CARE-HF CA rdiac RE synchronization in H eart F ailure Clinical Study

1. CARE-HF CArdiac REsynchronization in Heart FailureClinical Study Independent trial by Clinical Community Sponsored by Medtronic

2. EP specialists understand that: Drugs (ACEIs, BB, Aldo Antagonists) have a profound impact on HF progression and mortality Drugs (BB and Aldo Antagonists) significantly decrease SCD HF specialists understand that: 50% of HF patients die from SCD ICD decreases mortality CRT decreases morbidity and mortality “Electromechanical Associations”EP & HF Specialties Progressively More EntwinedRogers JG & Cain MENEJM 2004;350:2193-95

3. Prevalence and Prognosis of Ventricular dyssynchrony LBBB More Prevalent with Increased All-Cause Mortality with Impaired LV Systolic Function Wide QRS at 45 Months (3) P < 0.001 Preserved 49% 8% LVSF (1) 34% Impaired 24% LVSF (1) QRS QRS < 120 ms ≥ 120 ms Mod/Sev 38% HF (2) 3. Iuliano, et al. AHJ. 2002;143:1085-1091. 1. Masoudi, et al. JACC. 2003;41:217-223. 2. Aaronson, et al. Circulation. 1997;95:2660-2667.

4. Cardiac Resynchronization Intraventricular Synchrony Atrioventricular Synchrony Interventricular Synchrony  RV Stroke Volume  dP/dt,  EF,  CO ( Pulse Pressure)  LA Pressure  LV Diastolic Filling  MR  LVESV  LVEDV Reverse Remodeling Cardiac Resynchronization: Proposed Mechanisms Yu C-M, Chau E, Sanderson J, et al. Circulation 2002;105:438-445

5. Cumulative Benefit of ACE-I and Beta Blockers P < 0.01 P < 0.05 Exner DV et al. JACC; 1999; 33: 916-23

6. Total Mortality Benefit for an ICD Trial (AVID) and a Statin Trial (WOSCOP) 4.1% 3.2% 25% 18% • 27% Relative Risk Reduction • 7% Absolute Risk Reduction • 18% Residual Risk • 22% Relative Risk Reduction • 0.9% Absolute Risk reduction • 3.2% Residual Risk

7. Residual Risk of SCD in Treatment Arms of CHF-Beta Blocker Trials Sudden Death % of Total Death 31% 54% 54% No. Pts in Treatment Arm: n= 1327 n= 1990 n = 696 Average Follow Up: 16 months 12 months 6.5 months • CIBIS-II Investigators. Lancet 1999; 353: 9-13. 3. Packer, M, et al. N Engl J Med 1996: 334: 1349-55. • MERIT-HF Study Group. Lancet. 1999; 353: 2001-07.

8. MADIT II: Hospitalization for Heart Failure P= 0.009 Moss AJ et al. NEJM 2002; 346: 877-83

9. Moderate CHF Severe CHF Post-MI LV dysfunction Mild CHF SOLVD Treatment (enalapril) CONSENSUS (enalapril) AIRE/SAVE (ramipril/captopril) US Carvedilol/MERIT (carvedilol/metoprolol) COPERNICUS (carvedilol) CAPRICORN (carvedilol) RALES (spironolactone) EPHESUS (eplerenone) CHARM/Val-HeFT (candesartan/valsartan) Pharmacologic and Device Therapy Across the Continuum MADIT, MUSTT (ICD) SCD-HeFT, MADIT-II (ICD) MIRACLE, COMPANION, MUSTIC (CRT +/- ICD) CARE-HF

10. CRT Background • CRT has been shown to be consistently associated with: • Reductions in LV size and volume • Increased Stroke Volume • Increased Ejection Fraction • Reduced Mitral Regurgitation • Improved exercise capacity • Improved QOL and functional capacity • Effects of CRT on hospitalisation and mortality remain uncertain

11. CRT Improves Quality of Life and NYHA Functional Class * P < 0.05 Abraham et al., 2003

12. CRT Improves Exercise Capacity * P < 0.05 Abraham et al., 2003

13. Mean distance walked in 6 minutes (m) 500 P<0.001 P<0.001 P=0.01 P<0.001 400 300 Paired Data Displayed 200 100 0 Mean NYHA Functional Class P<0.001 P<0.001 P<0.001 P<0.001 4 Baseline Follow-up 3 2 1 100 P<0.001 P<0.001 P<0.001 P<0.001 Mean QoL Score 80 60 40 20 0 6 (N=1124) 12 (N=693) 18 (N=320) 24 (N=68) Months of Active CRT CRT Benefits Sustained Through 2 YearsMIRACLE Study Program Abraham et al., AHA 2003

14. † ‡ * † Improvement * ‡ * NS ‡ Comparison with Drug Trials: Digoxin, ACE-I and Beta-blocker Therapies * P.05 † P.01 ‡ P.001 4 Am J Cardiol 1993;71:1106-1107 (SOLVD Treatment) 5 J Cardiac Failure 1997;3:173-179 6 NEJM 2002;346:1845-53 (MIRACLE) 1 NEJM 1993;329:1-7 (RADIANCE) 2 Circulation 1996;94:2793-2799 (PRECISE) 3 JAMA 1988;259:539-544

15. Systematic Review of 9 clinical trials CRT reduces all-cause mortality by 21% (RR 0.79 [Ci 0.66-0.96] NNTB 24 McAlister FA et al. Ann Intern Med 2004; 141:381-90 CRT does not significantly reduce all-cause mortality Calvert M, Freemantle N and Cleland JGF Ann Intern Med 2005; 142 :305-7

16. Limitations of Previous Trials/Analyses orWhy Was CARE-HF Needed • No individual clinical trial found a statistically significant reduction in all-cause mortality • 8/9 trials required successful device implantation before pts. were randomly assigned to CRT on or off [omission of implant failures (10%) and procedural deaths (0.4%) and exposure of controls to the effects of implanted device] • CRT combined with ICD in some but not all studies (difficult to isolate effect of CRT alone on mortality)

17. Limitations of Previous Trials/Analyses orWhy Was CARE-HF Needed (cont’d) • COMPANION had unbalanced 3-arm design (OMT, CRT, CRT+ICD) • Inclusion of all 3 arms of COMPANION in meta-analyses inappropriately credits CRT with the mortality reduction due to the ICD

18. The CARE-HF StudyCArdiac REsynchronisation in Heart Failure John GF Cleland - Kingston-upon-Hull. UK Jean-Claude Daubert – Rennes. France Erland Erdmann – Cologne. Germany Nick Freemantle – Birmingham. UK Daniel Gras – Nantes. France Lukas Kappenberger – Lausanne. Switzerland Werner Klein – Graz. Austria Luigi Tavazzi – Pavia. Italy on behalf of the CARE-HF Study Investigators

19. CARE-HFIntent • To assess the effect on morbidity and mortality of adding CRT to optimised pharmacological therapy in patients with moderate and severe HF due to LVSD complicated by cardiac dyssynchrony • To investigate the mechanisms underlying the observed effect to identify markers predicting success or failure of CRT • To define long term effects and Health Economics.

20. CARE-HF Committees • Steering Committee (8) • Data Safety and Monitoring Board (4) • Ryden, Poole-Wilson, Wellens, Wedel • Blinded Endpoint Adjudication • Committee (2) • Uretsky, Thygesen • Independent device-related adverse event assessor (1) • (Bocker)

21. Sites - Investigators - Coordinators Steering Committee FCM/ Monitors BRC Core-labs Quintiles - SS&R - DM - CEVA USA Tolochenaz EPC CARE-HF Communication DSMB

22. CARE-HF Study Overview

23. Primary & Main Secondary Endpoints Primary Composite Endpoint • All-cause mortality or unplanned hosp. for a major CVS event (time to first event analysis) • Hospitalisations adjudicated by a blinded EP committee Main Secondary Endpoint • All-cause mortality

24. Statistical Methods • Assumptions for Death or Unplanned CV hospitalization • Event rate in the control group: 40% • Absolute reduction in risk: 5.7% • 80% power with 300 primary outcome events • Censoring data within first 10 post randomization for Hospitalization endpoint. (No influence on results when analyzed without 10 days)

25. Study Design Patient screening- consent Randomization Optimal medical therapy Optimal medical therapy & cardiac resynchronization Follow-up (min 1.5 year) Follow-up (min 1.5 year) Primary outcome Secondary outcomes Mechanistic & health economic outcomes

26. Intervention • InSync® or InSync® III -> CRT-alone • Atrial-based, biventricular stimulation • RV: from apex using a standard pacing lead • LV: from lateral or postero-lateral free wall via the coronary sinus and veins using an Attain™ lead • Echo guided optimization of AV delay

27. Main Inclusion Criteria • Heart failure for at least 6 weeks requiring loop diuretics • Currently in NYHA class III/IV • A high standard of pharmacological therapy • LV systolic dysfunction and dilation • EF 35%; EDD 30mm/height in metres

28. Main Inclusion Criteria (cont’d) • QRS 120 ms • Dyssynchrony confirmed by echo if QRS = 120-149 ms • Aortic pre-ejection delay >140ms • Inter-ventricular mechanical delay >40 ms • Delayed activation of postero-lateral LV wall Main Exclusion Criteria • Patients with chronic AF or requiring pacing excluded

29. Population – Baseline Characteristics • 813 pts predominantly class III (94%) • Mean age 65 (IQR 59-72) • 34% aged > 70 years • 27 % woman • 38 % Ischaemic Heart Disease, 46% Dilated CM • Mean HR adequately controlled at 70 BPM • 88% QRS > 150 msec. • Supine systolic BP : 117 (IQR 105-130) • 94 % diuretic, 95 % Ace or ARB, 72 % b-Blocker, 56% Spironolactone Baseline Characteristics of Patients Recruited into the CARE-HF Study; With Courtesy : JGF Cleland et al. Submitted to EJHF

30. Population – Baseline Characteristics (cont’d) • LV EF 26% • LVEDD 72 mm • 2D and Doppler date suggest that few patients had end-stage disease characterized by pulmonary hypertension and right ventricular dysfunction • Co-Morbidities: • Diabetes 21%, history Atrial Arrhythmias 21%, Pulmonary disease 19%, renal dysfunction 18% Baseline Echo Cardiographic Characteristics of HF Patients enrolled in a large European Multicenter trial (Cardiac Resynchronization in Heart Failure) With Courtesy : S. Ghio et al. Submitted to EJHF. Baseline Characteristics of Patients Recruited into the CARE-HF Study; With Courtesy : JGF Cleland et al. Submitted to EJHF

31. Baseline Characteristics

32. Baseline Characteristics (cont’d)

33. MIRACLE, COMPANION, CARE-HF: Similarities and Differences MIRACLE COMPANION CARE-HF 1 yr mortality (%) (Control Arm ) 12.6 19

34. CARE-HF vs. other CRT Trial Populations • CARE-HF patients did not need a hospitalization within the year preceding enrollment, as requested in the COMPANION trial. • Diabetes co-morbidity in COMPANION was 40-45% vs. 21% in CARE-HF. Ischaemic population 55-59 % vs. 38% in CARE-HF. • One-year mortality in Control group : COMPANION 19% / CARE-HF 12.6%. • Average patient in CARE-HF appear to be less symptomatic than in MIRACLE, as CARE-HF included over 94% NYHA Class III. However, in CARE-HF >90% of patients had EF < 30 %. • Since CRT proved effective in CARE-HF, this may provide evidence of benefit in a broader symptomatic group than previously studied. Quote from Baseline Characteristics of Patients Recruited into the CARE-HF Study; With Courtesy : JGF Cleland et al. Submitted to EJHF

35. CARE-HF Results

36. 1-14 Patients/Center >14 Patients/Center • Recruitment • 813 patients (Jan 2001 - Mar 2003) • 82 centers in 12 countries • Austria, Belgium, Denmark, Finland, France, Germany, Italy, Netherlands, Spain, Sweden, Switzerland, • and UK

37. 409 Patients Randomized to CRT Arm 1 Death 4 No implant attempt 404 Implant Attempts 390 pts CRT implanted 96% with 3 attempts, 86% at first attempt Time randomization to implant : 4 days [2,8] Implant success rate 96% Before activation of CRT therapy ->6 pts reached primary objective CRT Arm - Implantation

38. Conduct of the Study • Follow-up time • Minimum 18 month -> last patient Sep 2004 • Average (Mean) Follow up : 29.4 month accounting • Cut-off data (30 Sept. 2004 – Randomization date) • Maximum 44.7 months: 3years 8 months • At completion (30th September 2004) • <5% cross-over before primary endpoint • Survival status ascertained on all patients • 202/ 813 pts (25% reached secondary endpoint) • 383/813 pts (45% reached primary endpoint) • All Adverse Events were adjudicated into Major, Minor, Planned hospitalization and for mode, cause, place

39. Primary Endpoint(All-cause Mortality or Unplanned Hosp. for Major CVS Event) 1.00 0.75 Event-free Survival 0.50 Medical Therapy 0.25 0.00 0 500 1000 1500 Days Number at risk 409 323 273 166 68 7 CRT 404 292 232 118 48 3 Medical Therapy

40. 1.00 HR 0.63 (95% CI 0.51 to 0.77) 0.75 0.50 Event-free Survival P < .0001 Medical : 224 ptsTherapy (55 %) 0.25 0.00 0 500 1000 1500 Days Number at risk 409 323 273 166 68 7 CRT 404 292 232 118 48 3 Medical Therapy Primary Endpoint(All-cause Mortality or Unplanned Hosp. for Major CVS Event) CRT : 159 pts (39%)

41. All-Cause Mortality 1.00 0.75 0.50 Event-free Survival Medical Therapy 0.25 0.00 0 500 1000 1500 Days Number at risk 409 376 351 213 89 8 CRT 404 365 321 192 71 5 Medical Therapy

42. All-Cause Mortality 1.00 HR 0.64 (95% CI 0.48 to 0.85) 0.75 CRT : 82pts (20%) P = .0019 0.50 Event-free Survival Medical 120 pts Therapy (30%) 0.25 0.00 0 500 1000 1500 Days Number at risk 409 376 351 213 89 8 CRT 404 365 321 192 71 5 Medical Therapy

43. PrimaryEndpoint

44. Symptoms & Quality of Life at 90 days

45. Mechanistic Outcomes * Positive values indicate higher value with CRT compared to control

46. Serious Adverse Events

47. Cardiac Resynchronization Therapy:Patient Selection February 2005 •  18 years of age • NYHA Functional Class III or IV despite stable/optimal drug regimen • QRS duration  120-130 msec • LVEF  35%; LVEDD  55 millimeters • With or without indication for ICD

48. ICDs: Patient Selection February 2005 •  18 years of age • NYHA Functional Class II or III despite stable/optimal drug regimen • LVEF  35% • Ischemics must have “remote” MI (> 30 days) • Non-ischemics must have CHF of at least 3 (?9) months duration

49. Device Indications • Stage C heart failure • LVEF  35% • Optimal medical therapy 1. Abraham WT, Fisher WG, Smith AL, et al. Cardiac resynchronization in chronic heart failure. N Engl J Med 2002;346:1845-1853 2. Bardy GH, Lee KL, Mark DB, et al. Amiodarone or an implanatble cardioverter-defibrillator for congestive heart failure. N Engl J Med 2005;352:225-37

50. Remaining Questions About CRT • Effects of CRT in pts. with EF ≤ 35%, but NYHA class I or II ( MADIT-CRT, REVERSE) • Effects of CRT in pts. with NYHA class IV HF (< 5% of population in CRT trials) • Effects of CRT in pts. with narrow QRS but evidence of mechanical dyssynchrony • Effects of CRT in pts. with atrial fibrillation (excluded from CRT trials) • Predictors of response to CRT (PROSPECT trial) • Cost effectiveness of CRT