RISK STRATIFICATION IN
HEART FAILURE
ROLE OF CARDIAC
I-123- MIBG IMAGING :
Prof. Denis Agostini
Caen University Hospital
France
BARCELONA
2009
Most commonly used tracers for assessment
of cardiac pre-synaptic processes
Pre-synaptic
Adapted from Carrio I. J Nucl Med 2001; 42:1062–1076
MIBG & HEART FAILURE MILESTONE (1992-2009)
MIBG and pheo
neuroblastoma
1992
Prognosis
Merlet et al
J Nucl Med
Retro and prospective
Studies in US and Europe
2002
Impact of therapy
on neuronal
Function (exercise,
BB, ACI, Sartan)
and CRT
2008
European Retrospective
Study
Agostini et al
Verberne et al
EJNMMI
MIBG prospective
studies results
2009
Meta-analysis
Verberne et al
Eur Heart J
Arrhythmia
Bax J Circ Cardiovasc
Imaging 2008
JNM 1992
J Nucl Med 1992
100
100
Survival rate
H/M>120%
H/M>120%
H/M<120%
H/M<120%
DCM, n=90
0
IDCM, n=112
25
Elapsed time in months
0
24
Elapsed time in months
Cardiac Sympathetic Denervation
is more EXTENSIVE than the
Infarct Size
99mTc
SPECT
123I-mIBG
Infarct Size
15.2 %LV
59.3 %LV
Matsunari et al. Circ 2000
Patients with heart failure:
- Prognosis stratified by semi-quantitative 123I-MIBG myocardial
- parameters (i.e. early H/M, late H/M and myocardial washout).
Outcome measure:
- Cardiac death
- Cardiac event (combination of cardiac death, myocardial infarction,
heart transplantation and hospital admission due to progression of
heart failure).
Conclusion of
MIBG meta-analysis
• Reduced late H/M or increased myocardial
MIBG washout is associated with a poorer
prognosis
• In general poor quality of performed studies :
– Single center studies (Europe-Japan)
– Small samples of patients in each study
– No standardization of imaging methodology
(collimator, HM or WO ratios…)
– No MIBG-SPECT studies
– No MPI
Eur J Nucl Med Mol Imaging 2008
–
To demonstrate the feasibility of using a standardized
methodology for analysis of cardiac 123I-mIBG
scintigraphy performed at multiple centres
–
To demonstrate the utility of 123I-mIBG uptake as
measured by the heart–to-mediastinum (HMR) ratio for
identifying subjects with NYHA Class II-IV CHF who
experience a Major Cardiac Events (MCE) during a 24month follow-up period
Death Rate vs MIBG uptake
NYHA II-III Subjects,
LVEF ≤ 35% (n=182)
24
22
20
18
2-Yr Death 16
14
Rate (%)
12
10
8
6
4
2
0
n
38
78
43
23
*
All Cardiac
Deaths
(n=21)
MCE Deaths (n=14)
NO MCE!!
<1.4
1.4-1.79
1.8-2.19
H/M Ratio
≥ 2.2
*Including 6 deaths
post-transplant
and 1 post-CABG.
p<0.05
Prognostic Significance of [123I]mIBG
Myocardial Scintigraphy in Heart Failure
Patients: Results from the Prospective
Multicenter International ADMIRE-HF
Trial
Arnold F. Jacobson, MD, PhD
Roxy Senior, MD, DM, FRCP, FESC, FACC
Fred Weiland, MD
Harish Chandna, MD
Denis Agostini, MD, PhD
for the ADMIRE-HF* investigators (ACC 2009)
*ADMIRE-HF: AdreView Myocardial Imaging for Risk Evaluation in Heart Failure
ADMIRE HF: a landmark study
• Integration of two identical
open-label Phase III trials (MBG311 and
MBG312)
• Multicenter study 96 centres
(35 EU, 57 US, 4 Canada)
• July 2005 to September 2008
• 985 heart failure patients
– 110 age-matched control
ADMIRE-HF: AdreView Myocardial Imaging for Risk Evaluation in Heart Failure
Primary Objective of ADMIRE-HF:
To demonstrate the prognostic usefulness
of assessment of myocardial sympathetic
innervation, as determined by the heart
to mediastinum (H/M) ratio on planar
AdreView imaging as either normal (≥1.6)
or abnormal (<1.6), for identifying HF
subjects at higher risk of experiencing an
adverse cardiac event.
METHODS
– Primary eligibility criteria
• NYHA II/III HF (ischemic or non-ischemic)
• LVEF≤35%
• Guidelines-based management including ACE
inhibitors/ARBs and beta blockers
• No previous defibrillation to treat a ventricular
arrhythmic event
METHODS
– Composite Primary Endpoint
First occurrence of any of the following 3 categories of
adverse cardiac events
1. HF Progression: Progression of HF stage (NYHA II
to III or IV; NYHA III to IV).
2. Arrhythmic Event:
• Sustained ventricular tachyarrhythmia
• Appropriate ICD discharge
• Aborted cardiac arrest
3. Terminal Cardiac Event: Cardiac death
Demographics and Clinical
Characteristics
961 HF subjects were evaluable for efficacy
Variable
Data
Range
Mean Age (yr)
62.4
20-90
Gender (M/F) (%)
80/20
-
75/14/11
-
NYHA II/III (%)
83/17
-
HF Etiology (I/NI) (%)
66/34
-
Mean LVEF (%)
27
5-35
Median Follow-up (mo)
17
0.1-27
ACE Inhibitor/ARB (%)
94
Beta Blocker (%)
92
Race (White/Black/Other) (%)
I=Ischemic; NI=Non-ischemic
2-year mortality rate (%)
12.8
-
Primary Endpoint Events
237 subjects (25%) had an adverse cardiac event.
First Event
HF
Progression
Arrhythmic
Event
Cardiac
Death
Total
n=163 (68%)
n=50 (21%)
n=24 (10%)
237
Secondary Endpoint Events
52 subjects had a second event of a different category following a first
event of HF progression or arrhythmia.
All Events
HF
Progression
Arrhythmic
Event
Cardiac
Death
Total
n=176 (60%)
n=64 (22%)
n=53* (18%)
293
*23 SCD, 24 HF death, 5 MI, 1 cardiac surgery complication
Composite Primary Endpoint
Cumulative Rate (%)
40
p<0.0001
H/M<1.60
30
20
H/M≥1.60
10
0
H/M<1.60 760
H/M≥1.60 201
629
178
441
141
Months Follow-up
241
85
67
28
Heart Failure Progression
Cumulative Rate (%)
30
H/M<1.60
p=0.001
20
H/M≥1.60
10
0
Months Follow-up
All Arrhythmic Events
Cumulative Rate (%)
30
p=0.002
20
H/M<1.60
10
H/M≥1.60
0
H/M<1.60 760
H/M ≥1.60 201
678
171
503
116
299
95
Months Follow-up
84
29
Cardiac Death
Cumulative Rate (%)
30
p=0.001
20
H/M<1.60
10
H/M≥1.60
0
H/M<1.60 760
H/M≥1.60 201
701
176
536
121
Months Follow-up
328
99
94
32
Representative ADMIRE-HF Subjects
Based upon the H/M ratios, 2-year cardiac mortality risk for
patient 1 is 10 times that of patient 3.
1
65 y/o M
NYHA 2 DCM
LVEF=25%
H/M=0.96
Died at 8 mo
HF Progression
2
51 y/o M
NYHA 2 ICM
LVEF=33%
H/M=1.38
Died at 8 mo, SCD
(No ICD)
3
64 y/o M
NYHA 2 ICM
LVEF=30%
H/M=1.67
No event
Composite Primary Endpoint
Cumulative Rate (%)
50
P=0.0004
LVEF<30%, H/M<1.60
40
30
20
LVEF<30%, H/M≥1.60
10
0
Months Follow-up
Conclusions
•
•
1. ADMIRE-HF achieved its primary efficacy
objective, demonstrating the prognostic value
of the AdreView uptake (H/M ratio <1.60 vs
≥1.60 on sympathetic innervation imaging)
for identifying higher vs lower risk for
adverse cardiac events in HF patients with
LVEF≤35%.
2. The prognostic value of AdreView imaging
was demonstrated for each of the categories in
the composite endpoint (HF progression,
arrhythmic events, cardiac death).
3. Between the highest and lowest risk
subpopulations (H/M<1.20 and H/M≥1.60),
there was a tenfold difference in 2-year
cardiac mortality rate.
CONCLUSION
STRENGTHS:
• Address the crucial unmet need of
risk-stratifying heart failure pts
• Several clinical trials in Europe and
US using MIBG (700 €)
OPPORTUNITIES:
• Increasing # heart failure patients
• Prophylactic use of ICD (> 50 000€)
• Payers pressure
• New technology for dual perfusion
and MIBG-SPECT (ALCYONE-CZT)
Adreview Leiden Study, the
impact on sudden death
risk stratification
and ICD implantation
J Bax et al
Sudden Cardiac Arrest
Statistics
• One of the most common causes
of death in developed countries:
Incidence
Survival
(cases/year)
3,000,0001
<1%
U.S.
450,0002
5%
W. Europe
400,0003
<5%
Worldwide
• High recurrence rate
% Mortality Reduction w/ ICD Rx
Primary Prevention Post-MI Trials:
Reduction in Mortality with ICD
Therapy
73%
75%
80
Overall Death
Arrhythmic 61%
Death
55%
54%
60
31%
40
20
1
2
3, 4
0
MADIT
27 Months
MUSTT
39 Months
MADIT-II
20 Months
Annual ICD
implants
per million
inhabitants
Europe and USA
250
200
150
280
250
208
180
USA
154
132
105
100
84
38
31
56
44
03
20
02
20
20
01
Europe
00
20
99
27
19
98
19
97
19
96
19
95
22
18
14
10
19
19
19
92
19
91
19
90
8
6
2,5 4
0
19
31
93
24
44
37
94
50
63
54
Updated from S. Nisam, 2000
60
2008 AHA/ACC/HRS
guidelines
for ICD implantation in
primary prevention
• Heart failure – NYHA II / III
• ACS, MI > 40 days
• Revascularisation > 90 days
• LVEF ≤35%
Primary prevention
Leiden registry
N= 941, 80% male, age 63 ± 11 years
all CAD, 83% previous MI
LVEF 29±12%
ICD therapy
Treated with ICD
Follow-up 31 ± 24 mth
66%
34%
-
+
What is the pathophysiological
substrate for SCD in chronic
CAD?
• Depressed LVEF (scar)
• Previous MI (scar)
• Ischemia (jeopardized)
• Dysfunctional but viable tissue
(jeopardized)
Burger vd Borg Circ 2003
MIBG Leiden Study
Prediction of ICD therapy
by mIBG imaging:
Could mIBG imaging
be the gatekeeper for
ICD implantation
in primary prevention
of sudden death?
Study Population (n = 116)
116 consecutive patients referred for
ICD implantation based on
guidelines for primary prevention
Study Protocol
Before ICD implantation:
123-I MIBG scintigraphy
Planar and SPECT
Early and delayed imaging
99m-Tc Tetrofosmin perfusion imaging
Stress-rest protocol (adenosine)
MIBG Scintigraphy
Planar imaging
Early Heart /Mediastinum ratio
Late Heart /Mediastinum ratio
Cardiac washout rate
MIBG Scintigraphy
SPECT imaging
Early summed defect score
Late summed defect score
Perfusion Imaging
Resting 99m-Tc Tetrofosmin
Summed rest score
Stress 99m-Tc Tetrofosmin
Summed stress score
Summed difference score
123-I MIBG/perfusion mismatch score
Endpoints
Clinical Follow-up
From ICD implantation to first documented:
Appropriate ICD therapy (prim endpoint)
ATP or ICD shock induced by
ventricular tachyarrhythmia
ICD therapy + Cardiac mortality
(sec endpoint)
Study Protocol
Primary endpoint (n = 24)
Appropriate ICD therapy
Secundary endpoint (n = 32)
Composite of appropriate ICD therapy
or cardiac death
Predictors for Appropriate
ICD Therapy – clinical variables
Predictors for ICD therapy
(prim endpoint)
- Imaging variables
Predictors for ICD
therapy or cardiac death (sec endpoint)
– imaging variables
Case example: 75-year old male patient
ICD implantation, LVEF 28%
received ICD therapy
Rest Perfusion imaging
Delayed MIBG imaging
Cumulative event rate
for ICD therapy (n = 24)
Cumulative event rate 79% vs. 5%
4-year follow-up data
Cumulative event rate
for ICD therapy or cardiac death
(n = 32)
Cumulative event rate 83% vs. 10%
4-year follow-up data
Conclusion
• The extent of denervated myocardium is
related to induction of ventricular
arrhythmias
• Late MIBG SPECT defect size is the main
predictor for ventricular arrhythmias in
patients with cardiomyopathy undergoing
ICD implantation for primary prevention of
sudden death
• MIBG may be used as gatekeeper
for ICD selection