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 Study

Agostini et al

Verberne et al

EJNMMI

MIBG prospectivestudies results

Meta-analysis

Verberne et al

Eur Heart J

Arrhythmia

Bax J Circ Cardiovasc Imaging 2008

1992 2008 2009

Impact of therapy on neuronal Function (exercise, BB, ACI, Sartan) and CRT

2002

Su

rviv

al r

ate

Su

rviv

al r

ate

Su

rviv

al r

ate

Su

rviv

al 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)

0

24

6

810

12

1416

18

2022

24

<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 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.

– 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 Range

Mean Age (yr) 62.4 20-90

Gender (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 5-35

Median Follow-up (mo) 17 0.1-27

ACE Inhibitor/ARB (%) 94

Beta Blocker (%) 92

2-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 C

um

ula

tive R

ate

(%

)

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 ProgressionC

um

ula

tive R

ate

(%

)

Months Follow-up

H/M<1.60

H/M≥1.60

0

10

20

30p=0.001

All Arrhythmic Events C

um

ula

tive R

ate

(%

)

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 C

um

ula

tive R

ate

(%

)

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 EndpointC

um

ula

tive R

ate

(%

)

Months Follow-up

LVEF<30%, H/M<1.60

LVEF<30%, H/M≥1.60

0

10

20

30

40

P=0.000450

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 Death

Arrhythmic 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

ort

alit

y R

edu

cti

on

w/

ICD

Rx

31 37 4454

6384

105

132

154

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 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 scintigraphyPlanar and SPECT Early and delayed imaging

99m-Tc Tetrofosmin perfusion imagingStress-rest protocol (adenosine)

MIBG Scintigraphy

Planar imagingEarly Heart /Mediastinum ratioLate Heart /Mediastinum ratioCardiac washout rate

MIBG Scintigraphy

SPECT imagingEarly summed defect score Late summed defect score

Perfusion Imaging

Resting 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 Protocol

Primary 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