity and mortality in deferoxamine- or
`deferiprone-treated patients with thalassemia major,” Blood,
`vol. 107, no. 9, pp. 3733–3737, 2006.
`
`[6] L. J. Anderson, S. Holden, B. Davis, et al., “Cardiovascular
`∗
`T2-star (T2
`) magnetic resonance for the early diagnosis of
`myocardial iron overload,” European Heart Journal, vol. 22, no.
`23, pp. 2171–2179, 2001.
`[7] J. C. Wood, J. M. Tyszka, S. Carson, M. D. Nelson Jr., and T.
`D. Coates, “Myocardial iron loading in transfusion-dependent
`thalassemia and sickle cell disease,” Blood, vol. 103, no. 5, pp.
`1934–1936, 2004.
`[8] A. Aessopos, C. Fragodimitri, F. Karabatsos, et al., “Cardiac
`∗
`magnetic resonance imaging R2
`assessments and analysis of
`historical parameters in patients with transfusion-dependent
`thalassemia,” Haematologica, vol. 92, no. 1, pp. 131–132, 2007.
`[9] M. A. Tanner, R. Galanello, C. Dessi, et al., “Myocardial iron
`loading in patients with thalassemia major on deferoxamine
`chelation,” Journal of Cardiovascular Magnetic Resonance, vol.
`8, no. 3, pp. 543–547, 2006.
`[10] M. J. Cunningham, E. A. Macklin, E. J. Neufeld, and A.
`R. Cohen, “Complications of β-thalassemia major in North
`America,” Blood, vol. 104, no. 1, pp. 34–39, 2004.
`[11] A. Aessopos, A. Giakoumis, C. Fragodimitri, et al., “Correla-
`tion of echocardiography parameters with cardiac magnetic
`resonance imaging in transfusion-dependent thalassaemia
`major,” European Journal of Haematology, vol. 78, no. 1, pp.
`58–65, 2007.
`[12] N. F. Olivieri and G. M. Brittenham, “Iron-chelating therapy
`and the treatment of thalassemia,” Blood, vol. 89, no. 3, pp.
`739–761, 1997.
`[13] V. Berdoukas, C. Dakin, A. Freeman, I. Fraser, A. Aessopos,
`and T. Bohane, “Lack of correlation between iron overload
`cardiac dysfunction and needle liver biopsy iron concentra-
`tion,” Haematologica, vol. 90, no. 5, pp. 685–686, 2005.
`[14] A. Piga, personal communications.
`[15] D. H. Fitchett, D. J. Coltart, W. A. Littler, et al., “Car-
`diac involvement in secondary haemochromatosis: a catheter
`biopsy study and analysis of myocardium,” Cardiovascular
`Research, vol. 14, no. 12, pp. 719–724, 1980.
`[16] G. Barosi, E. Arbustini, A. Gavazzi, M. Grasso, and A.
`Pucci, “Myocardial iron grading by endomyocardial biopsy.
`A clinico-pathologic study on iron overloaded patients,”
`European Journal of Haematology, vol. 42, no. 4, pp. 382–388,
`1989.
`[17] L. J. Anderson, S. Holden, B. Davis, et al., “Cardiovascular
`∗
`T2-star (T2
`) magnetic resonance for the early diagnosis of
`myocardial iron overload,” European Heart Journal, vol. 22, no.
`23, pp. 2171–2179, 2001.
`[18] J. C. Wood, C. Enriquez, N. Ghugre, et al., “MRI R2 and
`∗
`R2
`mapping accurately estimates hepatic iron concentration
`in transfusion-dependent thalassemia and sickle cell disease
`patients,” Blood, vol. 106, no. 4, pp. 1460–1465, 2005.
`[19] E. Voskaridou, M. Douskou, E. Terpos, et al., “Magnetic
`resonance imaging in the evaluation of iron overload in
`patients with beta thalassaemia and sickle cell disease,” British
`Journal of Haematology, vol. 126, no. 5, pp. 736–742, 2004.
`[20] G. C. Ooi, P. L. Khong, G. C. F. Chan, et al., “Magnetic
`resonance screening of iron status in transfusion-dependent
`β-thalassaemia patients,” British Journal of Haematology, vol.
`124, no. 3, pp. 385–390, 2004.
`[21] N. F. Olivieri, G. M. Brittenham, S. A. M. Armstrong, et
`al., “First prospective randomized trial of the iron chelators
`deferiprone (L1) and deferoxamine,” Blood, vol. 86, no. 10,
`supplement 1, 1995, abstract no. 249a.
`[22] M. A. Westwood, D. N. Firmin, M. Gildo, et al., “Intercentre
`∗
`reproducibility of magnetic resonance T2
`measurements
`
`Apotex Tech.
`Ex. 2029
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