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CHRONIC CONGESTIVE HEART FAILURE American Heart Association in collaboration with

CHRONIC CONGESTIVE HEART FAILURE American Heart Association in collaboration with Sociedad Española de Cardiologia June, 1999. Committee on Post Graduate Education, Council on Clinical Cardiology, American Heart Association Developed in collaboration with the

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CHRONIC CONGESTIVE HEART FAILURE American Heart Association in collaboration with

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  1. CHRONIC CONGESTIVE HEART FAILURE American Heart Association in collaboration with Sociedad Española de Cardiologia June, 1999

  2. Committee on Post Graduate Education, Council on Clinical Cardiology, American Heart Association Developed in collaboration with the Sociedad Española de Cardiologia Prepared by: Ann F. Bolger, MD José Lopez Sendón, MD The content of these slides is current as of June, 1999. (Slide #62 updated 9/00) Future revisions will be posted on the American Heart Association website (www.americanheart.org).

  3. DEFINITION “The situation when the heart is incapable of maintaining a cardiac output adequate to accommodate metabolic requirements and the venous return." E. Braunwald

  4. Chronic Congestive Heart Failure EVOLUTION OF CLINICAL STAGES NORMAL No symptoms Normal exercise Normal LV fxn Asymptomatic LV Dysfunction Compensated CHF No symptoms Normal exercise Abnormal LV fxn Decompensated CHF No symptoms Exercise Abnormal LV fxn Symptoms Exercise Abnormal LV fxn Refractory CHF Symptoms not controlled with treatment

  5. - Synergistic LV contraction - LV wall integrity - Valvular competence DETERMINANTS OF VENTRICULAR FUNCTION CONTRACTILITY PRELOAD AFTERLOAD STROKE VOLUME HEART RATE CARDIAC OUTPUT

  6. TREATMENT OBJECTIVES Survival Morbidity Exercise capacity Quality of life Neurohormonal changes Progression of CHF Symptoms

  7. Pregnancy Arrhythmias (AF) Infections Hyperthyroidism Thromboembolism Endocarditis Obesity Hypertension Physical activity Dietary excess TREATMENT Correction of aggravating factors MEDICATIONS

  8. TREATMENT PHARMACOLOGIC THERAPY DIURETICS INOTROPES VASODILATORS NEUROHORMONAL ANTAGONISTS OTHERS (Anticoagulants, antiarrhythmics, etc)

  9. DRUGS HEMODYNAMIC EFFECTS Normal A I Stroke Volume A + V V CHF D Ventricular Filling Pressure

  10. PHARMACOLOGIC THERAPY Neurohormonal Control Improved symptoms Decreasedmortality Prevention of CHF yes ? DIURETICS NO ? yes = yes DIGOXIN minimal yes mort. no INOTROPES ? yes yes no Vasodil.(Nitrates) ? yes ACEI YES yes YES Other neurohormonal control drugs + / - yes YES ?

  11. TREATMENT Normal AsymptomaticLV dysfunction EF <40% Symptomatic CHF NYHA II ACEI Symptomatic CHF NYHA - III Diuretics mild Neurohormonal inhibitors Digoxin? Symptomatic CHF NYHA - IV Loop Diuretics Inotropes Specialized therapy Transplant Secondary prevention Modification of physical activity

  12. DIURETICS Thiazides Inhibit active exchange of Cl-Na in the cortical diluting segment of the ascending loop of Henle Cortex K-sparing Inhibit reabsorption of Na in the distal convoluted and collecting tubule Loop diuretics Inhibit exchange of Cl-Na-K in the thick segment of the ascending loop of Henle Medulla Loop of Henle Collecting tubule

  13. THIAZIDESMECHANISM OF ACTION Excrete 5 - 10% of filtered Na+ Elimination of K and Mg Inhibit carbonic anhydrase: increase elimination of HCO3 Reabsorption of uric acid No dose - effect relationship

  14. LOOP DIURETICSMECHANISM OF ACTION • Excrete 15 - 20% of filtered Na+ • Elimination of K+, Ca+ and Mg++ • Resistance of afferent arterioles • -Cortical flow and GFR • - Release renal PGs • - NSAIDs may antagonize diuresis

  15. Eliminate < 5% of filtered Na+ Inhibit exchange of Na+ for K+ or H+ Spironolactone = competitive antagonist for the aldosterone receptor Amiloride and triamterene block Na+ channels controlled by aldosterone K-SPARING DIURETICSMECHANISM OF ACTION

  16. DIURETIC EFFECTS • Volume and preload • Improve symptoms of congestion • No direct effect on CO, but • excessive preload reduction may • Improves arterial distensibility • Neurohormonal activation • Levels of NA, Ang II and ARP • Exception: with spironolactone

  17. DIGOXIN Na-K ATPase Na-Ca Exchange Na+ K+ Na+ Ca++ Ca++ Myofilaments K+ Na+ CONTRACTILITY

  18. DIGOXINPHARMACOKINETICPROPERTIES • Oral absorption (%) • Protein binding (%) • Volume of distribution (l/Kg) • Half life • Elimination • Onset (min) • i.v. • oral • Maximal effect (h) • i.v. • oral • Duration • Therapeutic level (ng/ml) 60 - 75 25 6 (3-9) 36 (26-46) h Renal 5 - 30 30 - 90 2 - 4 3 - 6 2 - 6 days 0.5 - 2

  19. DIGOXINDIGITALIZATION STRATEGIES Maintenance Dose Loading dose (mg) (mg) 0.125-0.5 / d 0.25 / d i.v 0.5 + 0.25 / 4 h ILD: 0.75-1 oral 12-24 h 0.75 + 0.25 / 6 h 1.25-1.5 oral 2-5 d 0.25 / 6-12 h 1.5-1.75 ILD = average INITIAL dose required for digoxin loading

  20. DIGOXINHEMODYNAMIC EFFECTS Cardiac output LVejection fraction LVEDP Exercisetolerance Natriuresis Neurohormonalactivation

  21. DIGOXINNEUROHORMONALEFFECTS PlasmaNoradrenaline Peripheral nervous system activity RAAS activity Vagaltone Normalizes arterial baroreceptors

  22. DIGOXIN EFFECT ON CHF PROGRESSION 30 Placebo n=93 DIGOXIN Withdrawal % WORSENING OF CHF 20 p = 0.001 DIGOXIN: 0.125 - 0.5 mg /d (0.7 - 2.0 ng/ml) EF < 35% Class I-III (digoxin+diuretic+ACEI) Also significantly decreased exercise time and LVEF. 10 DIGOXIN n=85 0 60 0 20 40 80 100 RADIANCE N Engl J Med 1993;329:1 Days

  23. 50 40 30 20 10 0 OVERALL MORTALITY Placebo n=3403 % p = 0.8 DIGOXIN n=3397 0 12 24 36 48 DIG N Engl J Med 1997;336:525 Months

  24. DIGOXIN LONG TERM EFFECTS Survival similar to placebo Fewer hospital admissions More serious arrhythmias More myocardial infarctions

  25. DIGOXINCLINICALUSES AF with rapid ventricular response CHF refractory to other drugs Other indications? Can be combined with other drugs

  26. POSITIVE INOTROPES • CARDIAC GLYCOSIDES • SYMPATHOMIMETICS • Catecholamines • ß-adrenergic agonists • PHOSPHODIESTERASE INHIBITORS • Amrinone • Enoximone • Others Milrinone Piroximone

  27. B2 Stimulants Produce arterial vasodilatation and reduce SVR Tretoquinol Salbutamol Soterenol Quinterenol Pirbuterol Carbuterol Rimiterol Fenoterol Terbutaline Salmefamol ß-ADRENERGIC STIMULANTS CLASSIFICATION B1 Stimulants Increase contractility Dobutamine Doxaminol Xamoterol Butopamine Prenalterol Tazolol Mixed Dopamine

  28. DOPAMINE AND DOBUTAMINEEFFECTS DA (µg / Kg / min) Dobutamine < 2 2 - 5 > 5 Receptors DA1 / DA2 ß1 ß1 + a ß1 Contractility ± ++ ++ ++ Heart Rate ± + ++ ± Arterial Press. ± + ++ ++ Renal perfusion ++ + ± + Arrhythmia - ± ++ ±

  29. POSITIVE INOTROPESCONCLUSIONS May increase mortality Safer in lower doses Use only in refractory CHF NOT for use as chronic therapy

  30. VASODILATOR DRUGSPRINCIPLES Normal Contractility Normal Contractility CO VV AV Diminished Contractility Diminished Contractility PRELOAD AFTERLOAD

  31. VASODILATORS CLASSIFICATION Venous Vasodilatation VENOUS Nitrates Molsidomine MIXED Calcium antagonistsa-adrenergic Blockers ACEI Angiotensin II inhibitors K+ channel activators Nitroprusside ARTERIAL Minoxidil Hydralazine Arterial Vasodilatation

  32. • Cardiac output• Blood pressure NITRATESHEMODYNAMIC EFFECTS 1- VENOUS VASODILATATION Preload2- Coronary vasodilatation Myocardialperfusion 3- Arterial vasodilatation Afterload 4- Others Pulmonary congestionVentricular sizeVent. Wall stressMVO2

  33. 400 300 200 100 NITRATESFUNCTIONALCAPACITY n=24 392 384 ** ** EXERCISE TIME, 267 seconds 4 weeks Control 1ST dose ISOSORBIDE 5 - MONONITRATE Jansen W et alMed Welt 1982;33:1756 20 mg / 8h

  34. NITRATESSURVIVAL 0.7 Placebo (273)Prazosin (183)Hz + ISDN (186) 0.6 0.5 PROBABILITYOFDEATH 0.4 0.3 0.2 0.1 0 0 6 12 18 24 30 36 42 VHefT-1 N Engl J Med 1986;314:1547 MONTHS

  35. Develops with all nitrates Is dose-dependent Disappears in 24 h. after stopping the drug Tolerance can be avoided -Using the least effective dose - Creating discontinuous plasma levels NITRATESTOLERANCE " Decrease in the effect of a drug when administered in a long-acting form"

  36. NITRATES TOLERANCE Can be avoided or minimized - Intermittent administration - Use the lowest possible dose - Intersperse a nitrate-free interval Allow peaks and valleys in plasma levels - Vascular smooth muscle recovers its nitrate sensitivity during the nadirs - Patches: remove after 8-10 h

  37. NITRATESCLINICALUSES Pulmonary congestion Orthopnea and paroxysmal nocturnal dyspnea CHF with myocardial ischemia In acute CHF and pulmonary edema: NTG s.l. or i.v.

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

  39. ACEI HEMODYNAMIC EFFECTS Arteriovenous Vasodilatation - PAD, PCWP and LVEDP - SVR and BP - CO and exercise tolerance No change in HR / contractility MVO2 Renal, coronary and cerebral flow Diuresis and natriuresis

  40. 4 8 10 14 18 20 2 6 12 ACEIFUNCTIONAL CAPACITY 100 No Additional Treatment Necessary (%) 95 Quinapril continued n=114 90 p<0.001 85 Quinapril stopped Placebo n=110 80 Class II-III 75 16 Quinapril Heart Failure Trial JACC 1993;22:1557 Weeks

  41. ACEIADVANTAGES • Inhibit LV remodeling post-MI • Modify the progression of chronic CHF • - Survival • - Hospitalizations • - Improve the quality of life • In contrast to others vasodilators, do not produce neurohormonal activationor reflex tachycardia • Tolerance to its effects does not develop

  42. ACEI SURVIVAL 0.8 0.7 Placebo 0.6 PROBABILITYOFDEATH p< 0.001 0.5 0.4 p< 0.002 0.3 Enalapril 0.2 0.1 0 CONSENSUS N Engl J Med 1987;316:1429 0 1 2 3 4 5 6 7 8 9 10 11 12 MONTHS

  43. ACEI SURVIVAL 50 p = 0.30 Placebo n=2117 40 % MORTALITY 30 20 Enalapril n=2111 10 n = 4228 No CHF symptoms EF < 35 0 0 6 12 18 24 30 36 42 48 SOLVD (Prevention)N Engl J Med 1992;327:685 Months

  44. 50 40 30 20 10 0 ACEI SURVIVAL p = 0.0036 Placebo n=1284 % MORTALITY Enalapril n=1285 n = 2589 CHF - NYHA II-III - EF < 35 48 0 6 12 18 24 30 36 42 SOLVD (Treatment)N Engl J M 1991;325:293 Months

  45. ACEI SURVIVAL 30 Asymptomatic ventricular dysfunction post MI Placebo n=1116 20 Mortality, % Captopril n=1115 10 n = 2231 3 - 16 days post AMI EF < 40 12.5 --- 150 mg / day ² -19% p=0.019 SAVE N Engl J Med 1992;327:669 0 0 3 4 1 2 Years

  46. ACEIINDICATIONS Clinical cardiac insufficiency - All patients Asymptomatic ventricular dysfunction - LVEF < 35 %

  47. ANGIOTENSIN II INHIBITORS MECHANISM OF ACTION RENIN Angiotensin IANGIOTENSIN II Angiotensinogen ACE Other paths AT1 RECEPTOR BLOCKERS RECEPTORS AT1 AT2 Vasoconstriction Proliferative Action Vasodilatation Antiproliferative Action

  48. AT1 RECEPTOR BLOCKERS DRUGS Losartan Valsartan Irbersartan Candersartan Competitive and selective blocking of AT1 receptors

  49. ALDOSTERONE INHIBITORS ALDOSTERONE Spironolactone Competitive antagonist of the aldosterone receptor (myocardium, arterial walls, kidney) Retention Na+ Retention H2O Excretion K+ Excretion Mg2+ Collagen deposition Fibrosis - myocardium - vessels Edema Arrhythmias

  50. ALDOSTERONE INHIBITORS INDICATIONS FOR DIURETIC EFFECT • Pulmonary congestion (dyspnea) • Systemic congestion (edema) FOR ELECTROLYTE EFFECTS • Hypo K+, Hypo Mg+ • Arrhythmias • Better than K+ supplements FOR NEUROHORMONAL EFFECTS • Please see RALES results, N Engl J Med 1999:341:709-717

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