prevention of sudden cardiac death in heart failure patients with left ventricular dysfunction: the role of drugs and

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 Heart Failure and Sudden Cardiac Arrest: Epidemiology, etiology, pathophysiology 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? Overview of ICD therapy to prevent SCD in heart failure patients 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)

6. As shown here, between 1971 and 1996, the rate of hospitalizations for heart failure tripled. This increase is especially striking in people aged 65 or older. As shown here, between 1971 and 1996, the rate of hospitalizations for heart failure tripled. This increase is especially striking in people aged 65 or older.

7. As shown here, between 1971 and 1996, the rate of hospitalizations for heart failure tripled. This increase is especially striking in people aged 65 or older. As shown here, between 1971 and 1996, the rate of hospitalizations for heart failure tripled. This increase is especially striking in people aged 65 or older.

8. CHF Patients Survival Results1

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. Death is universally arrhythmic sudden death Death is universally arrhythmic sudden death

11. Accounts for 63% of all cardiac related deaths in the US1. One of the most common causes of death in developed countries: Sudden Cardiac Arrest

12. Magnitude of SCA in the US

13. - ~450,000 per year1 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 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

16. Arrhythmic Cause of SCD

17. Underlying Arrhythmias of Sudden Cardiac Arrest

18. Incidence of SCD in Specific Populations and Annual SCD Numbers Focusing on cardiac arrest survivors is NOT the answer because these patients represent only a very small percentage of the total number of patients who experience SCA each year. To address the greatest number of patients, primary prevention therapies will be required. Today, we can effectively identify/treat a very small portion of the total number of patients who experience SCA. SCD-HeFT may siginficantly increase our ability to treat high-risk heart failure patients. Focusing on cardiac arrest survivors is NOT the answer because these patients represent only a very small percentage of the total number of patients who experience SCA each year. To address the greatest number of patients, primary prevention therapies will be required. Today, we can effectively identify/treat a very small portion of the total number of patients who experience SCA. SCD-HeFT may siginficantly increase our ability to treat high-risk heart failure patients.

19. Heart Failure and Sudden Cardiac Death

20. Heart Failure and Sudden Death The proportionate contribution of SCD to total mortality in HF associated with reduced left ventricular function has not changed substantially between the Framingham data and now. Kannel WB, Wilson PWF, D'Agostino RB, Cobb J. Sudden coronary death in women. Am Heart J 1998 Aug; 136: 205-212 The proportionate contribution of SCD to total mortality in HF associated with reduced left ventricular function has not changed substantially between the Framingham data and now. Kannel WB, Wilson PWF, D'Agostino RB, Cobb J. Sudden coronary death in women. Am Heart J 1998 Aug; 136: 205-212

21. Severity of Heart FailureModes of Death Interestingly, most patients who suffer from sudden cardiac death (64%) are the patients who are minimally symptomatic with Class II heart failure. The sickest, most symptomatic patient (Class IV) experience heart failure deaths (56%) from pump failure, rather than sudden cardiac death (33%). It is important to remember that although it can be said that a heart failure patient in NYHA class II may have a higher risk of SCD, their relative annual risk of dying is less than the other NYHA classes. The SCD-HeFT Trial (Sudden Cardiac Death in Heart Failure Trial) which enrolled NYHA class II and III patients, hopes to answer whether patients in these classes are truly at a higher risk for SCD and need protection. Interestingly, most patients who suffer from sudden cardiac death (64%) are the patients who are minimally symptomatic with Class II heart failure. The sickest, most symptomatic patient (Class IV) experience heart failure deaths (56%) from pump failure, rather than sudden cardiac death (33%). It is important to remember that although it can be said that a heart failure patient in NYHA class II may have a higher risk of SCD, their relative annual risk of dying is less than the other NYHA classes. The SCD-HeFT Trial (Sudden Cardiac Death in Heart Failure Trial) which enrolled NYHA class II and III patients, hopes to answer whether patients in these classes are truly at a higher risk for SCD and need protection.

22. Pathophysiology and Mechanisms in Heart Failure that Precipitate SCA

23. Pathological Progression of CV Disease 1

24. RAS Pathophysiology

26. Deleterious Effects of Norepinephrinein CV Disease Prolonged levels of increased norepinephrine lead to impaired cardiac function. Disease progression is affected by the SNS in 3 areas of the body: the heart, vascular system, and kidneys. Chronic elevation of norepinephrine can provoke a variety of deleterious effects that are mediated through actions on a1-, b1-, and b2-adrenergic receptors. Increased cardiac sympathetic activity via these receptors leads to myocyte hypertrophy, dilation, ischemia, and arrhythmias.1Prolonged levels of increased norepinephrine lead to impaired cardiac function. Disease progression is affected by the SNS in 3 areas of the body: the heart, vascular system, and kidneys. Chronic elevation of norepinephrine can provoke a variety of deleterious effects that are mediated through actions on a1-, b1-, and b2-adrenergic receptors. Increased cardiac sympathetic activity via these receptors leads to myocyte hypertrophy, dilation, ischemia, and arrhythmias.1

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 Electrophysiological abnormalities leading to potentially lethal arrhythmias After depolarizations can trigger torsades de pointes. Transient ischemia in a prior infarct zone can trigger VT/VF. The failing heart may be predisposed to ischemic-triggering of ventricular arrhythmias due to greater conduction slowing in ischemic zones. Sweeney MO. PACE 2001;24:871-888. Electrophysiological abnormalities leading to potentially lethal arrhythmias After depolarizations can trigger torsades de pointes. Transient ischemia in a prior infarct zone can trigger VT/VF. The failing heart may be predisposed to ischemic-triggering of ventricular arrhythmias due to greater conduction slowing in ischemic zones. Sweeney MO. PACE 2001;24:871-888.

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 Increased nor-epinephrine levels are toxic to myocytes in a failing heart.Increased nor-epinephrine levels are toxic to myocytes in a failing heart.

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 Conditions Predisposing to Ventricular Arrhythmia in Heart Failure Patients Patients with heart failure are also predisposed to to hyperkalemia. This is due to reduced renal clearance of K+ and concomitant use of potassium supplements, ACE inhibitors and possibly K+ sparing diuretics.Hyperkalemia classically depresses sinus node automaticity and causes AV block. Hyperkalemia slows action potential upstroke and conduction which may favor re-entry.Patients with heart failure are also predisposed to to hyperkalemia. This is due to reduced renal clearance of K+ and concomitant use of potassium supplements, ACE inhibitors and possibly K+ sparing diuretics.Hyperkalemia classically depresses sinus node automaticity and causes AV block. Hyperkalemia slows action potential upstroke and conduction which may favor re-entry.

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

31. Neurohormonal Blockade Across theCV Disease Continuum

32. Neurohormonal Blockade Across theCV Disease Continuum

33. Effect of ACE Inhibitors on Mortality Reduction in Patients With LVD or Heart Failure

39. Neurohormonal Blockade Across theCV Disease Continuum

40. Effect of ?-Blockade on Outcome in Patients With Heart Failure and Post-MI LVD

41. CAPRICORN: Killip Class at Randomization

42. CAPRICORN:All-Cause Mortality

43. CAPRICORN: Mortality Reduction inLVD Patients With No Symptoms of Heart Failure

44. CAPRICORN:Effect on Recurrent Infarction

46. *Values indicated death incidence rates per 100 person-years during follow-up; enalapril by itself in either SOLVD-T or SOLVD-P did not significantly reduce sudden-cardiac mortality; however, in a reanalysis of SOLVD-P, enalapril with beta-blockers, compared to enalapril along signifcantly reduced total (4.3% vs. 5.6%), P <0.01) and sudden death mortality (1.3% vs. 1.8%l p <0.05). ACE-I = angiotensin-converting enzyme I; LVEF = left ventricular ejection fraction; SCD-= sudden cardiac death; SOLVD-T and SOLVD-P refers to the treatment and prevention trials of SOLVD.*Values indicated death incidence rates per 100 person-years during follow-up; enalapril by itself in either SOLVD-T or SOLVD-P did not significantly reduce sudden-cardiac mortality; however, in a reanalysis of SOLVD-P, enalapril with beta-blockers, compared to enalapril along signifcantly reduced total (4.3% vs. 5.6%), P <0.01) and sudden death mortality (1.3% vs. 1.8%l p <0.05). ACE-I = angiotensin-converting enzyme I; LVEF = left ventricular ejection fraction; SCD-= sudden cardiac death; SOLVD-T and SOLVD-P refers to the treatment and prevention trials of SOLVD.

47. SCD Prevention by Ion Channel-Active Drugs

48. CAST-I

49. CAST-II

50. EMIAT and CAMIAT Trials

51. SWORD Survival Results

52. The Impact of Neurohormonal Interventions on SCD in Heart Failure:

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

55. Survival Trends: CHD and SCA Mayo Clinic; Olmsted County, Minnesota1: 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.�

56. Risk of Sudden Death in HF Trials 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. A Trial of the Beta-Blocker Bucindolol in patients with advanced chronic heart failure. N Engl J Med 2001; 344: 1659-67. The Cardiac Insufficiency Bisoprolol Study II (CIBIS II): a randomized trial. THE LANCET: 353: 9-13. The Effect of Carvedilol on Morbidity and Mortality in Patients with Chronic Heart Failure. N Engl J Med 1996; 334: 1349-55. Pitt B, et al. The Effect of Spironolactone on Morbidity and Mortality in Patients with Severe Heart Failure. N Engl J Med 1999: 341; 709-17. 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. A Trial of the Beta-Blocker Bucindolol in patients with advanced chronic heart failure. N Engl J Med 2001; 344: 1659-67. The Cardiac Insufficiency Bisoprolol Study II (CIBIS II): a randomized trial. THE LANCET: 353: 9-13. The Effect of Carvedilol on Morbidity and Mortality in Patients with Chronic Heart Failure. N Engl J Med 1996; 334: 1349-55. Pitt B, et al. The Effect of Spironolactone on Morbidity and Mortality in Patients with Severe Heart Failure. N Engl J Med 1999: 341; 709-17.

57. Residual Risk of SCD in Treatment Arms of CHF-Beta Blocker Trials

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? HF population: 4,780,000 Annual incidence: 400,000- 465,000 6 - 9 fold increased mortality than the general population HF patients are the largest single population of patients which could benefit from primary prevention of SCDHF population: 4,780,000 Annual incidence: 400,000- 465,000 6 - 9 fold increased mortality than the general population HF patients are the largest single population of patients which could benefit from primary prevention of SCD

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

60. MADIT/MUSTT/MADIT-IIStudy Criteria Comparison

61. MADITMulticenter Automatic Defibrillator Implantation TrialMoss AJ. N Engl J Med 1996:335:1933-40.

62. MADIT Survival Results MADIT I was the first major primary prevention study using ICD therapy; this study showed a 54% statistically significant reduction in mortality with ICD therapy compared to conventional therapy. In the conventional therapy arm, the majority of patients were taking Amiodarone (74%). Thus, MADIT I should be viewed as a comparison of ICD therapy and AAD therapy. Major inclusion criteria for this trial were: post-MI; LVEF ? 35%; asymptomatic, spontaneous ventricular tachyarrhythmias; inducible, non-suppressible, sustained ventricular tachyarrhythmias. Interestingly, MADIT I was actually published before AVID, the most important ICD study in the secondary prevention of SCA. MADIT I was the first major primary prevention study using ICD therapy; this study showed a 54% statistically significant reduction in mortality with ICD therapy compared to conventional therapy. In the conventional therapy arm, the majority of patients were taking Amiodarone (74%). Thus, MADIT I should be viewed as a comparison of ICD therapy and AAD therapy. Major inclusion criteria for this trial were: post-MI; LVEF ? 35%; asymptomatic, spontaneous ventricular tachyarrhythmias; inducible, non-suppressible, sustained ventricular tachyarrhythmias. Interestingly, MADIT I was actually published before AVID, the most important ICD study in the secondary prevention of SCA.

63. MADIT: ICDs Significantly Reduced Overall and Arrhythmic Mortality1

64. MUSTTMulticenter Unsustained Tachycardia TrialBuxton AE. N Engl J Med. 1999;341:1882-90.

65. MUSTT Randomized Patient Results: Total Mortality MUSTT was the next major primary prevention study that showed excellent results with ICD therapy. MUSTT was originally intended to compare EP-guided therapy (ICD or AAD) versus no antiarrhythmic therapy. On further analysis, the investigators found that ICD therapy was far superior to AAD drug therapy. The primary endpoint of MUSTT was arrhythmic mortality unlike all the other ICD trials which used overall mortality as the primary endpoint. The secondary endpoint in MUSTT was overall mortality. The entry criteria for MUSTT was similar to MADIT I: LVEF ? 40%, CAD, non-sustained VT, sustained VT on programmed electrical stimulation. Given the similar inclusion criteria, it is not surprising that the results of MUSTT were consistent with MADIT I. After adjusting for covariates, MUSTT showed a 73% reduction in arrhythmic mortality and a 55% reduction in overall mortality in the ICD arm compared to patients taking no antiarrhythmic therapy. After the publishing of the MUSTT results, physician adoption of the MADIT I indication increased significantly. This is not surprising given the consistent results and similar inclusion criteria of MADIT I and MUSTT. MUSTT was the next major primary prevention study that showed excellent results with ICD therapy. MUSTT was originally intended to compare EP-guided therapy (ICD or AAD) versus no antiarrhythmic therapy. On further analysis, the investigators found that ICD therapy was far superior to AAD drug therapy. The primary endpoint of MUSTT was arrhythmic mortality unlike all the other ICD trials which used overall mortality as the primary endpoint. The secondary endpoint in MUSTT was overall mortality. The entry criteria for MUSTT was similar to MADIT I: LVEF ? 40%, CAD, non-sustained VT, sustained VT on programmed electrical stimulation. Given the similar inclusion criteria, it is not surprising that the results of MUSTT were consistent with MADIT I. After adjusting for covariates, MUSTT showed a 73% reduction in arrhythmic mortality and a 55% reduction in overall mortality in the ICD arm compared to patients taking no antiarrhythmic therapy. After the publishing of the MUSTT results, physician adoption of the MADIT I indication increased significantly. This is not surprising given the consistent results and similar inclusion criteria of MADIT I and MUSTT.

66. MUSTT: ICDs Significantly Reduce Overall and Arrhythmic Mortality

67. MUSTT Registry Patients Mortality Results We note in the table above that EP testing predicted cardiac arrest or arrhythmic death at both 2 and 5 years with both clinical and statistical significance. While EP testing did predict overall mortality with statistical significance at 2 and 5 years, the predictive value of EP testing in the prediction of overall mortality appears to be less powerful over time as compared to its prediction of arrhythmic mortality. Importantly, at 5 years, the non-inducible registry patients still had a very high mortality rate of 44%. We note in the table above that EP testing predicted cardiac arrest or arrhythmic death at both 2 and 5 years with both clinical and statistical significance. While EP testing did predict overall mortality with statistical significance at 2 and 5 years, the predictive value of EP testing in the prediction of overall mortality appears to be less powerful over time as compared to its prediction of arrhythmic mortality. Importantly, at 5 years, the non-inducible registry patients still had a very high mortality rate of 44%.

68. MADIT-IIMulticenter Automatic Defibrillator Implantation Trial-IIMoss 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

70. MADIT-II Protocol We note that EP testing was done after randomization in patients in the ICD arm. More patients were randomized to the ICD arm (3:2 randomization scheme). Anti-arrhythmic drugs were discouraged in both arms in order to optimally compare ICD therapy to optimal medical therapy. � � We note that EP testing was done after randomization in patients in the ICD arm. More patients were randomized to the ICD arm (3:2 randomization scheme). Anti-arrhythmic drugs were discouraged in both arms in order to optimally compare ICD therapy to optimal medical therapy. � �

71. MADIT-II Survival Results The MADIT II study was recently published in the NEJM and is the most important primary prevention study to date. By examining the Kaplan-Meier survival curves, we note that the ICD benefit began after approximately one year. Importantly, as demonstrated by the widening of the curves over time, the ICD benefit appears to increase over time. In an important recent analysis, Dr. Moss announced that there was a 40% cumulative probability of appropriate ICD therapy (ATP or shock) for VT or VF during the 4-year follow-up after ICD implantation. This finding clearly shows the improving cost-effectiveness of ICD therapy with longer follow-up periods.[i] [i] Moss, Arthur. MADIT I and MADIT II. Journal of Cardiovascular Electrophysiology. Vol. 14, No. 9, September 2003 The MADIT II study was recently published in the NEJM and is the most important primary prevention study to date. By examining the Kaplan-Meier survival curves, we note that the ICD benefit began after approximately one year. Importantly, as demonstrated by the widening of the curves over time, the ICD benefit appears to increase over time. In an important recent analysis, Dr. Moss announced that there was a 40% cumulative probability of appropriate ICD therapy (ATP or shock) for VT or VF during the 4-year follow-up after ICD implantation. This finding clearly shows the improving cost-effectiveness of ICD therapy with longer follow-up periods.[i] [i] Moss, Arthur. MADIT I and MADIT II. Journal of Cardiovascular Electrophysiology. Vol. 14, No. 9, September 2003

72. MADIT II: All-Cause Mortality The MADIT II study showed a 31% statistically significant reduction in overall mortality with ICD therapy compared to conventional therapy at the end of study follow-up. The absolute mortality benefit was 5.6%. The MADIT II study showed a 31% statistically significant reduction in overall mortality with ICD therapy compared to conventional therapy at the end of study follow-up. The absolute mortality benefit was 5.6%.

73. MADIT II: Mortality Events

74. MADIT-IISurvival Results � Subgroup Analyses We note some interesting trends in the above data. Females, patients with lower ejection fractions, lower NYHA functional class and longer QRS duration appear to have more benefit with ICD therapy. After considering the confidence intervals, we note that there no subgroup that had a statistically significant different benefit from the overall group. The analysis of age renders one example that sub-group analyses need to be interpreted with caution. The analysis of age does not make sense. There is no clear reason that that middle age group should have a less benefit than the other two groups. Certainly sub-group analyses provide interesting hypotheses that can be confirmed in a prospective study. We note some interesting trends in the above data. Females, patients with lower ejection fractions, lower NYHA functional class and longer QRS duration appear to have more benefit with ICD therapy. After considering the confidence intervals, we note that there no subgroup that had a statistically significant different benefit from the overall group. The analysis of age renders one example that sub-group analyses need to be interpreted with caution. The analysis of age does not make sense. There is no clear reason that that middle age group should have a less benefit than the other two groups. Certainly sub-group analyses provide interesting hypotheses that can be confirmed in a prospective study.

75. How did MADIT II compare to other major trials that influenced the treatment of post-MI patients? The Beta-blocker Heart Attack Trial (BHAT) had a relative reduction in mortality of 26% at 25 months. The BHAT trial was the first major beta-blocker trial, which showed that beta-blockers reduced mortality by 27% (p < 0.01) compared to placebo. �At 24 months, the Coronary Artery Surgery Study (CASS) showed a trend towards benefit for patients randomized to CABG surgery versus medical therapy. However, the 11% reduction in mortality did not reach statistical significance. �The Survival And Ventricular Enlargement Study (SAVE) was the first major ACE-Inhibitor trial to demonstrate a mortality reduction (p = 0.019). SAVE showed a 3.8% absolute reduction in mortality and a 19% relative mortality reduction at 42 months. �The Multicenter Automatic Defibrillator Implantation Trial II (MADIT II) demonstrated a 31% relative reduction in mortality at 20 months and a 5.6% absolute mortality reduction. Thus, we see that the MADIT II study had a greater absolute and relative reduction in mortality when compared to the other studies. � How did MADIT II compare to other major trials that influenced the treatment of post-MI patients? The Beta-blocker Heart Attack Trial (BHAT) had a relative reduction in mortality of 26% at 25 months. The BHAT trial was the first major beta-blocker trial, which showed that beta-blockers reduced mortality by 27% (p < 0.01) compared to placebo. �At 24 months, the Coronary Artery Surgery Study (CASS) showed a trend towards benefit for patients randomized to CABG surgery versus medical therapy. However, the 11% reduction in mortality did not reach statistical significance. �The Survival And Ventricular Enlargement Study (SAVE) was the first major ACE-Inhibitor trial to demonstrate a mortality reduction (p = 0.019). SAVE showed a 3.8% absolute reduction in mortality and a 19% relative mortality reduction at 42 months. �The Multicenter Automatic Defibrillator Implantation Trial II (MADIT II) demonstrated a 31% relative reduction in mortality at 20 months and a 5.6% absolute mortality reduction. Thus, we see that the MADIT II study had a greater absolute and relative reduction in mortality when compared to the other studies. �

76. MADIT II: ComplicationsNew or Worsening HF1 There was a strong trend towards increased CHF hospitalizations in the ICD group compared to the conventional group. This is an important finding that probably stems from the ICD programming. Dr. Moss in his September article article in JCE stated that there was a strong correlation of the CHF hospitalization rate with the level of RV pacing. In fact, most patients with dual-chamber devices had their ICD programmed DDD at 70 beats per minute. Thus, it appears that this side effect of ICD therapy seen in MADIT II study could be prevented by a different programming approach. In fact, the SCD-HeFT study has used a proscribed programming approach aimed at minimizing RV pacing. Importantly, the increased CHF hospitalization rate in MADIT II study should lead to a less favorable cost-effectiveness value for ICD therapy. Given the above discussion, this may not accurately reflect the true cost of ICD therapy. There was a strong trend towards increased CHF hospitalizations in the ICD group compared to the conventional group. This is an important finding that probably stems from the ICD programming. Dr. Moss in his September article article in JCE stated that there was a strong correlation of the CHF hospitalization rate with the level of RV pacing. In fact, most patients with dual-chamber devices had their ICD programmed DDD at 70 beats per minute. Thus, it appears that this side effect of ICD therapy seen in MADIT II study could be prevented by a different programming approach. In fact, the SCD-HeFT study has used a proscribed programming approach aimed at minimizing RV pacing. Importantly, the increased CHF hospitalization rate in MADIT II study should lead to a less favorable cost-effectiveness value for ICD therapy. Given the above discussion, this may not accurately reflect the true cost of ICD therapy.

77. Mortality Benefits in ICD Trials Overall mortality reductions for the three studies were based on the hazard ratio for risk of death results for the time period of the study with the average follow-up time of the patients noted on the graph. Arrhythmic Death results: MADIT: Was calculated to be 75% based on the difference between the percent of arrhythmia deaths for the conventional therapy (12.9%) and the percent of arrhythmia deaths for ICD therapy (3.15%) over the time period of the study, with an average follow-up of 27 months. MUSTT: Was 73% - based on the relative risk of event of defibrillator therapy as compared with no arrhythmic therapy for the time period of the study with the average follow-up of 39 months. MADIT-II:Was calculated to be 62% based on the difference between the percent of arrhythmia deaths for the conventional therapy (9.39%) and the percent of arrhythmia deaths for ICD therapy (3.63%) over the time period of the study, with an average follow-up of 20 months. These arrhythmic death numbers were presented at by Dr. Moss before the ACC 51st Annual Scientific Sessions, Late Breaking Clinical Trials, March 19, 2002, but have not been published. Overall mortality reductions for the three studies were based on the hazard ratio for risk of death results for the time period of the study with the average follow-up time of the patients noted on the graph. Arrhythmic Death results: MADIT: Was calculated to be 75% based on the difference between the percent of arrhythmia deaths for the conventional therapy (12.9%) and the percent of arrhythmia deaths for ICD therapy (3.15%) over the time period of the study, with an average follow-up of 27 months. MUSTT: Was 73% - based on the relative risk of event of defibrillator therapy as compared with no arrhythmic therapy for the time period of the study with the average follow-up of 39 months. MADIT-II:Was calculated to be 62% based on the difference between the percent of arrhythmia deaths for the conventional therapy (9.39%) and the percent of arrhythmia deaths for ICD therapy (3.63%) over the time period of the study, with an average follow-up of 20 months. These arrhythmic death numbers were presented at by Dr. Moss before the ACC 51st Annual Scientific Sessions, Late Breaking Clinical Trials, March 19, 2002, but have not been published.

78. Post-MI trials are not heart failure trials but�

79. SCD Rates in Post-MI Patients with LV Dysfunction TRACE: Kober L, et al. N Engl J Med 1995; 333: 1670-6. CAPRICORN: The CAPRICORN Investigators. Lancet 2001; 357: 1385-90. EMIAT: Julian DG, et al. Lancet 1997; 349: 667-74. MADIT: Moss AJ. N Engl J Med. 1996;335:1933-40. MUSTT: 1) Buxton AE. N Engl J Med. 1999;341:1882-90. 2) Buxton AE, et al. Journal of Interventional Cardiac Electrophysiology 9, 203-206, 2003. 3) Buxton AE, et al. N Engl J Med 2000; 342: 1937-45. MADIT II: 1) Moss AJ. N Engl J Med. 2002;346:877-83, 2) Arrhythmic mortality data from: Moss AJ. Presented at ACC Latebreaking Clinical Trials, March 2002. TRACE: Kober L, et al. N Engl J Med 1995; 333: 1670-6. CAPRICORN: The CAPRICORN Investigators. Lancet 2001; 357: 1385-90. EMIAT: Julian DG, et al. Lancet 1997; 349: 667-74. MADIT: Moss AJ. N Engl J Med. 1996;335:1933-40. MUSTT: 1) Buxton AE. N Engl J Med. 1999;341:1882-90. 2) Buxton AE, et al. Journal of Interventional Cardiac Electrophysiology 9, 203-206, 2003. 3) Buxton AE, et al. N Engl J Med 2000; 342: 1937-45. MADIT II: 1) Moss AJ. N Engl J Med. 2002;346:877-83, 2) Arrhythmic mortality data from: Moss AJ. Presented at ACC Latebreaking Clinical Trials, March 2002.

80. SCD Rates in CHF Patients with LV Dysfunction CHF-STAT: Singh SN, et al. Amiodarone in patients with congestive heart failure and asymptomatic ventricular arrhythmia. N Engl J Med 1995; 333: 77-82. GESICA: Doval, HC. Lancet. 1994. SOLVD: Cooper H, et al. Dirueticsand Risk of Arrhythmic Death in Patients with Left Ventricularl Dysfunction. Circulation. 1999; 100: 1311-1315. V-HEFT I: Goldman S, Johnson G, Cohn JN, Cintron G, Smith R, Francis G. Mechanism of death in heart failure. The Vasodilator-Heart Failure Trials. The V-HeFT VA Cooperative Studies Group. Circulation. 1993 Jun;87(6 Suppl):VI24-31 MERIT-HF: 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. CIBIS II: The Cardiac Insufficiency Bisoprolol Study II (CIBIS II): a randomized trial. THE LANCET: 353: 9-13. CARVEDILOL-US: The Effect of Carvedilol on Morbidity and Mortality in Patients with Chronic Heart Failure. N Engl J Med 1996; 334: 1349-55. CHF-STAT: Singh SN, et al. Amiodarone in patients with congestive heart failure and asymptomatic ventricular arrhythmia. N Engl J Med 1995; 333: 77-82. GESICA: Doval, HC. Lancet. 1994. SOLVD: Cooper H, et al. Dirueticsand Risk of Arrhythmic Death in Patients with Left Ventricularl Dysfunction. Circulation. 1999; 100: 1311-1315. V-HEFT I: Goldman S, Johnson G, Cohn JN, Cintron G, Smith R, Francis G. Mechanism of death in heart failure. The Vasodilator-Heart Failure Trials. The V-HeFT VA Cooperative Studies Group. Circulation. 1993 Jun;87(6 Suppl):VI24-31 MERIT-HF: 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. CIBIS II: The Cardiac Insufficiency Bisoprolol Study II (CIBIS II): a randomized trial. THE LANCET: 353: 9-13. CARVEDILOL-US: The Effect of Carvedilol on Morbidity and Mortality in Patients with Chronic Heart Failure. N Engl J Med 1996; 334: 1349-55.

81. Primary Prevention ICD Trials: Extent of Beta-Blocker/ACE-I Use in Control Patients 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 4 The AVID Investigators. N Engl J Med. 1997;337:1576-83. 5 Kuck K. Circ. 2000;102:748-54. 6 Connolly S. Circ. 2000:101:1297-1302. (Control is in green, CRT in orange. Values shown are mean � SD.) There is a substantial placebo effect with the Quality of Life assessed by the Minnesota Living with Heart Failure Questionnaire. Rather than a weakness, this speaks to the strength of the blinding in the trial. Despite the placebo effect, there is a statistically significant treatment effect with CRT. Like the analysis for hall walk, a repeated measures analysis of variance was used in the statistical analysis. In this test, scores can range from 0 (best case) to 115 (worst case). For this QoL endpoint, at 6-months the same patients in the control group had an improvement in their total score of 11 points compared to baseline. Treatment patients improved by 19 points. The difference in this change between groups at 6-months of 8 points is statistically significant. There is a statistically significant treatment effect with CRT at 1 and 6-months and a favorable trend at 3-months.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 4 The AVID Investigators. N Engl J Med. 1997;337:1576-83. 5 Kuck K. Circ. 2000;102:748-54. 6 Connolly S. Circ. 2000:101:1297-1302. (Control is in green, CRT in orange. Values shown are mean � SD.) There is a substantial placebo effect with the Quality of Life assessed by the Minnesota Living with Heart Failure Questionnaire. Rather than a weakness, this speaks to the strength of the blinding in the trial. Despite the placebo effect, there is a statistically significant treatment effect with CRT. Like the analysis for hall walk, a repeated measures analysis of variance was used in the statistical analysis. In this test, scores can range from 0 (best case) to 115 (worst case). For this QoL endpoint, at 6-months the same patients in the control group had an improvement in their total score of 11 points compared to baseline. Treatment patients improved by 19 points. The difference in this change between groups at 6-months of 8 points is statistically significant. There is a statistically significant treatment effect with CRT at 1 and 6-months and a favorable trend at 3-months.

82. Number Needed to Treat To Save A Life NNT is a normalized measure of clinical effectiveness and efficiency that allows comparison among treatments/studies. NNT is calculated at a specific point in time. When comparable data is available it is best to compare NNT for different therapies at the same point in time. Take the mortality estimate at a specific point on time from the survival/mortality curve if available. When crude mortality percentages are used, the average follow-up time is used. MUSTT @ 5 years from Kaplan Meier (KM) curve: 55%-24%, NNT=3 N Engl. J Med. 1999;341:1882-1890 MADIT @ average follow-up of 2.4 yrs, crude mortality rate: 39%-16%, NNT=4 N Engl J Med. 1996;335:1933-1940 MADIT-II @ 3 years from KM curve: 31%-22%, NNT=11 N Engl J Med. 2002;346:877-883 AVID @ 3 years from the KM curve: 36%-25%, NNT=9 N Engl J Med. 1997;337:1576-1583 SAVE (captopril, an ACE inhibitor) crude rate with average follow-up of 42 months: 25%-20%, NNT=20 N Engl J Med, 1992; 327:669-677. Merit-HF (metoprolol, a BB in HF patients) @ 1 year from KM curve: 11%-7.2%, NNT 26 LANCET 1999; 353:2001-07. 4S (simvastatin) @ 6 years from KM curve: 12.3%-8.7%, NNT=28 LANCET 1994; 344: 1383-1389. Amiodarone Meta-analysis of 15 trial @ average follow-up of 2 years: 19.2%-16.5%, NNT=37 Circulation, 1997; 96: 2823-2829. NNT is a normalized measure of clinical effectiveness and efficiency that allows comparison among treatments/studies. NNT is calculated at a specific point in time. When comparable data is available it is best to compare NNT for different therapies at the same point in time. Take the mortality estimate at a specific point on time from the survival/mortality curve if available. When crude mortality percentages are used, the average follow-up time is used. MUSTT @ 5 years from Kaplan Meier (KM) curve: 55%-24%, NNT=3 N Engl. J Med. 1999;341:1882-1890 MADIT @ average follow-up of 2.4 yrs, crude mortality rate: 39%-16%, NNT=4 N Engl J Med. 1996;335:1933-1940 MADIT-II @ 3 years from KM curve: 31%-22%, NNT=11 N Engl J Med. 2002;346:877-883 AVID @ 3 years from the KM curve: 36%-25%, NNT=9 N Engl J Med. 1997;337:1576-1583 SAVE (captopril, an ACE inhibitor) crude rate with average follow-up of 42 months: 25%-20%, NNT=20 N Engl J Med, 1992; 327:669-677. Merit-HF (metoprolol, a BB in HF patients) @ 1 year from KM curve: 11%-7.2%, NNT 26 LANCET 1999; 353:2001-07. 4S (simvastatin) @ 6 years from KM curve: 12.3%-8.7%, NNT=28 LANCET 1994; 344: 1383-1389. Amiodarone Meta-analysis of 15 trial @ average follow-up of 2 years: 19.2%-16.5%, NNT=37 Circulation, 1997; 96: 2823-2829.

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 SCD-HeFT is a landmark trial with a solid design, sponsored and funded by NHLBI, managed by DCRI.SCD-HeFT is a landmark trial with a solid design, sponsored and funded by NHLBI, managed by DCRI.

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? As many of you are aware SCD-HeFT is an acronym for Sudden Cardiac Death In Heart Failure Trial The trial is sponsored by NHLBI, MDT and Wyeth � Medtronic is a funder we�re not a decision maker on the protocol or center selection Data collected, maintained and analyzed by Duke (DCRI) � an independent and objective organization The question that the SCD-HeFT trial poses is this: Will Amiodarone and/or an ICD improve survival compared to placebo in patients with Class II and III HF and EF < 35% without a history of sustained Ventricular Tachyarrhythmia?As many of you are aware SCD-HeFT is an acronym for Sudden Cardiac Death In Heart Failure Trial The trial is sponsored by NHLBI, MDT and Wyeth � Medtronic is a funder we�re not a decision maker on the protocol or center selection Data collected, maintained and analyzed by Duke (DCRI) � an independent and objective organization The question that the SCD-HeFT trial poses is this: Will Amiodarone and/or an ICD improve survival compared to placebo in patients with Class II and III HF and EF < 35% without a history of sustained Ventricular Tachyarrhythmia?

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

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 The primary endpoint of the trial is overall survival. The trial has a power to detect a 25% change in mortality. In addition to looking at survival in total the trial will assess the survival in a number of sub segments of the trial population. Although these are very interesting questions there are limitations since the trial is not designed to specifically test these questions. The subsegments include: ischemic, non-ischemic, New York Heart Class II and III The analysis will also look at the consistency of effect across age, gender, race, EF, QRS width and others In addition to examining overall survival the trial will examine cause specific survival, HF morbidity and mortality, quality of life and cost effectiveness. The trial has a power to detect a 25% change in mortality after 2.5 years of f/u and the fact that it hasn�t been stopped indicates that the treatment impact is not significantly worse than nor better than 25%. If the therapy was unsafe or if the trial was futile it would have been stopped by the data safety and monitoring board.The primary endpoint of the trial is overall survival. The trial has a power to detect a 25% change in mortality. In addition to looking at survival in total the trial will assess the survival in a number of sub segments of the trial population. Although these are very interesting questions there are limitations since the trial is not designed to specifically test these questions. The subsegments include: ischemic, non-ischemic, New York Heart Class II and III The analysis will also look at the consistency of effect across age, gender, race, EF, QRS width and others In addition to examining overall survival the trial will examine cause specific survival, HF morbidity and mortality, quality of life and cost effectiveness. The trial has a power to detect a 25% change in mortality after 2.5 years of f/u and the fact that it hasn�t been stopped indicates that the treatment impact is not significantly worse than nor better than 25%. If the therapy was unsafe or if the trial was futile it would have been stopped by the data safety and monitoring board.

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.

89. SCD-HeFT Protocol SCD-HeFT is a Landmark Study of SCA in HF Large, randomized, double-blind, placebo controlled 2.5 year follow-up Proscribed programming approach Minimized pacing therapy The study design is a prospective randomized control trial comparing Amiodarone or ICD to Optimal medical Therapy in patients who present with ischemic or non-ischemic dilated cardiomyopathy in NYHA class II or III who are on an ACE inhibitor and a beta blockers with an EF of less than or equal to 35% at the time of enrollment SCD-HeFT is a trial of ICDs and Amio in patients with HF The ICD in the study is the Medtronic MicroJewel II, 7223 CX The trial has the Power to detect a 25% change in mortality at 2.5 years of f/u. ACE, diuretics, Dig, BB, Spironolactone, statins HF of > 3 months duration SCD-HeFT is a Landmark Study of SCA in HF Large, randomized, double-blind, placebo controlled 2.5 year follow-up Proscribed programming approach Minimized pacing therapy The study design is a prospective randomized control trial comparing Amiodarone or ICD to Optimal medical Therapy in patients who present with ischemic or non-ischemic dilated cardiomyopathy in NYHA class II or III who are on an ACE inhibitor and a beta blockers with an EF of less than or equal to 35% at the time of enrollment SCD-HeFT is a trial of ICDs and Amio in patients with HF The ICD in the study is the Medtronic MicroJewel II, 7223 CX The trial has the Power to detect a 25% change in mortality at 2.5 years of f/u. ACE, diuretics, Dig, BB, Spironolactone, statins HF of > 3 months duration

90. SCD-HeFT Trial Design Versus MADIT II In this slide I will compare SCD-HeFT and MADIT II. These two trials have a number of similarities and also differences. SCD-HeFT as I indicated before was sponsored by NIH, Medtronic and Wyeth-Ayerst now American Home Products The study director is Gust Bardy and the PIs are Kerry Lee and Dan Marks at Duke Cardiovascular Research Institute. The SCD-HeFT trial design is a 3 arm randomized placebo controlled trial whereas MADIT II is two arms without a placebo control In terms of cardiac disease SCD-HeFT enrolls both ischemic with or without an MI and non-ischemic. MADIT II is only Ischemic + MI SCD-HeFT EF criteria allows for higher EF meaning that even within the Ischemic patients not all would qualify as MADIT II patients. SCD-HeFT enrolls NYHA class II, III while MADIT II allows I-III. In summary SCD-HeFT is a trial of ICDs/Amio in patients with HF and MADIT II is a trial of ICDs in patients with a low EF after an MI In this slide I will compare SCD-HeFT and MADIT II. These two trials have a number of similarities and also differences. SCD-HeFT as I indicated before was sponsored by NIH, Medtronic and Wyeth-Ayerst now American Home Products The study director is Gust Bardy and the PIs are Kerry Lee and Dan Marks at Duke Cardiovascular Research Institute. The SCD-HeFT trial design is a 3 arm randomized placebo controlled trial whereas MADIT II is two arms without a placebo control In terms of cardiac disease SCD-HeFT enrolls both ischemic with or without an MI and non-ischemic. MADIT II is only Ischemic + MI SCD-HeFT EF criteria allows for higher EF meaning that even within the Ischemic patients not all would qualify as MADIT II patients. SCD-HeFT enrolls NYHA class II, III while MADIT II allows I-III. In summary SCD-HeFT is a trial of ICDs/Amio in patients with HF and MADIT II is a trial of ICDs in patients with a low EF after an MI

91. SCD-HeFT Enrolled Patient Characteristics vs. MADIT II As you would expect with differing enrollment criteria the patients in the two trials are different. The patients in SCD-HeFT are younger, roughly 50% are non-ischemic, the mean EF is slightly higher and the distribution of NYHA is different with approx 70% NYHA class II in SCD-HeFT. The direct overlap is small.As you would expect with differing enrollment criteria the patients in the two trials are different. The patients in SCD-HeFT are younger, roughly 50% are non-ischemic, the mean EF is slightly higher and the distribution of NYHA is different with approx 70% NYHA class II in SCD-HeFT. The direct overlap is small.

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