1
Prevalence and Distribution of Iron Overload in Patients with
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Transfusion-dependent Anemias Differs across Geographic
3
Regions: Results from the CORDELIA Study
4
5
Yesim Aydinok,1 John B Porter,2 Antonio Piga,3 Mohsen Elalfy,4 Amal El-Beshlawy,5
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Yurdanur Kilinç,6 Vip Viprakasit,7 Akif Yesilipek,8 Dany Habr,9 Erhard Quebe-
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Fehling10 and Dudley J Pennell11
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9
1
Ege University Hospital, Izmir, Turkey; 2University College London, London, UK;
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3
11
University, Cairo, Egypt; 6Cukurova University Medical Faculty, Adana, Turkey;
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7
13
Turkey; 9Novartis Pharmaceuticals, East Hanover, NJ, USA;
14
Basel, Switzerland; 11 NIHR Cardiovascular Biomedical Research Unit, Royal
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Brompton Hospital, London, UK
University of Turin, Turin, Italy; 4Ain Shams University, Cairo, Egypt; 5Cairo
Siriraj Hospital, Mahidol University, Bangkok, Thailand; 8Akdeniz University, Antalya,
10
Novartis Pharma AG,
16
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Short title: Iron Burden in Transfusion-dependant Anemias (40 characters)
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Word count: 4144
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Figures/Tables: 2 figures/6 tables
1
20
Abstract
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Objectives: The randomized comparison of deferasirox to deferoxamine for cardiac
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iron removal in patients with transfusion-dependent anemias (CORDELIA) gave the
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opportunity to assess relative prevalence and body distribution of iron overload in
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screened patients.
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Methods: Patients aged ≥10 years with transfusion-dependent anemias from 11
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countries were screened. Data were summarized descriptively, overall and across
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regions.
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Results: Among 925 patients (99.1% with β thalassemia major; 98.5% receiving prior
29
chelation; mean age 19.2 years), 36.7% had cardiac iron overload (cardiac T2*
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≤20ms), 12.1% had low left ventricular ejection fraction. LIC (mean 25.8 mg Fe/g dw)
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and serum ferritin (median 3702 ng/mL) were high. Fewer patients in the Middle East
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(ME; 28.5%) had cardiac T2* ≤20ms versus patients in the West (45.9%) and Far
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East (FE, 40.9%). Patients in the West had highest cardiac iron burden, but lowest
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LIC (26.9% with LIC <7mg Fe/g dw) and serum ferritin. Among patients with normal
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cardiac iron, a higher proportion of patients from the ME and FE had LIC ≥15 than
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<7mg Fe/g dw (ME, 56.7 vs 17.2%; FE, 78.6 vs 7.8%, respectively), a trend which
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was less evident in the West (44.6 vs 33.9%, respectively). Transfusion and
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chelation practices differed between regions.
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Conclusions: Evidence of substantial cardiac and liver iron burden across regions
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revealed a need for optimization of effective, convenient iron chelation regimens.
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Significant regional variation exists in cardiac and liver iron loading that are not well
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explained; improved understanding of factors contributing to differences in body iron
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distribution may be of clinical benefit.
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Word count: 250 (max 250)
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Key words: Thalassemia; heart; liver; iron; prevalence; distribution
2
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Introduction
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Iron-induced cardiomyopathy has long been recognized as a leading cause of death
50
in patients with transfusion-dependent anemias (1-4). However, liver iron
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concentration (LIC) and serum ferritin, both established markers of liver iron overload,
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may not reliably reflect the presence of myocardial iron deposition (5, 6). Prompted
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by such observations, the development of reliable non-invasive techniques has
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facilitated investigation of myocardial iron burden in the setting of transfusion-related
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iron overload in clinical practice. Cardiovascular magnetic resonance (CMR), which
56
provides an estimate of myocardial iron load through the measurement of cardiac
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T2*, has been validated and recently calibrated (5, 7). A cardiac T2* value <20 ms
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indicates clinically significant cardiac iron above the normal limit which is associated
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with an increased risk of impaired ventricular function, with T2* <10 ms (ie severe
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cardiac iron overload) being associated with the highest risk of heart failure (8-10).
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Advances in the ability to measure myocardial T2* for the management of cardiac
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siderosis (10-15) (including the relationship between T2* and heart failure (10)); a
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greater understanding of normal ventricular function in thalassemia patients (16);
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and the availability of iron chelators with demonstrated efficacy for the removal of
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cardiac iron (15, 17-22), have all contributed to the decrease in cardiac-related
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mortality and morbidity over the last 10 years (23-25). Although cardiac-related
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mortality continues to remain a key challenge in treating these patients, an
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increasing number of deaths due to the long-term effects of iron-induced liver toxicity
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are also being observed (25).
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With these evolving management advances and challenges, it is important to re-
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examine the prevalence of iron overload among chronically transfused patients.
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Additionally, little is known about the distribution of iron burden across different
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geographic regions, as few studies had sufficient sample size to enable such
75
assessment. CORDELIA (NCT00600938) was an international, multicenter, open-
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label, randomized, Phase II clinical trial, which demonstrated the non-inferiority of
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deferasirox versus deferoxamine (DFO) for the removal of cardiac iron in patients
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with β thalassemia major (22). Overall, 925 patients were screened for entry into
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CORDELIA. We examined the prevalence and distribution of body iron burden and in
3
80
particular cardiac iron overload, overall and by geographic region, in this large and
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representative cohort of patients with transfusion-dependent anemias.
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Methods
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CORDELIA was a Phase II, open-label, randomized study (NCT00600938)
85
conducted between April 10, 2008 and March 1, 2012 to verify the non-inferiority of
86
deferasirox versus DFO in cardiac iron removal (22). Patients were screened for
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study entry from countries within three regions: West (Canada [n=4], Cyprus [n=10],
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Italy [n=2], Turkey [n=232], UK [n=11]); Middle East (Egypt [n=387], UAE [n=45],
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Lebanon [n=31]); and Far East (Taiwan [n=22], Thailand [n=122], China [n=59]).
90
Turkey was included in the Western region by definition of the World Health
91
Organization assignment to their European Region, and in order to balance patient
92
numbers between regions assessed here.
93
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Patients
95
Patients who underwent screening for entry into CORDELIA were aged ≥10 years
96
with a diagnosis of β thalassemia major, Diamond–Blackfan anemia (DBA),
97
sideroblastic anemia or Low/Int-1 risk myelodysplastic syndromes (MDS). Patients
98
were also required to have a lifetime history of ≥50 red blood cell (RBC) transfusions
99
(predominantly leucodepleted packed red cells, but also included whole blood, non-
100
leucodepleted red cells or washed red cells), and to be receiving RBC transfusions
101
amounting to ≥10 units per year. Prior chelation or requirement for chelation therapy
102
was also a criterion.
103
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Patients unable to undergo the study assessments (including magnetic resonance
105
imaging [MRI]) or who had psychiatric or addictive disorders that prevented them
106
from giving their informed consent were ineligible for screening.
107
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Patients provided written informed consent prior to any screening assessment. The
109
design and protocol of the CORDELIA study were approved by the relevant Ethics
110
Committees at each study site. The study was conducted in accordance with the
4
111
guidelines for Good Clinical Practice stipulated by the International Conference on
112
Harmonisation and Declaration of Helsinki.
113
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Screening assessments
115
Assessments were performed at screening for evaluation of myocardial siderosis
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(T2*), cardiac function (as evaluated by left ventricular ejection fraction [LVEF], %),
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and other iron parameters (as evaluated by LIC, mg Fe/g dry weight [dw] and serum
118
ferritin, ng/mL level).
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Cardiac T2* and LVEF were was measured using a standardized CMR protocol for
121
multigradient-echo T2* acquisition (5). Briefly, 10-mm midventricular short axis slices
122
were acquired at nine separate echo times (5.6–17.6 ms, with 1- to 2-ms increments)
123
in a single breath hold. The signal intensity at each echo time was measured using
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CMR tools software (Thalassemia-Tools; Cardiovascular Imaging Solutions) and an
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exponential fit was used to derive the myocardial T2* in milliseconds. The resulting
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images were assessed by a central CMR expert reader. LVEF was also measured
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by CMR. LVEF below the lower limit of normal (LLN) was identified using Westwood
128
criteria, (LLN for LVEF of 59% in males and 63% in females) (16).
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LIC was evaluated by measurement of the transverse relaxation parameter, R2
131
using a single breath-hold MRI technique that previously demonstrated high
132
sensitivity and specificity of R2 to liver biopsy LIC thresholds (26). Measurements
133
were read centrally.
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135
Serum ferritin levels were obtained from blood samples drawn at screening and were
136
analyzed by a central laboratory using a validated standard kit assay.
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Statistical analysis
139
All screened patients were included in the analysis population. Patient characteristics
140
were summarized by cardiac T2* categories of myocardial iron overload (<6 ms, 6–
141
<10 ms, 10–≤20 ms; or normal threshold >20 ms), by three geographic regions
142
(West, Middle East and Far East), and by splenectomy status (yes/no).
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5
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Results are presented descriptively. For measures of iron burden, cardiac T2* is
145
shown as the geometric mean (anti-log of the mean of the log data) with 95%
146
confidence intervals (CI), while LIC and serum ferritin are recorded as mean
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(standard deviation [SD]) and median (range), respectively. Data for cardiac function
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(LVEF) are summarized as mean (SD).
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Correlations between cardiac T2* and other iron parameters as well as age and
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LVEF were assessed using Pearson’s correlation coefficient (r).
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Results
154
Patient characteristics
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Overall, 925 patients screened for entry into CORDELIA were included in this
156
analysis, including patients from the West (n=259), Middle East (n=463) and Far
157
East (n=203) regions. The characteristics of patients are summarized in Table 1.
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Table 1. Patient demographics and clinical characteristics†
Overall
(n=925)
54.5:45.5
West
(n=259)
55.6:44.4
Middle East
(n=463)
57.5:42.5
Far East
(n=203)
46.3:53.7
19.2 (7.8)
19.6 (7.4)
19.3 (7.4)
18.8 (9.2)
Median
18.0
18.0
18.0
16.0
(range)
(9.0–80.0)
(10.0–49.0)
(9.0–66.0)
(9.0–80.0)
Caucasian
672 (72.6)
249 (96.1)
423 (91.4)
–
Asian
251 (27.1)
10 (3.9)
38 (8.2)
203 (100)
Other
2 (0.2)
–
2 (0.4)
–
46.6 (13.3)
49.7 (12.8)
47.0 (13.9)
41.8 (10.8)
47.0
49.9
47.0
41.8
(16.0–96.0)
(19.2–95.0)
(16.0–96.0)
(21.6–75.5)
902 (99.1)
257 (99.2)
446 (99.6)
199 (98.0)
DBA
1 (0.1)
1 (0.4)
–
–
Low/Int-risk MDS
4 (0.4)
–
1 (0.2)
3 (1.5)
Characteristic
Male:female, (%)
Age, years
Mean (SD)
Race, n (%)
Weight, kg
Mean (SD)
Median (range)
Disease, n (%)
β thalassemia major
6
Other‡
3 (0.3)
1 (0.4)
1 (0.2)
1 (0.5)
Splenectomy, n (%)
460 (49.7)
151 (58.3)
236 (51.0)
73 (36.0)
Hepatitis C, n (%)
101 (10.9)
14 (5.4)
76 (16.4)
11 (5.4)
are reported for patients with non-missing data; ‡β thalassemia intermedia, congenital
160
†Values
161
dyserythropoietic anemia, paroxysmal nocturnal hemoglobinuria (n=1 each).
162
DBA, Diamond–Blackfan anemia; MDS, myelodysplastic syndromes; SD, standard deviation.
163
164
Transfusion and chelation history
165
Despite a similar mean age, patients from the West region had received the greatest
166
number of transfusions (exposures to a transfusion episode) in their lifetime (median
167
257 [range 21–1950]), in comparison with patients from the Middle East and Far
168
East regions. However, the volume of blood per transfusion (median 200 mL [range
169
185–1400]) and the average hematocrit (median 60.0% [range 0.6–80.0]) were
170
lowest in the West when compared with the Middle East and Far East regions
171
However, the most recent transfusion policy (in the previous year) demonstrated a
172
shift towards more frequent transfusion exposure in patients from the Middle East
173
and Far East regions; in the year prior to screening, 91.4% of patients in the West
174
region were transfused monthly, whereas in the Middle East region, patients were
175
largely transfused monthly or every 2 weeks, with a similar observation in patients in
176
the Far East region (Table 2).
177
7
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Table 2. History of blood transfusion by geographic region
Overall
West
Middle East
Far East
Time since start of transfusions, years
Patients, n
839
257
383
199
Mean (SD)
17.6 (7.0)
18.6 (7.1)
18.0 (6.9)
15.8 (6.7)
16.5 (0–49.1)
17.3 (5.1–49.1)
17.4 (0–44.1)
14.2 (2.2–38.8)
Median (range)
Number of transfusions episodes
Patients, n
770
248
324
198
Mean (SD)
256 (184)
315 (228)
228 (145)
229 (163)
216 (15–1950)
257 (21–1950)
207 (15–840)
188 (30–1000)
Median (range)
Volume per blood transfusion, mL
Patients, n
774
201
375
198
Mean (SD)
364 (157)
279 (170)
400 (79)
380 (212)
350 (148–1400)
200 (185–1400)
350 (148–700)
300 (150–1000)
Patients, n
620
162
324
134
Mean (SD)
63.5 (8.1)
59.2 (5.5)
64.1 (6.5)
67.3 (11.3)
64.0 (0.6–80.0)
60.0 (0.6–80.0)
65.0 (35.0–76.0)
65.0 (50.0–80.0)
Median (range)
Average hematocrit, %
Median (range)
Usual transfusion frequency in the previous year, n (%)
Patients, n
859
257
401
201
Every 2 weeks
157 (18.3)
16 (6.2)
80 (20.0)
61 (30.3)
Every month
633 (73.7)
235 (91.4)
269 (67.1)
129 (64.2)
Every 6 weeks
30 (3.5)
5 (1.9)
23 (5.7)
2 (1.0)
Every 2 months
19 (2.2)
1 (0.4)
11 (2.7)
7 (3.5)
Every 3 months
12 (1.4)
–
10 (2.5)
2 (1.0)
Every 4 months
3 (0.3)
–
3 (0.7)
–
Every 6 months
5 (0.6)
–
5 (1.2)
–
179
180
Most patients (98.5%) had received previous iron chelation therapy with a range of
181
agents for a median of 12.3 years (0.0–37.1; Table 3). In the West region,
182
deferasirox was most frequently used (54.8%) just prior to study entry, compared
183
with 8.0% in the Middle East and 15.2% in the Far East regions. DFO was the most
8
184
frequent last prior therapy in both the Middle East (46.4%) and Far East (36.4%)
185
regions. Time since initiation of chelation therapy was shortest in patients in the Far
186
East region (9.1 years [0.1–31.3]), indicating that these patients, who had a mean
187
age at screening for the study similar to patients from other regions, initiated
188
chelation therapy at a later age than in other regions – although these patients had
189
also started transfusions more recently (Table 2). Indeed, the median (range) time
190
difference between start of transfusions and initiation of chelation therapy was
191
longest in patients in the Far East region (4.8 years [‒7.0‒35.2]) compared with the
192
West (2.8 years [‒8.0‒27.3]) and Middle East regions (3.0 years [‒16.1‒26.0]).
193
Patients in the West and Far East regions had no interruption of chelation therapy
194
after it was initiated (median of 0 months without chelation), while for patients in the
195
Middle East region, the median duration of interruption was 10.0 months (0.0–600.0;
196
Table 3).
197
198
Table 3. Prior chelation therapy by geographic region
Overall
(n=888)
875 (98.5)
West
(n=259)
259 (100.0)
Middle East
(n=427)
418 (97.9)
Far East
(n=202)
198 (98.0)
DFO
300 (34.5)
37 (14.3)
191 (46.4)
72 (36.4)
Deferiprone
113 (13.0)
29 (11.2)
51 (12.4)
33 (16.7)
DFO + deferiprone
205 (23.6)
50 (19.3)
104 (25.2)
51 (25.8)
Deferasirox
205 (23.6)
142 (54.8)
33 (8.0)
30 (15.2)
46 (5.3)
1 (0.4)
33 (8.0)
12 (6.1)
12.8 (6.7)
14.0 (7.2)
13.8 (6.1)
9.4 (5.7)
12.3 (0–37.1)
13.2 (0–37.1)
13.4 (0.2–34.1)
9.1 (0.1–31.3)
Previous chelation, n (%)
Other†
Time since start of chelation, years
Mean (SD)
Median (range)
Time without chelation after initiation, months
199
200
201
Mean (SD)
12.8 (38.0)
1.7 (10.9)
28.7 (54.2)
1.4 (8.6)
Median (range)
0 (0–600.0)
0 (0–108.0)
10.0 (0–600.0)
0 (0–87.0)
†Unknown
or patients received irregular deferiprone and/or DFO therapy.
DFO, deferoxamine; SD, standard deviation.
202
203
9
204
Cardiac iron overload
205
In the overall population, geometric mean cardiac T2* was 21.8 ms (n=764; Table 4).
206
Overall, 36.7% of patients had cardiac iron loading with cardiac T2* ≤20 ms; 19.9%
207
with a cardiac T2* of 10–≤20 ms (mild-to-moderate cardiac iron), 11.4% with T2* of
208
6–<10 ms (severe cardiac iron) and 5.4% having T2* <6 ms (severe cardiac iron and
209
high risk of heart failure).
210
211
Table 4. Iron overload and cardiac function parameters in patients with
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transfusion-dependent anemias across geographic regions
Overall
West
Middle East
Far East
(n=925)
(n=259)
(n=463)
(n=203)
21.8
19.4
24.5
20.0
(20.8, 22.9)
(17.8, 21.2)
(22.9, 26.3)
(18.0, 22.2)
Mean LVEF (SD), %
66.9 (5.8)
66.7 (5.5)
66.1 (6.1)
68.6 (5.2)
Mean LIC (SD), mg Fe/g dw
25.8 (17.1)
19.4 (14.6)
25.1 (16.5)
35.1 (16.9)
Median serum ferritin
(range), ng/mL
3702
(64–23,640)
2316
(334–11,682)
3742
(64–16,736)
5261
(685–23,640)
Geometric mean cardiac T2*
(95% CI), ms
213
CI, confidence interval; LIC, liver iron concentration; LVEF, left ventricular ejection fraction; SD,
214
standard deviation.
215
216
Geometric mean cardiac T2* differed across geographic regions, with the highest
217
value (indicating lower cardiac iron burden) in patients from the Middle East region
218
(Table 4). The distribution of cardiac iron overload severity categories also varied
219
between geographic regions as well as in comparison with the overall population
220
(Figure 1). In contrast to patients in the West (45.9%) and the Far East (40.9%)
221
regions, fewer patients in the Middle East regions had cardiac iron loading with T2*
222
≤20 ms (28.5%).
223
10
224
Figure 1. Prevalence of A) cardiac and B) liver iron overload in patients with
225
transfusion-dependent anemias across geographic regions
A
T2* <6ms
T2* 10–≤20ms
T2* 6–<10ms
T2* >20ms
Patients (%)
B
100
100
90
90
80
70
63.4
59.1
71.5
7.4
10.6
22.6
21.9
50
40
82.0
40
25.3
20.5
19.9
16.1
20
0
14.0
26.9
19.4
70
60
50
10
16.4
80
54.1
60
30
LIC ≥15 mg Fe/g dw
LIC 7–<15 mg Fe/g dw
LIC <7 mg Fe/g dw
11.4
5.4
Overall
(n=764)
13.6
7.9
6.8
5.6
4.5
West
Middle East Far East
(n=233)
(n=355)
(n=176)
15.0
64.1
30
51.2
20
63.4
10
0
Overall
(n=767)
West Middle East Far East
(n=242)
(n=336)
(n=189)
226
227
Geometric mean cardiac T2* also differed by splenectomy status, with a slightly
228
higher value in non-splenectomized patients versus splenectomized patients (23.2
229
ms [95% CI 21.7, 24.7] vs 20.6 ms [19.2, 22.1], respectively). More non-
230
splenectomized patients had cardiac T2* >20 ms (67.7 vs 59.3% of splenectomized
231
patients), and 12.5% of non-splenectomized patients had severe cardiac siderosis
232
compared with 20.7% of splenectomized patients.
233
234
Cardiac function
235
There were no differences across geographic regions in mean LVEF, which was in
236
the normal range among all patient populations (Table 4). Among T2* categories,
237
mean (SD) LVEF was lowest in patients with severe cardiac iron overload
238
(T2* 6–<10 ms: 63.8% [6.2%]; T2* <6 ms: 63.8% [6.1%]), compared with those
239
patients having mild-to-moderate (T2* 10–≤20 ms: 66.4% [6.4%]) or no significant
240
cardiac iron overload (>20 ms: 67.9% [5.2%]).
241
242
As shown in Figure 2, 24.4% of patients with T2* <6 ms had an LVEF below the LLN
243
(59% [males] or 63% [females]), compared with 8.2% of patients with cardiac T2*
244
>20 ms and 12.1% overall.
11
245
246
Figure 2. Prevalence of abnormal cardiac function across the T2* categories in
247
patients with transfusion-dependent anemias
Patients with LVEF <LLN, %
30
24.4
25
22.1
20
15
15.1
12.1
10
8.2
5
0
248
249
250
251
Overall
(n=754)
T2* >20 ms T2* 10-≤20 T2* 6-<10 T2* <6 ms
(n=475) ms (n=152) ms (n=86)
(n=41)
†Westwood
criteria (males <59%; females <63%) (16)
LLN, lower limit of normal
252
Other iron parameters
253
LIC
254
Mean (SD) LIC was severely elevated in the overall population of screened patients
255
(25.8 [17.1] mg Fe/g dw) and when analyzed by geographic region (Table 4).
256
However, the magnitude of mean LIC elevations differed according to region, with
257
the lowest and highest LIC values observed in the West and Far East regions,
258
respectively (Table 4).
259
260
The proportions of patients meeting predefined categories of LIC severity (<7,
261
7–<15 and ≥15 mg Fe/g dw) are shown by geographic region in Figure 1. Overall,
262
64.1% of patients had severe liver iron burden, as shown by LIC ≥15 mg Fe/g dw.
263
The distribution of patients across categories of LIC severity varied between the
264
West, Far East and Middle East regions. The overwhelming majority (82.0%) of
12
265
patients in the Far East region had LIC ≥15 mg Fe/g dw compared with
266
approximately half (51.2%) of patients from the West region and 63.4% from the
267
Middle East region (Figure 1). The proportion of patients with low liver iron burden
268
(LIC <7 mg Fe/g dw) was more than three-fold higher in the West region than in the
269
Far East region (Figure 1).
270
271
Distribution of cardiac and liver iron burden
272
We also examined the pattern of cardiac and liver iron distribution among screened
273
patients with data available for both assessments. Only four patients (all from the
274
West region) had severe cardiac iron burden but low LIC (T2* <10 ms and LIC
275
<7 mg Fe/g dw). Among patients with normal cardiac iron (T2* >20 ms), more than
276
half (58.5%) had an LIC ≥15 mg Fe/g dw, while 19.6 and 21.9% had LIC <7 or
277
7–<15 mg Fe/g dw, respectively. Within regions, a higher proportion of patients with
278
T2* >20 ms from the Middle East and Far East region had severe liver iron burden
279
(LIC ≥15 mg Fe/g dw) compared with those having LIC <7 mg Fe/g dw (Middle East
280
region, 56.7 vs 17.2%; Far East region, 78.6 vs 7.8%, respectively; Table 5). This
281
within-region trend for differences in liver iron loading among patients with normal
282
cardiac iron was less evident among patients from the West region (44.6% had LIC
283
≥15 mg Fe/g dw vs 33.9% with LIC <7 mg Fe/g dw).
284
13
285
Table 5. Distribution of cardiac and liver iron overload across geographic
286
regions in patients with transfusion-dependent anemias
Category
Geographic regions n (%)†
West
Middle East
Far East
n=121
n=215
n=103
<7
41 (33.9)
37 (17.2)
8 (7.8)
7–<15
26 (21.5)
56 (26.0)
14 (13.6)
≥15
54 (44.6)
122 (56.7)
81 (78.6)
n=116
n=195
n=144
>20
54 (46.6)
122 (62.6)
81 (56.3)
10–≤20
28 (24.1)
38 (19.5)
29 (20.1)
6–<10
22 (19.0)
24 (12.3)
22 (15.3)
<6
12 (10.3)
11 (5.6)
12 (8.3)
Cardiac T2* >20 ms
LIC, mg Fe/g dw
LIC ≥15 mg Fe/g dw
Cardiac T2*, ms
287
†Totals
288
LIC and T2*.
are calculated by region; values are reported for patients with non-missing data for both
289
290
In the overall population of patients with severe liver iron burden (LIC
291
≥15 mg Fe/g dw; n=455), 56.5% had a cardiac T2* >20 ms. Analysis by geographic
292
region of cardiac T2* categories in patients with LIC ≥15 mg Fe/g dw revealed a
293
relatively higher proportion of patients from the Middle East region with a T2* >20 ms
294
than from the Far East or West regions (Table 5). The distribution of severely liver
295
iron-overloaded patients among the remaining mild-to-moderate (T2* 10–≤20 ms) or
296
severe categories (T2* <6 or 6–<10 ms) of cardiac iron burden was generally
297
comparable (Table 5).
298
299
Serum ferritin
300
Median (range) serum ferritin level was 3702 (64–23,640) ng/mL overall. Across
301
regions, median serum ferritin level was lower in patients in the West region than
302
their counterparts in the Far East region (Table 2). Correspondingly, markedly fewer
303
patients in the West region (47.3%) recorded serum ferritin concentrations exceeding
304
2500 ng/mL compared with patients from the Middle East and Far East region
305
(Table 6).
306
14
307
Table 6. Comparison of the prevalence of iron overload, measured by serum
308
ferritin, across geographic regions in patients with transfusion-dependent
309
anemias
Geographic regions n (%)†
West
Middle East
Far East
n=256
n=452
n=201
≤1000
34 (13.3)
26 (5.8)
3 (1.5)
1000–≤2500
101 (39.5)
116 (25.7)
27 (13.4)
>2500
121 (47.3)
310 (68.6)
171 (85.1)
Serum ferritin, ng/mL
310
†Totals
are calculated by region; values are reported for patients with non-missing data.
311
312
Correlation analyses
313
Weak correlations were observed between cardiac T2* and age (r=–0.053),
314
LIC (r=–0.224), serum ferritin (r=–0.258) and LVEF (r=0.183).
315
316
Discussion
317
Although cardiac-related mortality remains a leading cause of death in patients with
318
transfusion-dependent anemias, changing management strategies have brought
319
about a reduction in the number of deaths attributed to iron-induced cardiomyopathy
320
(23-25). Since there is a lack of awareness of the impact of these changes on the
321
prevalence of cardiac iron, the CORDELIA study (a randomized comparison of
322
deferasirox versus DFO) provided the opportunity to investigate the prevalence of
323
cardiac iron overload from a broader geographical perspective, as well as body iron
324
burden overall.
325
326
We found that approximately one-third of patients screened for entry to CORDELIA
327
had significant cardiac iron loading, and that the prevalence of severe cardiac
328
siderosis (T2* <10 ms) was 16.8%. The overall prevalence of cardiac iron overload
329
(T2* ≤20 ms) was of 36.7% observed in this analysis (36.7%) is slightly lower than
330
previous observations (27-29). A recent survey undertaken in 35 worldwide centers
331
among 3445 patients with β thalassemia major identified a cardiac iron overload
332
prevalence of 42.3% (29). Similar observations have also been reported in other
333
studies (27, 28). Patients screened for CORDELIA had very high liver iron burden
15
334
overall, with a mean LIC of 25.8 mg Fe/g dw and 64.1% of patients having an LIC
335
>15 mg Fe/g dw. Serum ferritin levels were also elevated, with a median of 3702
336
ng/mL. Most patients screened for CORDELIA fell into the category for severe liver
337
iron burden (LIC >15 mg Fe/g dw), but with cardiac T2* in the normal range (>20
338
ms). However, we observed several differences in the distribution of iron overload
339
among patients across the regions from the West, Middle East and Far East regions,
340
and this may have had an impact on the observations made. Patients in the West
341
region had the highest cardiac iron burden, but the lowest liver iron burden and
342
serum ferritin levels. Cardiac iron burden was lowest in the Middle East region,
343
although the large majority of these patients with T2* in the normal range (>20 ms)
344
also had severely elevated LIC, a trend which was observed least often in patients
345
from the West region. Patients in the West and Middle Eastern regions were of a
346
similar age and had a similar duration since initiation of transfusions, so these factors
347
were unlikely to have significant impact on the differences in body iron distribution
348
across these groups. El-Beshlawy et al (2013) have also recently reported similar
349
observations in that in Middle Eastern patients, the prevalence of cardiac iron
350
loading was low despite severe liver iron burden (30). Finally, the proportion of
351
patients with T2* ≤20 ms reported in the Middle East region here (28.5%) contrasts
352
with data reported in 2009 among 81 patients from Oman, where 46% of patients
353
had abnormal cardiac T2* (27). Genetic differences in the thalassemia genotype or
354
other modifying genetic influences are unlikely to explain this difference, why Oman
355
has a higher proportion of patients with low T2* than other countries in the region.
356
These differences in prevalence but may reflect the smaller patient population in the
357
Omani study, but could also follow on from differences in patient management of
358
these patients among various Middle Eastern countries.
359
360
Age at starting transfusion or chelation therapy, the nature of transfusion or chelation
361
regimens and patient age at screening may all contribute to iron accumulation and
362
distribution. and requires further systematic investigation. Information on transfusion
363
and chelation practices was collected at screening, and examined in an attempt to
364
understand any potential impact on the observed regional differences. It is well
365
known that inefficient blood supply and/or difficulty in patient access leads to a lower
366
frequency of transfusion in some countries (31). The large majority of patients in the
16
367
West region were transfused monthly. Approximately two-thirds of patient in the
368
Middle East and Far East regions also received monthly transfusions, but a
369
significant proportion received transfusions every 2 weeks instead. Importantly, both
370
the volume of blood per transfusion and the hematocrit were typically higher in
371
patients from the Middle East and Far East regions as well, which could have
372
implications on the iron loading rate (32). Furthermore, the majority of patients from
373
the Far East region were not splenectomized. If hypersplenism was present in these
374
patients, perhaps as a result of inadequate transfusion policies in the past, it could
375
explain the observed higher transfusion frequency in the year prior to screening and
376
volume per blood transfusion compared with Western patients, and could also
377
contribute to the higher body iron burden despite lower transfusion chronicity. Later
378
onset of transfusion dependency in patients from the Far East region (despite being
379
of a similar mean age at screening compared to patients from the other regions) may
380
explain the shorter exposure to prior chelation therapy. It is possible that some
381
patients from this region were non-transfusion-dependent thalassemia (NTDT)
382
patients who later became regularly transfused; a scenario which is quite common in
383
patients with HbE/β thalassemia in the Far East. This could also help clarify why the
384
highest liver iron burden was seen in this group. Serum ferritin levels in patients with
385
NTDT tend to underestimate liver iron burden (33-35), unless patients are initiated
386
on a regular transfusion program as their disease severity worsens. Thus, in these
387
patients serum ferritin assessments alone may not have reflected body iron burden
388
until later in their lives once significant liver iron deposition had already developed.
389
Finally, Pre-transfusional hemoglobin levels were not available in the data collected,
390
as this would give further insight into the local transfusion practices and the
391
implications on iron loading and distribution.
392
393
With regard to the last prior iron chelation therapy at screening, information on
394
adherence was not systematically collected. Although information on adherence was
395
not systematically collected, deferasirox was reported as last prior chelation in over
396
half of patients in the West region, but only a small proportion of patients in the
397
Middle and Far East regions. In these latter regions, DFO use was most common,
398
perhaps due to limited patient access to oral therapies. A recent longitudinal analysis
399
highlighted differences between cardiac and liver iron changes depending on the
17
400
type of chelation regimen utilized, suggesting that chelation therapy should ideally be
401
tailored based on individual patient body iron burden (36).
402
403
Since the spleen may have a role in iron regulation (28, 37), differences in
404
splenectomy practices may also influence the disparity in body iron distribution
405
across the regions examined. A greater proportion of patients from the West region
406
had undergone splenectomy (58.3 vs 51.0 and 36.0% of patients from the Middle
407
East and Far East regions, respectively), which could contribute to the higher cardiac
408
iron burden in these patients as splenectomy has been implicated in increased
409
cardiac siderosis. A role for splenectomy in increased cardiac siderosis has been
410
suggested (28), where the intact spleen acts as a reservoir of excess iron, providing
411
a possible non-transferrin-bound iron scavenging function; hence, in the absence of
412
the spleen, there is less control over body iron in general (38). However, multiple
413
confounding factors could also contribute to this observation, such as local
414
transfusion practices and attitude to the safety of splenectomy. and particularly since
415
splenectomy is often considered in more severe disease.
416
Furthermore, the kinetics of iron accumulation may differ across geographic regions
417
depending on the genetic background of patients and may play an underlying role in
418
the observed differences in both the extent and pattern of iron burden between the
419
regions (39-42). For example, the genetic basis for hereditary and non-hereditary
420
iron overload in sub-Saharan Africans has been localized to a common mutation
421
within the ferroportin 1 (SLC40A1) gene, which is not present in Caucasians with
422
normal or abnormal iron load. Such genetic factors, among others, may play an
423
underlying role in the observed differences in both the extent and pattern of iron
424
burden between the regions examined here.
425
426
There was no clinically meaningful correlation between cardiac T2* and age, LIC,
427
serum ferritin or LVEF in this analysis, of 925 screened patients with transfusion-
428
dependent anemias. These findings are also which is consistent with previous
429
observations (6, 43), including an earlier study in 652 patients with β thalassemia
430
major, which concluded that among the relationships between cardiac T2*, liver T2*
431
and serum ferritin, only the relationship between liver iron and serum ferritin
432
remained clinically meaningful (10). In particular, even though LIC was severely
18
433
elevated in the majority of patients, this parameter was not a reliable predictor of
434
cardiac iron loading, consistent with a disparity in the kinetics of iron accumulation
435
and removal between these organs (5, 44). Nevertheless, high LIC may be relevant
436
however because since preliminary data suggest that there may be an association
437
between LIC and the rate of cardiac iron removal in patients treated with deferasirox
438
(22, 45). Additionally, although a strong relationship between LVEF and cardiac T2*
439
was not shown in this analysis – likely related to the substantial number of patients
440
with cardiac T2* in the normal range (5) – we did observe that nearly one-quarter of
441
patients with very severe cardiac iron loading (T2* <6 ms) had cardiac dysfunction
442
as observed by LVEF below the LLN for thalassemic patients. There was also a
443
trend for a greater proportion of cardiac dysfunction at lower cardiac T2* categories.
444
Kirk et al (2009) (10) provided convincing evidence to support a relationship between
445
the severity of myocardial siderosis (T2* <20 ms) and the risk of heart failure or
446
arrhythmias, thus supporting the validity of cardiac T2* as an early predictor of heart
447
complications. Interestingly, however, in our study, 8% of patients with normal
448
cardiac T2* had abnormal LVEF, highlighting the importance of monitoring both
449
cardiac iron burden and cardiac function.
450
451
Despite the majority of patients having documented receipt of some prior iron
452
chelation therapy, total body iron burden in this large cohort was severe, indicating
453
that compliance and/or dosage may have been sub-optimal. Liver iron burden in
454
particular was severely elevated, providing evidence to support recent observations
455
that liver complications are on the rise, relative to heart complications (25, 46). After
456
heart failure, liver disorders were the second most common cause of death among
457
thalassemia patients in a Greek hemoglobinopathy registry study, accounting for
458
18% of deaths in thalassemia patients, and an increase in the number of deaths
459
attributed to liver complications has been observed in the last decade (25). The fact
460
that a significant proportion of patients continue to show cardiac iron loading, as well
461
as the substantial liver iron burden demonstrates that there remains a need for the
462
optimization of effective and convenient iron chelation treatment regimens. This can
463
be achieved through more head-to-head comparisons of various chelation strategies
464
to help identify which patients will benefit most from the available chelation regimens.
465
Findings from the CORDELIA study, the first randomized trial to compare deferasirox
19
466
to DFO for the removal of cardiac iron, confirmed the non-inferiority of deferasirox,
467
with a trend for superiority (22). Although the combination of deferiprone and DFO is
468
not indicated in the product labels, randomized controlled trial data also supports the
469
benefit of this regimen in patients with significant cardiac siderosis (19). As removal
470
of iron from the heart occurs more slowly than for the liver (5, 44), longer study
471
durations are valuable to help gauge the true efficacy of chelation treatments.
472
473
As with studies of a non-interventional design, the potential influence of patient
474
selection bias for screening should be a consideration when interpreting these
475
results from this study. CORDELIA entry criteria were stringent with regard to body
476
iron burden and transfusion dependence, and physicians may have been mindful of
477
these when identifying patients who were appropriate for screening for a study on
478
cardiac iron overload, possibly selecting those patients most likely to have cardiac
479
iron. Additionally, a high number of patients screened for entry originated from the
480
Middle East region (463 of 925 patients). Observations of a lower prevalence of
481
cardiac iron burden in these patients may have impacted the findings of the results
482
reported here. Local country transfusion and chelation practices may influence
483
regional observations, particularly when groups were unbalanced such as the large
484
number of patients from Turkey compared with other countries in the West region.
485
Finally, cross-sectional analyses such as these should be interpreted with caution,
486
particularly since differences in previous chelation practices and patient compliance
487
are likely to impact on iron chelation efficacy and the relationship between heart and
488
liver iron unloading (36). It should also be noted that the results from this exploratory
489
analysis are presented descriptively, as the study was neither designed nor powered
490
to detect statistical differences between different populations.
491
492
In summary In these patients with transfusion-dependent anemias screened for entry
493
into the CORDELIA study, cardiac siderosis was observed in approximately one-third
494
of patients screened for entry into the CORDELIA study. The burden of liver iron
495
loading in particular was severe in the majority of patients, despite prior chelation
496
therapy in almost all patients examined. We observed differences in the pattern of
497
iron accumulation across geographic regions examined, which may be the result of
498
patient age, transfusion, chelation and other disease management practices, as well
20
499
as inherent population differences; further investigation into these differences is
500
warranted. Collectively, these results suggest a need to optimize effective and
501
convenient chelation regimens for personalized treatment to better manage both
502
cardiac and liver burden in patients with transfusion-dependent anemias.
503
21
504
Acknowledgements
505
We thank Debbi Gorman of Mudskipper Bioscience Ltd for medical editorial
506
assistance. Financial support for medical editorial assistance was provided by
507
Novartis Pharmaceuticals.
508
509
Funding source
510
The study was sponsored by Novartis Pharma AG and designed by the sponsor in
511
close collaboration with the Study Steering Committee. The sponsor conducted the
512
statistical analysis. Authors had full access to the data, and participated actively in
513
interpreting data and critically reviewing the article with the assistance of a medical
514
writer funded by the sponsor. All authors approved the final manuscript.
515
516
Authorship contributions
517
AE-B, AY, JBP, ME, VV, YA and YK served as investigators on this trial, screening
518
patients. They contributed to data interpretation, reviewed and provided their
519
comments on this manuscript. AP, DJP, JBP, and YA served as Study Steering
520
Committee members overseeing the conduct of the trial, from study design to
521
analysis plan and data interpretation. DH assisted in developing the trial protocol,
522
coordinating the execution of the trial and contributing to the analysis, interpretation
523
and reporting of the study data. EQF served as the study analysis statistician. All
524
authors approved the final manuscript.
525
526
Disclosures
527
YA reports participation in advisory boards consultancy and speaker’s bureau, and
528
receiving honoraria and research grant funding from Novartis Pharmaceuticals; and
529
participation in advisory boards consultancy and receiving research grant funding
530
from Shire. JBP reports consultancy, receiving research grant funding and honoraria
531
from Novartis Pharmaceuticals; consultancy and receiving research grant funding
532
from Shire; and consultancy for Celgene. AP reports participation in advisory boards
533
and receiving research grant funding from Novartis Pharmaceuticals, ApoPharma
534
and Shire. VV received research grant support, consultation and lecture fees from
535
Novartis
Pharmaceuticals,
Government
Pharmaceutical
Organization
(GPO)
22
536
Thailand and Shire. DH is an employee of Novartis Pharmaceuticals, and EQF is an
537
employee of Novartis Pharma AG. AE-B, AY, YK, and ME have no relevant conflicts
538
of interest to disclose. DJP reports consultancy and receiving research grant funding
539
and honoraria from Novartis Pharmaceuticals and AMAG; lecture fees from Novartis
540
Pharmaceuticals; consultancy and honoraria from ApoPharma Inc and from Shire;
541
and is a director and equity holder in Cardiovascular Imaging Solutions.
23
542
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