1. Current Therapies for the Management of Chronic and Acute Heart Failure John L. Tan, MD, PhD Heart Failure Program at the North Texas Heart Center Presbyterian Hospital of Dallas

2. Adapted from AHA Heart and Stroke Facts Statistical Update, 1999; Kannel and Belanger, 1991; Stevenson et al, 1993; O’Connell and Bristow, 1994 AHA. 2001 Heart and Stroke Statistical Update. Heart Failure: The Scope Prevalence 4.6 million Americans Incidence 550,000 new cases/year 10 per 1000 population after age 65 Morbidity 1,000,000 hospitalizations (2001) 5 to 10% of all admissions Most frequent cause of hosp in elderly Mortality Contributes to  260,000 deaths/year Up to 70% of patients die suddenly Five year mortality rate ~50%

3.  $38.1 billion in 1991  Rising to an estimated ~$54 billion in 1999  Accounting for approximately twice the cost for cancer or myocardial infarction  5.4% of total health care costs  Single largest expense for Medicare Adapted from AHA Heart and Stroke Facts Statistical Update, 1999; Kannel and Belanger, 1991; Stevenson et al, 1993; O’Connell and Bristow, 1994 AHA. 2001 Heart and Stroke Statistical Update. Cost of Heart Failure

4. Etiology of Heart Failure (SOLVD Registry) Bourassa et al. J Am Coll Cardiol. 1993;22:14A-19A. N=6063 Valvular heart disease Congenital heart disease Viral Toxic Thyroid Peripartum

5. The New Classification of Heart Failure StagePatient Description A High risk for developing heart failure (HF) Hypertension CAD Diabetes mellitus Family history of cardiomyopathy B Asymptomatic HF Previous MI LV systolic dysfunction Asymptomatic valvular disease C Symptomatic HF Known structural heart disease Shortness of breath and fatigue Reduced exercise tolerance D Refractory end-stage HF Marked symptoms at rest despite maximal medical therapy (eg, those who are recurrently hospitalized or cannot be safely discharged from the hospital without specialized interventions) Hunt SA et al. J Am Coll Cardiol. 2001;38:2101–2113.

6. Heart failure is more than a symptomatic disease Produces symptoms, limits functional capacity, and impairs quality of life Heart failure is a progressive disease Worsening symptoms and clinical deterioration, repeated hospitalization, and death Death occurs frequently even in the presence of minimal symptoms or the absence of progressive symptoms Symptoms do not always correspond with ejection fraction Symptom Relief is Not Sufficient

7. Ventricular Remodeling Ventricular Remodeling After Acute Infarction Ventricular Remodeling in Diastolic and Systolic HF Initial infarct Expansion of infarct (hours to days) Global remodeling (days to months) Normal heart Hypertrophied heart (diastolic HF) Dilated heart (systolic HF) Jessup M et al. N Engl J Med. 2003;348:2007

8. Myocardial Injury Fall in LV performance Activation of RAAS, SNS, ET, and others Myocardial toxicity Peripheral vasoconstriction Hemodynamic alterations Remodeling and progressive worsening of LV function Heart failure symptoms symptoms Morbidity and mortality ANPBNP - - Heart Failure Pathophysiology

9. Neurohormonal Targets in Heart Failure Angiotensinogen Angiotensin I AT II AT 1 Receptors ACE Inhibitors SNS Activation Epinephrine Norepinephrine Target Cells

10.  ~7000 patients evaluated in long-term placebo- controlled clinical trials  Improvement in cardiac function, symptoms, and clinical status; equivocal effects on exercise tolerance  Decrease in all-cause mortality by 20-25% (P<.001) and decrease in combined risk of death and hospitalization by 30-35% (P<.001) Garg and Yusuf, 1995. ACE Inhibitors in Heart Failure

11. 1.0 0.8 0.6 0.5 0 021345 Survival Year CONSENSUS PROMISE PRAISE SOLVD-Prevention SOLVD-Treatment DIG V-HeFT ACE inhibitor arms of CONSENSUS, V-HeFT, and SOLVD trials. Placebo arms of PRAISE, PROMISE, and DIG trials (all receiving ACE inhibitors). Mortality in Patients Receiving ACE Inhibitors

12. Neurohormonal Targets in Heart Failure Angiotensinogen Angiotensin I AT II AT 1 Receptors ACE Inhibitors SNS Activation Epinephrine Norepinephrine Target Cells  -Blockers

13. Effect of  -Blockade on All-Cause Mortality 00.250.50.7511.251.51.752 Relative risk and 95% confidence intervals CIBIS-I: 1.9 years placebo 67/321 (20%); bisoprolol 53/320 (16%) P=.22 CIBIS-II: 1.3 years placebo 228/1320 (17%); bisoprolol 156/1327 (12%) P=.0001 MERIT-HF: 12 months placebo 217/2001 (11%); metoprolol 145/1990 (7%) P=.006 US Carvedilol Trials: 7.6 months placebo 31/398 (8%); carvedilol 22/696 (3%) P=.001

14. All-cause mortality: 35% decreased risk. 100 90 80 60 70 50 2402016128428 Placebo (n=1133) Carvedilol (n=1156) Months % Survival P=0.00014 COPERNICUS

15. The CHF Trials in Perspective: Patients Needed to Treat for One Year to Save One Life HF Stage Trial# of Patients A HOPE 333 B SOLVD-Prevention 285 C SOLVD-Treatment 77 C CIBIS-II 23 C MERIT-HF 25 D COPERNICUS 14

16. Neurohormonal Targets in Heart Failure Angiotensinogen Angiotensin I AT II AT 1 Receptors ACE Inhibitors SNS Activation Epinephrine Norepinephrine Target Cells ARBs

17. 1276 1272 1176 1136 1063 1013 948 906 457 422 Number at risk: Candesartan Placebo Time (years) CHARM-Added: Primary Endpoint HF, heart failure; HR, hazard ratio; CI, confidence interval. McMurray JJV et al. Lancet. 2003;362:767-771. CV death or HF hospitalization (%) 0123 0 10 20 30 40 50 Placebo Candesartan 3.5 HR 0.85 (95% CI 0.75-0.96), P=0.011 Adjusted HR 0.85, P=0.010 483 (37.9%) 538 (42.3%) 15% risk reduction

18. A-HEFT: Role of Hydralazine/Nitrates Taylor AL, et al. N Engl J Med. 2004;351:2049-57 Mortality 43% Hospitalization 33%

19. A-HeFT: Hydralazine/Nitrates  African-Americans (n = 1050)  LVEF < 35% or <45% with increased LVEDD  NYHA Class III-IV  ~70% on ACE-I, ~74% on  -B  Baseline SBP ~125 mm Hg  Etiology of CMP ~40% Hypertension ~23% CAD Taylor AL, et al. N Engl J Med. 2004;351:2049-57

20. Neurohormonal Targets in Heart Failure Angiotensinogen Angiotensin I AT II AT 1 Receptors ACE Inhibitors SNS Activation Epinephrine Norepinephrine Target Cells Aldosterone Receptor Blockers

21. RALES: Aldosterone Receptor Blockade Pitt B, et al. N Engl J Med. 1999;341:709-717 Spironolactone n = 1663 NYHA III/IV LVEF < 40% mortality 27% hospitalization 36% (p<0.0002)

22. NYHA IINYHA III HF 12% Other 24% Sudden cardiac death 64% HF 26% Other 15% Sudden cardiac death 59% Mode of Death in MERIT-HF MERIT-HF Study Group. Lancet. 1999;353(9169):2001-2007.

23. Device Therapies in Heart Failure: Implantable Cardioverter-Defibrillators

24. Patients with prior MI within 30 days and LVEF < 30% randomized in a 3:2 ratio 71 US centers and 5 European centers Patients with prior MI within 30 days and LVEF < 30% randomized in a 3:2 ratio 71 US centers and 5 European centers Conventional medical therapy (n=490) Conventional medical therapy (n=490) Implantable defibrillator (n=742) Implantable defibrillator (n=742) All Cause Mortality - Average follow-up of 20 months Stopped early by Data Safety Monitoring Board MADIT II: Study Design

25. Conventional Therapy Conventional Therapy ICD P=0.016 Death Avg. follow-up=20 months Death Avg. follow-up=20 months MADIT II: All-Cause Mortality Hazard Ratio = 0.65

26. R SCD-HeFT: Enrollment Scheme DCM + CAD and CHF EF < 35% NYHA Class II or III 6 minute walk, Holter Placebo Amiodarone ICD Bardy G et al. NEJM 2005; 352:3 n=2521, 1:1:1

27. SCD-HeFT: Death from Any Cause Bardy G et al. NEJM 2005; 352:3 23% RR Reduction in Death 7.2% Absolute Reduction at 5 yrs

28. Bardy G et al. NEJM 2005; 352:3 SCD-HeFT: Death from Any Cause in Ischemic CHF

29. Bardy G et al. NEJM 2005; 352:3 SCD-HeFT: Death from Any Cause in Nonischemic CHF

30. SCD-HeFT: Primary Conclusions  In class II or III CHF patients with EF < 35% on good background drug therapy, the mortality rate for placebo-controlled patients is 7.2% per year over 5 years  Simple, single lead, shock-only ICDs decrease mortality by 23%  Amiodarone, when used as a primary preventative agent, does not improve survival Bardy G et al. NEJM 2005; 352:3

31. Mortality Benefits of HF Therapies Absolute Annual Mortality Reduction During Trial % Absolute Reduction

32. Indications for ICDs in CHF  CHF for at least 3 months  Ejection fraction less than or equal to 35%  NYHA Class II or III symptoms  Greater than 1 year life expectancy  Ischemic or non-ischemic cardiomyopathy  No QRS duration requirements CMS Website

33. Device Therapies in Heart Failure: Cardiac Resynchronization

34. Myocardial Dyssynchrony

35. Cardiac Resynchronization in Heart Failure Indications:  EF <35%  NYHA III-IV  QRS >130-150ms

36. Change in 6-minute Walking Distance (m) Months after Randomization 60 40 20 0 -20 0 1 3 6 P = 0.005 P = 0.003 P = 0.004 MIRACLE Trial, N Engl J Med 2002;346:1845-53 Control Resynchronized Cardiac Resynchronization in Heart Failure

37. Change in Quality-of-Life Score Months after Randomization 0 1 3 6 0 -5 -10 -15 -20 -25 P < 0.001 P = 0.001 MIRACLE Trial, N Engl J Med 2002;346:1845-53 Control Resynchronized Cardiac Resynchronization in Heart Failure

38. The COMPANION Trial  1520 patients (1:2:2)  NYHA Class III-IV  EF </=35%  QRS > 120 ms  11.9-16.5 month f/u  Study withdrawal 26% Placebo 6% Bi-V Pacemaker 7% Bi-V-ICD

39. The COMPANION Trial Bristow MR, et al. N Engl J Med. 2004;350:2140-50

40. The COMPANION Trial Bristow MR, et al. N Engl J Med. 2004;350:2140-50

41. Optimal Therapy for Chronic Heart Failure In Symptomatic Patients:  Diuretics  Digoxin

42. Optimal Therapy for Chronic Heart Failure  ACE Inhibitors (or ARBII Blockers)  Beta-blockers  ARBII Blockers or Hydralazine/Nitrates  ICD Therapy (Class II or higher CHF)

43. Optimal Therapy for Chronic Heart Failure In Persistent Class III-IV CHF:  Spironalactone  Bi-ventricular pacer (Prolonged QRS)

44. Conventional Therapy Conventional Therapy ICD P=0.09 New or Worsening Heart Failure MADIT II: CHF

45. Heart Failure Heart Failure Hospitalizations AHA, 1998 Heart and Statistical Update NCHS, National Center for Health Statistics The number of heart failure hospitalizations is increasing in both men and women CDC/NCHS: Hospital discharges include patients both living and dead. AHA Heart and Stroke Statistical Update 2001

46. Rising Hospital Admissions for Heart Failure  Inevitable progression of disease  Rising incidence of chronic heart failure (population aging, improved survival with AMI/revascularization)  Incomplete treatment during hospitalization  Poor application of chronic heart failure management guidelines  Noncompliance with diet and drugs

47. Emergency Department Visits for Congestive Heart Failure Initial Episode * 21% Repeat Visit 79% Rates of Hospital Readmission 2% within 2 days 20% within 1 month 50% within 6 months Approximately 80% of the ED visits for CHF result in hospitalizations Cardiology Roundtable 1998

48. Utilization of HF Medications 2300/7883 patients hospitalized with HF; prior known LV systolic dysfunction; outpatient medical regimen ADHERE ™ Registry Report Q1 2002 (4/01–3/02) of 180 US Hospitals. Presented at the HFSA Satellite Symposium, September 23, 2002 *Excludes patients with documented contraindications Patients Treated (%)

49. Causes of Hospital Readmission for Heart Failure 17% Other 19% Failure to Seek Care 16% Inappropriate Rx Rx Noncompliance 24% Diet Noncompliance 24% Vinson J Am Geriatr Soc 1990;38:1290-5

50. Heart Failure Costs 60.6% Hospitalizations $23.1 billion 38.6% Outpatient care $14.7 billion (3.4 visits/year/patient) O’Connell and Bristow. J Heart Lung Transplant. 1994;13:S107-S112. 0.7% Transplants $270 million Total = $38.1 billion (5.4% of total healthcare costs)

51. Congestion at Rest Cardiac output/ Perfusion at Rest Normal NoYes Low Warm & Dry (normal) Warm & Wet Cold & WetCold & Dry Signs/symptoms of congestion  Orthopnea/PND  JVD  Ascites  Edema  Rales Possible evidence of low perfusion  Narrow pulse pressure  Sleepy/obtunded  Low serum sodium  Cool extremities  Hypotension with ACE inhibitor  Renal dysfunction (one cause) Stevenson LW. Eur J Heart Fail. 1999;1:251 ADHF: Clinical Assessment

52. Risk Stratification of Patients with ADCHF SYS BP 115 n=24,933 SYS BP 115 n=7,147 6.41% n=5,102 15.28% n=2,048 21.94% n=620 12.42% n=1,425 5.49% n=4,099 2.14% n=20,834 BUN 43 N=32,324 2.68% n=25,122 8.98% n=7,202 Cr 2.75 n=2,045 Fonarow et al. 2003 %’s = mortality rates <> < <> > ><

53. The ESCAPE Trial  Tested safety and efficacy of PA catheter use in ADCHF  433 patients with Class IV symptoms  Randomized to usual care versus PA catheter- guided therapy  No difference in mortality or length of stay  However, patients felt better with the PA catheter Stevenson, LW. AHA 2004

54. Therapies for Acute Decompensated Heart Failure Yes R. Bourge, UAB Cardiology (adapted from L. Stevenson), Stevenson LW. Eur J Heart Failure 1999;1:251-257 No Warm and Dry PCW and CI normal Warm and Wet PCW elevated CI normal Cold and Wet PCW elevated CI decreased Cold and Dry PCW low/normal CI decreased Vasodilators Diuretics Inotropes Nl SVRHigh SVR Congestion at Rest Low Perfusion at Rest No Yes

55. Parenteral Therapies for Decompensated Heart Failure TreatmentLimitations Dobutamine  Heart rate, arrhythmias, Milrinone Nitroglycerin Tolerance, side effects Nitroprusside Difficult administration (titration), side effects  Heart rate, arrhythmias, hypotension MVO 2, ischemia, and tolerance

56. Intravenous Inotropic Agents for Decompensated Heart Failure OPTIME. Gheorghiade et al. ACC Meeting 2000 Late Breaking Trials Session Milrinone n=477 Control n=472 60 Day Follow-up Days until Discharge 48-hour infusion of milrinone (0.5mcg/kg/min) within 48 hours for worsening of CHF. Adverse Events Sustained Hypotension Acute MI Rehospitalized or Death Death 5.7 + 135.9 + 13 12.6%2.1% 10.7% 1.5% 3.2% 0.4% 35.3% 2.3% 35.0% 3.8% * * * P<0.001

57. * P<0.05 pooled nesiritide compared to nitroglycerin VMAC: PCWP Through 48 Hours Young JB et al. AHA Meeting 2000 Late Breaking Trials Session -11 -10 -9 -8 -7 -6 -5 -4 -3 -2 0 Time        NTGNesiritide  Mean Change (mm Hg) 3 h6 h9 h 12 h24 h36 h48 h

58. Dobutamine (n=141) Nes 0.015  g/kg/min (n=187) Cumulative Mortality Rate (%) Time from start of treatment (days) Nes 0.030  g/kg/min (n=179) Precedent: 6 Month Survival 0 5 10 15 20 25 30 35 0 306090120150180 Log - rank Test: Dobutamine vs nesiritide 0.015  g/kg/min p=0.041 Dobutamine vs nesiritide 0.030  g/kg/min p=0.445 Nes 0.015  g/kg/min vs nes 0.030  g/kg/min p=0.187 Elkayam U. et al, J. Cardiac Failure 2000;6 (Suppl 2):169

59. 0306090120150180 0 10 20 30 40 50 60 70 80 90 100 Time Observed from the Start of Treatment (days) NTG (n = 216) Nesiritide 0.01 µg/kg/min (n = 211) All Nesiritide (n = 273) Stratified Log - rank Test: NTG vs Nesiritide 0.01 µg/kg/min p=0.616 NTG vs All Nesiritide doses p=0.319 VMAC: Mortality Rates Cumulative Mortality Rate % No increase in ischemic events in the acute coronary syndrome patients. ( AMI Events 3 NTG, 1 nesiritide) Young JB et al. AHA Meeting 2000 Late Breaking Trials Session

60. Scios. Natrecor label update. Revised April 25, 2005. Available at: http://www.natrecor.com/pdf/natrecor_pi.pdf. Pooled mortality outcomes, extracted from revised nesiritide labeling* End point, number of studies pooled Nesiritide (%) Control (%) 30-day mortality, 7 studies (n=1717) 5.34.3 180-day mortality, 4 studies (n=1167) 21.721.5 *Mortality hazard-ratio confidence intervals for nesiritide relative to control therapy include 1.00 for both pooled analyses as well as each individual study.

61. ADHF: Summary  There are currently NO long-term mortality data on ANY therapies currently in use  Risk stratification may be useful in guiding therapy  Best therapy may be to prevent decompensation Adherence to guidelines for the treatment of chronic HF Patient support network to increase compliance Adequate treatment of signs/symptoms of HF during hosp

62. Diuretics Digoxin ACE-I  -Blocker ARB AldoRB BNP Bi-V Pacing ICD LVAD/Transplant...The Forest for the Trees