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  1. 1. Keynote Presentation Optimal Medical Management and Device Therapy for Chronic Heart Failure Dallas, Texas December 12, 2008 7:30 AM – 8:30 AM
  2. 2. Session 1: Keynote: Optimal Medical Management and Device Therapy for Chronic Heart Failure Learning Objectives • Discuss clinical data and guideline recommendations for heart failure therapies that offer advantages in terms of morbidity and mortality for specific patient populations. • Compare emerging therapies that target heart failure. Faculty Gregg C. Fonarow, MD Eliot Corday Professor of Cardiovascular Medicine and Science Director, Ahmanson-UCLA Cardiomyopathy Center Codirector, University of California at Los Angeles Preventative Cardiology Program Associate Chief, UCLA Division of Cardiology UCLA Medical Center Dr Fonarow serves as the director of the Ahmanson-UCLA Cardiomyopathy Center and is the director of the Cardiology Fellowship Program at the University of California at Los Angeles. His research interests center on heart failure management and implementing treatment algorithms to improve clinical outcome. Dr Fonarow has published a number of research studies and clinical trials in heart failure management. New therapies and management strategies for advanced heart failure and research into the pathophysiology of this disease are conducted at UCLA under his direction. He wrote the UCLA Clinical Practice Guidelines for heart failure, acute myocardial infarction, atherosclerosis prevention and treatment, and unstable angina. He has also developed and successfully implemented a comprehensive atherosclerosis treatment program at the UCLA Medical Center (Cardiac Hospitalization Atherosclerosis Management Program: CHAMP). Faculty Financial Disclosure Statement The presenting faculty report the following: Dr Fonarow is a member of the speakers bureau for GlaxoSmithKline; Pfizer Inc.; and Merck & Co., Inc. He is a consultant for Bristol-Myers Squibb/sanofi-aventis. He receives research grants from Guidant and Medtronic. Drug and Device Lists Generic Trade Devices captopril Capoten DDDR dual-chamber rate-adaptive pacemaker carvedilol Coreg VVI single-chamber ventricular demand pacer enalapril Vasotec OptiVol Fluid Status Monitoring — eplerenone Inspra automatic intrathoracic fluid status monitoring metoprolol Toprol-XL ramipril Altace spironolactone Aldactone Suggested Reading List Abraham WT, Fisher WG, Smith AL, et al. Cardiac resynchronization in chronic heart failure. N Engl J Med. 2002;346(24):1845-1853. Abraham WT, Young JB, Leon AR, et al. Effects of cardiac resynchronization on disease progression in patients with left ventricular systolic dysfunction, an indication for an implantable cardioverter-defibrillator, and mildly symptomatic chronic heart failure. Circulation. 2004;110(18):2864-2868. Bleeker GB, Schalij MJ, Holman ER, et al. Cardiac resynchronization therapy in patients with systolic left ventricular dysfunction and symptoms of mild heart failure secondary to ischemic or nonischemic cardiomyopathy. Am J Cardiol. 2006;98(2):230-235. Session 1
  3. 3. Bradley DJ, Bradley EA, Baughman KL, et al. Cardiac resynchronization and death from progressive heart failure: a meta-analysis of randomized controlled trials. JAMA. 2003;289(6):730-740. Bristow MR, Saxon LA, Boehmer J, et al. Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) investigators. Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure. N Engl J Med. 2004;350(21):2140-2150. Cazeau S, Leclercq C, Lavergne T, et al. Effects of multisite biventricular pacing in patients with heart failure and intraventricular conduction delay. N Engl J Med. 2001;344(12):873-880. Cleland JG, Daubert JC, Erdmann E, et al; the Cardiac Resynchronization-Heart Failure (CARE-HF) Study Investigators. The effect of cardiac resynchronization on morbidity and mortality in heart failure. N Engl J Med. 2005;352(15):1539-1549. Hunt SA, Abraham WT, Chin MH, et al; American College of Cardiology; American Heart Association Task Force on Practice Guidelines; American College of Chest Physicians; International Society for Heart and Lung Transplantation; Heart Rhythm Society. ACC/AHA 2005 Guideline Update for the Diagnosis and Management of Chronic Heart Failure in the Adult: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure): developed in collaboration with the American College of Chest Physicians and the International Society for Heart and Lung Transplantation: endorsed by the Heart Rhythm Society. Circulation. 2005;112(12):e154-235. Spragg DD, Leclercq C, Loghmani M, et al. Regional alterations in protein expression in the dyssynchronous failing heart. Circulation. 2003;108(8):929-932. Session 1
  4. 4. Notes ___________________________________________________________________________________________________ ___________________________________________________________________________________________________ ___________________________________________________________________________________________________ ___________________________________________________________________________________________________ ___________________________________________________________________________________________________ ___________________________________________________________________________________________________ ___________________________________________________________________________________________________ ___________________________________________________________________________________________________ ___________________________________________________________________________________________________ ___________________________________________________________________________________________________ ___________________________________________________________________________________________________ ___________________________________________________________________________________________________ ___________________________________________________________________________________________________ ___________________________________________________________________________________________________ ___________________________________________________________________________________________________ ___________________________________________________________________________________________________ ___________________________________________________________________________________________________ ___________________________________________________________________________________________________ ___________________________________________________________________________________________________ ___________________________________________________________________________________________________ ___________________________________________________________________________________________________ ___________________________________________________________________________________________________ ___________________________________________________________________________________________________ ___________________________________________________________________________________________________ ___________________________________________________________________________________________________ ___________________________________________________________________________________________________ ___________________________________________________________________________________________________ ___________________________________________________________________________________________________ ___________________________________________________________________________________________________ ® TM
  5. 5. Presenter Disclosure Information Optimal Medical Management “Heart Failure Care” and Device Therapy for I will discuss off label use of medications or devices Chronic Heart Failure DISCLOSURE INFORMATION: Gregg C. Fonarow, MD The following relationships exist related to this presentation: Eliot Corday Professor of Cardiovascular Medicine and Science Director, Ahmanson-UCLA Cardiomyopathy Center Gregg C. Fonarow, MD, FACC – GlaxoSmithKline, Co-director, UCLA Preventative Cardiology Program Merck, AstraZeneca, Bristol Myers Squibb, Sanofi, Associate Chief, UCLA Division of Cardiology Pfizer, Novartis, Scios, Medtronic, and Guidant: Research, Consultant, Speaker Heart Failure Background Prognosis with Heart Failure Population Hospital 1 Overall 100 Group Prevalence Incidence Mortality Discharges Cost 5-year mortality 50% 90 80 Total 50% at 5 $33.2 Women 5,200,000 550,000 1,100,000 Hospitalized Patients 70 population years billion Men rvival % 1-year mortality: 60 50 Heart f il H t failure (HF) i a major public h lth problem resulting i is j bli health bl lti in Sur Mild to Moderate 40 substantial morbidity and mortality Symptoms 30 20 10-20% Major cost-driver of HF is high incidence of hospitalizations1,2 10 0 Severe Symptoms Despite treatment advances large number of eligible patients are 0 1 2 3 4 5 6 7 8 9 10 40-60% not receiving optimal care Years 1American Heart Association. 2007 Heart and Stroke Statistical Update. Dallas, Tex: American Heart Association; 2007. 2Hunt Survival after the onset of congestive heart failure in Framingham Heart Study subjects AHA, 1998 Heart and Statistical Update SA et al. ACC/AHA guidelines for the evaluation and management of chronic heart failure in the adult. 2005. Ho Circulation 1993;88:107-115 Statistics NCHS, National Center for Health Outcomes During and After HF National Trends in Outcomes Among Hospitalization Patients Hospitalized with HF Trends in Crude and Adjusted Mortality Rates In-hospital Year N Crude Mortality (%) Adjusted Mortality (OR, 95% CI) – Length of stay (mean) 6.2 days 30-day 1-year 30-day 1-year – Mortality rate 4.1% 1992 483,560 11.0 32.5 NA NA Hospital readmissions p 1993 509,549 , 10.9 33.9 1.00 (referent) ( ) 1.00 (referent) ( ) – 20% at 30 days 1994 509,245 10.6 31.7 0.99 (0.98-1.00) 0.91 (0.90-0.92) – 50% at 6 months 1995 510,529 10.5 31.5 1.00 (0.98-1.01) 0.91 (0.90-0.92) 1996 505,661 10.3 31.4 0.99 (0.97-1.00) 0.91 (0.90-0.92) Longer-term mortality 1997 507,986 10.2 31.7 0.98 (0.97-0.99) 0.92 (0.92-0.93) – 11.6% at 30 days 1998 436,257 10.2 31.8 0.99 (0.97-1.00) 0.93 (0.92-0.93) – 33.1% at 12 months 1999 494,733 10.3 31.7 1.01 (1.00-1.02) 0.93 (0.92-0.94) Fonarow GC et al. J Card Failure. 2003;9:S79 National sample of 3,957,520 Medicare beneficiaries >65 who were hospitalized with HF between 1992 and 1999 Jong P et al. Arch Intern Med. 2002;162:1689 Kosiborod AJM 2006;119:e1-e7. 1
  6. 6. Natural History of Heart Failure Heart Failure Pathophysiology Myocardial injury Fall in LV performance Mechanism of Death 100% Sudden Death 40% Worsened HF 40% Activation of RAAS, SNS, ET, Progression Other 20% and others vival Surv ANP Peripheral vasoconstriction Myocardial toxicity BNP Hemodynamic alterations Annual Mortality 10% 10-20% 20 - 30 % 30 - 80% Remodeling and 0% progressive Asymptomatic Mild Moderate Severe worsening of Left Ventricular Dysfunction and Symptoms LV function Heart failure symptoms Morbidity and mortality Fonarow GC. Rev Cardiovasc Med..2001;2:7–12. Pathophysiologic Effects of Angiotensin II ACC/AHA HF Guidelines: and Epinephrine/Norepinephrine Management of Heart Failure (Stage C) Life Prolonging Therapy ACE inhibitors (Class I, evidence A) all patients without contraindications or intolerance Cardiac Myocyte C di M Fibroblast Fib bl Peripheral A P i h l Artery Coronary A C Artery β-Blockers β Blockers (Class I evidence A) all patients without I, Hypertrophy Hyperplasia Vasoconstriction Endothelial Dysfunction Vasoconstriction Endothelial Dysfunction contraindications or intolerance Apoptosis Collagen Synthesis Cell Sliding Fibrosis Hypertrophy Atherosclerosis Aldosterone antagonists (Class I, evidence B) all Decreased Compliance Restenosis Increased Wall Stress Thrombosis patients with moderately severe or severe symptoms Increased O2 Consumption Impaired Relaxation without contraindications or intolerance, when close monitoring can be assured Hunt SA et al. J Am Coll Cardiol. 2005 Effect of ACE Inhibitors on Mortality Effect of ACE Inhibitors on Mortality and Hospitalizations in Patients with HF and Hospitalizations in Patients with HF Subgroup ACE Inhibitor Controls OR Male 22.9 33.2 0.63 10 Female 20.2 29.5 0.78 < 60 22.2 31.1 0.71 0 % Risk of Mortality > 60 24.9 36.9 0.79 -10 Class I 17.5 24.8 0.69 Class II 19.5 28.4 0.68 M -20 -23 Class III 22.1 43.2 0.58 -30 -31 Class IV 46.2 59.2 0.69 -35 Ischemic 28.3 40.1 0.63 -40 Nonischemic 23.2 29 0.72 -50 LVEF >25 23.6 29.6 0.85 OR 0.77 (0.67-0.88) p<0.001 LVEF < 25 33.7 48 0.53 -60 Total Mortality Death or Hospitalization CHF Hospitalization All Patients 22.4 32.6 0.65 Total Mortality or Hospitalization for Congestive Heart Failure 32 Trials of ACEI in Heart Failure ACEI (n = 3870) Placebo (n = 3235) 32 Trials of ACEI in Heart Failure ACEI (n = 3870) Placebo (n = 3235) Collaborative Group on ACE Inhibitor Trails JAMA 1995;273:1450-1456 Collaborative Group on ACE Inhibitor Trails JAMA 1995;273:1450-1456 2
  7. 7. Survival Rates in Patients Receiving ACE ValHeFT: ARB added to Standard Inhibitors Across NYHA Classes HF Care Including ACEI 1.0 Mortality 100 SOLVD-Prevention 95 Valsartan vival (%) 0.8 Survival 90 Placebo SOLVD-Treatment SOLVD T t t Probability of Surv PROMISE 85 0.6 DIG 80 CONSENSUS V-HeFT 0.5 PRAISE 75 P=.80 70 0 0 1 2 3 4 5 0 0 3 6 9 12 15 18 21 24 27 Year Months since Randomization ACE inhibitor arms of CONSENSUS, V-HeFT, and SOLVD trials. Placebo arms of PRAISE, PROMISE, and DIG trials (all receiving ACE inhibitors). Cohn J et al. N Engl J Med. 2001;345:1667–1675. CHARM-Alternative ACEI/ARB in Heart Failure Primary outcome of CV death or CHF hospitalization Indicated for all patients with asymptomatic LV 50 dysfunction and for Class I to IV heart failure. 406 (40.0%) pitalization (%) (Contraindications: hyperkalemia, angioedema, Proportion With CV Death Placebo 40 334 (33.0%) pregnancy) 30 Candesartan Titrate to target doses (example enalapril 10 mg bid, W or CHF Hosp 20 lisinopril 20 qd, ramipril 10 mg qd, benazepril 40 qd) Monitor serum potassium and renal function. Advise 10 HR 0.77 (95% CI 0.67-0.89), P=.0004 checking chemistry panel 1-2 weeks after first dose. Adjusted HR 0.70, P<.0001 0 If ACE inhibitor not tolerated or side effects, 0 1 2 3 3.5 angiotensin receptor antagonist recommended. Number at risk Years Candesartan 1,013 929 831 434 122 Placebo 1,015 887 798 427 126 Hunt SA, et al. ACC/AHA 2005 Practice Guidelines Granger CB, et al. Lancet. 2003;362:772-776. RALES: Aldosterone Antagonist Reduces Effects of Aldosterone All-Cause Mortality in Chronic HF 1.00 Spironolactone (25 mg) + standard care (n = 822) 0.95 Placebo + standard care (n = 841) Probability of Survival (%) 0.90 0.85 0.80 HR = 0.70 (95% CI, 0.60 to 0.82) 0.75 0.70 o Cardiac Myocyte C di M Fibroblast Fib bl Peripheral A P i h l Artery Kidney Kid 0.65 Hypertrophy Hyperplasia Vasoconstriction Potassium Loss 0.60 Norepinephrine Release Collagen Synthesis Endothelial Dysfunction Sodium Retention 0.55 Hypertrophy 0.50 P<.001 Fibrosis Decreased Compliance 0.45 0 0 3 6 9 12 15 18 21 24 27 30 33 36 Months HR = hazard ratio; RR = risk reduction. *Ejection fraction ≤35% Class III or IV symptoms at some point in prior 2 months. Pitt B et al. N Engl J Med. 1999;341:709-717. 3
  8. 8. Eplerenone Post-AMI Heart Failure Post- Efficacy and Survival Study (EPHESUS) Post AMI, LVEF < 40, Rales or S3 Standard post-AMI Care ASA, BB, ACEI, statin, revascularization Randomization n=6644 Eplerenone Initiation Matching 25 qd, 50 mg at 4wks Placebo Follow-up Pitt NEJM 2003;348:1309-21 EPHESUS Co-Primary Endpoint: Early Benefits of Eplerenone When Total Mortality Added to Standard Post MI Patient Care 30 Days 22 Eplerenone + standard care (16.7%) 20 (n = 3319) 10 Cardiovascular Sudden Cardiac Heart Failure All Cause Cumulative Incidence (%) 18 (14.4%) 5 Mortality Placebo + standard care Mortality Death Hospitalization 16 (n = 3313) 0 14 -5 Relative Risk (%) 12 -10 0 I 10 -15 8 6 -20 -18 HR = 0.85 (95% CI, 0.75 to 0.96) 4 -25 P = .008 2 -30 0 -35 -31 -32 0 3 6 9 12 15 18 21 24 27 -40 -37 Months Since Randomization -45 HR = hazard ratio. -50 Adapted from Pitt B et al. N Engl J Med. 2003;348:1309-1321. Pitt et al. N Engl J Med. 2003;348:1309-1321. Aldosterone Antagonists in Heart Failure Effect of Digoxin on Mortality in Heart Failure Failure: The Digitalis Investigation Group Indicated for patients with moderately severe or severe HF 50 due to LVD (LVEF < 0.40). (Contraindications: hyperkalemia, Mortality From Any Cause (%) Cr > 2.5 in men and > 2.0 in women) CV Mortality Relative Risk 0.99 40 95% CI 0.91–1.07 Placebo 0% Spironolactone 12.5 mg PO qd starting dose (or 6.25 mg in P=.80 Digoxin higher risk patients) or Eplerenone 25 mg qd. Decrease 30 potassium supplementation and loop diuretic dose at time of HF Hospitalizations 28% initiation. initiation 20 Critical to very closely monitor serum potassium and renal Total Hospitalizations 10 function. Advise checking chemistry panel at 48 hours, 1 6% week, and 4 weeks. 0 All-cause mortality rates: Placebo 35.1%; Digoxin 34.8% 0 4 8 12 16 20 24 28 32 36 40 44 48 52 Advance Spironolactone dose at 4 weeks to 25 mg PO qd Number of patients at risk: Months or Eplerenone 50 mg which is the target dose. Avoid higher Placebo Digoxin 3,403 3,397 3,239 3,269 3,105 2,976 3,144 3,019 2,868 2,758 2,652 2,551 2,882 2,759 2,644 2,531 2,205 2,184 1,881 1,506 1,168 1,840 1,475 1,156 734 737 339 335 doses due to risk of hyperkalemia. DIG (Digitalis Investigation Group): 6,800 patients with LVEF <45% randomized to digoxin (n=3,403) or placebo (n=3,397) in addition to therapy with diuretics and ACEI followed for 37 months. Hunt SA et al. J Am Coll Cardiol. 2005 The DIGITALIS Investigation Group. N Engl J Med. 1997;336:525–532. 4
  9. 9. The Use of Beta Adrenergic Blocking Effect of Carvedilol in Heart Failure US Heart Failure Trials Program Agents in Heart Failure Survival Proportion 15 100 65% LVEF % change 10 90 5 80 P<0.001 Carvedilol Placebo 0 70 -5 60 -10 50 0 6 12 18 24 0 50 100 150 200 250 300 350 400 Time (weeks) Follow-up (days) Initial hemodynamic deterioration followed by reverse remodeling (decrease in EDV and 1094 Class II-IV CHF pts on triple therapy (ACEI, digoxin, diuretics) ESV) with improved ventricular function over time (increased LVEF) Carvedilol 6.25 bid test 2 weeks, then 12.5 bid, then 25 bid vs placebo Packer NEJM 1996;334:1349-55 Effect of Metoprolol CR/XL in Heart Failure Major Trials of β-Blockade MERIT-HF in Heart Failure Survival Proportion 100 Patients Follow-up NYHA LVEF Effects on RR 0.66 (0.53-0.81) (n) (yrs) Class (%) Outcomes P=0.0062 95 CIBIS 641 1.9 II-III < 35 All-cause mortality: Metoprolol CR/XL ↓ 22% NS 90 Placebo CIBIS-II 2647 1.3 II-III < 35 y All-cause mortality: ↓ 34% (P<.0001) 85 MDC 383 1 II-III < 40 Death or need for transplant: ↓ 30%, P<0.05 MERIT-HF 3991 1 II-III < 40 All-cause mortality: 80 ↓ 34% (P=.0062) 0 3 6 9 12 15 18 21 US Carvedilol 1094 7.5 II-III < 35 All-cause mortality*: Follow-up (months) Trials months ↓ 65% (P=.0001) COPERNICUS 2289 10.5 IV < 25 months 3991 pts with CHF Class II-IV, ave age 64 and LVEF 0.28 Randomized to Metoprolol CR/XL 12.5 mg or 25 mg PO qd, target dose 200 mg qd Lancet 1999;353:2001-07 Effect of Carvedilol in Severe Heart Failure Effect of Carvedilol in Severe Heart Failure COPERNICUS Effect of Carvedilol on Mortality Survival Proportion 100 Annual placebo mortality n=1133 HR 0.65 (0.52-0.81) rate (per patient-year) 95 n=1156 P=0.0001 90 All Carvedilol 19.7% 85 Placebo Pl b patients 80 75 28.5% Recent or recurrent 70 decompensation 0 2 4 6 8 10 12 Follow-up (months) 0 0.25 0.5 0.75 1.0 1.25 2289 Class IV CHF pts, LVEF < 0.25, (not on inotropes x 4days) ave age 63, LVEF 0.20 Carvedilol 3.125 bid, q 2 wks titration. 75% to target. withdrawl 16% placebo, 13% carvedilol Favors treatment Favors placebo Packer NEJM 2001;344:1651-8 5
  10. 10. Safety of Initiating Carvedilol in Early Benefits and Early Safety of Patients with Severe Heart Failure Carvedilol in Severe HF: COPERNICUS Permanent Withdrawals Early Mortality Reduction Lower Risk for Worsening CHF 40 3 Risk Reduction P = .02 ↓25% (−35%–59%) 15 30 Placebo Patients With Eve (%) nently 2 (n=1,133) 11.4 Placebo Placebo ent % Patients Perman 10 Carvedilol Withdrawn 8.8 20 6.4 1 Carvedilol 5.1 Carvedilol (n=1,156) 5 10 0 Event rates: Placebo 2.3%; Carvedilol 1.7% 0 0 0 2 4 6 8 All Patients Highest-Risk Subgroup 0 3 6 9 12 15 18 21 Weeks After Randomization (n=1,133) (n=1,156) (n=316) (n=308) Months Packer NEJM 2001;344:1651-8 Packer M. N Engl J Med. 2001;344:1651–1658. Krum H. JAMA. 2003;289:712–718. Effects of Sympathetic Not All β-Blockers Reduce Mortality Activation in Heart Failure in HF BEST1 SENIORS2 ↑ CNS sympathetic outflow Risk Reduction Risk Reduction 100 ↓ 10% 100 ↓ 12% (−2%, 22%) 90 (-8%, 29%) 80 rvival (%) ↑ Cardiac sympathetic activity ↑ Sympathetic activity to kidneys vival (%) 80 + blood vessels 60 70 Surv P 214 Sur 40 P=.105 P=.214 60 Nebivolol (n=1,067) β1- β2- α1 - α 1- β1- Activation 20 Bucindolol (n=1,354) 50 Placebo (n=1,061) receptors receptors receptors of RAS Placebo (n=1,354) 0 40 0 6 12 18 24 30 36 0 3 6 9 12 15 18 21 24 Follow-Up (months) Time (months) Myocyte death Vasoconstriction 2,708 patients (CHF Class III–IV, average age 60, LVEF .23) 2,128 patients (CHF Class II–III, average age 76, average LVEF .36 with approximately 65% of patients with LVEF ≤.35) randomized to Increased arrhythmias Sodium retention randomized to placebo or bucindolol (3 mg titrated to 50 mg po BID). Number of events: bucindolol 411 (30%); placebo 449 (33%). Placebo or nebivolol (1.25 mg titrated to 10 mg po QD). All-cause mortality was a secondary endpoint. Number of events: nebivolol 169 (15.8%); placebo 192 (18.1%). Disease progression 1BEST Investigators. N Engl J Med. 2001;344:1659-1667. 2Flather, M et al. Eur Heart J. 2005;26:215-225. Bristow MR. Circulation. 2000;101:558-569. β-Blockers Differ in Their Long-Term COMET: Effect Carvedilol vs Metoprolol Effects on Mortality in HF Tartrate on Mortality in HF Metoprolol Risk Reduction Bisoprolol1 Beneficial 40 Tartrate ↓ 17% Bucindolol2 No effect 30 (7%, 26%) P=.0017 Carvedilol Carvedilol3-5 Beneficial Mortalit (%) Metoprolol tartrate6 Not well studied 20 Extrapolation from the survival curves p ty suggested that carvedilol extended median Metoprolol succinate7 Beneficial 10 survival by 1.4 years as compared with metoprolol tartrate † Nebivolol8 No effect Mortality rates: metoprolol 40%; Carvedilol 34%. Xamoterol9 Harmful 0 0 1 2 3 4 5 Time (years) 1CIBIS II Investigators and Committees. Lancet. 1999;353:9-13. 2The BEST Investigators. N Engl J Med 2001; 344:1659-1667. 3Colucci WS, et al. Circulation 1996;94:2800-2806. 4Packer M, et al. N Engl J Med 2001;344:1651-1658. 5The Metoprolol tartrate mean dose: 85 mg QD; Carvedilol mean dose: 42 mg QD. CAPRICORN Investigators. Lancet. 2001;357:1385-1390. 6Waagstein F, et al. Lancet. 1993;342:1441-1446. 7MERIT-HF Study Group. COMET did not evaluate metoprolol succinate, the agent used in the MERIT-HF Trial Lancet. 1999;353:2001-2007. 8SENIORS Study Group. Eur Heart J. 2005; 26:215-225. 9The Xamoterol in Severe heart Failure Study Group. Lancet. 1990;336:1-6. Poole-Wilson PA, et al. Lancet. 2003;362:7-13. 6
  11. 11. Beta Blocker Therapy in Heart Failure Neurohormonal Activation as the Indicated for all patients with asymptomatic LVD Therapeutic Target in Heart Failure dysfunction and for Class I to IV Heart Failure with LVEF < Therapies with Demonstrated Benefit in Clinical Trials 0.40 Contraindications: cardiogenic shock, severe reactive airway disease, 2/3rd degree HB Use U one th 3 evidence-based beta blockers in HF: eg the id b d b t bl k i HF carvedilol, metroprolol succinate, bisoprolol Sympathetic Nervous System Start at very low HF doses and up-titrate to target doses at Beta Adrenergic Blockers (carvedilol) two week intervals, or highest dose short of target dose that Renin Angiotensin Aldosterone System is well tolerated Angiotensin Converting Enzyme Inhibitors ( Angiotensin II Receptor Antagonists) Monitor HR and BP Aldosterone Antagonists Hunt SA et al. J Am Coll Cardiol. 2005. AHeFT: Trial Summary Device Therapy for Heart Failure 100 43% Decrease in Mortality • Cardiac resynchronization therapy (CRT) • Implantable cardioverter-defibrillators (ICD) Fixed-dose HYD/ISDN 95 • Ventricular assist devices Surviva (%) al • B id to transplant Bridge t t l t 90 • Destination therapy Placebo Hazard ratio=0.57 • Totally implanted artificial hearts P=.01 85 • Cardiac reshaping devices 0 100 200 300 400 500 600 Days Since Baseline Visit Date • Ultrafiltration devices 1050 African Americans with Class III to IV HF, LVEF 24%, on ACEI, BB, AA Adapted from Taylor AL, et al. N Engl J Med. 2004;351:2052. Cardiac Resynchronization Cardiac Resynchronization Therapy: Therapy for Heart Failure Weight of Evidence >4,000 patients evaluated in randomized controlled In patients with heart failure 27 to 53% of patients trials have IVCDs (RBBB, LBBB, IVCD) Consistent improvement in quality of life, functional Abnormal conduction contributes to abnormal status, and exercise capacity ventricular activation/contraction and subsequent ti l ti ti / t ti d b t Strong evidence of reverse remodeling dysynchrony between the RV and LV ↓ LV volumes and dimensions – Reduced systolic performance ↑ LVEF – Mechanical inefficiency ↓ Mitral regurgitation – Worsened prognosis Reduction in HF and all-cause morbidity and mortality Aarronson Circulation 1997;96. Grines Circulation 1989;79 Xiao Int J Cardiol 1996;53 Abraham WT. Circulation. 2003;108:2596-2603. 7

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