1. SCD-HeFT Sudden Cardiac Death in Heart Failure Trial Bardy GH. N Engl J Med. 2005;352:225-237.

2. SCD-HeFT Sponsors NHLBI: All research costs at CCC, ICD Core, DCC, QoL Medtronic: Site clinical costs, ICD donations, meetings/travel Wyeth-Ayerst: Placebo and Amiodarone Duke University Pharmacy: Study drug distribution Washington DC Veterans Hospital: Holter Core Lab Cambridge Heart: Meetings, TWA sub-study Knoll Pharmaceuticals: Meetings NIH Nursing Institute: Psychosocial sub-study Bardy GH. N Engl J Med. 2005;352:225-237.

3. SCD-HeFT Hypothesis Determine if amiodarone or ICD will decrease the risk of death from any cause in patients with mild-to-moderate heart failure Bardy GH. N Engl J Med. 2005;352:225-237.

4. SCD-HeFT Inclusion Criteria Symptomatic CHF (NYHA Class II and III) due to ischemic or non-ischemic dilated cardiomyopathy LVEF ≤ 35% ≥ 18 years of age; no upper age limitation CHF ≥ 3 months On optimal medical therapy for > 3 months –Appropriate dose of ACE-I –Beta blocker, if tolerated Bardy GH. N Engl J Med. 2005;352:225-237.

5. SCD-HeFT Exclusion Criteria Asymptomatic patients with LV dysfunction NYHA Class I or IV Class I ICD indications Pacemaker indications < 18 years Death expected ≤ 1 year due to cardiac causes Amiodarone or other AA drugs contraindicated Current Class I or II AA drugs Unexplained syncope ≤ 5 years AF patients requiring catheter ablation or amiodarone MI ≤ 30 days CABG or PTCA ≤ 30 days Bardy GH. N Engl J Med. 2005;352:225-237.

6. SCD-HeFT Centers (2) (3) (2) (4) (2) (8) (2) (3) (2) (5) (2) (3) 148 sites in the US, Canada, and New Zealand. Enrollment 2521 (10) (3) Bardy GH. N Engl J Med. 2005;352:225-237.

7. SCD-HeFT Endpoints Primary: Overall Mortality Secondary: Mortality: ischemic vs. non-ischemic Mortality: NYHA Class II vs. III Mortality by Sub Groups: age, gender, LVEF, MI Hx, time of MI, QRS width Cause-Specific Death HF Morbidity and Mortality Quality of Life Cost of Care and Cost-Effectiveness Bardy GH. N Engl J Med. 2005;352:225-237.

8. SCD-HeFT Protocol DCM + CAD and CHF Placebo N = 847 ICD Implant N = 829 Minimum of 2.5 years follow-up required 45 months average follow-up Optimized  B, ACE-I, Diuretics Amiodarone N = 845 EF < 35% NYHA Class II or III 6-Minute Walk, Holter R 2521 Patients Bardy GH. N Engl J Med. 2005;352:225-237.

9. Study Power Calculations Predicted control mortality rate:10% per year Presumed minimum follow-up: 2.5 years 90% power to detect a 25%  in mortality in either amiodarone or ICD arm compared to placebo Alpha = 0.025 for each comparison Intention-to-treat study design Bardy GH. N Engl J Med. 2005;352:225-237.

10. SCD-HeFT Assessments Background Medical Therapies Electrocardiography 6-minute walk test 24-hour ambulatory electrocardiography Liver and thyroid function tests Chest radiography Drugs if required: beta blocker, ACE-I, aldosterone, aspirin, and statins Bardy GH. N Engl J Med. 2005;352:225-237.

11. SCD-HeFT Background Medications BaselineLast Follow-Up ACE Inhibitor85%72% ACE Inhibitor or ARB96%87% Beta Blocker69%78% Spironolactone19%31% Loop Diuretics82%80% Aspirin56%55% Statin38%47% Bardy GH. N Engl J Med. 2005;352:225-237.

12. SCD-HeFT Study Drug Dosing Outpatient administration < 800 mg qd for week 1 < 400 mg qd for weeks 2-4 Chronic dose weight dependent: –200 mg/d if < 150 lbs –300 mg/d if 150-200 lbs –400 mg/d if > 200 lbs Bardy GH. N Engl J Med. 2005;352:225-237.

13. SCD-HeFT ICD Guidelines Medtronic Model 7223Cx – Micro Jewel® II Follow-Up: 1-week, 1-month, 3-month, then every 3 months Nominals: –VF Settings: ON, 320 ms, NID 18/24, 30 J –FVT and VT Settings: OFF –VVI 50 (Hysteresis 34 bpm) –Pre-VT/VF memory activation Bardy GH. N Engl J Med. 2005;352:225-237.

14. SCD-HeFT Baseline Patient Characteristics Amiodarone N = 845 Placebo N = 847 ICD N = 829 NYHA II71%70%68% NYHA III29%30%32% Ischemic CHF50%53%52% Non-ischemic CHF50%47%48% Bardy GH. N Engl J Med. 2005;352:225-237.

15. SCD-HeFT Baseline Patient Characteristics Amiodarone N = 845 Placebo N = 847 ICD N = 829 Age (median) 60 Male76%77% Caucasian77%76%77% Weight (median) 190 SBP mm Hg (median) 118120118 DBP mm Hg (median) 70 Hypertension56% 55% Bardy GH. N Engl J Med. 2005;352:225-237.

16. SCD-HeFT Baseline Patient Characteristics Amiodarone N = 845 Placebo N = 847 ICD N = 829 LVEF (median) 0.25 0.24 Diabetes29%32%31% Pulmonary Disease17%19%21% AF or Atrial Flutter16%14%17% NSVT23%21%25% Syncope6%7%6% Heart Rate bpm (median) 727374 Bardy GH. N Engl J Med. 2005;352:225-237.

17. SCD-HeFT Baseline Patient Characteristics Amiodarone N = 845 Placebo N = 847 ICD N = 829 Hypercholesterolemia (median) 52%54%52% EP study18%15%16% Serum Sodium mEq/liter (median) 139 Serum Creatinine mg/dl (median) 1.1 Bardy GH. N Engl J Med. 2005;352:225-237.

18. SCD-HeFT Medication Use Last Follow-Up Amiodarone N = 845 Placebo N = 847 ICD N = 829 ACE-I71%74%70% ARB18%17%18% ACE or ARB85%88%86% Beta Blocker72%79%82% Aspirin56%54%55% Warfarin32%36%34% Bardy GH. N Engl J Med. 2005;352:225-237.

19. SCD-HeFT Medication Use Last Follow-Up Amiodarone N = 845 Placebo N = 847 ICD N = 829 Digoxin59%62%63% Statin48%46%48% Diuretic: Loop79%80%79% Potassium-Sparing28%33%32% Thiazide11% 10% Bardy GH. N Engl J Med. 2005;352:225-237.

20. SCD-HeFT Mortality Rate Overall Results Months of Follow-Up Mortality Rate 483624120 Amiodarone Placebo ICD 0.4 0.3 0.2 0.1 0.0 60 No. at Risk Amiodarone84577271548428097 Placebo84779772450530489 ICD 829778733501304103 Hazard Ratio (97.5% Cl)P-Value Amiodarone vs. Placebo1.06 (0.86 - 1.30)0.53 ICD vs. Placebo0.77 (0.62 - 0.96)0.007 Bardy GH. N Engl J Med. 2005;352:225-237.

21. SCD-HeFT Overall Mortality Results Hazard Ratio (97.5% CI) P-Value Amiodarone vs. Placebo 1.06 (0.86 - 1.30)0.53 ICD vs. Placebo 0.77 (0.62 - 0.96)0.007 ICDs reduce mortality by 23% Bardy GH. N Engl J Med. 2005;352:225-237.

22. SCD-HeFT 5-Year Mortality Rate Overall Results 34% 36.1% 28.9% Mortality Rate Bardy GH. N Engl J Med. 2005;352:225-237.

23. SCD-HeFT Mortality Rate Ischemic CHF Patients Months of Follow-Up Mortality Rate 483624120 Amiodarone Placebo ICD 0.4 0.3 0.2 0.1 0.0 60 No. at Risk Amiodarone42638434622713046 Placebo45341537024415248 ICD 43139536524414448 Hazard Ratio (97.5% Cl)P-Value Amiodarone vs. Placebo1.05 (0.91 - 1.36)0.66 ICD vs. Placebo0.79 (0.60 - 1.04)0.05 Bardy GH. N Engl J Med. 2005;352:225-237.

24. No. at Risk Amiodarone41938836925715051 Placebo39438235426115241 ICD 39838336825716055 SCD-HeFT Mortality Rate Non-Ischemic CHF Patients Months of Follow-Up Mortality Rate 483624120 Amiodarone Placebo ICD 0.4 0.3 0.2 0.1 0.0 60 Hazard Ratio (97.5% Cl)P-Value Amiodarone vs. Placebo1.07 (0.76 - 1.51)0.65 ICD vs. Placebo0.73 (0.50 - 1.07)0.06 0.5 Bardy GH. N Engl J Med. 2005;352:225-237.

25. SCD-HeFT 5-Year Mortality Rate Ischemic vs. Non-Ischemic 41.7% 43.2% 21.4% 25.8% 27.9% 35.9% IschemicNon- Ischemic IschemicNon- Ischemic IschemicNon- Ischemic Amiodarone Placebo ICD Mortality Rate Bardy GH. N Engl J Med. 2005;352:225-237.

26. No. at Risk Amiodarone60156353637822276 Placebo59456352236721872 ICD 56655053137123680 SCD-HeFT Mortality Rate NYHA Class II Patients Months of Follow-Up Mortality Rate 483624120 Amiodarone Placebo ICD 0.4 0.3 0.2 0.1 0.0 60 Hazard Ratio (97.5% Cl) P-Value Amiodarone vs. Placebo0.85 (0.65 - 1.11) 0.17 ICD vs. Placebo0.54 (0.40 - 0.74)< 0.001 Bardy GH. N Engl J Med. 2005;352:225-237. 0.5 0.6

27. No. at Risk Amiodarone2442091791065821 Placebo2532342021388617 ICD 2632282021306823 SCD-HeFT Mortality Rate NYHA Class III Patients Months of Follow-Up Mortality Rate 483624120 Amiodarone Placebo ICD 60 Hazard Ratio (97.5% Cl)P-Value Amiodarone vs. Placebo1.44 (1.05 - 1.97)0.010 ICD vs. Placebo1.16 (0.84 - 1.61)0.30 Bardy GH. N Engl J Med. 2005;352:225-237. 0.4 0.3 0.2 0.1 0.0 0.5 0.6

28. SCD-HeFT 5-Year Mortality Rate NYHA Class II vs. III 26.4% 32% 48.4% 52.8% 45.6% 20% NYHA IINYHA III NYHA IINYHA III NYHA IINYHA III Amiodarone Placebo ICD Mortality Rate Bardy GH. N Engl J Med. 2005;352:225-237.

29. SCD-HeFT Mortality Results NYHA Class III Patients No survival benefits for ICD therapy in NYHA Class III patients in SCD-HeFT 1 These results are not consistent with other trial results and need to be further evaluated: –DEFINITE Class III patients had the largest survival benefits with ICD therapy 2 –Patients with the worst LVEF in MADIT-II and AVID trials had the largest benefit from ICD therapy 3,4 1 Bardy GH. N Engl J Med. 2005;352:225-237. 2 Kadish A. N Engl J Med. 2004;350:2151-2158. 3 Moss AJ. N Engl J Med. 2002;346:877-883. 4 AVID Investigators. N Engl J Med. 1997;337:1576-1884.

30. SCD-HeFT Mortality Results Ischemic – Non-Ischemic and NYHA Class II-III Hazard Ratio (97.5% CI) ICD vs. Placebo P-Value Reduction in Death w/ICD Ischemic CHF 0.79 (0.60 -1.04)0.0521% Non-Ischemic CHF 0.73 (0.50 - 1.07)0.0627% NYHA Class II 0.54 (0.40 - 0.74)< 0.00146% NYHA Class III 1.16 (0.84 - 1.61)0.30None Bardy GH. N Engl J Med. 2005;352:225-237.

31. SCD-HeFT Discontinuations and Crossovers Discontinue Study Rx ICD Crossover Amiodarone Crossover Amiodarone32% 11% Placebo22%10% ICD6%14% Bardy GH. N Engl J Med. 2005;352:225-237.

32. SCD-HeFT Complications Amiodarone (different than placebo): 4% increased tremor (P = 0.02) 6% increased hypothyroidism (P < 0.001) ICD Therapy: 5% implant complications 9% follow-up complications Bardy GH. N Engl J Med. 2005;352:225-237.

33. SCD-HeFT ICD Shock History Results 31% received shock for any reason 21% received shock for rapid VT or VF During 5 years follow-up the average annual rate of shock for rapid VT or VF was 5.1 Bardy GH. N Engl J Med. 2005;352:225-237.

34. SCD-HeFT Rhythm Precursors to VT/VF VT VF Frequent Extra Systoles 52.3% 58.8%Decel. by > 100 ms of Prevailing Rhythms 7.3% 10.3% Accel. > 100ms of Prevailing Rhythms 22.9% 22.1%Sustained SVT, not AF 7.3% 1.5% Short-Long- Short Sequence 13.8% 32.4%Acute Onset AF1.8% 1.5% Initiating Beat of VT Morphology Different 20.2% NAVVI Pacing Triggered by Bradycardia 0% 4.4% NSVT11% 8.8%None Identified17.4% 17.7% Poole JE. Heart Rhythm 2005. May;2 (1suppl):AB20-5.

35. SCD-HeFT Change in NYHA Class Baseline to 3 Years Surviving patient’s HF condition appeared to improve progressively over time. Good drug management likely contributed to these results. % Patients -2 0 +1 +2 Changes in NYHA Class Bardy GH. Heart Rhythm 2005. May;2 (1suppl):AB20-3.

36. SCD-HeFT Mode of Death Cause of Death Amiodarone N = 845 Placebo N = 847 ICD N = 829 Cardiac19%20%15% Tachyarrhythmia 9%11%4% Bradyarrhythmia< 1% Heart Failure8% 9% Nonarrhythmic1%< 1%1% Packer DL. Heart Rhythm 2005. May;2 (1suppl):AB20-2.

37. SCD-HeFT Tachyarrhythmia Deaths Cause of Death Amiodarone N = 845 Placebo N = 847 ICD N = 829 Tachyarrhythmia9%11%4% ICD therapy reduced tachyarrhythmia deaths by 60% Packer DL. Heart Rhythm 2005. May;2 (1suppl):AB20-2.

38. SCD-HeFT Hazard Rate Results ICD vs. Placebo ICD Better 4.02.01.00.50.25 Placebo Better Subgroup ICD Therapy vs. Placebo NHazard Ratio (97.5% Cl) Female Sex 3820.96 (0.58 - 1.61) Male Sex12940.73 (0.57 - 0.93) Age 65 Yrs 5780.86 (0.62 - 1.18) White Race12830.78 (0.61 - 1.00) Nonwhite Race 3930.75 (0.48 - 1.17) LVEF 30% 2851.08 (0.57 - 2.07) Bardy GH. N Engl J Med. 2005;352:225-237.

39. SCD-HeFT Hazard Rate Results ICD vs. Placebo ICD Better 4.02.01.00.50.25 Placebo Better Subgroup ICD Therapy vs. Placebo NHazard Ratio (97.5% Cl) QRS 120 ms 6990.67 (0.49 - 0.93) 6-Min Walk Test 1275 ft 5260.45 (0.27 - 0.76) Beta Blocker11570.68 (0.51 - 0.91) No Beta Blocker 5190.92 (0.65 - 1.30) Diabetes 5240.95 (0.68 - 1.33) No Diabetes11520.67 (0.50 - 0.90) Bardy GH. N Engl J Med. 2005;352:225-237.

40. New SCD-HeFT Cost-Effectiveness Analysis Incremental Cost-Effectiveness Analysis 1 SCD-HeFT 2 Total Cost A – Total Cost B Life Expectancy A – Life Expectancy B = $ Per Life-Year Saved $LYS 1 Roberts PR. European Heart Journal. 2001;21:712-719. 2 Mark DB. www.theheart.org. AHA News. November 11, 2004.www.theheart.org ICD = $33,192 LYS (discounted 3% lifetime analysis) Placebo $159,147 $90,759 10.78 Years* 8.41 Years* * ICD patients had an average increase in life expectancy of 2.5 years

41. Incremental Cost-Effectiveness Cardiovascular Interventions Hypertension Therapy (diastolic 95 - 104 mmHg) Expensive Borderline Cost-Effective Highly Cost-Effective Incremental Cost per Life-Year Saved Economically Unattractive Lovastatin (chol. = 290 mg/dL, 50 yrs old, male, no risk factors ) PTCA (chronic CAD, severe angina 1 VD) CABG (chronic CAD mild angina, 3 VD) End Stage Renal Disease Treatment Exercise SPECT (atypical angina who can walk on treadmill) Routine Coronary Angiography (35 - 84 yrs old, low risk MI, has CHF) $8,461 $17,701 $40,750 $67,000 $135,000 $150,000 Carotid Disease Screening (65 yrs old, male, no symptoms) $200,000 $120,000

42. Incremental Cost-Effectiveness ICD, CRT, and CRT-D Therapies COMPANION CRT-D 1 Incremental Cost per Life-Year Saved COMPANION CRT 1 MADIT-II ICD 3 AVID ICD 4 $28,000 $38,200 $50,000 $67,000 Expensive Borderline Cost-Effective Highly Cost-Effective Economically Unattractive SCD-HeFT ICD 2 $33,000 1 Feldman AM. www.theheart.org. ACC News. March 16, 2005.www.theheart.org 2 Mark DB. www.theheart.org. AHA News. November 11, 2004.www.theheart.org 3 Ak-Khatib S. Ann Intern Med. 2005;142:593-600. 4 Larsen G. Circulation. 2002;105:2049-2057.

43. SCD-HeFT Conclusions SCD-HeFT was the largest device trial (ICD, CRT, CRT-D) ever completed and had a longer follow-up period than other major device trials In NYHA Class II-III patients with LVEF ≤ 35% on optimal drug therapy: –ICDs reduced mortality by 23% –ICDs reduced tachyarrhythmia deaths by 60% –Amiodarone did not improve survival Bardy GH. N Engl J Med. 2005;352:225-237.

44. SCD-HeFT Conclusions ICD therapy provided the largest mortality reduction in NYHA Class II patients Surviving patients had improvements in their heart failure condition over time. Good drug management likely contributed to this improvement. Compared to other CV therapies, ICDs are a cost-effective therapy

45. SCD-HeFT Implications SCD-HeFT ischemic CHF results are similar to findings from recently completed post-MI ICD trials and provide additional support for ICD therapy in ischemic CHF patients SCD-HeFT non-ischemic CHF results support the new use of ICDs in the non-ischemic CHF patient population SCD-HeFT Class II results provide new evidence that “less sick” heart failure patients can benefit from ICD therapy Recent CMS Coverage Decisions allow reimbursement for all SCD-HeFT patients