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Current Therapies for the Management of Chronic and Acute Heart Failure

This article provides an overview of the current therapies available for the management of chronic and acute heart failure. It discusses the prevalence, incidence, morbidity, and mortality of heart failure, as well as the cost burden associated with the disease. The article also highlights the etiology and pathophysiology of heart failure, and explores the role of neurohormonal targets in its management.

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Current Therapies for the Management of Chronic and Acute Heart Failure

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  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. 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% 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.

  3. Cost of Heart Failure • $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.

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

  5. The New Classification of Heart Failure Hunt SA et al. J Am Coll Cardiol. 2001;38:2101–2113.

  6. Symptom Relief is Not Sufficient 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

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

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

  9. Neurohormonal Targets in Heart Failure Angiotensinogen ACEInhibitors Angiotensin I SNS Activation AT II AT1 Receptors Epinephrine Norepinephrine Target Cells

  10. ACE Inhibitors in Heart Failure • ~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.

  11. 1.0 SOLVD-Prevention 0.8 Survival SOLVD-Treatment PROMISE DIG 0.6 V-HeFT CONSENSUS 0.5 PRAISE 0 0 1 2 3 4 5 Year Mortality in Patients Receiving ACE Inhibitors ACE inhibitor arms of CONSENSUS, V-HeFT, and SOLVD trials. Placebo arms of PRAISE, PROMISE, and DIG trials (all receiving ACE inhibitors).

  12. Neurohormonal Targets in Heart Failure Angiotensinogen ACEInhibitors b-Blockers Angiotensin I SNS Activation AT II AT1 Receptors Epinephrine Norepinephrine b-Blockers Target Cells

  13. CIBIS-I: 1.9 yearsplacebo 67/321 (20%); bisoprolol 53/320 (16%) P=.22 CIBIS-II: 1.3 yearsplacebo 228/1320 (17%); bisoprolol 156/1327 (12%) P=.0001 MERIT-HF: 12 monthsplacebo 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 Effect of b-Blockade on All-Cause Mortality 0 0.25 0.5 0.75 1 1.25 1.5 1.75 2 Relative risk and 95% confidence intervals

  14. COPERNICUS All-cause mortality: 35% decreased risk 100 90 Carvedilol (n=1156) 80 %Survival 70 Placebo (n=1133) 60 P=0.00014 50 0 4 8 12 16 20 24 28 Months .

  15. The CHF Trials in Perspective: Patients Needed to Treat for One Year to Save One Life HF StageTrial# 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 ACEInhibitors Angiotensin I SNS Activation AT II ARBs AT1 Receptors Epinephrine Norepinephrine Target Cells

  17. CHARM-Added: Primary Endpoint 50 Placebo 538 (42.3%) 40 483 (37.9%) 15% risk reduction 30 Candesartan CV death or HF hospitalization (%) 20 HR 0.85 (95% CI 0.75-0.96), P=0.011 Adjusted HR 0.85, P=0.010 10 0 0 1 2 3 3.5 Time (years) Number at risk: Candesartan Placebo 1276 1272 1176 1136 1063 1013 948 906 457 422 HF, heart failure; HR, hazard ratio; CI, confidence interval. McMurray JJV et al. Lancet. 2003;362:767-771.

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

  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-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 ACEInhibitors Angiotensin I SNS Activation AT II AT1 Receptors Epinephrine Norepinephrine Aldosterone Receptor Blockers Target Cells

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

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

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

  24. MADIT II: Study Design 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) Implantable defibrillator (n=742) All Cause Mortality - Average follow-up of 20 months Stopped early by Data Safety Monitoring Board

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

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

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

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

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

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

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

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

  45. Heart Failure Hospitalizations The number of heart failure hospitalizations is increasing in both men and women AHA, 1998 Heart and Statistical Update NCHS, National Center for Health Statistics 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% Approximately 80% of the ED visits for CHF result in hospitalizations Repeat Visit 79% Rates of Hospital Readmission 2% within 2 days 20% within 1 month 50% within 6 months Cardiology Roundtable 1998

  48. Utilization of HF Medications Patients Treated (%) *Excludes patients with documented contraindications 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

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

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

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