1. Management of Chronic Heart Failure DR.SAMEER AMBAR DEPT OF CARDIOLOGY JNMC BELGAUM, INDIA [email_address]

7. ACEI MECHANISM OF ACTION VASOCONSTRICTION VASODILATATION Kininogen Kallikrein Inactive Fragments Angiotensinogen Angiotensin I RENIN Kininase II Inhibitor ALDOSTERONE SYMPATHETIC VASOPRESSIN PROSTAGLANDINS tPA ANGIOTENSIN II BRADYKININ A.C.E.

15. Granger CB, et al. Lancet . 2003;362:772-776. CHARM-Alternative Number at risk Candesartan 1,013 929 831 434 122 Placebo 1,015 887 798 427 126 0 1 2 3 Years 0 10 20 30 40 50 Placebo Candesartan HR 0.77 (95% CI 0.67-0.89), P =.0004 Adjusted HR 0.70, P <.0001 3.5 406 (40.0%) 334 (33.0%) Proportion With CV Death or CHF Hospitalization (%) Primary outcome of CV death or CHF hospitalization

16. 55% on BB

27. Sympathetic Activation B1 Receptors B2 Receptors A1 Receptors Cardiotoxicity Carvedilol Metoprolol Propranolol

34. MERIT-HF METOPROL-XL: Mortality and Morbidity MERIT-HF Study Group. Lancet. 1999;353:2001-2007

36. Total Mortality Months of follow-up Per cent 20 15 10 5 0 Placebo Metoprolol CR/XL p = 0.0004 Risk reduction = 40% 0 3 6 9 12 15 18 Jánosi A et al, Am Heart J 2003;146:721-8 MERIT-HF Post-MI Patients

37. Per cent 12 9 6 3 0 Risk reduction = 50% Sudden Death Placebo Metoprolol CR/XL p = 0.0004 0 3 6 9 12 15 18 Jánosi A et al, Am Heart J 2003;146:721-8 MERIT-HF Post-MI Patients Months of follow-up

38. Per cent 5 4 3 1 0 Risk reduction = 49% Death from Worsening Heart Failure Placebo Metoprolol CR/XL p = 0.021 2 0 3 6 9 12 15 18 Jánosi A et al, Am Heart J 2003;146:721-8 MERIT-HF Post-MI Patients Months of follow-up

39. Total Number of Hospitalizations Heart failure p=0.006 -32% All-cause ns -8% CV cause p=0.037 -17% MERIT-HF Post-MI Patients Jánosi A et al, Am Heart J 2003;146:721-8

40. Post-MI severe CHF Total mortality Cardiac death/nonfatal MI History of revasc. (PTCA or CABG) 40% 45% Risk reduction Events Plac/Beta 122/74 44/24 37/26 132/74 46/22 42/27 All Post-MI patients Post-MI severe CHF All Post-MI patients Relative risk and 95% CI 0.0 1.0 History of revasc. (PTCA or CABG) Jánosi A et al, Am Heart J 2003;146:721-8 MERIT-HF Post-MI Patients

41. Effect of metoprolol and placebo treatment on survival and hospitalization risk in class III and IV HF MERIT-HF Goldstein S et al. J Am Coll Cardiol 2001; 38(4):932-8 Endpoint Metoprolol (N) Placebo (N) Risk reduction (%) p value Total mortality 45 72 39% 0.0086 CV mortality 40 70 44% 0.0028 Sudden death 22 39 45% 0.024 Death from worsening HF 13 28 55% 0.015 Total hospitalizations 273 363 27% 0.0037 Total hospitalizations due to worsening HF 105 187 45% <0.0001

42. Comparison of findings in subanalysis and entire MERIT-HF cohort MERIT-HF Goldstein S et al. J Am Coll Cardiol 2001; 38(4):932-8 Endpoint Reductions in entire MERIT-HF cohort Reductions in class III and IV MERIT-HF subset Total mortality -34% -39% Sudden death -41% -45% Death due to worsening HF -49% -55%

46. COPERNICUS: Effect of carvedilol on the combined risk of morbidity and mortality Death or hospitalization for HF 0.000004 p value Endpoint COPERNICUS and CAPRICORN 0.00004 31% Death or hospitalization for a CV reason 0.76 Death or hospitalization for any reason Relative risk reduction 24% 0.00002 Odds ratio 27% 0.73 0.69

53. Outcome in Post-MI Patients with Heart Failure CAPRICORN and MERIT-HF 1 Time to first event CAPRICORN All-cause mortality All-cause mortality/CV hosp. 1 MERIT-HF 23% 8% Risk reduction p- value p=0.03 Plac/Beta 151/116 122/74 40% p=0.0004 CAPRICORN MERIT-HF 367/340 326/258 ns 22% p=0.002 The CAPRICORN Investigators, Lancet 2001;357:1385-90 Jánosi A et al, Am Heart J 2003;146:721-8 Relative risk and 95% CI 0.0 1.0 Metoprolol CR/XL  1 Metoprolol CR/XL  1 Carvedilol  1  2 (  1 ) Carvedilol  1  2 (  1 )

54. LVEF: Change From Baseline Within Treatment-arm Comparison * P < 0.05; ** P < 0.01; *** P < 0.001 Enalapril Carvedilol & Enalapril Carvedilol -1 0 1 2 3 4 5  LVEF (%) *** *** *** *** *** ** * M6 M12 M18 M6 M18 M12 M6 M12 M18

55. Diuretics

57. Diuretics

74. Thank you