Ferriprox prevents heart failure deaths in thalassaemia

A new study shows the oral iron-chelator Ferriprox (deferiprone) prevents patients with thalassaemia experiencing heart complications and dying of heart failure.  Patients with the condition require frequent blood transfusions with the unwanted effect of excess iron that can build up in organs and endocrine glands. Iron overload in the heart can produce fatal complications so effective treatment with iron chelation therapy to remove iron is vital. The finding that an oral treatment achieves better results than injectable therapy is especially good news for patients who find it hard to comply with repeated infusions.

Data from the study show Ferriprox, an oral bidentate hydropyroxidine, compared very favourably against the standard chelation therapy Desferal (deferoxamine) administered by subcutaneous infusion. Results were presented during the 10th International Conference on Thalassaemia and Haemoglobinopathies, held in Dubai and are available in the online publication of the haematology journal Blood.

The study led by Professor Caterina Borgna-Pognatti of University of Ferrara, Italy compared cardiac events and heart-related deaths among patients with beta thalassaemia major aged between 2 and 25 years who had received blood transfusions and iron-chelating therapy over the 8-year period between 1995 ad 2003.  Currently over 70 per cent of patients with thalassaemia die from heart failure due to iron-overload in the heart muscle, said Professor Borgna-Pognati.  However, patients born after 1970 who receive blood transfusions and who start and comply with chelation therapy from an early age, have a better chance of survival.

A total of 359 patients from seven Italian centres received the standard iron-chelating therapy Desferal by subcutaneous infusion 30-50mg/kg per day, 5-6 times per week, over the entire study period.  A further 157 patients were included who had originally received Desferal but who were switched at some point during the 8-year period to Ferriprox, usually 75mg/kg body weight in a divided dose administered orally three times daily.  Patients are switched to oral treatment either because they are unable to tolerate, are not responding, or are not complying with, Desferal.  The median duration of Ferriprox therapy in the study was 4.3 years.  No patient had experienced a cardiac complication, defined as heart failure or arrhythmias requiring drug therapy, prior to entering the study. The two treatment groups were similar except that more patients receiving Ferriprox (31 per cent vs 21 per cent) had high blood iron levels (serum ferritin > 2500mcg/litre) – a measure usually regarded as a strong predictor of early mortality.

Results showed no patients experienced a cardiac event or died whilst receiving Ferriprox.  However, patients receiving standard Desferal therapy experienced 52 cardiac events including 15 deaths.

Professor Borgna-Pignatti commented:  “A possible explanation is that Ferriprox is more efficient than Desferal in accessing intracellular iron in the myocardium because it is smaller and more lipophilic.”

MRI technique aids management

A second study presented in Dubai by Professor Dudley Pennell, Professor of Cardiology at Imperial College, London and Director of the Cardiovascular Magnetic Resonance Unit at the Royal Brompton Hospital, London, showed heart tissue iron concentrations were reduced significantly more by Ferriprox treatment than by Desferal in a randomised controlled trial of 61 patients with beta-thalassaemia major.  Tissue iron in the heart was assessed by the Magnetic Resonance Imaging (MRI) T2* measure.  Patients with a T2* of below 20 milliseconds are at increased risk of left ventricular dysfunction, arrhythmias and heart failure; those with a T2* below 10 milliseconds are at very high risk, he noted.

In the study, left ventricular ejection fraction (EF) increased significantly more in the Ferriprox-treated group than in the Desferal-treated group (3.1 per cent vs. 0.3 per cent).  Patients receiving Ferriprox also had a significantly greater increase in myocardial T2* after six months than patients receiving Desferal.  Altogether, after 12 months, 66 per cent of the Ferriprox group saw a rise in both T2* and EF compared to 45 per cent of the Desferal group.  The result is highly significant p=0.003.

“Desferal works fast in clearing iron from the liver.  It works in the heart, too, but there it is exceedingly slow.  It probably needs two years to clear iron adequately,” Prof Pennell commented.  “Ferriprox clearly showed superior cardiac iron clearance and cardiac function improvement.”  The rate of clearance with Ferriprox was 2.5 times higher in patients with intermediate iron overload. In patients with acute heart failure, outcome may be affected considerably by choice of therapy, he added. 

Ferriprox’s smaller, less charged, structure is probably the reason why it has better intracellular access in and out of cardiac myosites, he suggested.  When Desferal goes into heart cells and binds to iron it undergoes a conformational change that can leave it, along with the bound iron, trapped inside.  In the liver this is not a problem because the liver has an active excretion mechanism to get iron out and into bile, he explained.

Preliminary results of studies revealed during the conference indicate both drugs in combination may provide the best results.  A study by Professor Pennell shows a combination of Ferriprox and Desferal is better than Desferal alone.  However, a comparison of the combination against Ferriprox alone has not been performed.  To date Ferriprox has been licensed only In Europe and is indicated for second-line therapy.

Professor Pennell is a leading scientist in the Royal Brompton team that developed the MRI T2* scanning technique permitting direct assessment of iron overload in the heart. This is now regarded as the gold standard for measuring cardiac iron.  In the past clinicians have measured serum ferritin and liver iron concentration to assess the extent of iron overload in patients’ tissues.  However, numerous investigators have found these measures do not correlate with iron overload in the heart, says Prof Pennell.  “The liver and the heart can be out of synch with regard to iron concentration.  This is why it is important to measure iron in the heart directly so that therapy can be adjusted accordingly.”   Because Desferal clear iron from the liver very effectively, physicians can wrongly assume iron has been cleared from the heart too when this is not the case, he explained.

The technique has deliberately never been patented so that it can be made available in countries where thalassaemia is highly prevalent but resources are scarce, he said.  A grant from the US National Institutes of Health has enabled the software for the T2* technique produced by Thalassaemia Tools to be rolled out in several centres worldwide.

“We now have a direct measure of iron in the organ responsible for three quarters of premature deaths.  That is a huge step forward,” he commented.  “We can use that measurement to understand which chelator is the best to use.  When we put those two things together we have an extremely powerful way of managing thalassaemia.”

Desferal is produced by Novartis Pharma AG, Switzerland and Ferriprox by ApoPharma, the innovative drug division of Apotex Inc, Canada.  Details of the MRI technique are available from www.cmrtools.com.

To see more features by Olwen Glynn Owen follow this link to his first feature article and scroll to the end for a list:
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