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Prof. Denis Agostini Caen University Hospital France BARCELONA 2009. RISK STRATIFICATION IN HEART FAILURE ROLE OF CARDIAC I-123- MIBG IMAGING :. Most commonly used tracers for assessment of cardiac pre-synaptic processes. Pre-synaptic. Adapted from Carrio I. J Nucl Med 2001; 42:1062–1076. - PowerPoint PPT Presentation
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RISK STRATIFICATION IN HEART FAILURE
ROLE OF CARDIAC I-123- MIBG IMAGING :
Prof. Denis AgostiniCaen University Hospital
France
BARCELONA
2009
Most commonly used tracers for assessment of cardiac pre-synaptic processes
Adapted from Carrio I. J Nucl Med 2001; 42:1062–1076
Pre-synaptic
MIBG & HEART FAILURE MILESTONE (1992-2009)
MIBG and pheoneuroblastoma
Prognosis Merlet et alJ Nucl Med
Retro and prospectiveStudies in US and Europe
European Retrospective StudyAgostini et alVerberne et alEJNMMI
MIBG prospectivestudies results
Meta-analysisVerberne et alEur Heart JArrhythmia Bax J Circ Cardiovasc Imaging 2008
1992 2008 2009
Impact of therapy on neuronal Function (exercise, BB, ACI, Sartan) and CRT
2002
Sur
viva
l rat
eS
urvi
val r
ate
Sur
viva
l rat
eS
urvi
val r
ate
JNM 1992
Elapsed time in months0
100
25
100
0 24Elapsed time in months
H/M>120%H/M>120%
H/M<120%H/M<120%
H/M>120%H/M>120%
H/M<120%H/M<120%
IDCM, n=112IDCM, n=112DCM, n=90DCM, n=90
J Nucl Med 1992
Cardiac Sympathetic Denervation is more
EXTENSIVE than the Infarct Size
Matsunari et al. Circ 2000
123I-mIBG
15.2 %LV 59.3 %LV
99mTc SPECT Infarct Size
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
– 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 24-month follow-up period
Eur J Nucl Med Mol Imaging 2008
Death Rate vs MIBG uptakeNYHA II-III Subjects, LVEF ≤ 35% (n=182)
02468
1012141618202224
<1.4 1.4-1.79 1.8-2.19 ≥ 2.2
All Cardiac Deaths(n=21)MCE Deaths (n=14)
H/M Ratio
2-Yr Death Rate (%)
n 38 78 43 23
*
*Including 6 deaths post-transplant
and 1 post-CABG.p<0.05
NO MCE!!
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 identicalopen-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 controlADMIRE-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.
– 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 events1. 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
METHODS
Demographics and Clinical Characteristics
Variable Data RangeMean Age (yr) 62.4 20-90Gender (M/F) (%) 80/20 -Race (White/Black/Other) (%)
75/14/11 -
NYHA II/III (%) 83/17 -HF Etiology (I/NI) (%)I=Ischemic; NI=Non-ischemic
66/34 -
Mean LVEF (%) 27 5-35Median Follow-up (mo) 17 0.1-27ACE Inhibitor/ARB (%) 94Beta Blocker (%) 922-year mortality rate (%) 12.8 -
961 HF subjects were evaluable for efficacy
Primary Endpoint Events
HF Progression
Arrhythmic Event
Cardiac Death
Total
First Event n=163 (68%) n=50 (21%) n=24 (10%)
237
237 subjects (25%) had an adverse cardiac event.
Secondary Endpoint Events
HF Progression
Arrhythmic Event
Cardiac Death
Total
All Events n=176 (60%) n=64 (22%) n=53* (18%)
293
52 subjects had a second event of a different category following a first event of HF progression or arrhythmia.
*23 SCD, 24 HF death, 5 MI, 1 cardiac surgery complication
Composite Primary Endpoint Cu
mul
ativ
e Ra
te (
%)
Months Follow-up
H/M<1.60
H/M≥1.60
0
10
20
30
40p<0.0001
H/M<1.60 760 629 441 241 67 H/M≥1.60 201 178 141 85 28
Heart Failure ProgressionCu
mul
ativ
e Ra
te (
%)
Months Follow-up
H/M<1.60
H/M≥1.60
0
10
20
30 p=0.001
All Arrhythmic Events Cu
mul
ativ
e Ra
te (
%)
Months Follow-up
H/M<1.60
H/M≥1.60
0
10
20
30 p=0.002
H/M<1.60 760 678 503 299 84 H/M ≥1.60 201 171 116 95 29
Cardiac Death Cu
mul
ativ
e Ra
te (
%)
Months Follow-up
H/M<1.60
H/M≥1.60 0
10
20
30p=0.001
H/M<1.60 760 701 536 328 94 H/M≥1.60 201 176 121 99 32
65 y/o MNYHA 2 DCMLVEF=25%H/M=0.96
Died at 8 moHF Progression
51 y/o MNYHA 2 ICMLVEF=33%H/M=1.38
Died at 8 mo, SCD (No ICD)
64 y/o MNYHA 2 ICMLVEF=30%H/M=1.67
No event
1 2 3
Based upon the H/M ratios, 2-year cardiac mortality risk for patient 1 is 10 times that of patient 3.
Representative ADMIRE-HF Subjects
Composite Primary EndpointCu
mul
ativ
e Ra
te (
%)
Months Follow-up
LVEF<30%, H/M<1.60
LVEF<30%, H/M≥1.60
0
10
20
30
40P=0.0004
50
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
OPPORTUNITIES:• Increasing # heart failure patients• Prophylactic use of ICD (> 50
000€)• Payers pressure • New technology for dual perfusion
and MIBG-SPECT (ALCYONE-CZT)
STRENGTHS:• Address the crucial unmet need of
risk-stratifying heart failure pts• Several clinical trials in Europe and
US using MIBG (700 €)
Adreview Leiden Study, the impact on sudden death
risk stratification and ICD implantation
J Bax et al
• One of the most common causes of death in developed countries:
Sudden Cardiac Arrest Statistics
• High recurrence rate
<5% 400,0003W. Europe 5% 450,0002U.S.<1%3,000,0001Worldwide
SurvivalIncidence(cases/year)
0
20
40
60
80
MADIT MUSTT MADIT-II
Overall DeathArrhythmic Death
1 2 3, 4
54%
75%
55%
73%
31%
61%
Primary Prevention Post-MI Trials: Reduction in Mortality with ICD
Therapy
27 Months 39 Months 20 Months
% M
orta
lity
Red
uctio
n w
/ IC
D R
x
31 37 4454 63
84105
132154
180
208
250
280
2,5 4 6 8 10 14 18 27 31 38 4456 60
24 220
50
100
150
200
250
1990
1991
1992
1993
1994
1995
1996
1997
1998
1999
2000
2001
2002
2003
Annual ICD implantsper million inhabitantsEurope and USA
Europe
USA
Updated from S. Nisam, 2000
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%
Treated with ICD
Follow-up 31 ± 24 mth
+-
66%
34%
ICD therapy
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 StudyPrediction 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 ProtocolBefore ICD implantation:
123-I MIBG scintigraphyPlanar and SPECT Early and delayed imaging
99m-Tc Tetrofosmin perfusion imagingStress-rest protocol (adenosine)
MIBG ScintigraphyPlanar imagingEarly Heart /Mediastinum ratioLate Heart /Mediastinum ratioCardiac washout rate
MIBG Scintigraphy
SPECT imagingEarly summed defect score Late summed defect score
Perfusion ImagingResting 99m-Tc Tetrofosmin Summed rest score
Stress 99m-Tc Tetrofosmin Summed stress scoreSummed difference score
123-I MIBG/perfusion mismatch score
Endpoints Clinical Follow-upFrom 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 ProtocolPrimary endpoint (n = 24)Appropriate ICD therapy
Secundary endpoint (n = 32)Composite of appropriate ICD therapyor 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 imagingDelayed 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 gatekeeperfor ICD selection