1. RCTs in Cardiac Resynchronization Therapy StudyPtNYHALVEFLVEDDRhythmQRSICD PATH-CHF41III,IV≤35%AnySR≥120N MUSTIC58III≤35%≥60SR≥150N MIRACLE453III,IV≤35%≥55SR≥130N MUSTIC AF43III,IV≤35%≥60AF≥200N MIRACLE ICD369III,IV≤35%≥55SR, AF≥130Y CONTAK CD227II-IV≤35%AnySR≥120Y MIRACLE ICD II186II≤35%≥55SR≥130Y PATH-CHF II101II-IV≤35%AnySR≥120Y/N COMPANION1520III,IV≤35%AnySR≥120Y/N CARE-HF814III,IV≤35%≥30 indexed SR≥120N 3812

2. Reverse remodeling in CRT Pts: Importance of etiology St.John Sutton Circ. 2006 Left Ventricular End-Diastolic Volume (ml) Left Ventricular End-Systolic Volume (ml) Left Ventricular Ejection Fraction (%) Left Ventricular Mass (g) ** * ** * ** * * * * * Baseline 6 Month 12 Month

3. LVEF change at 6 month predicts long-term outcome independently from etiology 0.00 0.25 0.50 0.75 1.00 LVEF =<6 LVEF >=6 Kaplan Meier Event-free survival P < 0.0001 01224364860728496 Follow-up (months since response) Di Biase, Auricchio et al. EHJ 2008

4. Effect of CRT on Death, Hospitalization, and i.v. Medications N=461 0.58 N=362 0.69 MIRACLE MIRACLE ICD [QRS >130 ms, EF III] [QRS >130 ms, EF III, ICD Indication] Hazard Ratio 0.60 COMPANION (CRT-D) COMPANION (CRT-P) [QRS >120 ms, EF III, recent Hospitalization] N=1520 0.65 0.60.81.01.21.40.4 CRT Better 1.61.8 CARE-HF N=813 0.63 [QRS >160 ms or IntraVD, EF III, recent Hospitalization]

5. Consistency in Survival Rate 10-12 %/yr 8.5 %/yr 8%/yr MILOS Registry CARE-HF (x-phase)COMPANION (Magdeburg) (Brescia) (Rozzano) (BadOeynhausen) Auricchio et al. AJC 2007

6. Marginal Benefit in AF Patients MUSTIC AF. Leclercq et al Eur Heart J 2002: 23: 1780

7. Role of underlying rhythm LVEF All-cause mortality Upadhyay GA et al JACC 2008

8. Effect of Ablation and CRT in HF patients with AF Sinus Rhythm Atrial Fibrillation with AVJ Ablation Atrial Fibrillation without AVJ Ablation 0 10 20 30 40 50 60 Baseline6122436 months Left Ventricular Ejection Fraction (%) -15 -10 -5 0 5 Changes of Left Ventricular End-Diastolic Diameter from Baseline (%) 0 10 15 20 25 Baseline6122436 months Peak Oxygen Consumption (ml/min/Kg) Gasparini M, et al. JACC 2006 N=687

9. Device Therapy for Advanced HF: Cardiac Resynchronization Therapy ESC/EHRA 2007 Guidelines on pacing and CRT ESC/HFA/ESICM 2008 Guidelines for the diagnosis and treatment of acute and chronic heart failure ACC/AHA/HRS 2008 Cardiac Pacemakers & Antiarrhythmia devices Class I LVEF ≤35% QRS ≥120 ms NYHA III - NYHA IV OMT LV Dilatation Sinus rhythm LVEF ≤35% QRS ≥120 ms NYHA III - NYHA IV OMT LVEF ≤35% QRS ≥120 ms NYHA III - NYHA IV ambulatory OMT Sinus rhythm As above Class I for an ICD (upgrade or replacement) Class IIa As above Permanent pacing (upgrade or replacement) As above Frequent dependence on ventricular pacing As above Permanent atrial fibrillation and indication for AV junction ablation As above Atrial fibrillation A A (CRT-P) B (CRT-D) A (CRT-P) B (CRT-D) B CC CB Vardas et al. EHJ 2007Dickstein et al. EHJ 2008Epstein et al. Circulation 2008

10. Mode of Death in COMPANION Bristow et al. Circulation 2006 Time to Sudden Cardiac Death Time to Heart Failure Death OPT CRT CRT-D

11. Effect of CRT-P on SCD (CARE-HF) Definitive SCD Probable SCD Possible SCD Uretsky et al. J Cardiac Fail 2008

12. Mode of Death in CRT-D and CRT-P Patients (n=1298): The MILOS Registry Multicenter Longitudinal Observational Study (MILOS) 2,5% per year 0,06% per year Auricchio et al. (MILOS Study) Am J Cariol 2006

13. Effect of CRT on Time to SCD or to HF Death in Stable NYHA IV Patients Time to Sudden Cardiac Death Time to Heart Failure Death CRT-D CRT OPT CRT-D CRT OPT No difference in 2-year survival between CRT and CRT-D patients. In patients with Class IV symptoms in whom resynchronization is inadequate to restore clinical stability, the presence of a ICD often complicates the impending transition to end-of-life care. Lindenfeld et al. Circulation 2007

14. No reliable criteria to predict clinical responders Control (n = 123)CRT (n = 131) MIRACLE: Functional NYHA Class

15. PROSPECT study: Selected echocardiographic methods and cut-offs Chung et al. Circulation 2008

16. PROSPECT study: End-points Chung et al. Circulation 2008

17. Predictive Value of Echo Dyssynchrony Measures The presence of single MD measures added 11-13% response to CCS and 13-23% to LVESV Chung et al. Circulation 2008

18. ASE Expert Consensus Statement: Conclusion JASE 2008

19. COMPANION Trial: All subgroups equally benefited Bristow et al. NEJM 2005

20. CARE-HF: All subgroups equally benefited Cleland et al. NEJM 2005

21. Specific situations Patients with RBBBAged patientsPatients with diabetes Patients with chronic renal failure

22. CRT in RBBB Patients: COMPANION Study Is CRT delivery suboptimal in these patients ? Are these patients sicker ? Is CRT delivery suboptimal in these patients ? Are these patients sicker ? Bristow et al. NEJM 2005

23. RBBB vs LBBB Fantoni et al. JCE 2005

24. RCTs and Registry (Age Issue) MIRACLE (2002) COMPANION (2005) CARE-HF (2005) Piccini et al. (2008) Age64 6667 71 Gender (W)32%33%26%31% Race (W/B/I)90/NA/NANA 82/12/3 DiabetesNA40%25%16% CAD50%55%67%57% LVEF0.22 0.25 QRS167 ms160 ms NA

25. Comparison of end point after 6 months in young and aged patients Kron et al. J Interv Cardioll 2009

26. Outcome of young and aged patients Delnoy et al AHJ 2008

27. Effect of Starting Age and Device Longevity on Cost per QALY – Base case 0 10,000 20,000 30,000 40,000 50,000 60,000 70,000 80,000 5560657075 Age at Starting Treatment Incremental Cost Per QALY Gained € CRT+MT vs MT CRT+ICD+MT vs CRT + MT CRT+ICD+MT vs MT 8 Years 5 Years 7 Years Freemantle N. on behalf of CARE-HF Investigators

28. Diabetes and CRT Diabetes No Diabetes Diabetes No Diabetes Diabetes No Diabetes Diabetes No Diabetes Fantoni et al. EHFJ 2008

29. Diabetes and CRT Diabetes Care 2007

30. Renal dysfunction Bai et al JCE 2008 CRT-D both BB and no-BB CRT-D and BB Normal renal function Chronic renal failure Normal renal function Chronic renal failure

31. Dyssynchrony-Scar-Creatinine Index β coefficient (95% CI) HR (95% CI)Z-scorep Posterolateral scar location 2.50 (1.60 to 3.40)12.2 (4.97 to 30.1)5.46 <0.0001 CMR-TSI, ms* 0.01 (0.00 to 0.02)1.01 (1.00 to 1.02)3.26 0.0011 Creatinine, µmol/L 0.01 (0.00 to 0.02)1.01 (1.00 to 1.02)2.83 0.0046 Model LR χ 2 : 73.4, p<0.0001 Leyva et al in press

32. Device Therapy for Advanced HF: Cardiac Resynchronization Therapy ESC/EHRA 2007 Guidelines on pacing and CRT ESC/HFA/ESICM 2008 Guidelines for the diagnosis and treatment of acute and chronic heart failure ACC/AHA/HRS 2008 Cardiac Pacemakers & Antiarrhythmia devices Class I LVEF ≤35% QRS ≥120 ms NYHA III - NYHA IV OMT LV Dilatation Sinus rhythm LVEF ≤35% QRS ≥120 ms NYHA III - NYHA IV OMT LVEF ≤35% QRS ≥120 ms NYHA III - NYHA IV ambulatory OMT Sinus rhythm As above Class I for an ICD (upgrade or replacement) Class IIa As above Permanent pacing (upgrade or replacement) As above Frequent dependence on ventricular pacing As above Permanent atrial fibrillation and indication for AV junction ablation As above Atrial fibrillation A A (CRT-P) B (CRT-D) A (CRT-P) B (CRT-D) B CC CB Vardas et al. EHJ 2007Dickstein et al. EHJ 2008Epstein et al. Circulation 2008