Transcript Navigator Echos - Respiratory Gating

Cardiac Effects of Iron Overload
Dudley Pennell, MD, FRCP, FACC, FES
Director, CMR Unit
Royal Brompton Hospital
Professor of Cardiology
National Heart and Lung Institute
Imperial College
London, United Kingdom
Why Is the Heart Important in Thalassemia Major?
Death by heart failure in 71% of patients
Median age at death: 35 years
IO = iron overload
Modell B, et al. J Cardiovasc Magn Reson. 2008;10:42-50.
Cardiac Iron Toxicity
Fibroblast
Stimulate fibrotic response
Ryanodine-sensitive
calcium reuptake
Sarcoplasmic
reticulum
Excitation/contraction
coupling
Mitochondria
K+
Depolarization and
repolarization
Na+
Na+ - Ca2+
Intracellular ion
concentrations
Na+ - K+ ATPase
LVDC
Lysosomes
More free iron
Liposomal
membrane
damage
Respiratory chain
enzymes
Fe 2+
Fe2+
DMT1
Fe3+
NTBI
???
Fe 3+
Tf-mediated
(minimal)
Tf-Fe
Nucleus
Gene expression
Iron interactions
Iron storage
Iron uptake
DMT1 = divalent metal transporter 1; LVDC = Ltype voltage-dependent channels; NTBI = nontransferrin-bound iron; Tf = transferrin
When the antioxidant capacity of the cell is exceeded, ROS are formed, damaging organelles,
interfering with electrical and mechanical processes, and triggering apoptosis.
ROS = reactive oxygen species.
Wood JC, et al. Ann NY Acad Sci. 2005;1054:386-395.
Measuring Myocardial T2*
5 ms
6 ms
7 ms
8 ms
9 ms
11 ms
13 ms
Signal = Ke-TE/T2*
Normal
Moderate
Severe
TE = echo time
Anderson LJ. Eur Heart J. 2001;22:2171-2179.
15 ms
17 ms
Proportion of Patients With Heart Failure
Kaplan-Meier Curves: T2* and Heart Failure
Kirk P. Circulation. 2009;120:1961-1968.
< 6 ms
6-8 ms
8-10 ms
> 10 ms
Follow-up Time (days)
Left Ventricular Ejection Fraction (%)
T2* - Cardiac Risk Ranging
90
80
70
60
50
40
30
20
10
0
10
20
30
40
50
60
70
80
Heart T2* (ms)
High
Anderson LJ. Eur Heart J. 2001;22:2171-2179.
Intermediate
Low
90
100
Deferiprone vs DFO in Beta Thalassemia Major
With Asymptomatic Myocardial Siderosis
• RCT in 61 pts previously maintained on sc DFO
– Compared continued DFO maintenance 43 mg/kg/d vs switch to
oral deferiprone 90 mg/kg/d
• At 12 months:
– Improvement in myocardial T2* 27% with deferiprone vs 13%
with DFO; P = .023
– Increase in LVEF 3.1% with deferiprone vs 0.3% with DFO; P = .003
DFO = deferoxamine; LVEF = left ventricular ejection fraction
Pennell D, et al. Blood. 2006;107:3738-3744.
Effect of Combined DFO + Deferiprone vs
Placebo on Cardiac Iron in Thalassemia Major
• Randomized, placebo-controlled trial in 65 pts previously
maintained on subcutaneous DFO
– Compared continued DFO maintenance + placebo vs
continued DFO maintenance + deferiprone
• At 12 months:
– Increase in geometric mean for myocardial T2* 50% with
combination vs 24% with placebo; P = .02
– Increase in absolute LVEF 2.6% with combination vs 0.6% with
placebo; P = .05
Tanner MA. Circulation. 2007;115:1876-1884.
EPIC Cardiac Substudy: Cardiac T2* in Treatment
Arm
> 5 to < 10 ms
all patients
10 to < 20 ms
20
18
16
14
12
10
8
6
4
2
0
No change
17.4**
14.6
12.9†
11.2
8.2‡
7.4
75
Mean LVEF (%)
Mean Cardiac T2* (ms)
80
70
68.7
68.4
67.4
65
67.7
68.2
67.1
65.2
65.8
66.1
60
P = .53
55
Baseline
12
Time (months)
**n = 64, P < .0001; †n = 105, P < .0001; ‡n = 41, P = .0002.
Pennell D, et al. Blood. 2010;115:2364.
Baseline
6
Time (months)
12
EHA 2010: EPIC Cardiac Substudy Extension
Geometric Mean Myocardial T2* (ms)
Myocardial T2* Over 2 Years in Patients With Beta Thalassemia and Myocardial Siderosis
*
*
*
*
*
*
* P < .001 versus baseline
N = 101
N = 101
Time (months)
Pennell D, et al. Presented at EHA 2010. Abstract 498.
N = 85
Mean deferasirox
dose:
•33.1 mg/kg/d in core
study
•36.1 mg/kg/d during
extension
EHA 2010: EPIC Cardiac Substudy Extension
(cont)
After 2 years of deferasirox treatment:
• 57% of patients with mild-to-moderate baseline cardiac siderosis
(10 to < 20 ms) were normalized ( ≥ 20 ms)
• 43% of patients with severe baseline cardiac siderosis (> 5 to < 10
ms) improved to mild-to-moderate category
Pennell D, et al. Presented at EHA 2010. Abstract 498.
EHA 2010: EPIC Cardiac Substudy Extension: Stratified
by Previous Chelation Regimen
• Evaluated effect of 2 years of deferasirox treatment in
patients with beta thalassemia and myocardial siderosis
– Stratified by prior chelation (DFO or combined DFO-DPO)
Prior DFO Monotherapy
Prior DFO-DPO
(n = 63)
(n = 32)
↑ in geometric mean for
myocardial T2*
28%1
35%1
% of pts with increase > 4%
in T2*
79%
69%
1.2% ± 4.5%2
−1.7 % ± 5.8% [NS]
↓ in mean LIC
9.6 ± 12.7 mg Fe/g dw3
12.4 ± 12.5 mg Fe/g dw3
↓ in median SF
2227 ng/mL3
2559 ng/mL3
Mean change in LVEF
1. P < .0001. 2. P = .046. 3. P < .001.
DPO = deferiprone; dw = dry weight; LIC = liver iron concentration; SF = serum ferritin
Pennell D, et al. Published at EHA 2010. Abstract 1805.
CORDELIA: RCT Deferasirox vs DFO
1-year study Rx in Core study
1-year study Rx in Extension study
96 patients
deferasirox
96 patients
deferasirox
96 patients DFO
96 patients DFO
Screening
23 days
Randomize eligible patients
(1:1 ratio)
Followed by 5-day washout
End Core / Start
Extension
End
Extension
Continuing in the extension is optional and requires re-consent by participants.
Conclusions
• Cardiac disease is the leading cause of death in beta
thalassemia major
• T2* MRI scan is useful for early detection of cardiac IO
and cardiac risk ranging
• Deferasirox, deferiprone, and deferiprone+DFO are shown
to significantly improve myocardial T2*
• Deferiprone is shown to improve LVEF
• EHA 2010: First prospective 2-year data on cardiac iron
removal with chelation
– Continued therapy with deferasirox ≥ 30 mg/kg/d effectively
removed cardiac iron, well tolerated