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

Reverse remodeling in CRT Pts: Importance of etiology St.John Sutton Circ 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

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

Effect of CRT on Death, Hospitalization, and i.v. Medications N= N= 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= CRT Better CARE-HF N= [QRS >160 ms or IntraVD, EF III, recent Hospitalization]

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

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

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

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

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

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

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

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

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

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

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

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

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

ASE Expert Consensus Statement: Conclusion JASE 2008

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

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

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

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

RBBB vs LBBB Fantoni et al. JCE 2005

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

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

Outcome of young and aged patients Delnoy et al AHJ 2008

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, 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

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

Diabetes and CRT Diabetes Care 2007

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

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 < CMR-TSI, ms* 0.01 (0.00 to 0.02)1.01 (1.00 to 1.02) Creatinine, µmol/L 0.01 (0.00 to 0.02)1.01 (1.00 to 1.02) Model LR χ 2 : 73.4, p< Leyva et al in press

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