ARTICLES
`
`Comparison of effects of oral deferiprone and subcutaneous
`desferrioxamine on myocardial iron concentrations and ventricular
`function in beta-thalassaemia
`
`Lisa J Anderson, Beatrix Wonke, Emma Prescott, Sally Holden, J Malcolm Walker, Dudley J Pennell
`
`Summary
`
`Background Despite the introduction of the parenteral iron
`chelator desferrioxamine more than 30 years ago, 50% of
`patients with thalassaemia major die before the age of
`35 years, predominantly from iron-induced heart failure. The
`only alternative treatment is oral deferiprone, but its long-
`term efficacy on myocardial iron concentrations is unknown.
`
`Methods We compared myocardial iron content and cardiac
`function in 15 patients receiving long-term deferiprone
`treatment with 30 matched thalassaemia major controls who
`were on
`long-term
`treatment with desferrioxamine.
`Myocardial iron concentrations were measured by a new
`magnetic-resonance T2* technique, which shows values
`inversely related to tissue iron concentration.
`
`Findings The deferiprone group had significantly
`less
`myocardial iron (median 34·0 ms vs 11·4 ms, p=0·02) and
`higher ejection fractions (mean 70% [SD 6·5] vs 63% [6·9],
`p=0·004)
`than
`the desferrioxamine controls. Excess
`myocardial iron (T2* <20 ms) was less common in the
`deferiprone group than in the desferrioxamine controls (four
`[27%] vs 20 [67%], p=0·025), as was severe (T2* <10 ms)
`iron overload (one [7%] vs 11 [37%], p=0·04). The odds ratio
`for excess myocardial iron in the desferrioxamine controls
`versus the deferiprone group was 5·5 (95% CI 1·2–28·8).
`
`Interpretation Conventional chelation
`treatment with
`subcutaneous desferrioxamine does not prevent excess
`cardiac iron deposition in two-thirds of patients with
`thalassaemia major, placing them at risk of heart failure and
`its complications. Oral deferiprone is more effective than
`desferrioxamine in removal of myocardial iron.
`
`Lancet 2002; 360: 516–20
`See Commentary page 501
`
`Cardiovascular Magnetic Resonance Unit, Royal Brompton
`Hospital, London SW3 6NP, UK (L J Anderson MB,
`Prof D J Pennell MD); University College Hospital, London
`(S Holden BA, J M Walker MD); and Whittington Hospital, London
`(B Wonke MD, E Prescott BSc)
`Correspondence to: Prof Dudley J Pennell
`(e-mail: d.pennell@ic.ac.uk)
`
`Introduction
`Heart failure due to iron overload can develop either as a
`result
`of
`excess dietary
`absorption
`(hereditary
`haemochromatosis) or from repeated blood transfusions.
`The most striking model of cardiac iron overload is seen
`in thalassaemia major, in which heart failure remains the
`major cause of death (60%), greatly exceeding deaths
`from infection (13%) and liver disease (6%).1 Despite the
`introduction of the iron-chelating agent desferrioxamine
`more than 30 years ago in the UK, 50% of patients still
`die before reaching the age of 35 years.2 This high
`mortality
`is partly
`the result of difficulties with
`administration of desferrioxamine. This drug requires
`long subcutaneous or intravenous infusions on at least
`4 days a week; compliance with treatment is inadequate in
`many cases. The need for an effective alternative approach
`with an oral iron chelator has long been acknowledged,3
`and medium-term results from prospective trials of the
`oral chelator deferiprone (1,2-dimethyl-3-hydroxypyridin-
`4-one) seemed promising;4–6 however, the long-term
`effectiveness of this drug has been questioned because
`liver iron content is high in some patients.7,8 Since the
`primary objective of iron-chelation therapy is to prevent
`the lethal cardiac complications from myocardial iron
`deposition, myocardial iron and ventricular function
`should also be taken into account in assessment of the
`effectiveness of chelating agents. New magnetic resonance
`techniques can assess both myocardial
`iron and
`ventricular function
`in the same study.9 Our aim,
`therefore, was to investigate whether deferiprone is
`effective in controlling myocardial iron.
`
`Methods
`Participants
`We included all patients based at the Whittington
`Hospital, London, UK, who received chelation with
`deferiprone alone for longer than 3 years (mean duration
`5·7 years [SD 1·8]), between May, 1999, and December,
`2000. For each deferiprone patient, we assigned two
`controls with thalassaemia major, matched for age, sex,
`and current ferritin concentration, who were receiving
`standard subcutaneous desferrioxamine. Controls were
`chosen from the thalassaemic population also treated at
`this centre. The criteria for matching were a maximum
`age difference of 5 years (mean difference 2·4 years) and
`a maximum ferritin difference of 1000 ␮g/L (mean
`difference 447 ␮g/L). When more than two controls were
`identified, those with the smallest age differences were
`chosen. All patients received transfusions every 2–3 weeks
`to maintain the pretransfusion haemoglobin concentration
`at 90–95 g/L, and all had received iron-chelation therapy
`since the late 1970s or from early childhood in patients
`born after this time. Exclusion criteria were the inability to
`undergo magnetic-resonance scanning (claustrophobia,
`pregnancy, or pacemaker fitted). The reason for starting
`deferiprone was refusal or inability to comply with the
`
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`Apotex Tech.
`Ex. 2016
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`

`

`A
`
`Normal myocardial iron
`
`B
`
`Severe myocardial iron overload
`
`Figure 1: Magnetic-resonance scans in patients with
`thalassaemia
`Left scans are horizontal long axis, the right ones mid-short axis. A: low
`myocardial iron deposition. The left-ventricular volumes are normal, and
`myocardial signal intensity (long arrow) is similar to that arising from
`skeletal muscle (short arrow). Left-ventricular ejection fraction was 70%.
`In this case, the liver is very dark (dotted arrow), indicating heavy hepatic
`iron deposition despite the normal myocardial appearances. B: severe
`myocardial iron overload. The myocardial signal intensity is dark (long
`arrow) compared with skeletal muscle (short arrow). The ventricle is
`dilated and thickened. Cine imaging showed greatly reduced systolic
`function (left-ventricular ejection fraction 39%) with a restrictive filling
`pattern. Liver signal in this case is well preserved (dotted arrow).
`
`subcutaneous regimen in 12 patients and toxic effects of
`desferrioxamine in three (auditory in two and growth
`impairment in one). The mean administered dose of
`deferiprone was 80·5 mg/kg bodyweight (SD 10·1),
`divided
`into three doses per day. The drug was
`manufactured by Pfertec Pharmaceuticals, Essex, UK,
`under licence from Apotex, Toronto, Canada. The mean
`dose of desferrioxamine was 37·4 mg/kg bodyweight (7·9)
`on 5·1 days (0·8) per week; desferrioxamine treatment
`had been started a mean of 18·3 years (2·8) earlier. At the
`time of magnetic-resonance assessment, the drug was
`administered via 24 h subcutaneous
`infusions
`in
`13 patients and via overnight subcutaneous infusions
`in 17.
`At the time of this analysis, 224 patients with
`thalassaemia major had been referred for magnetic-
`resonance scanning (of a total UK population of around
`820 patients). Of these, 160 patients had received long-
`term chelation therapy with subcutaneous desferrio-
`xamine. We compared this group with the desferrio-
`xamine control group to assess whether the controls were
`representative of the general thalassaemic population.
`
`Protocol
`To quantify iron loading in the heart and the liver (figure
`1), we measured T2*, a magnetic-resonance variable that
`is inversely related to tissue iron concentration, by a
`previously validated method.9 The technique has high
`reproducibility both in the liver (coefficient of variation
`3·3%) and in the heart (5·0%).9 All patients were
`scanned, using the same sequence, with a Picker 1·5 T
`Edge Scanner (Marconi Medical Systems, Cleveland,
`OH, USA). Each scan included the measurement of liver
`and heart iron by means of T2*. For the calculation of
`liver T2* a single transverse slice through the liver was
`acquired at eight different echo times, and for the
`measurement of myocardial T2* a single short-axis mid-
`
`ARTICLES
`
`ventricular slice was acquired at nine separate echo times.
`After subtraction of background noise, the signal intensity
`of the liver or myocardial parenchyma was plotted against
`the echo time for the image. A trendline was fitted to the
`resulting exponential decay curve, with an equation of the
`form y=Ke-TE/T2* (where K is a constant, TE the echo
`time, and y the signal intensity). Myocardial T2* values
`measured
`in healthy volunteers showed a normal
`distribution with a mean value of 52 ms and a lower 95%
`confidence limit of 20 ms. We measured ventricular
`volumes, mass, and ejection
`fraction by standard
`cardiovascular magnetic-resonance techniques,10 which
`are highly reproducible,11 with published normal ranges.12
`Serum ferritin was measured by enzyme immunoassay,
`and all values are referable to the WHO Ferritin 80/602
`First International Standard (normal range 15–300 ␮g/L).
`Follow-up echocardiographic data in the form of
`M-mode
`left-ventricular dimensions and shortening
`fraction (defined as the difference between left-ventricular
`end-diastolic and end-systolic dimensions as a percentage
`of end-diastolic dimension) were available for nine of
`15 patients who received deferiprone and 20 of
`30 desferrioxamine controls. These echocardiograms were
`taken for clinical reasons for annual or biannual review.
`
`Statistical analysis
`We compared patients’ characteristics by means of
`Student’s t test (age and serum ferritin) or Fisher’s exact
`test (presence or absence of diabetes mellitus, hypo-
`pituitarism, hypothyroidism, hepatitis C). Myocardial
`T2* and liver iron values were positively skewed in all
`groups, and non-parametric analyses were used for
`comparison of these variables. Paired comparisons were
`made between the deferiprone and desferrioxamine
`groups with each deferiprone patient paired to the mean
`value of the two matched desferrioxamine patients.
`Wilcoxon’s signed-rank test was used for myocardial T2*
`and liver iron concentrations, and Student’s t test for
`indices of left-ventricular function. Since left-ventricular
`volumes and mass vary with the height and weight of a
`patient, we normalised these indices to body surface area.
`We assessed comparisons of proportions of patients with
`excess myocardial iron deposition in the groups with
`Fisher’s exact test. Unpaired comparisons between the
`30 desferrioxamine control patients and a
`larger
`population of 160 patients receiving subcutaneous
`desferrioxamine were made with the Mann-Whitney U
`test (myocardial T2* and liver iron) and the unpaired
`Student’s t test (age, left-ventricular ejection fraction, and
`serum ferritin). The odds ratio for the prevalence of
`excess myocardial
`iron
`in
`the deferiprone group
`compared with the desferrioxamine group was calculated
`with a 95% CI.
`
`Role of the funding source
`The sponsors of the study had no role in study design,
`data collection, data analysis, data interpretation, or
`writing of the report.
`
`Deferiprone
`group (n=15)
`
`Desferrioxamine
`controls (n=30)
`
`Age (mean, SD) (years)
`M/F
`Serum ferritin (mean, SD) (␮g/L)
`Diabetes mellitus
`Hypopituitarism
`Hypothyroidism
`Hepatitis C
`
`29·0 (6·3)
`12/3
`1236 (651)
`6 (40%)
`7 (47%)
`2 (13%)
`4 (27%)
`
`Data are number (%) unless otherwise indicated.
`Table 1: Characteristics of patients
`
`29·4 (7·1)
`24/6
`1250 (508)
`11 (37%)
`20 (67%)
`2 (7%)
`9 (30%)
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`ARTICLES
`
`Variable
`Myocardial T2* (median, IQR) (ms)
`Left-ventricular measurements (mean, SD)
`Ejection fraction (%)
`End-systolic volume index (mL/m2)
`End-diastolic volume index (mL/m2)
`Mass index (g/m2)
`Liver iron (median, IQR) (mg/g liver dry
`weight)
`
`Normal range
`
`Deferiprone group
`
`Desferrioxamine controls
`
`Mean difference (95% CI)
`
`p
`
`>20
`
`34·0 (18·0–56·0)
`
`11·4 (7·0–25·0)
`
`··
`
`56–78
`12–32
`44–89
`64–109
`0·35–1·36
`
`70 (6·5)
`24 (10)
`81 (19)
`87 (18)
`5·1 (2·8–10·0)
`
`63 (6·9)
`36 (11)
`94 (13)
`94 (11)
`3·5 (2·7–4·6)
`
`7·5 (2·8 to 12·2)
`–11 (–17 to –5)
`–12 (–23 to –1)
`–6·9 (–15 to 1·3)
`··
`
`0·02
`
`0·004
`0·03
`0·01
`0·09
`0·03
`
`All measurements made by magnetic resonance. Normal ranges are those derived from cardiovascular magnetic resonance for the measured variables.12
`Table 2: Paired comparisons of heart and liver iron content and indices of left-ventricular function
`
`Results
`Clinically relevant characteristics for patients in the two
`study groups are compared in table 1.
`The deferiprone-treated group had significantly less
`myocardial iron than the desferrioxamine-treated group
`(median myocardial T2* 34·0 vs 11·4 ms, p=0·02, table 2).
`The deferiprone group also had a higher mean left-
`ventricular ejection fraction (p=0·004) and
`less
`left-
`ventricular dilatation in systole (p=0·03) and diastole
`(p=0·01) than the control group. The left-ventricular mass
`index was lower, but not significantly so, in the deferiprone
`patients (p=0·09). Excess myocardial iron (myocardial T2*
`<20 ms) was noted in four (27%) deferiprone-treated
`patients compared with 20 (67%) desferrioxamine-treated
`patients (p=0·025), and severe iron overload (T2* <10 ms)
`was seen in one (7% ) and 11 (37%), respectively (p=0·04).
`The odds ratio for excess myocardial
`iron
`in the
`desferrioxamine versus the deferiprone group was 5·5
`(95% CI 1·2–28·8).
`Liver T2* measurements were converted into dry-weight
`liver iron measurements as previously described.9 Despite
`the lower myocardial iron and improved left-ventricular
`function in the deferiprone-treated patients (table 2), this
`group had significantly higher liver iron content than did the
`desferrioxamine group (median 5·1 vs 3·5 mg/g liver dry
`weight, p=0·03).
`To ensure that the myocardial iron and ventricular
`function in the desferrioxamine group were representative
`of these features in the wider population with thalassaemia
`major, we also compared the results of the desferrio-
`xamine control group with those of a further 160 patients
`Normal
`Desferrioxamine Desferrioxamine p
`range
`controls (n=30) population
`(n=160)
`
`..
`
`29 (7·1)
`
`27 (8·1)
`
`0·2
`
`>20
`
`11·4 (7·0–25·0) 14·8 (9·2–30·0) 0·2
`
`56–78
`
`63 (6·9)
`
`65 (9·3)
`
`0·2
`
`Variable
`Age (mean,
`SD) (years)
`Myocardial T2*
`(median, IQR) (ms)
`Left-ventricular
`ejection fraction
`(mean, SD) (%)
`Serum ferritin
`(mean, SD)
`(␮g/L)
`Liver iron
`(median, IQR)
`(mg/g dry weight)
`Patients with
`excess myocardial
`iron
`Patients with
`severe myocardial
`iron
`Table 3: Comparison of the desferrioxamine control group with
`a larger population of patients with thalassaemia major
`treated with subcutaneous desferrioxamine
`
`15–300
`
`1250 (508)
`
`2034 (1252)
`
`0·0004
`
`0·35–1·36 3·5 (2·7–4·6)
`
`4·8 (2·7–10·0)
`
`0·07
`
`..
`
`..
`
`20 (67%)
`
`101 (63%)
`
`0·8
`
`11 (37%)
`
`46 (29%)
`
`0·6
`
`treatment with
`subcutaneous
`standard
`receiving
`desferrioxamine. The two sets of desferrioxamine-treated
`patients were similar in age, and there was no significant
`difference in myocardial iron or left-ventricular ejection
`fraction, although serum ferritin was higher in the large
`group (table 3). The proportion of patients with excess
`myocardial iron deposition (T2* <20 ms) was similar in
`the two desferrioxamine groups, as was the proportion
`with severe iron overload.
`The median follow-up times with echocardiography in
`the deferiprone (nine patients) and desferrioxamine
`(20 patients) groups were 2·5 years (range 1·1–5·9) and
`2·1 years (1·4–6·6). The initial and final shortening
`fractions in the deferiprone group were 33% (SD 9) and
`36% (6); the mean improvement was 3·1% (p=0·1), with
`great improvement seen in two patients (figure 2).
`The initial and final shortening fractions in the des-
`ferrioxamine group were 32% (7) and 33% (5); the mean
`improvement was 0·7% (p=0·6) (figure 3). Although
`there was no significant difference
`in end-systolic
`dimensions between the groups at the initial scan
`(deferiprone patients 3·4 cm, desferrioxamine patients
`3·5 cm, p=0·4), end-systolic dimensions were significantly
`smaller in the deferiprone group at the final scan (3·1 vs
`3·6 cm, p=0·02).
`
`1992
`
`Patient 1
`1993
`
`1998
`
`LVEDD 5·5 cm
`LVESD 4·7 cm
`
`LVEDD 5·3 cm
`LVESD 4·4 cm
`
`LVEDD 4·6 cm
`LVESD 2·8 cm
`
`Patient 2
`
`LVEDD 6·2 cm
`LVESD 5·1 cm
`
`LVEDD 5·7 cm
`LVESD 4·5 cm
`
`1996
`
`2000
`
`Figure 2: M-mode echocardiography in patients treated with
`deferiprone
`Patient 1: images of left ventricle from a 24-year-old man at the start of
`treatment with deferiprone alone and after 1 year and 6 years of
`treatment. The initial scan showed severely impaired ventricular function
`with a dilated ventricle. There was some improvement by 1 year. After
`6 years, ventricular dimensions and systolic function have normalised.
`Patient 2: images of left ventricle from a 21-year-old man at the start of
`treatment with deferiprone alone and after 4 years of treatment. The
`initial image shows a dilated, impaired left ventricle. After 4 years the
`ventricular dimensions have improved but have not yet normalised.
`LVEDD=left-ventricular end-diastolic dimension; LVESD=left-ventricular
`end-systolic dimension.
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`

`LVEDD 5·0 cm
`LVESD 3·8 cm
`
`1996
`
`LVEDD 4·9 cm
`LVESD 3·3 cm
`
`2000
`
`Figure 3: M-mode echocardiology in patient treated with
`intravenous and subcutaneous desferrioxamine
`Images of left ventricle from a 28-year-old man with poor compliance to
`subcutaneous desferrioxamine treatment and who presented with poor
`left ventricular function and was treated for 1 year with intensive
`intravenous desferrioxamine. The first image (upper) was acquired in
`1996 when the patient was switched back from intravenous to
`subcutaneous desferrioxamine. Subsequent to this change in regimen,
`compliance to standard subcutaneous treatment was good, and by 2000
`(lower) echocardiographic appearances had improved.
`
`Discussion
`The iron chelator desferrioxamine was introduced more
`than 30 years ago13,14 and remains the only chelator
`approved for regular use in North America and the only
`first-line agent approved for use in Europe. Desferrio-
`xamine
`improves hepatic, cardiac, and endocrine
`dysfunction and lengthens survival in patients with iron
`overload.15–17 The disadvantages include high cost,18 the
`requirement for daily parenteral administration, and local
`and systemic toxic effects, which include visual19 and
`auditory neurotoxic effects,20 skeletal abnormalities,21 and
`growth retardation.22 Toxicity is increased in the presence
`of low hepatic iron,23 so the risk of side-effects could be
`lessened by reducing the dose when hepatic
`iron
`concentrations are low; however, patients should be
`regularly monitored for such adverse effects.23 Despite the
`administration of this arduous regimen for more than
`20 years, or from early childhood in younger patients,
`iron-induced heart failure remains the principal cause of
`premature death in these patients.15,24
`To date, only deferiprone has been introduced for
`clinical use as an orally active alternative
`to
`desferrioxamine. Deferiprone is a bidentate chelator,
`binding iron in a ratio of three to one, whereas
`desferrioxamine is a larger hexadentate molecule, binding
`
`ARTICLES
`
`iron in a one-to-one ratio. Side-effects of deferiprone
`include discoloured urine
`(40%), nausea
`(24%),
`arthropathy (11%), and reversible agranulocytosis (0·5%).
`Although results of formal dose-response studies have
`shown that iron excretion is worse with deferiprone than
`with desferrioxamine, findings of medium-term clinical
`trials have shown that it is effective,4,6,25,26 possibly because
`compliance is better. However, in a longer trial of
`18 patients over 4·6 years,7 eight patients had hepatic iron
`concentrations above 80 ␮mol/g liver wet weight (a value
`previously believed to be associated with increased risk of
`cardiac disease, and about equivalent to 15 mg/g dry
`weight). The investigators concluded that deferiprone
`“does not adequately control body iron burden”. This
`conclusion is, however, arguable. First, all patients had
`previously been treated with desferrioxamine, yet ten had
`hepatic iron concentrations of more than 80 ␮mol/g liver
`wet weight at the beginning of the trial. Second, during
`treatment with deferiprone, the mean liver iron content
`fell from a mean of 88·7 ␮mol/g (SD 12·1) to 65·5 ␮mol/g
`(7·9) liver wet weight. Third, myocardial iron content was
`not measured. We aimed to assess the effect of
`deferiprone on myocardial iron, because heart failure is
`the main cause of death in thalassaemia, greatly exceeding
`deaths from liver disease.1 Thus, the primary role of iron-
`chelation therapy is to prevent premature death from
`myocardial iron overload.
`The emergence of advanced magnetic-resonance
`techniques has made possible accurate assessment of both
`liver and cardiac
`iron
`in
`the same study. Such
`measurements have shown that myocardial iron cannot be
`predicted from liver iron concentration, and that left-
`ventricular ejection fraction is unrelated to liver iron or
`serum ferritin concentrations in thalassaemic patients.9,27
`Thus, direct myocardial iron measurements are essential.
`Our results indicate significantly lower myocardial iron
`content and a lower proportion of patients with excess
`myocardial iron in the deferiprone group than in the
`desferrioxamine controls, combined with better left-
`ventricular ejection fractions. These findings suggest a
`cardioprotective effect of deferiprone, arising despite the
`higher liver iron contents in the deferiprone group. These
`results show that deferiprone is an effective chelator for
`myocardial iron, and emphasise the importance of the
`variation between organs in iron concentrations and most
`notably the poor correlation between liver and myocardial
`iron.9,27 A possible mechanism for better cardioprotection
`from deferiprone than from desferrioxamine is its greater
`ability to penetrate myocardial cells, where excess iron is
`stored
`in
`lysosomes as
`ferritin and haemosiderin.
`Deferiprone can cross cell membranes more effectively
`than desferrioxamine because it is of lower molecular
`weight and is lipophilic.28,29 Conversely, in the liver,
`desferrioxamine has the advantage of facilitated transport
`into cells via an active uptake mechanism.30 Although our
`results indicate better myocardial iron concentrations with
`deferiprone and better hepatic iron concentrations with
`desferrioxamine, there is much variability among patients
`that remains to be explained. An individualised approach
`to iron-chelation therapy, with assessment of iron in each
`target organ might, therefore, be necessary to optimise
`care of patients.
`Our study had some limitations. The retrospective
`analysis used a magnetic-resonance technique that was
`not available when treatment with deferiprone was
`instituted. Ideally, the controls would be matched for
`baseline myocardial iron deposition, but this information
`was not available for either group. Although all our
`patients on long-term deferiprone were included, the
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`number is small; a larger, randomised prospective study,
`assessing tissue iron and ventricular function, is needed to
`confirm our findings. In this small group, myocardial iron
`could have been low before deferiprone treatment started.
`However, the echocardiographic data that are available
`show striking improvement in end-systolic dimension
`after the introduction of deferiprone, which would argue
`against this possibility. Alternatively, the desferrioxamine
`controls could have had unusually high myocardial iron
`concentrations, but the comparison with the larger group
`of 160 patients shows that myocardial iron concentrations
`and left-ventricular ejection fractions in the controls are
`representative.
`Excess myocardial iron deposition happens in more
`than half of patients with thalassaemia major treated with
`desferrioxamine long term. Oral deferiprone seems to be
`more effective than subcutaneous desferrioxamine in
`removing iron from the myocardium, but a larger
`prospective trial is needed to confirm our results. Since
`heart failure remains the most frequent cause of death in
`thalassaemia, the effectiveness of iron-chelation therapy
`should be assessed by monitoring of both cardiac iron and
`liver iron content, and these measurements can be made
`by the T2* magnetic-resonance technique.
`
`Contributors
`S Holden and E Prescott managed the cardiology and haematology
`clinics, co-designed the study, and entered patient data. B Wonke and
`J M Walker managed the patients in clinics, set up the databases,
`co-designed the study, and did the research investigations. L Anderson
`co-designed the study, did the CMR scans, and coordinated the study,
`and co-wrote the paper. D Pennell co-designed the study, managed the
`research, and co-wrote the paper.
`
`Conflict of interest statement
`B Wonke received £2000 from Apotex (manufacturers of deferiprone) for
`speaking at a conference. J M Walker received £1500 from Novartis
`(manufacturers of desferrioxamine) as a research equipment grant. The
`other authors have no conflict of interest to declare.
`
`Acknowledgments
`LJA was supported by a British Heart Foundation Junior Fellowship
`Grant (FS/98064). This work was also supported by the Wellcome Trust,
`and CORDA, the heart charity.
`
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`THE LANCET • Vol 360 • August 17, 2002 • www.thelancet.com
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