1. Prevention of Sudden Cardiac Death in Heart Failure Patients with Left Ventricular Dysfunction: The Role of Drugs and Devices William T. Abraham, MD, FACP, FACC Professor of Medicine Chief, Division of Cardiovascular Medicine Associate Director, Davis Heart & Lung Research Institute The Ohio State University Columbus, Ohio

2. Presentation Objectives Review the scientific evidence to support the contentions that: –In patients with LV dysfunction, the combined use of ACE inhibition and beta-blockade is recommended as the cornerstone of therapy. –Modest incremental benefit may be seen with the addition of other antagonists of the RAS in post-MI LV dysfunction and in chronic heart failure. –While neurohormonal interventions reduce morbidity and mortality across the cardiovascular disease continuum, post-MI and HF patients with LV dysfunction still have a high rate of sudden cardiac death. –Therapy with ICDs significantly reduces mortality in post-MI patients with LV dysfunction. These mortality benefits are on top of optimal pharmacologic therapy. ICD therapy should be considered standard of care in these patients. –Data from SCD-HeFT will be critical to understand the role of ICD therapy in ischemic and non-ischemic CHF patients with LV dysfunction.

3. Presentation Overview 1.Heart Failure and Sudden Cardiac Arrest: –Epidemiology, etiology, pathophysiology 2.SCD Prevention in Heart Failure: –Suppression of the Adrenergic Renin-Angiotension- Aldosterone Pathway and the Sympathetic Nervous System –Are we making progress in reducing SCD with neurohormonal interventions? 3.Overview of ICD therapy to prevent SCD in heart failure patients 4.Summary and conclusions

4. The Epidemic of Heart Failure

5. Key Heart Failure Statistics Prevalence –~5 million Americans with heart failure –>10% of adults in their 70s and 80s Incidence –550,000 new cases HF/year Morbidity –~1,000,000 HF hospitalizations Mortality –Causes or contributes to >600,000 deaths/yr –>50% of patients die suddenly (SCD) American Heart Association. Heart Disease and Stroke Statistics—2003 Update. Dallas, Tex: American Heart Association; 2002.

6. Projected increase in the US population 65 years of Age or Older US Census Bureau Millions of persons >65 Yr Old Millions of persons Percent of population Percent of population > 65 Yr Old 0 20 40 60 80

7. Heart Failure: A Public Health Crisis Hospitalizations Have Tripled in last 25 Years NHLBI. Morbidity and Mortality: 2000 Chartbook on Cardiovascular, Lung, and Blood Diseases. Geneva: World Health Organization; 1996. Hospitalizations/100,000 Population 1970 0 50 100 150 200 250 19751980198519901995 Year 65+ years 45-64 years

8. 100 90 80 70 60 50 40 30 20 10 0 Probability of survival, % Men (n = 237) Women (n = 230) Men (n = 237) Women (n = 230) Time after CHF diagnosis, years 02468 10 1 Framingham Heart Study (1948 – 1988) in Atlas of Heart Diseases. 2 American Heart Association. Heart Disease and Stroke Statistics—2003 Update. CHF Patients Survival Results 1 80% of men and 70% of women who have CHF will die within 8 years. 2

9. The Epidemic of Sudden Cardiac Arrest

10. Sudden Cardiac Death: Definition Sudden cardiac death is natural death due to cardiac causes, heralded by abrupt loss of consciousness within one hour of the onset of acute symptoms, as in an individual with or without known pre- existing heart disease, but in whom the time and mode of death are unexpected. Gaziano JM in Braunwald Zipes Libby Heart Disease,6 th ed.W.B. Saunders 2001:1

11. Accounts for 63% of all cardiac related deaths in the US 1. One of the most common causes of death in developed countries: 1 MMWR. Vol 51(6) Feb. 15, 2002. 2 Myerberg RJ, Catellanos A. Cardiac Arrest and Sudden Cardiac Death. In: Braunwald E, ed. Heart Disease: A Textbook of Cardiovascular Medicine. 5 th Ed. New York: WB Saunders. 1997: 742-779. 3 Zheng Z. Circulation. 2001;104:2158-2163. 4 Vreede-Swagemakers JJ et al. J Am Coll Cardiol 1997; 30: 1500-1505. Sudden Cardiac Arrest GeographyIncidenceSurvival Worldwide3,000,000 2 <1% 2 US450,000 3 ~5% 2 W. Europe400,000 4 <5% 4

12. 1 U.S. Census Bureau, Statistical Abstract of the United States: 2001. 2 American Cancer Society, Inc., Surveillance Research, Cancer Facts and Figures 2001. 3 2002 Heart and Stroke Statistical Update, American Heart Association. 4 Circulation. 2001;104:2158-2163. Magnitude of SCA in the US AIDS 1 Breast Cancer 2 Lung Cancer 2 Stroke 3 Sudden Cardiac Arrest 4 SCA claims more lives each year than these other diseases combined The #1 Cause of Death

13. - ~ 450,000 per year 1  1200 per day 50 every hour 1 every 80 seconds - The majority of SCA occurs in patients with clinically recognized heart disease, particularly previous myocardial infarction and congestive heart failure. 2,3 1 Circulation. 2001;104:2158-2163. 2 Myerburg RJ, Castellanos A. Cardiac Arrest and Sudden Cardiac Death, in Braunwald E, Zipes DP, Libby P, Heart Disease, A textbook of Cardiovascular Medicine. 6 th ed. 2001. W.B. Saunders, Co. 3 Every N, et al. Risk of Sudden versus Non Sudden Cardiac Death in Patient with Coronary Artery Disease. Am Heart J 2002; 144: 390-6. Magnitude of SCA in the US

14. Etiology of Sudden Cardiac Death

15. Coronary Heart Disease An estimated 13 million people had CHD in the U.S. in 2002. 1 Sudden death was the first manifestation of coronary heart disease in 50% of men and 63% of women. 1 CHD accounts for at least 80% of sudden cardiac deaths in Western cultures. 3 1 American Heart Association. Heart Disease and Stroke Statistics—2003 Update. Dallas, Tex.: American Heart Association; 2002. 2 Adapted from Heikki et al. N Engl J Med, Vol. 345, No. 20, 2001. 3 Myerberg RJ. Heart Disease, A Textbook of Cardiovascular Medicine. 6 th ed. P. 895. Etiology of Sudden Cardiac Death 2,3 * ion-channel abnormalities, valvular or congenital heart disease, other causes 80% Coronary Heart Disease 15% Cardiomyopathy 5% Other*

16. Arrhythmic Cause of SCD Albert CM. Circulation. 2003;107:2096-2101. 12% Other Cardiac Cause 88% Arrhythmic Cause

17. Bayés de Luna A. Am Heart J. 1989;117:151-159. Underlying Arrhythmias of Sudden Cardiac Arrest Bradycardia 17% VT 62% Primary VF 8% Torsades de Pointes 13%

18. Incidence of SCD in Specific Populations and Annual SCD Numbers Adapted from: Myerburg RJ. Sudden Cardiac Death: Exploring the Limits of Our Knowledge. J Cardiovasc Electrophysiol Vol. 12, pp. 369- 381, March 2001. 300,000200,000100,0000 Incidence of Sudden Deaths Per Year (number) Multiple risk subgroups Patients with any previous coronary event Patients with ejection fraction <35% or CHF Cardiac arrest, VT/VF survivors High-risk post-MI subgroups General adult population 30 25 20 10 5 0 Incidence of Sudden Death (% of group) MADIT, MUSTT, MADIT II AVID, CASH, CIDS SCD-HeFT

19. Heart Failure and Sudden Cardiac Death

20. Heart Failure and Sudden Death During a 39-year follow-up of subjects in the Framingham Heart Study, the presence of CHF significantly increased sudden death and overall mortality in both men and women. 1 1 Redrawn from Kannel WB, Wilson PWF, D'Agostino RB, Cobb J. Sudden coronary death in women. Am Heart J 1998 Aug; 136: 205-212 60-115% increase in sudden death if CHF present.

21. Severity of Heart Failure Modes of Death MERIT-HF Study Group. Effect of Metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL randomized intervention trial in congestive heart failure (MERIT-HF). LANCET. 1999;353:2001-07. 12% 24% 64% CHF Other Sudden Death n = 103 NYHA II 26% 15% 59% CHF Other Sudden Death n = 103 NYHA III 56% 11% 33% CHF Other Sudden Death n = 27 NYHA IV The greatest opportunity for SCD prevention is in patients that have mild to moderate CHF.

22. Pathophysiology and Mechanisms in Heart Failure that Precipitate SCA

23. 1 Adapted from Cohn JN. N Engl J Med. 1996;335:490–498. 2 He J, Ogden LG, Bazzano LA, et al. Risk Factors for Congestive Heart Failure in US Men and women: NHANES I epidemiologic follow-up study. Arch Intern Med 2001, 161: 996-1002. Pathologic remodeling Low ejection fraction Death Symptoms: Dyspnea Fatigue Edema Chronic heart failure Neurohormonal stimulation Endothelial dysfunction Myocardial toxicity Vasoconstriction Renal sodium retention Arrhythmia Pump failure Coronary artery disease  Hypertension  Cardiomyopathy  Valvular Disease Left ventricular injury Pathological Progression of CV Disease 1 Underlying etiology in ~60% of CHF 1 Underlying etiology in ~40% of CHF 1

24. RAS Pathophysiology Angiotensin I Angiotensin II Hypertrophy Apoptosis AT receptor antagonist ACE inhibitor ACE inhibitors also  kinins (  positive effect on hypertrophy/apoptosis)

25. Deleterious Effects Of Angiotensin II In CV Disease Angiotensin II  AVP  Aldosterone Vaso- constriction Mesangial Contraction Efferent Constriction CNS Dypsogenia Na + Retention Increased NE Release Myocardial Hypertrophy Vessel Hypertrophy

26. Deleterious Effects of Norepinephrine in CV Disease  Levels of norepinephrine Negative cardiac effectsNegative renal effects Sodium retention Cardiac injury Hypertrophy Arrhythmias Disease progression 11 11 11 22 11 Negative vascular effects Vasoconstriction 11 Activation of RAS Injury to the heart (eg, MI, HTN, DM)

27. Conditions Predisposing to Ventricular Arrhythmia in Heart Failure Patients Electrophysiological abnormalities –Cellular hypertrophy & interstitial fibrosis can result in prolongation of the action potential –Increases propensity for early after depolarizations –Mechanical stretch can produce electrical activity with slow conduction favoring reentry Singh S.J Cardiovas Electrophysiol 1997;8:89-97

28. Conditions Predisposing to Ventricular Arrhythmia in Heart Failure Patients Neurohormonal Activation –Chronic heart failure triggers maladaptive neurohormonal responses that may predispose to arrhythmia –Persistent adrenergic stimulation of the failing heart is maladaptive & arrhythmogenic –Adrenergic stimulation enhances automaticity in the His-Purkinje system & areas of scar and  the incidence of VF during ischemia in animal models Sweeney MO. PACE 2001;24:871-888.

29. Electrolyte abnormalities –Predisposition to hypokalemia is caused by diuretic therapy, activation of the renin-angiotensin- aldosterone system, and sympathetic activation –The effects of hypokalemia on ventricular arrhythmias are amplified in the setting of structural heart disease Sweeney MO. PACE 2001;24:871-888. Conditions Predisposing to Ventricular Arrhythmia in Heart Failure Patients

30. SCD Prevention: Suppression of the Adrenergic Renin-Angiotension-Aldosterone Pathway and the Sympathetic Nervous System

31. Neurohormonal Blockade Across the CV Disease Continuum  Angiotensin II (Renin-Angiotensin System [RAS])  Norepinephrine (Sympathetic Nervous System [SNS]) RAS Inhibition  -Blockade Disease Progression

32. Neurohormonal Blockade Across the CV Disease Continuum  Angiotensin II (Renin-Angiotensin System [RAS])  Norepinephrine (Sympathetic Nervous System [SNS]) RAS Inhibition  -Blockade Disease Progression

33. Effect of ACE Inhibitors on Mortality Reduction in Patients With LVD or Heart Failure TrialACEIControlsRR (95% CI) CONSENSUS I SOLVD (Treatment) SOLVD (Prevention) Chronic CHF Post MI SAVE TRACE AIRE 39%54%0.56 (0.34–0.91) 40%35%0.82 (0.70–0.97) 15%16%0.92 (0.79–1.08) 25%20%0.81 (0.68–0.97) 17%23%0.73 (0.60–0.89) SMILE6.5% 8.3%0.78 (0.52–1.12) Average 0.78 (0.67–0.91)35%42% 21%25% Mortality Garg R et al. JAMA. 1995;273:1450–1456.

34. Neurohormonal Interventions Across the Continuum Moderate CHF Severe CHF Mild CHF Post-MI LV dysfunction SOLVD Treatment (enalapril) CONSENSUS (enalapril) AIRE/SAVE/TRACE (ramipril/captopril/ trandolapril)

35. Angiotensin Receptor Blockade CHARM and Val-HEFT Trials: Addition of candesartan or valsartan to ACE inhibitor and  -blocker in class II-III heart failure 0-10% lower risk of death (P > 0.05) 13-15% lower risk of death or hospitalization for heart failure in both trials, both P < 0.01 Higher risk of hypotension, renal insufficiency and hyperkalemia with ARB treatment

36. Neurohormonal Interventions Across the Continuum Moderate CHF Severe CHF Mild CHF Post-MI LV dysfunction SOLVD Treatment (enalapril) CONSENSUS (enalapril) AIRE/SAVE/TRACE (ramipril/captopril/ trandolapril) CHARM/Val-HeFT (candesartan/valsartan) ??

37. Trials with Aldosterone Blockade 554/3319 478/3313 0.85 0.008 (0.75,0.96) HazardLog-rank Placebo Aldosterone Blockade RatioP-Value Primary Endpoint: All-Cause Mortality EPHESUS 284/822 386/841 0.70 < 0.001 (0.60,0.82) RALES

38. Moderate CHF Severe CHF Mild CHF Post-MI LV dysfunction SOLVD Treatment (enalapril) CONSENSUS (enalapril) AIRE/SAVE/TRACE (ramipril/captopril/ trandolapril) RALES (spironolactone) EPHESUS (eplerenone) ? Neurohormonal Blockade Across the CV Disease Continuum

39.  Angiotensin II (Renin-Angiotensin System [RAS])  Norepinephrine (Sympathetic Nervous System [SNS]) RAS Inhibition  -Blockade Disease Progression

40. Target HFDosage StudyDrugSeverity (mg/day) Outcome US Carvedilol 1 carvedilol mild/6.25 to 25  48% disease progression † moderatebid(P=.001) CIBIS-II 2 bisoprolol moderate/ 10 qd  34% mortality severe(P<.0001) MERIT-HF 3 metoprolol mild/ 200 qd  34% mortality succinatemoderate(P=.0062) COPERNICUS 4 carvedilol severe 25 bid  35% mortality (P=.0014) CAPRICORN 5 carvedilol Post-MI LVD 25 bid  23% mortality (P=.031) 1 Colucci WS et al. Circulation. 1996;94:2800–2806. 2 CIBIS II Investigators and Committees. Lancet. 1999;353:9–13. 3 MERIT-HF Study Group. Lancet. 1999;353:2001–2007. 4 Packer M et al. N Engl J Med. 2001;344:1651–1658. 5 The CAPRICORN Investigators. Lancet. 2001;357:1385–1390. Effect of  -Blockade on Outcome in Patients With Heart Failure and Post-MI LVD

41. CAPRICORN: Killip Class at Randomization Placebo (n=984) Carvedilol (n=975) n(%)n Killip Class* Class I 670(68)672(69) Class II 279(28)277(28) Class III/IV 33(3)24(2) Missing 2(<1)2 Class I: No hemodynamic compromise Class II: Few bibasilar pulmonary crackles Class III: Frank pulmonary edema (extensive crackles, hypoxia) Class IV: Cardiogenic shock (hypotension, organ hypoperfusion) *Definitions in CAPRICORN protocol:

42. CAPRICORN: All-Cause Mortality 0.7 0.75 0.8 0.85 0.9 0.95 1 00.511.522.5 Carvedilol Placebo Years Proportion Event Free  23% P=.03 The CAPRICORN Investigators. Lancet. 2001;357:1385–1390.

43. CAPRICORN: Mortality Reduction in LVD Patients With No Symptoms of Heart Failure Carvedilol Placebo Data on file, GlaxoSmithKline.  31% P=.07

44. CAPRICORN: Effect on Recurrent Infarction Among first events leading to death or CV hospitalization (co-primary end point), 45 of such events on placebo and 27 such events on carvedilol were due to a recurrent infarction. Total number of hospitalizations for myocardial infarction (including first and recurrent) was 60 in the placebo group and 37 in the carvedilol group. The CAPRICORN Investigators. Lancet. 2001;357:1385–1390.

45. Moderate CHF Severe CHF Mild CHF Post-MI LV dysfunction Neurohormonal Interventions Across the Continuum SOLVD Treatment (enalapril) CONSENSUS (enalapril) AIRE/SAVE/TRACE (ramipril/captopril/ trandolapril) US Carvedilol Trials (carvedilol) MERIT-HF (metoprolol) CIBIS II (bisoprolol) COPERNICUS (carvedilol) CAPRICORN (carvedilol)

46. Drug Effects on Total and Sudden Cardiac Death Risks 1 Patients Randomized LVEFDrug Tested ACE-I (% of Pts) Total Death Risk Reduction (p-value) SCD Risk Reduction (p-value) TRACE2,606<36% Trandolapril 100%-22% (<0.001)-24% (<0.03) HOPE9.297Nominal lly >40% Ramipril 100%-26% (<0.005)-38% (<0.02) RALES1,66325% Spironolactone 95%-30% (<0.001)-29% (<0.02) CIBIS-II2,64728% Bisoprolol 96%-34% ( <0.0001)-44% (<0.001) MERIT-HF3,99128% Metoprolol 96%-34% (< 0.00009) -41% (<0.0002) COPERNICUS2,28920% Carvedilol 97%-35% (< 0.001)Not reported SOLVD-T2,56925% Enalapril 100%-16% (0.004)-10% (NS) SOLVD-P4,22828% Enalapril 100%-8% (0.3)-7% (NS) 1 Pacifico A, Henry P. J Cardiovasc Electrophysiol, Vol. 14, pp. 764-775, July 2003. Neurohormonal Interventions in Heart Failure

47. SCD Prevention by Ion Channel-Active Drugs

48. CAST-I Echt DS. N. Engl J Med. 1991;324:781-788. Prognosis of Post-MI Patients Treated with Placebo vs. Encainide/Flecainide 80 85 90 95 100 091182273364455 Days After Randomization Patients Without Event (%) Placebo (n = 743) Encainide or Flecainide (n = 755) P = 0.001

49. CAST-II CAST-II Investigators. N Engl J Med. 1992;327:227-233. Moricizine 100 80 60 40 20 0 0123 Year Adjusted P = 0.40 Survival (%) Placebo No. at risk (% surviving) Placebo Moricizine 574 (100) 581 (100) 351 (95.2) 350 (94.9) 175 (89.6) 181 (88.8) 56 (88.0) 56 (85.0) Absence of Benefit of Moricizine Over Placebo

50. EMIAT and CAMIAT Trials 1 Julian DG. Lancet. 1997;349:667-674. 2 Cairns JA. Lancet. 1997;349:675-682. FACTOR EMIAT 1 CAMIAT 2 ProtocolAmiodarone vs. placebo Patient characteristics Poor LV function (LVEF < 40%) Frequent ventricular ectopic activity (VEA; > 10 VPDs/hr) Recruitment5-21 days post-MI6-45 days post-MI Risk reduction of arrhythmic death at 24 months 35%48.5% All-cause mortality at 24 months No difference While amiodarone was effective in reducing arrhythmic death, it did not reduce total mortality.

51. SWORD Survival Results Waldo AL. Lancet. 1996;348:7-12. Patients at risk Placebo15721170874551330 d-sotalol15491150844544323 1.00 0 Time from randomisation (days) Z = -2.5, P = 0.006 Proportion event-free Placebo d- sotalol 60 120 180 240 300.99.98.97.96.95.94.93.92.91.90.89.88.87 Study stopped prematurely in Nov. 1994 due to increased mortality in patient population treated with d-sotalol

52. The Impact of Neurohormonal Interventions on SCD in Heart Failure: Are We Making Any Progress?

53. Neurohormonal Interventions: Impact on Survival and Sudden Death Use of ace-inhibitors and beta blockers has yielded substantial reductions in mortality due to progressive pump failure and have provided some protection from sudden cardiac death. However, mortality from heart failure remains high. Several recent studies suggest that perhaps more work is needed to prevent SCD in heart failure.

54. Survival Trends in Heart Failure Temporal Trends in Age-Adjusted Survival after the Onset of Heart Failure among Men (Panel A) and Women (Panel B). Values were adjusted for age (<55, 55 to 64, 65 to 74, 75 to 84, and 85 years). Estimates are shown for subjects who were 65 to 74 years of age. Despite favorable trends in survival, heart failure remains highly fatal; among subject who were given a diagnosis of heart failure in the 1990s, more than 50% were dead in 5 years. 1 1 Levy D, et al. Long-Term Trends in the Incidence of and Survival with Heart Failure. N Engl J Med 2002; 347: 1397-402.

55. Survival Trends: CHD and SCA Mayo Clinic; Olmsted County, Minnesota 1 : Analyzed secular trends in CHD deaths and unexpected SCD over a 20-year period (1979-1998) In-hospital deaths declined at a greater rate than out-of-hospital: –RRR of in-hospital death in 1998: 0.36 –RRR of out-of-hospital death in 1998: 0.71 50% of deaths were unexpected –Similar to Framingham results from two decades earlier—even with the intensified secondary and primary prevention efforts “…these data underscore the increasing importance of primary prevention in sustaining the decline in CHF mortality.” 1 Goraya TY, et al. Coronary Heart Disease and Sudden Cardiac Death: A 20-Year Population-based Study. Am J Epidemiol 2003; 157: 763-770.

56. Risk of Sudden Death in HF Trials StudyHF Class Control (n) Treatment (n) Total Mortality Reduction w/Treatment Sudden Death as a % of Total Death in Control Arm Sudden Death- as a % of Total Death in Treatment Arm MERIT-HF 1 (Metroprolol) 2-42001199034%(60%)132/217(54%)79/145 BEST 2 (Bucindolol) 3,41354 10%(45%)203/449(44%)182/411 CIBIS-II 3 (Bisoprolol) 3,41320132734%(36%) 83/228(31%) 48/156 CARVEDILOL - (U.S.) 4 2-439869665%(48%) 15/31(54%) 12/22 RALES 5 3, 484188230%(28%) 110/386(29%) 162/478 References in slide notes.

57. Residual Risk of SCD in Treatment Arms of CHF-Beta Blocker Trials 1.CIBIS-II Investigators. Lancet 1999; 353: 9-13. 2.MERIT-HF Study Group. Lancet. 1999; 353: 2001-07. 3.Packer, M, et al. N Engl J Med 1996: 334: 1349-55. Average Follow Up: 54%31%54% n = 696 12 months16 months No. Pts in Treatment Arm:n= 1327n= 1990 6.5 months Sudden Death % of Total Death

58. SCD in Heart Failure 1, 2 Despite improvements in medical therapy, symptomatic HF still confers a 20-25% risk of pre-mature death in the first 2.5 yrs after diagnosis. –  50% of these premature deaths are SCD (VT/VF) The role of device therapy? 1 Bardy G. The Sudden Cardiac Deatth-Heart Failure Trial (SCD-HeFT) in Woosley RL, Singh S, Arrhythmia Treatment and Therapy, Copyright 2000 by Marcel Dekker, Inc., pp. 323-342, 2 Sweeney MO PACE 2001;24:871-888.

59. SCD Prevention by Implantable Device Therapy 1.Post-MI and LV Dysfunction: MADIT/MUSTT/MADIT II 2.Heart Failure and LV Dysfunction: SCD-HeFT

60. MADIT/MUSTT/MADIT-II Study Criteria Comparison Inclusion CriteriaMADIT 1 (196 patients) MUSTT 2 (704 patients) MADIT II 3 (1232 patients) CAD/Post-MI LV Dysfunction (<35%) (<40%) (<30%) NSVT Inducible VT on EPS Inducible, non- suppressible VT on EPS 1 Moss AJ. N Engl J Med. 1996;335:1933-40. 2 Buxton AE. N Engl J Med. 1999;341:1882-90. 3 Moss AJ. N Engl J Med. 2002; 346:877-83.

61. MADIT M ulticenter A utomatic D efibrillator I mplantation T rial Moss AJ. N Engl J Med 1996:335:1933-40.

62. MADIT Survival Results No. of patients Defibrillator95805331173 Conventional 101674829170 therapy Year 1.0 0.8 0.6 0.4 0.2 0.0 012345 Probability of survival Conventional therapy Defibrillator P-value = 0.009 Moss AJ. N Engl J Med. 1996;335:1933-40.

63. 1. Moss AJ. N Engl J Med. 1996;335:1933-1940. 54% 75% Reduction in Overall Death Reduction in Arrhythmic Death MADIT: ICDs Significantly Reduced Overall and Arrhythmic Mortality 1

64. MUSTT M ulticenter U nsustained T achycardia T rial Buxton AE. N Engl J Med. 1999;341:1882-90.

65. MUSTT Randomized Patient Results: Total Mortality Buxton AE. N Engl J Med. 1999;341:1882-90. Time after Enrollment (Years) 012345 0 0.1 0.2 0.3 0.4 0.5 0.6 Event Rate p < 0.001 EP-Guided Without Defibrillator No Antiarrhythmic Therapy EP-Guided Therapy with Defibrillator

66. MUSTT: ICDs Significantly Reduce Overall and Arrhythmic Mortality * P<0.001 for adjusted estimates of relative risk for each end point. Adjusted estimates were made from all available clinical and prognostic factors. Buxton AE. N Engl J Med. 1999;341:1882-90. 76% 60% 73% 55% % Mortality Reduction w/ ICDs

67. Rate of Cardiac Arrest or Arrhythmic Death Overall Mortality Rate Registry (non-inducible) No AA Rx (inducible) Registry (non-inducible) No AA Rx (inducible) N= 1397N= 353N= 1397N=353 2-year rate (%)12182128 5-year rate (%)24324448 Adjusted P- Value <0.0010.005 MUSTT Registry Patients Mortality Results Buxton AE. et al. N Engl J Med 2000; 342: 1937-45.

68. MADIT-II M ulticenter A utomatic D efibrillator I mplantation T rial- II Moss AJ. N Engl J Med. 2002;346:877-83.

69. MADIT-II Inclusion Criteria Q-wave or enzyme-positive MI > 4 weeks LVEF < 30% as measured by angiographic, radionuclide or echocardiographic method > 21 years of age; no upper age limitation No requirement for NSVT or EPS Moss AJ. N Engl J Med. 2002;346:877-83.

70. Inclusion criteria ICD implant n=742No-ICD implant n=490 (EPS after implant)(Conventional Post-MI drug Rx) 20 months mean follow- up Avoid AAD Optimize:  B, ACE-I, Diuretics MADIT-II Protocol Moss AJ. N Engl J Med. 2002;346:877-83.

71. MADIT-II Survival Results Moss AJ. N Engl J Med. 2002;346:877-83. Defibrillator Conventional P = 0.007 1.0 0.9 0.8 0.7 0.6 0.0 Probability of Survival 01234 Year No. At Risk Defibrillator742502 (0.91)274 (0.94)110 (0.78)9 Conventional490329 (0.90)170 (0.78) 65 (0.69)3

72. Moss AJ. N Engl J Med. 2002;346:877-83. MADIT II: All-Cause Mortality Hazard Ratio= 0.69 (p= 0.016) 31% Relative Reduction N= 490 N= 742

73. MADIT II: Mortality Events Moss AJ. Presented at ACC Latebreaking Clinical Trials, March 2002. 61% relative risk reduction 31% relative risk reduction

74. MADIT-II Survival Results – Subgroup Analyses Moss AJ. N Engl J Med. 2002;346:877-83. There were no statistically significant interactions in the various subgroups. Note the overlapping error bars.

75. MADIT II: In Context with Other Landmark Trials Mortality (%) 0 15 30 BHAT CASS SAVEMADIT II p<0.01 p=NS p=0.019 p=0.016 Non-active Rx Active Rx N=3800N=780 N=2200 N=1200 9.8 7.2 9.0 8.0 24.6 20.419.8 14.2 HR=0.73 HR=0.89 HR=0.81 HR=0.69 Moss, AJ. MADIT II and its implications. European Heart Journal (2003); 24, 16-18.

76. 1 Moss AJ. N Engl J Med. 2002;346:877-83. 2 The DAVID Trial Investigators. JAMA 2002; 288: 3115-3123. 3 Sweeney MO, Hellkamp AS, Ellenbogen KA, et al. Circulation. 2003 Jun 17;107(23):2932-7 4 Steinberg JS. Presented at the 24 th Annual Scientific Sessions of the North American Society of Pacing and Electrophysiology, Late breaking Clinical Trials, Section 2; May 17, 2003. 5 The DAVID Trial Investigators. JAMA 2002; 288: 3115-3123. 6 BEST. PACE. 1999;22 (1, part I):79-85. MADIT II: Complications New or Worsening HF 1 (p= 0.09) N= 490 N= 742 RV pacing causes ventricular dysynchrony and may lead to worsening HF. 2,3,4 Intrinsic ventricular activation is better for ICD patients with left ventricular dysfunction who do not “need” pacing. 2,3 <10% of ICD patients have a Class I pacing indication at the time of implant. 5,6 Physicians, when appropriate, should consider programming of ICDs to avoid frequent RV pacing. 4

77. 1 Moss AJ. N Engl J Med. 1996;335:1933-40. 2 Buxton AE. N Engl J Med. 1999;341:1882-90. 3 Moss AF. N Engl J Med. 2002;346:877-83. 4 Moss AJ. Presented before ACC 51st Annual Scientific Sessions, Late Breaking Clinical Trials, March 19, 2002. 5 The AVID Investigators. N Engl J Med. 1997;337:1576-83. Mortality Benefits in ICD Trials 1 2 3, 4 54% 75% 55% 73% 31% 61% 27 Months 39 Months20 Months % Mortality Reduction w/ ICD Rx 31% 56% 5 24 Months

78. 1 Moss A, et al. N Engl J Med. 1996;335:1933–40. 2 Buxton, A, et al; N Engl J Med. 1999;341:1882–90. 3 AVID Investigators; N Engl J Med. 1997;337:1576–83. 4 Moss, A. et al; N Engl J Med. 2002;346:877–83. MADIT 1 (n=196) MADIT II 2 (n=1232) MUSTT 3 (n=704) Age636468 LVEF0.260.230.30 NYHA I37%39%37% NYHA II or III63%57%63% NYHA IVExcluded4%Excluded CAD (%)100 Previous CABG/PTCA (%)73/2760/4556/23 Post-MI trials are not heart failure trials but… … there’s a high % of symptomatic heart failure and LV dysfunction in the post-MI trials

79. References in slide notes. * MADIT II mortality values at 20 months. SCD Rates in Post-MI Patients with LV Dysfunction Total Mortality ~20-30%; SCD accounts for ~50% of the total deaths.

80. References in slide notes. * MADIT II mortality values at 20 months. Total Mortality ~15-40%; SCD accounts for ~50% of the total deaths. 12 months16 months41.4 months27 months 13 months45 months6 months SCD Rates in CHF Patients with LV Dysfunction

81. % Primary Prevention ICD Trials: Extent of Beta-Blocker/ACE-I Use in Control Patients 199619971999 2002 Year of Publication References for each study in slide notes.

82. Number Needed to Treat To Save A Life (5 Yr) (2.4 Yr) (3 Yr) (3 Yr) (3.5 Yr) (1 Yr) (6 Yr) (2 Yr) NNT x years = 100 / (% Mortality in Control Group – % Mortality in Treatment Group) ICD Therapy simvastatin captopril metoprolol amiodarone Drug Therapy

83. Sudden Cardiac Death SCD -HeFT Heart Failure Trial Sponsored by The National Heart, Lung, & Blood Institute, Medtronic, Inc., & Wyeth-Ayerst

84. Key Points Largest Study – Landmark –2,521 patients, 150 centers, min 2.5 yr f/u Randomized Placebo Controlled Design DCRI – Best in class study management Sponsored by NHLBI, additional funding by Medtronic, Wyeth

85. Key Trial Question Will Amiodarone and/or an ICD improve survival compared to placebo in patients with NYHA Class II and III CHF and reduced left ventricular ejection fraction (< 35%) without a history of sustained VT or VF?

86. SCD-HeFT Inclusion Criteria Symptomatic CHF (NYHA class II and III) due to ischemic or nonischemic dilated cardiomyopathy LVEF < 35% > 18 years of age; no upper age limitation CHF  3 months Appropriate dose of ACE I and Beta Blocker therapy, if tolerated, for at least 1 month prior to randomization Bardy G

87. SCD-HeFT Endpoints Primary –To compare all cause mortality after 2.5 years of follow-up (Power: 90% to detect 25% benefit) Secondary –Mortality – Ischemic, Non-Ischemic, Class II, III –Cause-Specific Death –HF Morbidity & Mortality –Consistency of treatment effects across sub groups defined by other variables – age, gender, EF, Hx of MI, time of MI, QRS width –Quality of Life –Cost of Care & Cost Effectiveness

88. Recommended ACE I & BB Dosages Ace inhibitor: E.g., enalapril 10 mg bid Administered for at least 1 month prior to randomization Beta Blocker: Carvedilol: 3.125 mg bid for first 2 weeks; 6.25 mg bid for weeks 2- 4; 12.5 mg bid for weeks 4-6; and 25 mg bid for weeks 6-8. Metoprolol (Toprol XL): 12.5 mg qd for first 2 weeks; 25 mg qd for weeks 2-4; 37.5 mg qd for weeks 4-6; and 50 mg qd for weeks 6-8. Wait 2 weeks after last anticipated increase in beta-blocker dosage or wait 2 weeks after maximally tolerated dose prior to randomization. Bardy G

89. Inclusion criteria Placebo n=847 ICD implant n=829 2.5 years minimum follow- up Optimize:  B, ACE-I, Diuretics SCD-HeFT Protocol Amiodarone n=845

90. SCD-HeFT Trial Design Versus MADIT II

91. SCD-HeFT Enrolled Patient Characteristics vs. MADIT II

92. Moderate CHF Severe CHF Mild CHF Post-MI LV dysfunction Pharmacologic and Device Therapy Across the Continuum 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) MADIT, MUSTT MADIT II (ICD) SCD-HeFT (?) (ICD)

93. –In patients with LV dysfunction, the combined use of ACE inhibition and beta-blockade is recommended as the cornerstone of therapy. –Modest incremental benefit may be seen with the addition of other antagonists of the RAS in post-MI LV dysfunction and in chronic heart failure. –While neurohormonal interventions reduce morbidity and mortality across the cardiovascular disease continuum, post-MI and HF patients with LV dysfunction still have a high rate of sudden cardiac death. –Therapy with ICDs significantly reduces mortality in post-MI patients with LV dysfunction. These mortality benefits are on top of optimal pharmacologic therapy. ICD therapy should be considered standard of care in these patients. –Data from SCD-HeFT will be critical to understand the role of ICD therapy in ischemic and non-ischemic CHF patients with LV dysfunction. Conclusions