1. The Problem of Heart Failure Fathi Maklady . MD,FRCP Suez Canal University

8. A Public Health Crisis: Heart Failure Hospitalizations have Tripled in 25 Years NHLBI. Morbidity and Mortality: 2000 Chartbook on Cardiovascular, Lung, and Blood Diseases . Geneva: World Health Organization; 1996. Hospitalizations/100,000 Population 1970 1975 1980 1985 1990 1995 Year 65+ years 45-64 years 0 50 100 150 200 250

10. Prevalence of Heart Failure Worldwide 19,000 2.4 Japan 18,000 North America 14,000 5.3 Western Europe Rate (per million pop.) Absolute Numbers (millions of patients ) Murray CJL, Lopez AD. Global health statistics: a compendium of incidence, prevalence and mortality estimates for over 200 conditions . Geneva: World Health Organization;.

12. Hospitalization: The Major Factor in Heart Failure Costs in the US 60.6% Hospitalization $23.1 billion 38.6% Outpatient care $14.7 billion (3.4 visits/year /patient) 0.7% Transplants $270 million Total = $38.1 billion (5.4% of total health care costs) O’Connell JB, Bristow MR. J Heart Lung Transplant . 1994;13:S107-S112 .

19. ACC/AHA Staging System for HF -Marked symptoms at rest -Maximal medical therapy D: Refractory HF -Known structural Ht disease -SOB& Fatigue –reduced exercise tolerance C: Symptomatic HF -Previous MI -LVH -LVSD -Asymptomatic valvular Ht disease B: Asymptomatic HF -HTN -CAD -DM -Dyslipidaemia -FH of CM A: High risk for developing HF Patient description Stage

24. Systolic Heart Failure Diastolic Heart Failure

28. The Progressive Development of Cardiovascular Disease Endstage Heart Disease Congestive Heart Failure Ventricular Dilation Remodeling Arrhythmia & Loss of Muscle Myocardial Infarction Myocardial Ischemia CAD Atherosclerosis Endothelial Dysfunction Risk Factors Coronary Thrombosis

33. CHF Patient Population by NYHA Class Class I No limitations of physical activity Class II Slight limitations of physical activity Class III Marked limitations of physical activity Class IV Inability to carry out physical activities without discomfort and/or symptoms at rest Class II 1.68 M (35%) Class IV 240 K (5%) Class III 1.20 M (25%) Class I 1.68 M (35%) AHA Heart and Stroke Statistical Update 2001

48. Stage B Patients with Asymptomatic LV Dysfunction

50. Stage C Patients with Past or Current Symptoms of Heart Failure

53. Calcium channel blocking drugs are not indicated as routine treatment for HF in patients with current or prior symptoms of HF and reduced LVEF. Hormonal therapies other than to replete deficiencies are not recommended and may be harmful to patients with current or prior symptoms of HF and reduced LVEF. Routine combined use of an ACEI, ARB, and aldosterone antagonist is not recommended for patientswith current or prior symptoms of HF and reduced LVEF. Unproven/Not Recommended Drugs and Interventions Stage C Therapy (Reduced LVEF with Symptoms)

54. Long-term use of an infusion of a positive inotropic drug may be harmful and is not recommended for patients with current or prior symptoms of HF and reduced LVEF, except as palliation for patients with end-stage disease who cannot be stabilized with standard medical treatment (see recommendations for Stage D). Use of nutritional supplements as treatment for HF is not indicated in patients with current or prior symptoms of HF and reduced LVEF. Unproven/Not Recommended Drugs and Interventions Stage C Therapy (Reduced LVEF with Symptoms)

56. Patients with LVEF less than or equal to 35%, sinus rhythm, and NYHA functional class III or ambulatory class IV symptoms despite recommended, optimal medical therapy and who have cardiac dyssynchrony, which is currently defined as a QRS duration greater than 120 ms, should receive cardiac resynchronization therapy unless contraindicated. Cardiac Resynchronization Stage C Therapy (Reduced LVEF with Symptoms)

57. An ICD is recommended as secondary prevention to prolong survival in patients with current or prior symptoms of HF and reduced LVEF who have a history of cardiac arrest, ventricular fibrillation, or hemodynamically destabilizing ventricular tachycardia. ICD therapy is recommended for primary prevention to reduce total mortality by a reduction in sudden cardiac death in patients with ischemic heart disease who are at least 40 days post-MI, have an LVEF less than or equal to 30%, with NYHA functional class II or III symptoms while undergoing chronic optimal medical therapy, and have reasonable expectation of survival with a good functional status for more than 1 year. Implantable Cardioverter- Defibrillators (ICDs) Stage C Therapy (Reduced LVEF with Symptoms)

58. ICD therapy is recommended for primary prevention to reduce total mortality by a reduction in sudden cardiac death in patients with nonischemic cardiomyopathy who have an LVEF less than or equal to 30%, with NYHA functional class II or III symptoms while undergoing chronic optimal medical therapy, and who have reasonable expectation of survival with a good functional status for more than 1 year. Placement of an ICD is reasonable in patients with LVEF of 30% to 35% of any origin with NYHA functional class II or III symptoms who are taking chronic optimal medical therapy and who have reasonable expectation of survival with good functional status of more than 1 year. ICDs (cont’d) Stage C Therapy (Reduced LVEF with Symptoms) I I I IIa IIa IIa IIb IIb IIb III III III I I I IIa IIa IIa IIb IIb IIb III III III I I I IIa IIa IIa IIb IIb IIb III III III IIa IIa IIa IIb IIb IIb III III III B I I I IIa IIa IIa IIb IIb IIb III III III I I I IIa IIa IIa IIb IIb IIb III III III I I I IIa IIa IIa IIb IIb IIb III III III IIa IIa IIa IIb IIb IIb III III III B

59. Stage D Patients with Refractory End-Stage HF

61. Stage D Therapy Continuous intravenous infusion of a positive inotropic agent may be considered for palliation of symptoms in patients with refractory end-stage HF. Routine intermittent infusions of positive inotropic agents are not recommended for patients with refractory end-stage HF. Medical Therapy

62. Stage D Therapy Referral for cardiac transplantation in potentially eligible patients is recommended for patients with refractory end-stage HF. The effectiveness of mitral valve repair or replacement is not established for severe secondary mitral regurgitation in refractory end-stage HF. Surgical Therapy I I I IIa IIa IIa IIb IIb IIb III III III I I I IIa IIa IIa IIb IIb IIb III III III I I I IIa IIa IIa IIb IIb IIb III III III IIa IIa IIa IIb IIb IIb III III III B

63. Stage D Therapy Consideration of an LV assist device as permanentor “destination” therapy is reasonable in highly selected patients with refractory end-stage HF and an estimated 1-year mortality over 50% with medical therapy. Pulmonary artery catheter placement may be reasonable to guide therapy in patients with refractory end-stage HF and persistently severe symptoms. Device Use I I I IIa IIa IIa IIb IIb IIb III III III I I I IIa IIa IIa IIb IIb IIb III III III I I I IIa IIa IIa IIb IIb IIb III III III IIa IIa IIa IIb IIb IIb III III III B

64. Stage D Therapy Partial left ventriculectomy is not recommended inpatients with nonischemic cardiomyopathy and refractory end-stage HF. Routine intermittent infusions of positive inotropic agents are not recommended for patients with refractory end-stage HF. Therapies NOT Recommended

65. DIURETICS

69. CHF THERAPY ACE-Inhibitors B-blockers

70. Beta Blockers

75. What is the evidence

76. Effect of Carvedilol on Disease Progression in Mild or Moderate Heart Failure *Disease progression was defined as HF death or hospitalization or the need for sustained increase in medications for HF. Patients were on a background of diuretics, ACE inhibitors, ± digoxin. Colucci WS et al. Circulation . 1996;94:2800–2806. Probability of event-free survival  1.0 0.8 0.6 0 50 100 150 200 250 300 350 400 Carvedilol (n=232) Placebo (n=134) P =.008 R isk reduction 48% Days 0

78. Total Mortality Percent of patients Months of follow-up 0 3 6 9 12 15 18 21 20 15 5 0 10 P =0.0062 Risk reduction: 34% Placebo n=2001 Metoprolol XL n=1990

83. ACE - I

84. Aldosterone Sympathetic activation Growth factor stimulation NA + retention H 2 O retention K + excretion Mg + excretion Vascular smooth muscle constriction Angiotensin converting enzyme (ACE) Angiotensin II Liver secretes angiotensinogen Kidneys secrete renin The Renin-Angiotensin-Aldosterone (RAA) System Angiotensinogen Angiotensin I Adrenal cortex secretes aldosterone Blood Renin Pro- Inflamm tory Apoptosis

85. Angiotensin I Angiotensinogen (Liver) Angiotensin II ACE-inhibitor ARBs AT 1 receptor blocker Bradykinin Peptides Chymase Pathways of Ang II generation de Gasparo et al. Pharmacol Rev. 2000; 52: 415 Bad Good X X X AT 1 AT 2

86. Effect of ACE Inhibitors on Mortality Reduction in Patients With CHF Trial ACEI Controls RR (95% CI) CONSENSUS I SOLVD (Treatment ) SOLVD (Prevention) Chronic CHF Post MI SAVE TRACE AIRE 39% 54% 0.56 (0.34–0.91) 40% 35% 0.82 (0.70–0.97) 15% 16% 0.92 (0.79–1.08) 25% 20% 0.81 (0.68–0.97) 17% 23% 0.73 (0.60–0.89) SMILE 6.5% 8.3% 0.78 (0.52–1.12) Average 0.78 (0.67–0.91) 35% 42% 21% 25% Mortality Garg R et al. JAMA. 1995;273:1450–1456. Data shown from individual trials–not direct comparison data.

87. Placebo Enalapril 12 11 10 9 8 7 6 5 PROBABILITY OF DEATH MONTHS 0.1 0.8 0 0.2 0.3 0.7 0.4 0.5 0.6 p< 0.001 CONSENSUS 4 3 2 1 0 N Engl J Med 1987;316:1429 30% risk reduction

88. Mortality % N Engl J Med 1992;327:669 SAVE 20% risk reduction P<0.019 4 Years 30 20 10 0 1 2 3 Placebo Captopril 0 n=1115 n=1116 Asymptomatic ventricular dysfunction post MI

89. Months 0 6 12 p = 0.0036 % MORTALITY 24 18 30 36 42 48 Enalapril n=1285 Placebo n=1284 N Engl J M 1991;325:293 SOLVD (Treatment) 16% risk reduction 50 40 30 20 10 0

92. Patients Not Receiving ACE-Is Possible underuse Contraindication Other AEs Cough 73% 27% 22% 20% 33% 25% 167 Cardiology and 250 Internal Medicine Clinics, Feb 14-25, 2000. Data from TEMISTOCLE Registry, ANMCO. N = 2127

93. Utilization of Evidence Based Therapies in Heart Failure ACE Inhibitors Beta Blockers 0 20 40 60 80 100 Percent of Patients 29 19 69 University Hospital Consortium HF Registry: 33 Centers, 1239 patients, Year 2000 Discharge Medications Spironolactone

94. Under treatment of HF in Europe Diuretics ACE-inhibitor  blocker Digitalis glycoside Nitrate Spironolactone ARB 0 20 40 60 80 100 Percent of patients receiving agent Cardiovascular drug use Cleland et al. Eur Heart J. 2001; 22: 494

95. ARBs

108. THANK YOU