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CHRONIC CONGESTIVE HEART FAILURE American Heart Association in collaboration with Sociedad Española de Cardiologia June, 1999 Chronic Congestive Heart Failure 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. Future revisions will be posted on the American Heart Association website (www.americanheart.org). Chronic Congestive Heart Failure DEFINITION “The situation when the heart is incapable of maintaining a cardiac output adequate to accommodate metabolic requirements and the venous return." E. Braunwald Chronic Congestive Heart Failure EVOLUTION OF CLINICAL STAGES NORMAL Asymptomatic LV Dysfunction No symptoms Compensated Normal exercise CHF Abnormal LV fxn No symptoms Decompensated Exercise CHF Abnormal LV fxn Symptoms Refractory Exercise CHF Abnormal LV fxn No symptoms Normal exercise Normal LV fxn Symptoms not controlled with treatment Chronic Congestive Heart Failure DETERMINANTS OF VENTRICULAR FUNCTION CONTRACTILITY PRELOAD AFTERLOAD STROKE VOLUME - Synergistic LV contraction - LV wall integrity - Valvular competence CARDIAC OUTPUT HEART RATE Chronic Congestive Heart Failure TREATMENT OBJECTIVES Survival Morbidity Exercise capacity Quality of life Neurohormonal changes Progression of CHF Symptoms Chronic Congestive Heart Failure TREATMENT Correction of aggravating factors Pregnancy Arrhythmias (AF) Infections Hyperthyroidism Thromboembolism Endocarditis Obesity Hypertension Physical activity Dietary excess MEDICATIONS Chronic Congestive Heart Failure TREATMENT PHARMACOLOGIC THERAPY DIURETICS INOTROPES VASODILATORS NEUROHORMONAL ANTAGONISTS OTHERS (Anticoagulants, antiarrhythmics, etc) Chronic Congestive Heart Failure DRUGS HEMODYNAMIC EFFECTS Normal I Stroke Volume A A+V V D CHF Ventricular Filling Pressure Chronic Congestive Heart Failure PHARMACOLOGIC THERAPY Improved Decreased Prevention Neurohumoral Control symptoms mortality of CHF DIURETICS yes ? ? NO DIGOXIN yes = minimal yes INOTROPES yes ? no Vasodil.(Nitrates) yes yes ? no yes YES yes YES yes +/- ? YES ACEI Other neurohormonal control drugs mort. Chronic Congestive Heart Failure TREATMENT Normal Asymptomatic LV dysfunction EF <40% Symptomatic CHF ACEI NYHA II Symptomatic CHF NYHA - III Diuretics mild Neurohormonal Symptomatic CHF Loop inhibitors NYHA - IV Diuretics Digoxin? Inotropes Specialized therapy Transplant Secondary prevention Modification of physical activity Chronic Congestive Heart Failure 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 Medulla Loop of Henle Loop diuretics Inhibit exchange of Cl-Na-K in the thick segment of the ascending loop of Henle Collecting tubule Chronic Congestive Heart Failure THIAZIDES MECHANISM OF ACTION Excrete 5 - 10% of filtered Na+ Elimination of K Inhibit carbonic anhydrase: increase elimination of HCO3 Excretion of uric acid, Ca and Mg No dose - effect relationship Chronic Congestive Heart Failure LOOP DIURETICS MECHANISM 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 Chronic Congestive Heart Failure K-SPARING DIURETICS MECHANISM OF ACTION 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 Chronic Congestive Heart Failure 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 Chronic Congestive Heart Failure DIURETICS ADVERSE REACTIONS Thiazide and Loop Diuretics Changes in electrolytes: Volume Na+, K+, Ca++, Mg++ metabolic alkalosis Metabolic changes: glycemia, uremia, gout LDL-C and TG Cutaneous allergic reactions Chronic Congestive Heart Failure DIURETICS ADVERSE REACTIONS Thiazide and Loop Diuretics Idiosyncratic effects: Blood dyscrasia, cholestatic jaundice and acute pancreatitis Gastrointestinal effects Genitourinary effects: Impotence and menstrual cramps Deafness, nephrotoxicity (Loop diuretics) Chronic Congestive Heart Failure DIURETICS ADVERSE REACTIONS K-SPARING DIURETICS Changes in electrolytes: Na+, K+, acidosis Musculoskeletal: Cramps, weakness Cutaneous allergic reactions : Rash, pruritis Chronic Congestive Heart Failure DIGOXIN Na-K ATPase Na+ K+ K+ Na+ Na-Ca Exchange Na+ Myofilaments Ca++ Ca++ CONTRACTILITY Chronic Congestive Heart Failure DIGOXIN PHARMACOKINETIC PROPERTIES 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 Chronic Congestive Heart Failure DIGOXIN DIGITALIZATION STRATEGIES Loading dose (mg) i.v 0.5 + 0.25 / 4 h ILD: 0.75-1 oral 12-24 h oral 2-5 d 0.75 + 0.25 / 6 h 0.25 / 6-12 h 1.25-1.5 1.5-1.75 Maintenance Dose (mg) 0.125-0.5 / d 0.25 / d ILD = average INITIAL dose required for digoxin loading Chronic Congestive Heart Failure DIGOXIN HEMODYNAMIC EFFECTS Cardiac output LV ejection fraction LVEDP Exercise tolerance Natriuresis Neurohormonal activation Chronic Congestive Heart Failure DIGOXIN NEUROHORMONAL EFFECTS Plasma Noradrenaline Peripheral nervous system activity RAAS activity Vagal tone Normalizes arterial baroreceptors Chronic Congestive Heart Failure 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) 10 EF < 35% Class I-III (digoxin+diuretic+ACEI) Also significantly decreased exercise time and LVEF. 0 RADIANCE N Engl J Med 1993;329:1 DIGOXIN n=85 0 20 40 60 Days 80 100 Chronic Congestive Heart Failure OVERALL MORTALITY 50 40 30 % 20 Placebo n=3403 10 DIG 0 0 p = 0.8 DIGOXIN n=3397 12 N Engl J Med 1997;336:525 24 Months 36 48 Chronic Congestive Heart Failure DIGOXIN LONG TERM EFFECTS Survival similar to placebo Fewer hospital admissions More serious arrhythmias More myocardial infarctions Chronic Congestive Heart Failure DIGOXIN CLINICAL USES AF with rapid ventricular response CHF refractory to other drugs Other indications? Can be combined with other drugs Chronic Congestive Heart Failure DIGOXIN CONTRAINDICATIONS ABSOLUTE: - Digoxin toxicity RELATIVE - Advanced A-V block without pacemaker - Bradycardia or sick sinus without PM - PVC’s and TV - Marked hypokalemia - W-P-W with atrial fibrillation Chronic Congestive Heart Failure DIGOXIN TOXICITY CARDIAC MANIFESTATIONS ARRHYTHMIAS : - Ventricular (PVCs, TV, VF) - Supraventricular (PACs, SVT) BLOCKS: - S-A and A-V blocks CHF EXACERBATION Chronic Congestive Heart Failure DIGOXIN TOXICITY EXTRACARDIAC MANIFESTATIONS GASTROINTESTINAL: - Nausea, vomiting, diarrhea NERVOUS: - Depression, disorientation, paresthesias VISUAL: - Blurred vision, scotomas and yellow-green vision HYPERESTROGENISM: - Gynecomastia, galactorrhea Chronic Congestive Heart Failure POSITIVE INOTROPES CARDIAC GLYCOSIDES SYMPATHOMIMETICS Catecholamines ß-adrenergic agonists PHOSPHODIESTERASE INHIBITORS Amrinone Enoximone Others Milrinone Piroximone Chronic Congestive Heart Failure ß-ADRENERGIC STIMULANTS CLASSIFICATION B1 Stimulants Increase contractility Dobutamine Doxaminol Xamoterol Butopamine Prenalterol Tazolol B2 Stimulants Produce arterial vasodilatation and reduce SVR Pirbuterol Rimiterol Tretoquinol Terbutaline Soterenol CarbuterolFenoterol Salbutamol SalmefamolQuinterenol Mixed Dopamine Chronic Congestive Heart Failure DOPAMINE AND DOBUTAMINE EFFECTS DA (µg / Kg / min) Dobutamine <2 DA1 / DA2 2-5 ß1 >5 ß1 + a ß1 Contractility ± ++ ++ ++ Heart Rate ± + ++ ± Arterial Press. ± + ++ ++ ++ + ± + - ± ++ ± Receptors Renal perfusion Arrhythmia Chronic Congestive Heart Failure POSITIVE INOTROPES CONCLUSIONS May increase mortality Safer in lower doses Use only in refractory CHF NOT for use as chronic therapy Chronic Congestive Heart Failure VASODILATOR DRUGS PRINCIPLES Normal Contractility Normal Contractility CO VV Diminished Contractility PRELOAD AV Diminished Contractility AFTERLOAD Chronic Congestive Heart Failure VASODILATORS CLASSIFICATION VENOUS Nitrates Molsidomine Venous Vasodilatation MIXED Calcium antagonists a-adrenergic Blockers ACEI Angiotensin II inhibitors K+ channel activators Nitroprusside Arterial Vasodilatation ARTERIAL Minoxidil Hydralazine Chronic Congestive Heart Failure NITRATES HEMODYNAMIC EFFECTS 1- VENOUS VASODILATATION Preload Pulmonary congestion Ventricular size Vent. Wall stress MVO2 2- Coronary vasodilatation Myocardial perfusion 3- Arterial vasodilatation Afterload 4- Others • Cardiac output • Blood pressure Chronic Congestive Heart Failure NITRATES FUNCTIONAL CAPACITY 400 EXERCISE TIME, 300 seconds 200 384 392 ** ** 267 100 Jansen W et al Med Welt 1982;33:1756 n=24 4 1ST dose weeks ISOSORBIDE 5 - MONONITRATE 20 mg / 8h Control Chronic Congestive Heart Failure NITRATES SURVIVAL 0.7 Placebo (273) 0.6 Prazosin (183) Hz + ISDN (186) 0.5 PROBABILITY 0.4 OF DEATH 0.3 0.2 0.1 0 VHefT-1 0 N Engl J Med 1986;314:1547 6 12 18 24 30 MONTHS 36 42 Chronic Congestive Heart Failure NITRATES TOLERANCE " Decrease in the effect of a drug when administered in a long-acting form" 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 Chronic Congestive Heart Failure 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 Chronic Congestive Heart Failure NITRATES TOLERANCE H A L F L I F E s.l. NTG ISDN I 5-MN Percutaneous NTG T O L E R A N C E Chronic Congestive Heart Failure NITRATES CONTRAINDICATIONS Previous hypersensitivity Hypotension ( < 80 mmHg) AMI with low ventricular filling pressure 1st trimester of pregnancy WITH CAUTION: ž Constrictive pericarditis ž Intracranial hypertension ž Hypertrophic cardiomyopathy Chronic Congestive Heart Failure NITRATES CLINICAL USES Pulmonary congestion Orthopnea and paroxysmal nocturnal dyspnea CHF with myocardial ischemia In acute CHF and pulmonary edema: NTG s.l. or i.v. Chronic Congestive Heart Failure ACEI MECHANISM OF ACTION VASOCONSTRICTION ALDOSTERONE VASOPRESSIN SYMPATHETIC VASODILATATION PROSTAGLANDINS Kininogen tPA Kallikrein Angiotensinogen RENIN Angiotensin I A.C.E. ANGIOTENSIN II Inhibitor BRADYKININ Kininase II Inactive Fragments Chronic Congestive Heart Failure 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 Chronic Congestive Heart Failure ACEI FUNCTIONAL 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 2 Quinapril Heart Failure Trial JACC 1993;22:1557 4 6 8 10 12 Weeks 14 16 18 20 Chronic Congestive Heart Failure ACEI ADVANTAGES 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 activation or reflex tachycardia Tolerance to its effects does not develop Chronic Congestive Heart Failure ACEI SURVIVAL 0.8 0.7 Placebo 0.6 PROBABILITY 0.5 OF 0.4 DEATH p< 0.001 p< 0.002 0.3 Enalapril 0.2 0.1 CONSENSUS N Engl J Med 1987;316:1429 0 0 1 2 3 4 5 6 7 8 MONTHS 9 10 11 12 Chronic Congestive Heart Failure ACEI SURVIVAL 50 p = 0.30 Placebo n=2117 40 % MORTALITY n = 4228 No CHF symptoms EF < 35 30 20 10 0 SOLVD (Prevention) 0 N Engl J Med 1992;327:685 Enalapril n=2111 6 12 18 24 30 Months 36 42 48 Chronic Congestive Heart Failure ACEI SURVIVAL 50 p = 0.0036 Placebo n=1284 40 % MORTALITY 30 Enalapril 20 n = 2589 CHF - NYHA II-III - EF < 35 10 0 SOLVD (Treatment) 0 N Engl J M 1991;325:293 n=1285 6 12 18 24 30 Months 36 42 48 Chronic Congestive Heart Failure ACEI SURVIVAL 30 Asymptomatic ventricular dysfunction post MI Placebo n=1116 20 Captopril Mortality, % n = 2231 3 - 16 days post AMI EF < 40 12.5 --- 150 mg / day n=1115 10 0 N Engl J Med 1992;327:669 0 SAVE ² -19% p=0.019 1 2 Years 3 4 Chronic Congestive Heart Failure ACEI SURVIVAL POST MI ACEI Benefit Pt Selection ISIS-4 Captopril 0.5 / 5 wk All with AMI GISSI-3 Lisinopril 0.8 / 6 wk All with AMI SAVE Captopril 4.2 / 3.5 yr EF < 40 asymptomatic SMILE Zofenopril 4.1 / 1 yr Ant. AMI, No TRL TRACE Trandolapril 7.6 / 3 yr Vent Dysfx / Clinical CHF 6 / 1 yr Clinical CHF AIRE Ramipril EF < 35 Chronic Congestive Heart Failure ACEI INDICATIONS Clinical cardiac insufficiency - All patients Asymptomatic ventricular dysfunction - LVEF < 35 % Chronic Congestive Heart Failure ACEI UNDESIRABLE EFFECTS Inherent in their mechanism of action - Hypotension - Hyperkalemia - Angioneurotic edema - Dry cough - Renal Insuff. Due to their chemical structure - Cutaneous eruptions - Neutropenia, thrombocytopenia - Digestive upset - Dysgeusia - Proteinuria Chronic Congestive Heart Failure ACEI CONTRAINDICATIONS Renal artery stenosis Renal insufficiency Hyperkalemia Arterial hypotension Intolerance (due to side effects) Chronic Congestive Heart Failure ANGIOTENSIN II INHIBITORS MECHANISM OF ACTION RENIN Angiotensinogen Other paths AT1 RECEPTOR BLOCKERS AT1 Vasoconstriction Angiotensin I ACE ANGIOTENSIN II RECEPTORS Proliferative Action AT2 Vasodilatation Antiproliferative Action Chronic Congestive Heart Failure AT1 RECEPTOR BLOCKERS DRUGS Losartan Valsartan Irbersartan Candersartan Competitive and selective blocking of AT1 receptors Chronic Congestive Heart Failure ALDOSTERONE INHIBITORS Spironolactone ALDOSTERONE Competitive antagonist of the aldosterone receptor (myocardium, arterial walls, kidney) Retention Na+ Retention H2O Edema Excretion K+ Arrhythmias Excretion Mg2+ Collagen deposition Fibrosis - myocardium - vessels Chronic Congestive Heart Failure 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 • ? Pending the RALES results Chronic Congestive Heart Failure ALDOSTERONE INHIBITORS CONTRAINDICATIONS • Hyperkalemia • Severe renal insufficiency • Metabolic acidosis Chronic Congestive Heart Failure ß-ADRENERGIC BLOCKERS POSSIBLE BENEFICIAL EFFECTS Density of ß1 receptors Inhibit cardiotoxicity of catecholamines Neurohormonal activation HR Antihypertensive and antianginal Antiarrhythmic Antioxidant Antiproliferative Chronic Congestive Heart Failure 50 ß BLOCKERS SURVIVAL ß Blocker Placebo 40 30 % 20 10 0 BHAT JACC 1990;16:1327 < 30% 30-40% > 40% LV EJECTION FRACTION Chronic Congestive Heart Failure ß BLOCKERS Mortality ß BLOCKER n=2231 YES No Yes 13.3% 24.3% No 19.5% 27.7% ACEI SAVE Circulation 1995;92:3132 Chronic Congestive Heart Failure ß BLOCKERS CARVEDILOL 4 studies in U.S.; 1 in Australia/New Zealand U.S. studies with control group Mortality with Placebo 8.2% p < 0.0001 Mortality with Carvedilol 2.9% Initial low doses, progressive Chronic Congestive Heart Failure ß-ADRENERGIC BLOCKERS INDICATIONS and UTILIZATION Not clearly established Begin with very low doses Slow augmentation of dose Slow withdrawal ? Chronic Congestive Heart Failure ß-ADRENERGIC BLOCKERS IDEAL CANDIDATE? Suspected adrenergic activation Arrhythmias Hypertension Angina Chronic Congestive Heart Failure ß-ADRENERGIC BLOCKERS CONTRAINDICATIONS Hypotension: BP < 100 mmHg Bradycardia: HR < 50 bpm Clinical instability Chronic bronchitis, ASTHMA Severe chronic renal insufficiency Chronic Congestive Heart Failure CALCIUM ANTAGONISTS POTENTIAL EFFECTS Antiischemic Peripheral Vasodilatation Inotropy Chronic Congestive Heart Failure CALCIUM ANTAGONISTS POSSIBLE UTILITY Diltiazem contraindicated Verapamil and Nifedipine not recommended Vasoselective (amlodipine, nisoldipine), may be useful in ischemia + CHF Amlodipine may be useful in nonischemic CHF Chronic Congestive Heart Failure ANTICOAGULANTS PREVIOUS EMBOLIC EPISODE ATRIAL FIBRILLATION Identified thrombus LV Aneurysm (3-6 mo post MI) Class III-IV in the presence of: - EF < 30 - Aneurysm or very dilated LV Phlebitis Prolonged bed rest Chronic Congestive Heart Failure ANTIARRHYTHMICS Sustained VT, with/without symptoms - ß Blockers - Amiodarone Sudden death from VF - Consider implantable defibrillator Chronic Congestive Heart Failure ANTIARRHYTHMICS MORTALITY 15 13.6 ns 13.7 MORTALITY AT 2 YEARS 10 % n=1486 5-21d post MI Amiodarone 5 200 mg/d Follow up 1 - 4 years EMIAT Am Coll Cardiol 1996 0 101 / 743 102 / 743 Placebo Amiodarone Chronic Congestive Heart Failure American Heart Association in collaboration with Sociedad Española de Cardiologia CHRONIC CONGESTIVE HEART FAILURE The content of these slides is current as of June, 1999. Future revisions will be posted on the American Heart Association website (www.americanheart.org)
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