1. RISK STRATIFICATION IN HEART FAILURE ROLE OF CARDIAC I-123- MIBG IMAGING : Prof. Denis Agostini Caen University Hospital France BARCELONA 2009

2. Most commonly used tracers for assessment of cardiac pre-synaptic processes Adapted from Carrio I. J Nucl Med 2001; 42:1062–1076 Pre-synaptic

3. MIBG & HEART FAILURE MILESTONE (1992-2009) MIBG and pheo neuroblastoma Prognosis Merlet et al J Nucl Med Retro and prospective Studies in US and Europe European Retrospective Study Agostini et al Verberne et al EJNMMI MIBG prospective studies 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

4. Survival rate JNM 1992 Elapsed time in months 0 100 25 100 024 Elapsed time in months H/M>120% H/M<120% H/M>120% H/M<120% IDCM, n=112 DCM, n=90 J Nucl Med 1992

5. Cardiac Sympathetic Denervation is more EXTENSIVE than the Infarct Size Matsunari et al. Circ 2000 123 I-mIBG 15.2 %LV 59.3 %LV 99m Tc SPECT Infarct Size

6. Patients with heart failure: -Prognosis stratified by semi-quantitative 123 I-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).

7. 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

8. – To demonstrate the feasibility of using a standardized methodology for analysis of cardiac 123 I-mIBG scintigraphy performed at multiple centres – To demonstrate the utility of 123 I-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

9. Death Rate vs MIBG uptake NYHA II-III Subjects, LVEF ≤ 35% (n=182) 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!!

10. Prognostic Significance of [ 123 I]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

11. 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

12. 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.

13. – 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

14. – 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 METHODS

15. Demographics and Clinical Characteristics VariableDataRange Mean Age (yr)62.420-90 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 (%)275-35 Median Follow-up (mo)170.1-27 ACE Inhibitor/ARB (%)94 Beta Blocker (%)92 2-year mortality rate (%)12.8- 961 HF subjects were evaluable for efficacy

16. Primary Endpoint Events HF Progression Arrhythmic Event Cardiac Death Total First Eventn=163 (68%)n=50 (21%)n=24 (10%)237 237 subjects (25%) had an adverse cardiac event.

17. Secondary Endpoint Events HF Progression Arrhythmic Event Cardiac Death Total All Eventsn=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

18. Composite Primary Endpoint Cumulative Rate (%) Months Follow-up H/M<1.60 H/M≥1.60 0 10 20 30 40 p<0.0001 H/M<1.60 760 629 441 241 67 H/M≥1.60 201 178 141 85 28

19. Heart Failure Progression Cumulative Rate (%) Months Follow-up H/M<1.60 H/M≥1.60 0 10 20 30 p=0.001

20. All Arrhythmic Events Cumulative Rate (%) 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

21. Cardiac Death Cumulative Rate (%) Months Follow-up H/M<1.60 H/M≥1.60 0 10 20 30 p=0.001 H/M<1.60 760 701 536 328 94 H/M≥1.60 201 176 121 99 32

22. 65 y/o M NYHA 2 DCM LVEF=25% H/M=0.96 Died at 8 mo HF Progression 51 y/o M NYHA 2 ICM LVEF=33% H/M=1.38 Died at 8 mo, SCD (No ICD) 64 y/o M NYHA 2 ICM LVEF=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

23. Composite Primary Endpoint Cumulative Rate (%) Months Follow-up LVEF<30%, H/M<1.60 LVEF<30%, H/M≥1.60 0 10 20 30 40 P=0.0004 50

24. 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.

25. 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 €)

26. Adreview Leiden Study, the impact on sudden death risk stratification and ICD implantation J Bax et al

27. One of the most common causes of death in developed countries: Sudden Cardiac Arrest Statistics High recurrence rate <5% 400,000 3 W. Europe 5% 450,000 2 U.S. <1%3,000,000 1 Worldwide SurvivalIncidence (cases/year)

28. 12 3, 4 54% 75% 55% 73% 31% 61% Primary Prevention Post-MI Trials: Reduction in Mortality with ICD Therapy 27 Months 39 Months20 Months % Mortality Reduction w/ ICD Rx

29. Annual ICD implants per million inhabitants Europe and USA Europe USA Updated from S. Nisam, 2000

30. 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%

31. 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

32. 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

33. 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?

34. Study Population (n = 116) 116 consecutive patients referred for ICD implantation based on guidelines for primary prevention

35. 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)

36. MIBG Scintigraphy Planar imaging Early Heart /Mediastinum ratio Late Heart /Mediastinum ratio Cardiac washout rate

37. MIBG Scintigraphy SPECT imaging Early summed defect score Late summed defect score

38. 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

39. 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)

40. Study Protocol Primary endpoint (n = 24) Appropriate ICD therapy Secundary endpoint (n = 32) Composite of appropriate ICD therapy or cardiac death

41. Predictors for Appropriate ICD Therapy – clinical variables

42. Predictors for ICD therapy (prim endpoint) - Imaging variables

43. Predictors for ICD therapy or cardiac death (sec endpoint) – imaging variables

44. Case example: 75-year old male patient ICD implantation, LVEF 28% received ICD therapy Rest Perfusion imagingDelayed MIBG imaging

45. Cumulative event rate for ICD therapy (n = 24) Cumulative event rate 79% vs. 5% 4-year follow-up data

46. Cumulative event rate for ICD therapy or cardiac death (n = 32) Cumulative event rate 83% vs. 10% 4-year follow-up data

47. 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