INSUFICIÊNCIA CARDÍACA
Propaganda
MORTALIDADE CARDIOVASCULAR Cadeia de eventos Trombose coronária Enfarte do miocárdio Isquemia miocárdica D.Coronária Perda de músculo Morte súbita Activação neurohumoral Remodelagem Aterosclerose HVE Dilatação ventricular Factores de risco: • Hipertensão Arterial • Hiperlipidemia • Diabetes • Obesidade • Tabagismo Insuficiência cardíaca Morte Adaptado de Dzau V e col., 1991 INSUFICIÊNCIA CARDÍACA INSUFICIÊNCIA CARDÍACA • SINDROME COMPLEXO, COM ETIOLOGIAS VÁRIAS • ATINGE CERCA DE 20 MILHÕES DE PESSOAS EM TODO O MUNDO • NÚMERO DE CASOS SOBE EXPONENCIALMENTE SOBRETUDO NO IDOSO 10% DOS IDOSOS COM IDADE > 75 ANOS TÊM INSUFICIÊNCIA CARDÍACA INSUFICIÊNCIA CARDÍACA O PROGNÓSTICO É MAU • A MORBILIDADE É MUITO SIGNIFICATIVA • AS ADMISSÕES HOSPITALARES SÃO MUITO FREQUENTES ( CAUSA MAIS HABITUAL DE INTERNAMENTO EM IDADE > 65 ANOS) INSUFICIÊNCIA CARDÍACA PORQUE É QUE A INS. CARDÍACA AUMENTA? • POPULAÇÃO MAIS ENVELHECIDA • SUCESSO DA TERAPÊUTICA NA MELHORIA DA SOBREVIVÊNCIA PÓS-EAM (trombólise ou outras medidas) • AUMENTO NA DURAÇÃO DA SOBREVIDA DOS DOENTES COM INSUFICIÊNCIA CARDÍACA DEFINITION “The situation when the heart is incapable of maintaining a cardiac output adequate to accommodate metabolic requirements and the venous return." E. Braunwald New York Heart Association Functional Classification Class I: No symptoms with ordinary activity Class II: Slight limitation of physical activity. Comfortable at rest, but ordinary physical activity results in fatigue, palpitation, dyspnea, or angina Class III: Marked limitation of physical activity. Comfortable at rest, but less than ordinary physical activity results in fatigue, palpitation, dyspnea, or anginal pain Class IV: Unable to carry out any physical activity without discomfort. Symptoms of cardiac insufficiency may be present even at rest Severity of Heart Failure Modes of Death NYHA II NYHA III CHF CHF 12% Other 26% 59% Sudden Death 24% 64% Other 15% n = 103 Sudden Death n = 103 NYHA IV CHF Other 33% 56% 11% Sudden Death n = 27 MERIT-HF Study Group. Effect of Metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL randomized intervention trial in congestive heart failure (MERIT-HF). LANCET. 1999;353:2001-07. Etiology of Heart Failure What causes heart failure? • The loss of a critical quantity of functioning myocardial cells after injury to the heart due to: – – – – – – – Ischemic Heart Disease Hypertension Idiopathic Cardiomyopathy Infections (e.g., viral myocarditis, Chagas’ disease) Toxins (e.g., alcohol or cytotoxic drugs) Valvular Disease Prolonged Arrhythmias Left Ventricular Dysfunction • Systolic: Impaired contractility/ejection – Approximately two-thirds of heart failure patients have systolic dysfunction1 • Diastolic: Impaired filling/relaxation 30% (EF > 40 %) (EF < 40%) 70% Diastolic Dysfunction Systolic Dysfunction 1 Lilly, L. Pathophysiology of Heart Disease. Second Edition p 200 DETERMINANTS OF VENTRICULAR FUNCTION CONTRACTILITY PRELOAD AFTERLOAD STROKE VOLUME - Synergistic LV contraction - LV wall integrity - Valvular competence HEART RATE CARDIAC OUTPUT Hemodynamic Basis for Heart Failure Symptoms Hemodynamic Basis for Heart Failure Symptoms LVEDP Left Atrial Pressure Pulmonary Capillary Pressure Pulmonary Congestion Left Ventricular Dysfunction Systolic and Diastolic • Symptoms • Physical Signs – Dyspnea on Exertion – Basilar Rales – Paroxysmal Nocturnal Dyspnea – Pulmonary Edema – Tachycardia – S3 Gallop – Cough – Pleural Effusion – Hemoptysis – Cheyne-Stokes Respiration ICC - Fase de respostas compensatórias Melhoria transitória Activação neurohumoral Retenção H2O e sal Vasoconstrição Redistribuição fluxo Inotropia + Taquicardia Disfunção miocárdica Melhoria transitória Dilatação e hipertrofia Frank-Starling < stress da parede Compensatory Mechanisms • Frank-Starling Mechanism • Neurohormonal Activation • Ventricular Remodeling Compensatory Mechanisms Frank-Starling Mechanism a. At rest, no HF b. HF due to LV systolic dysfunction c. Advanced HF Compensatory Mechanisms Neurohormonal Activation Many different hormone systems are involved in maintaining normal cardiovascular homeostasis, including: • Sympathetic nervous system (SNS) • Renin-angiotensin-aldosterone system (RAAS) • Vasopressin (a.k.a. antidiuretic hormone, ADH) Equilíbrio sistemas neuro-humorais reguladores perfusão Vasodilatores Natriuréticos Anti-proliferativos Anti-inflamatórios Antitrombogénicos Dopamina ANF, BNF, CNF Adrenomedulina Prostaciclina Bradicinina NO Vasoconstritores Anti-natriuréticos Pró-proliferativos Pró-inflamatórios Trombogénicos Angiotensina 2 Aldosterona Adrenalina Noradrenalina Endotelina VSP TBX A2 Ubaína Neurohormonal Responses to Impaired Cardiac Performance Initially Adaptive Response Short-Term Effects Salt and Water Retention Augments Preload Vasoconstriction Maintains BP for perfusion of vital organs Sympathetic Stimulation Increases HR and ejection Jaski, B, MD: Basics of Heart Failure: A Problem Solving Approach Sympathetic Activation in Heart Failure CNS sympathetic outflow Cardiac sympathetic activity 1receptors 2receptors Sympathetic activity to kidneys + peripheral vasculature 1receptors Myocardial toxicity Increased arrhythmias 1- Activation of RAS Vasoconstriction Sodium retention Disease progression Packer. Progr Cardiovasc Dis. 1998;39(suppl I):39-52. 1- 1 and 2 receptor densities in the failing and non-failing heart Receptor density (ƒ mol/mg) 80 Non-failing Failing 60 *p<0.05 **p=NS 40 * ** 20 0 1 2 Compensatory Mechanisms: Renin-Angiotensin-Aldosterone (RAAS) Angiotensinogen Renin Angiotensin I Angiotensin Converting Enzyme Angiotensin II Na+ retention AT I receptor Vasoconstriction Oxidative Stress Cell Growth Vascular remodeling LV remodeling Proteinuria Other Neurohormones • Natriuretic Peptides: Three known types – Atrial Natriuretic Peptide (ANP) • Predominantly found in the atria • Diuretic and vasodilatory properties – Brain Natriuretic Peptide (hBNP) • Predominantly found in the cardiac ventricles • Diuretic and vasodilatory properties – C-type Natriuretic Peptide (CNP) • Predominantly found in the central nervous system • Limited natriuretic and vasodilatory properties Pharmacological Actions of hBNP Hemodynamic (balanced vasodilation) R I S S D S M S K G R L G H G F R C R C S S K V L G K P M V S Q G S • veins • arteries • coronary arteries Neurohormonal aldosterone norepinephrine Renal diuresis & natriuresis Abraham WT and Schrier RW, 1994 Endothelium-Derived Vasoactive Substances Produced by a thin lining of cells within the arteries and veins called the endothelium Endothelium-derived relaxing factors (EDRF) – Vasodilators: • Nitric Oxide (NO) • Bradykinin • Prostacyclin Endothelium-derived constricting factors (EDCF) – Vasoconstrictors: • Endothelin I Mediators of Heart Failure Cytokines • Small protein molecules produced by a variety of tissues and cells • Negative inotropes • Elevated levels associated with worse clinical outcomes • Examples: – Tumor necrosis factor (TNF)-alpha – Interleukin 1-alpha – Interleukin-2 – Interleukin-6 – Interferon-alpha Neurohormonal Responses to Impaired Cardiac Performance Initially Adaptive, Deleterious if Sustained Long-Term Effects Response Short-Term Effects Salt and Water Retention Augments Preload Pulmonary Congestion, Anasarca Vasoconstriction Maintains BP for perfusion of vital organs Exacerbates pump dysfunction (excessive afterload), increases cardiac energy expenditure Sympathetic Stimulation Increases HR and ejection Increases energy expenditure Jaski, B, MD: Basics of Heart Failure: A Problem Solving Approach ICC - Fase de descompensação agravamento Disfunção miocárdica Dilatação ventricular Remodelagem Activação neurohumoral Stress oxidativo Citocinas Apoptose Mitogénese Proliferação celular Alterações estruturais, miocárdio, tecido conjuntivo, vasos Perda de miócitos, necrose e fibrose Dilatação e hipertrofia General Measures Lifestyle Modifications: Medical Considerations: • Weight reduction • Treat HTN, hyperlipidemia, diabetes, arrhythmias • Discontinue smoking • Coronary revascularization • Avoid alcohol and other cardiotoxic substances • Anticoagulation • Exercise • Immunization • Sodium restriction • Daily weights • Close outpatient monitoring Objectivos terapêuticos sobrevida Morbilidade Capacidade de Exercicio Qualidade de vida Alterações Neurohormonais Progressão da CHF Sintomas Tratamento da Ins. cardiaca Diureticos e digitalicos Vasodilatadores Directos e nitratos Inibidores da ECA Antagonistas dos receptores AT1 Bloqueadores beta Antiarrítmicos, anticoagulantes Inibidores das fosfodiesterases redutores da produçãode FNT e outras citocinas) Ressincronização cardíaca DRUGS HEMODYNAMIC EFFECTS Normal I Stroke Volume A A+V V D CHF Ventricular Filling Pressure Pharmacologic Management Digoxin • Enhances inotropy of cardiac muscle • Reduces activation of SNS and RAAS • Controlled trials have shown long-term digoxin therapy: – Reduces symptoms – Increases exercise tolerance – Improves hemodynamics – Decreases risk of HF progression – Reduces hospitalization rates for decompensated HF – Does not improve survival Genina OH CH3 Tri-digitoxose (açucares) o CH3 CH 3 CH 3 o HO - o - o- OH CH 3 o - oEsteroide Figura 1. Estrutura da digoxina, protótipo dos digitálicos Lactona DIGOXIN Na-K ATPase Na+ K+ K+ Na+ Na-Ca Exchange Na+ Myofilaments Ca++ Ca++ CONTRACTILITY Figura 2. Efeitos inotrópicos e neurais dos digitálicos Efeito simpático-inibidor aferências doses terapêuticas Digitálicos Estimulação vagal 2K + 3Na + > saída de sódio Trocador Na+/Ca2+ Estimulação simpática Doses tóxicas Taquiarritmias > sódio intracelular > Ca 2+ intracelular EFEITO INOTRÓPICO POSITIVO Aumento Ca2+ intracelular Adaptado de Opie, 1990 Normal Conduction Pathway in the Heart and the ECG Sinoatrial (SA) Node Atrioventricular (AV) Node Left Bundle Branches Right Bundle Branch Purkinje Fibers P T QRS P= Atrial Depolarization QRS = Ventricular Depolarization T= Ventricular Repolarization 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 DIGOXIN HEMODYNAMIC EFFECTS Cardiac output LV ejection fraction LVEDP Exercise tolerance Natriuresis Neurohormonal activation DIGOXIN NEUROHORMONAL EFFECTS Plasma Noradrenaline Peripheral nervous system activity RAAS activity Vagal tone Normalizes arterial baroreceptors DIGOXIN LONG TERM EFFECTS Survival similar to placebo Fewer hospital admissions More serious arrhythmias More myocardial infarctions DIGOXIN CLINICAL USES AF with rapid ventricular response CHF refractory to other drugs Other indications? Can be combined with other drugs 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 DIGOXIN TOXICITY CARDIAC MANIFESTATIONS ARRHYTHMIAS : - Ventricular (PVCs, TV, VF) - Supraventricular (PACs, SVT) BLOCKS: - S-A and A-V blocks CHF EXACERBATION DIGOXIN TOXICITY EXTRACARDIAC MANIFESTATIONS GASTROINTESTINAL: - Nausea, vomiting, diarrhea NERVOUS: - Depression, disorientation, paresthesias VISUAL: - Blurred vision, scotomas and yellow-green vision HYPERESTROGENISM: - Gynecomastia, galactorrhea POSITIVE INOTROPES CARDIAC GLYCOSIDES SYMPATHOMIMETICS Catecholamines ß-adrenergic agonists PHOSPHODIESTERASE INHIBITORS Amrinone Enoximone Others Milrinone Piroximone 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 Carbuterol Fenoterol Salbutamol Salmefamol Quinterenol Mixed Dopamine DOPAMINE AND DOBUTAMINE EFFECTS DA (µg / Kg / min) Dobutamine <2 DA1 / DA2 2-5 ß1 >5 ß1 + ß1 Contractility ± ++ ++ ++ Heart Rate ± + ++ ± Arterial Press. ± + ++ ++ ++ + ± + - ± ++ ± Receptors Renal perfusion Arrhythmia POSITIVE INOTROPES CONCLUSIONS May increase mortality Safer in lower doses Use only in refractory CHF NOT for use as chronic therapy 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 Medulla Inhibit exchange of Cl-Na-K in the thick segment of the ascending loop of Henle Loop of Henle Collecting tubule THIAZIDES MECHANISM OF ACTION Excrete 5 - 10% of filtered Na+ Elimination of K Inhibit carbonic anhydrase: increase elimination of HCO3 No dose - effect relationship 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 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 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 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 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) Pharmacologic Management Diuretics • Used to relieve fluid retention • Improve exercise tolerance • Facilitate the use of other drugs indicated for heart failure • Patients can be taught to adjust their diuretic dose based on changes in body weight • Electrolyte depletion a frequent complication • Should never be used alone to treat heart failure • Higher doses of diuretics are associated with increased mortality DIURETICS ADVERSE REACTIONS K-SPARING DIURETICS Changes in electrolytes: Na+, K+, acidosis Musculoskeletal: Cramps, weakness Cutaneous allergic reactions : Rash, pruritis VASODILATOR DRUGS PRINCIPLES Normal Contractility Normal Contractility CO VV Diminished Contractility PRELOAD AV Diminished Contractility AFTERLOAD VASODILATORS CLASSIFICATION VENOUS Nitrates Molsidomine MIXED Calcium antagonists -adrenergic Blockers ACEI Angiotensin II inhibitors K+ channel activators Nitroprusside Arterial Vasodilatation ARTERIAL Minoxidil Hydralazine Venous Vasodilatation 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 NITRATES SURVIVAL 0.7 Placebo (273) Prazosin (183) Hz + ISDN (186) 0.6 0.5 PROBABILITY OF DEATH 0.4 0.3 0.2 0.1 0 VHefT-1 N Engl J Med 1986;314:1547 0 6 12 18 24 MONTHS 30 36 42 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 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 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 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 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. Pharmacologic Management ACE Inhibitors • Blocks the conversion of angiotensin I to angiotensin II; prevents functional deterioration • Recommended for all heart failure patients • Relieves symptoms and improves exercise tolerance • Reduces risk of death and decreases disease progression • Benefits may not be apparent for 1-2 months after initiation 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 Retenção de Na+ Libertação de Aldosterona e ET-1 Hipertrofia cardíaca Fibrose intersticial Pro-ateromatose Efeitos centrais Angiotensina II Estimulação de protooncogenes Estimulação simpática Hipertrofia/Hiperplasia Remodelagem vascular Inflamação/procoagulabilidade Stress oxidativo 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 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 ACEI SURVIVAL 0.8 0.7 Placebo 0.6 PROBABILITY OF DEATH p< 0.001 0.5 0.4 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 MONTHS 8 9 10 11 12 ACEI INDICATIONS Clinical cardiac insufficiency - All patients Asymptomatic ventricular dysfunction - LVEF < 35 % 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 ACEI CONTRAINDICATIONS Renal artery stenosis Renal insufficiency Hyperkalemia Arterial hypotension Intolerance (due to side effects) IECAS VANTAGENS DESVANTAGENS - reduzem mortalidade - efeitos acessórios e morbilidade (tosse /angioedema) - melhoram sintomas - aumentam tolerância ao esforço - reduzem hospitalizações - eficazes na I C assintomática NEJM 1987: 316;1429 NEJM 1991: 325; 303 JAMA 1988:259; 539 NEJM 1991:325;293 ANN INTERN MED 1992:117 ; 234 Mortality trials with ACE inhibitors in heart failure Trial Treatment Treatments n Enalapril 253 Placebo V-HeFT-II 2 years Enalapril (treatment) 41 months Enalapril Placebo ISDN=isosorbide dinitrate; Hydral=hydralazine 26 0.002 44 804 ISDN/Hydral SOLVD p value (%) duration CONSENSUS-1 6 months Mortality 18 0.016 25 2569 35 40 0.004 ACE inhibitor trials in heart failure following AMI n Mortality p value (%) Trial Treatment Treatments duration AIRE 15 months Ramipril Placebo 2006 17 23 0.002 SAVE 42 months Captopril Placebo 2231 20 25 0.019 Trandolapril 1749 Placebo 35 42 0.001 TRACE 4 years Estudos de mortalidade com In ECA na insuficiência cardíaca e E. miocárdio • 32 estudos randomizados em 7105 doentes • Redução significativa da mortalidade global – odds ratio 0.77 (95% C.I. 0.67-0.88); p<0.001 • Redução significativa da mortalidade + hospitalizações por insuficiência cardíaca de 25% – odds ratio 0.65 (95% C.I. 0.57-0.74); p<0.001 • Maiores benefícios em doentes com maior deterioração da função cardíaca SISTEMA RENINA - ANGIOTENSINA Angiotensinogénio Cathepsin G, Calicreína, Tonina, Tripsina Renina Angiotensina I Chymase CAGE, Calicreína, ... Bradicinina ECA Peptídeos inactivos Angiotensina II - ? Antagonistas (AT1) Receptores BK 2 ALDO Vasoconstrição Antinatriurese Proliferação celular Inflamação, aterogenese Hipercoagulação Receptores AT1 Receptores AT2 Vasodilatação Efeito antiproliferativo antiaterogenico ? Óxido nítrico PG ANGIOTENSIN II INHIBITORS MECHANISM OF ACTION RENIN Angiotensin I Angiotensinogen ACE Other paths ANGIOTENSIN II AT1 RECEPTOR BLOCKERS AT1 Vasoconstriction RECEPTORS Proliferative Action AT2 Vasodilatation Antiproliferative Action Pharmacologic Management Angiotensin Receptor Blockers (ARBs) • Block AT1 receptors, which bind circulating angiotensin II • Examples: irbesartan, valsartan, candesartan, losartan • Should not be considered equivalent or superior to ACE inhibitors • In clinical practice, ARBs should be used to treat patients who are ACE intolerant due to intractable cough or who develop angioedema Angiotensin II Receptors AT1 receptor AT2 receptor • Vasoconstriction • Vasodilation • Growth Promotion • Growth inhibition • Anti-apoptotic • Pro-apoptotic • Pro-fibrotic • ? Fibrosis • Pro-thrombotic • ? Thrombosis • Pro-oxidant • ? redox AT1 RECEPTOR BLOCKERS DRUGS Losartan Valsartan Irbersartan Candesartan Competitive and selective blocking of AT1 receptors The ELITE-study 400 350 Losartan Captopril 300 250 200 150 100 p = 0.075 p = 0.035 50 0 Number of patients Adverse events Death and hospitalization Death Pitt et al. Lancet 1997: 349: 747-52 Losartan Heart Failure Survival Study ELITE II Study Design 60 years; NYHA II-IV; EF 40% ACEI/AIIA naive or <7 days in 3 months prior to entry Standard Rx (± Dig/Diuretics), -blocker stratification Captopril 50 mg 3 times daily (n=1574) Event-driven (Target 510 Deaths) ~2 years Losartan 50 mg daily (n=1578) Primary Endpoint: All-Cause Mortality Secondary Endpoint: Sudden Cardiac Death and/or Resuscitated Arrest Other Endpoints: All-Cause Mortality/Hospitalizations Safety and Tolerability Losartan Heart Failure Survival Study – ELITE II Mortality by Cause (Adjudicated) % of Patients 15 Losartan (n=1578) Captopril (n=1574) 10 5 0 Sudden death Heart failure MI Stroke Other CV Non-CV INSUFICIÊNCIA CARDÍACA VALOR DOS ANTAGONISTAS DA AII • MELHORAM OS SINTOMAS, AUMENTAM A QUALIDADE DE VIDA E AUMENTAM A TOLERÂNCIA AO EXERCÍCIO • REDUZEM A MORBILIDADE E O NÚMERO DE HOSPITALIZAÇÕES. • AUMENTAM A ADERÊNCIA AO TRATAMENTO (poucos efeitos secundários). ÓPTIMA ALTERNATIVA AOS IECAS CONCEITO DOS INIBIDORES DAS VASOPEPTIDASES - DUPLO BLOQUEIO DA NEP e da ECA Inibição das vasopeptidases NEP ANP e peptideos Análogos Adrenomedulina Vasodilatação Excreção sódio Efeitos antihipertróficos ECA BK Angiotensina II Vasoconstrição Retenção sódio Efeitos hipertróficos Pressão arterial Melhoria da performance cardíaca Protecção dos orgãos-alvo Omapatrilat: Survival Benefit Cardiomyopathic hamsters 100 Survival (%) 80 60 146 d 221 d 290 d 40 20 Placebo Omapatrilat Captopril 0 40 Start treatment 80 120 160 200 240 280 Days of treatment Trippodo et al. J Cardiovasc Pharmacol 1999;34:782 320 360 400 440 Pharmacologic Management Aldosterone Antagonists • Generally well-tolerated • Shown to reduce heart failure-related morbidity and mortality • Generally reserved for patients with NYHA Class III-IV HF • Side effects include hyperkalemia and gynecomastia. Potassium and creatinine levels should be closely monitored • REDUÇÂO MORTALIDADE ASSOCIADOS AOS InECA • (estudo RALES) ALDOSTERONE INHIBITORS Spironolactone ALDOSTERONE Competitive antagonist of the aldosterone receptor (myocardium, arterial walls, kidney) Retention Na+ Retention H2O Excretion K+ Excretion Mg2+ Edema Collagen deposition Fibrosis Arrhythmias - myocardium - vessels 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 ALDOSTERONE INHIBITORS CONTRAINDICATIONS • Hyperkalemia • Severe renal insufficiency • Metabolic acidosis Pharmacologic Management Beta-Blockers • Cardioprotective effects due to blockade of excessive SNS stimulation • In the short-term, beta blocker decreases myocardial contractility; increase in EF after 1-3 months of use • Long-term, placebo-controlled trials have shown symptomatic improvement in patients treated with certain beta-blockers1 • When combined with conventional HF therapy, betablockers reduce the combined risk of morbidity and mortality, or disease progression1 1 Hunt, SA, et al ACC/AHA Guidelines for the Evaluation and Management of Chronic Heart Failure in the Adult, 2001 p. 20. ß-ADRENERGIC BLOCKERS POSSIBLE BENEFICIAL EFFECTS Density of ß1 receptors Inhibit cardiotoxicity of catecholamines Neurohormonal activation HR Antihypertensive and antianginal Antiarrhythmic Antioxidant Antiproliferative 50 ß BLOCKERS SURVIVAL ß Blocker Placebo 40 30 % 20 10 0 BHAT JACC 1990;16:1327 < 30% 30-40% > 40% LV EJECTION FRACTION ß-ADRENERGIC BLOCKERS IDEAL CANDIDATE? Suspected adrenergic activation Arrhythmias Hypertension Angina US Carvedilol Study blockers in heart failure all-cause mortality Survival 1.0 Carvedilol (n=696) 0.9 Placebo (n=398) 0.8 Risk reduction = 65% 0.7 p<0.001 0.6 0.5 0 50 100 150 200 250 300 350 400 Days Mortality % 20 Survival CIBIS-II 1.0 Packer et al (1996) MERIT-HF Placebo Bisoprolol 15 0.8 Metoprolol CR/XL 10 Placebo Risk reduction = 34% Risk reduction = 34% 5 0.6 p=0.0062 p<0.0001 0 0 0 200 400 Time after inclusion (days) 600 800 Lancet (1999) 0 3 6 9 12 Months of follow-up 15 18 21 The MERIT-HF Study Group (1999) Additional benefits of carvedilol in CHF • Antioxidant effects – reduction in myocyte apoptosis – decreased lipid peroxidation • Antiproliferative effects – inhibition of vascular smooth muscle cell proliferation • Reduction in circulating endothelin-1 Treatment Approach for the Patient with Heart Failure Stage A Stage B Stage C Stage D At high risk, no structural disease Structural heart disease, asymptomatic Structural heart disease with prior/current symptoms of HF Refractory HF requiring specialized interventions Therapy Therapy Therapy Therapy • Treat Hypertension • Treat lipid disorders • Encourage regular exercise • Discourage alcohol intake • ACE inhibition • All measures under stage A • All measures under stage A • All measures under stages A,B, and C • ACE inhibitors in appropriate patients Drugs: • Mechanical assist devices • Beta-blockers in appropriate patients • Diuretics • ACE inhibitors • Beta-blockers • Digitalis • Dietary salt restriction • Heart transplantation • Continuous (not intermittent) IV inotropic infusions for palliation • Hospice care Hunt, SA, et al ACC/AHA Guidelines for the Evaluation and Management of Chronic Heart Failure in the Adult, 2001 Tratamento da Ins. cardiaca Inibidores das fosfodiesterases redutores da produçãode FNT e outras citocinas Pimobendam, vesnarinona, pentoxifilina Ressincronização cardíaca
