Evidence that supports the current management of Chronic Systolic Heart Failure.

1. Evidence-based medicine: The CHF trials Moises Auron MD Department of Hospital Medicine Cleveland Clinic Foundation September 21, 2007.

4. Cardiorenal Model of HF (1940-1960) Am J Cardiol 1993; 71: 3C-11C

6. Cardiocirculatory Model of HF (1960 – 1990) Am J Cardiol 1993; 71: 3C-11C

9. VHeFT-I (Vasodilator-Heart Failure Trial) African-american patients White patients NEJM. 1986 Jun 12;314(24):1547-52. J Card Fail. 1999; 5(3):178-87 Hydralazine (300 mg) + Isosorbide dinitrate (160 mg) vs. Prazosin (20 mg) vs. Placebo N = 642 (male) – on Digoxin and diuretics

12. From: Shrier, R. U. Colorado. 2004

13. Neurohormonal Model of Heart Failure Shah M et al. Rev Cardiovasc Med. 2001; 2 (suppl 2): S2–S6.

14. Renin – Angiotensin – Aldosterone System Modified from Swedberg K. ESC –Heart Failure Lisbon 2005.

16. Alterations in Myocyte Morphology with Ventricular Dysfunction Katz, AM. Heart Failure. Lippincott Williams & Wilkins, 2000 NEJM. 2003; 348: 2007-18 .

17. Cardiac hypertrophy From: Tornoci L. Semmelweis U.

18. CONSENSUS: Cooperative North Scandinavian Enalapril Survival Study NEJM 1987; 316: 1429–35. N = 253 NYHA IV on diuretics and digoxin Enalapril 20 mg BID vs Placebo Probability of death

19. CONSENSUS: Cooperative North Scandinavian Enalapril Survival Study NEJM 1987; 316: 1429–35.

20. ACEI Trials Adapted from Yan AT, et al. Ann Intern Med. 2005; 142: 132-145

24. VHeFT-II (Vasodilator-Heart Failure Trial) J Card Fail. 1999; 5(3):178-87

25. Catecholamines in Heart Failure Am J Cardiol. 1984; 54: 783-6

26. Relationship between plasma NE and survival in Heart Failure NEJM. 1984: 311: 819-823.

30. MERIT-HF (Metoprolol CR/XL Randomized Intervention Trial in CHF). Lancet 1999; 353 (9169):2001-7. 34% P=0.0062 N = 3991 NYHA II-IV

31. MERIT-HF (Metoprolol CR/XL Randomized Intervention Trial in CHF). Lancet 1999; 353 (9169):2001-7.

34. COPERNICUS (Carvedilol Prospective Randomized Cumulative Survival) NEJM 2001; 344(22): 1651-8. 35% (P = 0.0014) N = 2289 NYHA III-IV Carvedilol 25 mg BID vs. Placebo

35. Beta-Blockers: Trials Adapted from Yan AT, et al. Ann Intern Med. 2005; 142: 132-145 No difference (P= 0.16) Benefit in non-black patients All cause mortality Bucindolol 50 – 100 mg BID vs. placebo BEST (24 mos) Absolute risk ↓ 6% favor carvedilol (P= 0.0017) All-cause mortality Carvedilol 25 mg BID vs. Metoprolol tartrate 50 mg BID COMET (58 mos) Early termination. ↓ in mortality rate 38% (P < 0.001) All cause mortality, exercise tolerance, QOL. Carvedilol 25 – 50 mg BID vs. placebo US Carvedilol (6 mos) ↓ in overall mortality 35% (P = 0.0014). Not worsening HF when initiating Rx. All-cause mortality Carvedilol 25 mg BID vs. placebo COPERNICUS (10.4 mos) Early termination; ↓ in mortality 32% (P< 0.001) All-cause mortality Bisoprolol 10 mg/d vs. placebo CIBIS II (16 mos) Overall ↓ in mortality 34% (P = 0.0062) All-cause mortality Metoprolol succinate 200 mg Qday vs. placebo MERIT (12 mos)

37. COMET (Carvedilol or Metoprolol European Trial) Lancet 2003; 362(9377):7-13. 6% P= 0.017 Carvedilol 25 mg BID vs. Metoprolol tartrate 50 mg BID N = 3029 NYHA II-IV

39. Treatment Strategies Amer. J. Cardiol. 1993;71:3C-11C

41. Neurohormones in HF: Aldosterone NEJM. 1999; 341(8): 577-585. Int J Clin Pract. 2006 Jul;60(7):835-46. NEJM. 2001 Dec; 345(23): 1689-1697.

46. Angiotensin II Receptor Blockage: Trials Adapted from Yan AT, et al. Ann Intern Med. 2005; 142: 132-145 Absolute risk ↓ 7% (P<0.001) Trend toward lower all-cause mortality (P= 0.11) CV death or hospitalization for heart failure Candesartan 32 mg/d vs. placebo N = 2028 NYHA II-IV EF < 40% Intolerance to ACEI CHARM – Alternative (33.7 mos) Absolute risk ↓ 4% (P=0.011) Trend toward lower all-cause mortality (P= 0.086) CV death or hospitalization for heart failure Candesartan 32 mg/d vs. placebo N = 2548 NYHA II-IV EF < 40% On ACEI CHARM-Added (41 mos) Similar mortality (P > 0.2) Absolute risk ↓3.3% (P<0.002) in composite end-point. (Decreased admissions) ↑ LVID ↓EF  ↑ Benefit All-cause mortality; mortality or cardiac arrest or hospitalization for HF Valsartan 160 mg BID vs. Placebo N = 5010 NYHA II-IV EF < 40%; LV dilatation Val-HeFT (23 mos) No superiority of one agent vs. other (P = 0.16) All-cause mortality Losartan 50 mg/d vs. Captopril 50 mg TID. N = 3152 Age > 60 y/o NYHA II-IV EF < 40% ELITE II (18.5 mos)

49. Vasodilators in Heart Failure: Hydralazine and Isosorbide NEJM. 2004; 351(20): 2112-2114

52. Summary of Major Therapeutic Options for Systolic Heart Failure 2005 ACC/AHA Guidelines.

53. Stages of Heart Failure and Treatment options NEJM 2003; 348 (20): 2007-18.