Eliminating Death from Heart Failure in Thalassaemia Major Using T2* Cardiovascular Magnetic Resonance
Submitting InstitutionImperial College London
Unit of AssessmentClinical Medicine
Summary Impact TypeHealth
Research Subject Area(s)
Medical and Health Sciences: Cardiorespiratory Medicine and Haematology, Clinical Sciences
Summary of the impact
The development of a cardiac magnetic resonance technique at Imperial
College and Royal Brompton Hospital to quantify myocardial iron
concentration has resulted in the early identification of thalassaemia
major patients at risk of heart failure and targeted cardiac treatment
with a hitherto little used iron chelator, deferiprone, following
randomised controlled trials of efficacy. Since 2008 these advances have
resulted in a 71% reduction in cardiac death from myocardial siderosis in
thalassemia major in the UK.
Key Imperial College London researchers:
Professor Dudley Pennell, Professor of Cardiology (1992-present)
Professor David Firmin, Professor of Biomedical Imaging (1990-present)
Thalassaemia major (TM) is a condition causing profound anaemia that is
fatal in childhood unless regular blood transfusions are given. Each unit
of blood contains approximately 200mg of iron that cannot be excreted.
Unless effective iron chelation treatments are taken throughout life, the
iron accumulates causing organ damage and death. Prior to 1998, most TM
patients died from heart failure (~75% of patients), and standard
monitoring of TM patients consisted of measuring serum ferritin and liver
iron concentration. Attempts were made to find empiric thresholds that
indicated myocardial siderosis (iron overload). However, the very high
death rate from heart failure clearly demonstrated the futility of this
approach. The Royal Brompton Hospital and Imperial College Cardiovascular
Magnetic Resonance (CMR) Unit therefore launched a research program to
directly measure myocardial iron non-invasively.
In 1998, we began assessing cardiac iron from the magnetic disturbance
caused by haemosiderin deposited in tissues as a consequence of breakdown
of excess ferritin. We wrote CMR pulse sequences to assess T1, T2 and T2*
in the heart, which are magnetic relaxation parameters that are affected
by the local biochemical environment and T2* was found to be the most
robust and sensitive technique in TM patients to identify iron. The new
T2* sequence was applied systematically, and we demonstrated the
revolutionary finding that liver iron and ferritin did not correlate with
cardiac iron. This implied that it was not possible to manage patients in
the conventional way, and expect to prevent heart failure and cardiac
death. Patients would require direct cardiac iron assessment and treatment
directed at cardiac iron (1).
The second major finding was that cardiac iron was unequivocally high in
patients with heart failure, and could be reversed with prolonged
intensive intravenous chelation with deferoxamine — a difficult and
hazardous treatment, but a treatment that saved 6 of 7 lives of the first
patients managed in intensive care, a huge improvement on the mortality of
historical cohorts with heart failure.
The third major finding was that a little used oral iron chelator,
deferiprone, was associated with substantially lower levels of cardiac
iron, and higher ejection fractions than matched patients treated with
conventional subcutaneous deferoxamine infusions given over 8 hours each
In 2004, we attracted National Institute of Health funding to validate
the T2* technique. Using an international consortium of collaborators, we
led the collection of post-mortem hearts from TM patients who died of
heart failure and achieved human calibration of myocardial T2* (3). We
demonstrated that lethal levels of cardiac iron were very low compared to
dangerous levels in the liver. We also scanned nearly all the UK TM
patients and follow them up for clinical events in relation to their
baseline T2*. This work proved that a T2* level of 10ms was the threshold
for increased heart failure risk, and this is now used internationally to
treat TM patients with aggressive chelation (4).
In order to determine best treatment for cardiac iron overload, we ran
two randomised controlled trials (2004-2006) to identify how best to
remove iron from the heart. Working with ApoPharma, we proved that
deferiprone removed cardiac iron better than conventional deferoxamine
(5). We also showed in a further trial, that deferiprone could be combined
with deferoxamine, especially in severe myocardial siderosis, for
synergistic chelation (6).
References to the research
(1) Anderson, L.J., Holden, S., Davies, B., Prescott, E., Charrier, C.,
Bunce, N.H., Firmin, D.N., Porter, J.B., Wonke, B., Walker, J.M., Pennell,
D.J. (2001). Cardiovascular T2-star (T2*) magnetic resonance for the early
diagnosis of myocardial iron overload. Eur Heart J, 22, 2171-2179.
DOI. Times cited:
531 (as at 22nd October 2013 on ISI Web of Science). Journal
Impact Factor: 14.09.
(2) Anderson, L.J., Wonke, B., Prescott, E., Holden, S., Walker, J.M.,
Pennell, D.J. (2002). Comparison of effects of oral deferiprone and
subcutaneous desferrioxamine on myocardial iron concentrations and
ventricular function in beta-thalassaemia. Lancet, 360, 516-520. DOI.
Times cited: 272 (as at 22nd October 2013 on ISI Web of
Science). Journal Impact Factor: 39.06.
(3) Carpenter, J.P., He, T., Kirk, P., Roughton, M., Anderson, L.J., de
Noronha, S.V., Sheppard, M.N., Porter, J.B., Walker, J.M., Wood, J.C.,
Galanello, R., Forni, G., Catani, G., Matta, G., Fucharoen, S., Fleming,
A., House, M.J., Black, G., Firmin, D.N., St. Pierre, T.G., Pennell, D.J.
(2011). On T2* magnetic resonance and cardiac iron. Circulation,
123, 1519-1528. DOI.
Times cited: 42 (as at 22nd October 2013 on ISI Web of
Science). Journal Impact Factor: 15.20.
(4) Kirk, P., Roughton, M., Porter, J.B., Walker, J.M., Tanner, M.A.,
Patel, J., Wu, D., Taylor, J., Westwood, M.A., Anderson, L.J., Pennell,
D.J. (2009). Cardiac T2* magnetic resonance for prediction of cardiac
complications in thalassemia major. Circulation, 120, 1961-1968. DOI.
Times cited: 103 (as at 22nd October 2013 on ISI Web of
Science). Journal Impact Factor: 15.20.
(5) Pennell, D.J., Berdoukas, V., Karagiorga, M., Ladis, V., Piga, A.,
Aessopos, A., Gotsis, E.D., Tanner, M.A., Smith, G.C., Westwood, M.A.,
Wonke, B., Galanello, R. (2006). Randomized controlled trial of
deferiprone or deferoxamine in beta-thalassemia major patients with
asymptomatic myocardial siderosis. Blood, 107, 3738-3744. DOI.
Times cited: 199 (as at 22nd October 2013 on ISI Web of
Science). Journal Impact Factor: 9.06.
(6) Tanner, M.A., Galanello, R., Dessi, C., Smith, G.C., Westwood, M.A.,
Agus, A., Roughton, M., Assomull, R., Nair, S.V., Walker, J.M., Pennell,
D.J. (2007). A randomized, 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,
115, 1876-1884. DOI.
Times cited: 177 (as at 22nd October 2013 on ISI Web of
Science). Journal Impact Factor: 15.20.
• British Heart Foundation (BHF; 1998-2000; £83,637), Principal
Investigator (PI), D. Pennell and J. Walker, Assessment of myocardial iron
using magnetic resonance T2-relaxometry: Optimisation of chelation therapy
in thalassemia for prevention of cardiac mortality (Junior Fellowship)
• BHF (2000-2001; £44,191), PI D. Pennell, Junior fellowship extension •
National Institutes of Health, USA (2004-2009; $1million), PI D. Pennell,
MR of Heart Iron: T2*/T2 Calibration and Application
• Novartis (2007-2010; £300,000), PI D. Pennell, Randomised controlled
trial comparing oral deferasirox with deferoxamine in patients with
transfusion dependent iron overload.
• BHF (2009-2012; £191,140), Co-Principal Investigators (Co-PIs) D.
Pennell, J. Carpenter, S. Cook, T. Aitman, E. Petretto, Genetic modifiers
of cardiac iron loading in thalassaemia major
• Novartis (2010-2012; £86,269), PI D. Pennell, Evaluation of
deferoxamine combined with deferasirox for treatment of cardiac siderosis
Details of the impact
Impacts include: health and welfare, practitioners and services, public
policy and services, commerce
Main beneficiaries include: patients, health professionals, industry
Before the introduction of T2* MR measures, patients at high risk of
cardiac complications went undetected. The Imperial research described has
allowed early detection of cardiac iron overload in TM major patients
which has been incorporated into national and international guidelines.
Follow-up of the UK cohort of TM patients (which represents 97% of the TM
population in the UK) has shown a 71% reduction in mortality since the
introduction of T2* CMR operating in concert with targeted cardiac iron
chelation. This is related to earlier detection of cardiac iron overload
and improved treatment, which prevents the onset of heart failure that is
associated with a very high mortality rate . A significant reduction in
mortality associated with the use of cardiac T2* CMR has been published
that is independent of Imperial College in Greece, Cyprus, Italy and Hong
Kong. Large studies internationally have demonstrated that the use of
deferiprone is associated with lower rates of cardiac death and
complications. This confirms the population effect of the cardioprotective
nature of deferiprone first demonstrated in our randomised controlled
Consequently, cardiac T2* is cited as pivotal to the management of TM
patients in four international sets of guidelines. The guidelines
published by the Thalassemia International Federation describe T2* as the
standard method for effectively and rapidly assessing cardiac iron levels
[4; see page 40] to determine the course and intensity of treatment [4;
see page 49). The UK specific guidelines also state that all patients
should have access to T2* MR imaging modalities for monitoring myocardial
and liver iron [5; see page 3]. Children with cardiac complications should
have the myocardial iron monitored by cardiac T2* from the age of eight,
with cardiac T2* maintained at >20 milliseconds by the appropriate
adjustment of chelation therapy [5; see page 5]. The Italian guidelines
also state that cardiac T2* should be monitored in patients with a poor
chelation history [6; see page 747]. US guidelines are currently in press
which will also incorporate the use of cardiac T2* . All the guidelines
above reference the research of Professor Pennell and colleagues.
Cardiac T2* has been installed in >100 centres worldwide, with
calculations suggesting that there is potential for 30,000 lives per year
to be saved if universal access to T2* and appropriate treatment can be
achieved. Worldwide survey of cardiac T2* at these centres shows that 42%
of TM patients have cardiac iron overload .
Furthermore, the Summary of Product Characteristics for deferiprone was
amended by the European Medicines Agency (EMA) in 2011 to indicate that
deferiprone use was associated with a lower mortality . The mortality
and cardiac data for deferiprone were used to gain approval for
deferiprone from the US Food and Drugs Administration (FDA) in 2011 .
The FDA is requiring new chelators (such as deferasirox) to show cardiac
efficacy through T2* as part of their assessment program (Novartis,
ApoPharma, AMAG, Shire).
An Imperial spin out company named CVIS has been created to commercialise
cardiac T2* analysis software.
Magnetic resonance T2* sequences and analysis software have been
developed by Siemens, Philips and GE. Siemens state that the availability
of T2* MR has been instrumental to the sale of scanners in some regions.
ApoPharma's drug Deferiprone has had a significant increase in sales and
has become profitable (letters available upon request from Siemens and
Sources to corroborate the impact
 Modell, B., Khan, M., Darlison, M., Westwood, M.A., Ingram, D.A.,
& Pennell, D.J. Improved survival of thalassaemia major in the UK and
relation to T2* cardiovascular magnetic resonance. J Cardiovasc Magn
Reson, 2008, 10, 42. DOI.
 Maggio, A., Vitrano, A., Capra, M., Cuccia, L., Gagliardotto, F., et
al. Improving survival with deferiprone treatment in patients with
thalassemia major: a prospective multicenter randomised clinical trial
under the auspices of the Italian Society for Thalassemia and
Hemoglobinopathies. Blood Cells Mol Dis, 2009, 42, 247-251. DOI.
 Telfer, P.T., Warburton, F., Christou, S., Hadjigavriel, M., et al.
Improved survival in thalassemia major patients on switching from
desferrioxamine to combined chelation therapy with desferrioxamine and
deferiprone. Haematologica, 2009, 94, 1777-1778. DOI.
 Cappellini MD, et al. Guidelines for the Clinical Management of
Thalassaemia. 2nd Edition Revised. Thalassemia International Federation
2008 (see page 40 and 49). PDF.
on 22nd October 2013.
 Yardumian A, et al. Standards
for the Clinical Care of Children and Adults with Thalassaemia in the
UK. United Kingdom Thalassaemia Society 2008 (see page 3 and 5).
 Angelucci E, et al. Italian Society of Hematology practice guidelines
for the management of iron overload in thalassemia major and related
disorders. Haematologica, 2008, 93, 741-752 (see page 747). DOI.
 Pennell, D.J., Udelson, J., Arai, A., Bozkurt, B., Cohen, A.,
Galanello, R., Hoffman, T., Kiernan, M., Lerakis, S., Piga, A., Porter,
J.B., Walker, J.M., Wood, J. on behalf of the American Heart Association
Committee on Heart Failure and Transplantation of the Council on Clinical
Cardiology and Council on Cardiovascular Radiology and Imaging. (2013).
Cardiovascular function and treatment in beta-thalassemia major: a
consensus statement from the American Heart Association. Circulation,
128, 281-308. DOI
 Carpenter, J.P., Roughton, M., & Pennell, D.J. (2013).
International survey of T2* cardiovascular magnetic resonance in beta
thalassemia major. Haematologica, 98, see page 248. DOI.
 EMA amendment of the Summary of Product Characteristics for
deferiprone 2011. PDF
(see page 7). Archived
on 22nd October 2013.
approval of deferiprone (2011). Archived
on 22nd October 2013. Factual statements available from the
Director MR Collaborative Management (Siemens) and the Vice President of
Medical Affairs (ApoPharma).