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CHRONIC HEART FAILURE Faculty of Medicine University of Brawijaya Introduction Definition : Heart Failure “The situation when the heart is incapable of maintaining a cardiac output adequate to accommodate metabolic requirements and the venous return.“ E. Braunwald “Pathophysiological state in which an abnormality of cardiac function is responsible for the failure of the heart to pump blood at a rate commensurate with the requirements of the metabolizing tissues.” Euro Heart J; 2001. 22: 1527-1560 DEFINITION OF HEART FAILURE. Criteria 1 and 2 should be fulfilled in all cases 1. Symptoms of heart failure (at rest or during exercise) And 2. Objective evidence of cardiac dysfunction (at rest) And (in cases where the diagnosis is in doubt) 3. Response to treatment directed towards heart failure Task Force Report. Guidelines for the diagnosis and treatment of chronic heart failure. European Society of Cardiology.2001 EPIDEMIOLOGY Europe The prevalence of symptomatic HF range from 0.4-2%. 10 million HF pts in 900 million total population Guidelines for the diagnosis and treatment of chronic heart failure European Heart Journal (2001) 22, 1527-1560 USA nearly 5 million HF pts. ± 500,000 pts are D/ HF for the 1st time each year. Last 10 years number of hospitalizations has increased. Nearly 300,000 patients die of HF each year. ACC/AHA Guidelines for the Evaluation and Management of Chronic Heart Failure in the Adult 2001 DESCRIPTIVE TERMS in HEART FAILURE Acute vs Chronic Heart Failure Systolic vs Diastolic Heart Failure Right vs Left Heart Failure Mild , Moderate, Severe Heart Failure Guidelines for the diagnosis and treatment of chronic heart failure European Heart Journal (2001) 22, 1528 New York Heart Association (NYHA) Classification of Heart Failure Class – I No limitation : ordinary physical exercise does not cause undue fatigue, dyspnoea or palpitations. Class – II Slight limitation of physical activity : comfortable at rest but ordinary activity results in fatigue, dyspnoea, or palpitation. Class - III Marked limitation of physical activity : comfortable at rest but less than ordinary activity results in symptoms. Class - IV Unable to carry out any physical activity without discomfort : symptoms of heart failure are present even at rest with increased discomfort with any physical activity. Guidelines for the diagnosis and treatment of chronic heart failure European Heart Journal (2001) 22, 1531 (Adapted from Williams JF et al., Circulation. 1995; 92 : 2764-2784) ACC/AHA – A New Approach To The Classification of HF Stage Descriptions Examples A Patient who is at high risk for developing HF but has no structural disorder of the heart. Hypertension; CAD; DM; rheumatic fever; cardiomyopathy. B Patient with a structural disorder of the heart but who has never developed symptoms of HF. LV hypertrophy or fibrosis; LV dilatation; asymptomatic VHD; MI. C Patient with past or current symptoms of HF associated with underlying structural heart disease. Dyspnea or fatigue ec LV systolic dysfunction; asymptomatic patients with HF. D Patient with end-stage disease Frequently hospitalized pts ; pts awaiting heart transplantation etc ACC/AHA Guidelines for the Evaluation and Management of Chronic Heart Failure in the Adult 2001 Stages in the evolution of HF and recommended therapy by stage • • • • • • Stage A Stage B Pts with : • Hypertension • CAD • DM • Cardiotoxins • FHx CM Pts with : • Previous MI • LV systolic dysfunction • Asymptomatic Valvular disease Struct. Heart Disease THERAPY Treat Hypertension Stop smoking Treat lipid disorders Encourage regular exercise Stop alcohol & drug use ACE inhibition THERAPY • All measures under stage A • ACE inhibitor • Beta-blockers Stage C Stage D Pts with : Develop Symp.of HF • Struct. HD Refract. • Shortness of Symp.of breath and fatigue, HF at rest reduce exercise tolerance THERAPY • All measures under stage A • Drugs for routine use: • diuretic • ACE inhibitor • Beta-blockers • digitalis • • • • Pts who have marked symptoms at rest despite maximal medical therapy. THERAPY All measures under stage A,B and C Mechanical assist device Heart transplantation Continuous IV inotrphic infusions for palliation ACC/AHA Guidelines for the Evaluation and Management of Chronic Heart Failure in the Adult 2001 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 Evolution of the Concept of Heart Failure 1950 to 2000 1950 2000 Aetiology Hypertension Valvular heart dis CHD Hypertension Dilated CMP Natural Course Slowly progressive Understanding Hemodynamic model Slowly progressive (remodelling) or unpredictable and rapid ( coronary event ) Neurohormonal model Common cause of death Pulmonary infection Sudden death Pump failure Arrhythmia Atrial Ventricular Treatment goal Control edema Slowing Heart Rate Improve quality of life + reduce mortality + reduce hospitalization Patophysiology of C H F g a b c d e g f a AO Aortic closure Aortic pressure Ventricular pressure Crossover Heart sounds A2 P2 S 3 M1 T1 S4 MO Atrial pressure Cardiologic systole a c v Opie (2001) JVP T P P ECG Q S 0 800 msec The Wiggers cycle g f e a b iso c d iso PULMONARY VENOUS PRESSURE Input Filling Emptying Stroke EF ED volume x effective = volume LV Distensibility x Contractility Relaxation Afterload Heart Left atrium Preload rate Mitral valve Pericardium Structure Diastolic function Systolic function Output CARDIAC OUTPUT Block diagram of left ventricular pump performance (Little, 2001) PRESSURE – VOLUME CURVE OF SYSTOLIC AND DIASTOLIC FAILURE DIASTOLIC FAILURE Normal Normal diastolic chamber distensibility Left Ventricular Volume Left Ventricular Pressure Left Ventricular Pressure SYSTOLIC FAILURE Decreased diastolic chamber distensibility Left Ventricular Volume (Zile & Brutsaert 2002) Left ventricular pressure Abnormal relaxation Pericardial restraint B A Chamber dilation Increased chamber stiffness C D Left ventricular volume Mechanisms that cause diastolic dysfunction. (Zile, 1990) DETERMINANTS OF VENTRICULAR FUNCTION CONTRACTILITY PRELOAD AFTERLOAD STROKE VOLUME - Synergistic LV contraction - LV wall integrity - Valvular competence CARDIAC OUTPUT HEART RATE Frank-Starling Law Normal Cardiac Output Compensated Normal C.O. CHF LVEDP Ventricular Function Curve: Frank-Starlings Normal SV LVEDV Congestion The Pathophysiology of Heart Failure Hurst. The Heart. Diagnosis and Management of Heart Failure.10th ed. 688 Pathophysiological Sequence of CHF Heart Failure Inadequate Cardiac Output ( ) O2 Delivery (rest and/or exercise) Systemic Vasoconstriction SAS (NE)) RAAS (A-II) () Flow to Skin, Gut, and Renal Circulations Neurohormonal Activation Activation of RAS and ANS Hurst. The Heart. Diagnosis and Management of Heart Failure.10th ed. 688 Frank-Starling Effect Ventricular dilatation Wall stress O2 consumption Coronary perfusion SNS Preload Afterload Renin release Angiotensin II Growth factors ALDO Vasoconstriction Hypertrophy Apoptosis Fluid accumulation Collagen deposition SNS: sympathetic nervous system Myofibril necrosis Sympathetic nervous system up-regulation Increased Norepinephrine levels Activation of the RAA system Increased Angiotensin II & Aldosteron Na+ & water retention Vasoconstriction Direct Myocardial toxicity Decreased Renal blood flow Myocyte dysfunction Increased HR, PVR & arteriolar vasoconstriction Increased myocardial oxygen demand Cardiac remodeling Myocyte necrosis Intracellular Ca2+ overload/ Energy depletion Apoptosis Cesario et.al; Reviews in cardiovascular medicine, vol 3, no.1, 2002 Causes of Heart Failure Myocardial Damage or Disease Infarction (Acute) / Ischemia Myocarditis Hypertrophic Cardiomyopathy Excess Load on Ventricle Volume/ Pressure Overload Resistance to Flow into Ventricle Cardiac Arrhythmias Primary Changes in CHF Site of Failure Backward Failure Right Heart () Systemic Failure Venous Pressure Left Heart Failure Forward Failure () ejection into Pulmonary Artery () Pulmonary () ejection Venous into aorta Pressure MI-INDUCED HEART FAILURE Myocardial Damage Contractility Pump Performance () Systolic Work Load Vasoconstriction RAAS SYSTEM FLUID RETENTION () SAS Drive Diagnosis of C H F IDENTIFICATIONS OF HF PATIENTS With a Syndrome of Decrease Exercise Tolerance With a Syndrome of Fluid Retention With No Symptoms or Symptoms of Another Cardiac or Non Cardiac Disorder (MI, Arrythmias, Pulmonary or Systemic Thromboembolic Events) SYMPTOMS AND SIGN Breathlessness, Ankle Swelling, Fatique → Characteristic Symptoms Peripheral Oedema, JVP ↑, Hepatomegaly → Signs of Congestion of Systemic Veins S3 , Pulmonary Rales , Cardiac Murmur ECG A low Predictive Value LAH and LVH May Be Associated wit LV Dysfunction Anterior Q-wave and LBBB a good predictors of EF ↓↓ Detecting Arrhytmias as Causative of HF CHEST X-RAY A Part of Initial Diagnosis of HF → Cardiomegaly, Pulmonary Congestion Relationship Between Radiological Signs and Haemodynamic Findings may Depend on the Duration and Severity HF HAEMATOLOGY & BIOCHEMISTRY A Part of Routine Diagnostic Hb, Leucocyte, Platelets Electrolytes, Creatinine, Glucose, Hepatic Enzyme, Urinalysis TSH, C-RP, Uric Acid ECHOCARDIOGRAPHY The Preferred Methods Helpful in Determining the Aetiology Follow Up of Patients Heart Failure PULMONARY FUNCTIONS A Little Value in Diagnosis Heart Failure Usefull in Excluding Respiratory Diseases EXERCISE TESTING Focused on Functional, Treatment Assessment and Prognostic STRESS ECHOCARDIOGRAPHY For Detecting Ischaemia Viability Study NUCLEAR CARDIOLOGY Not Recommended as a Routine Use CMR ( CARDIAC MAGNETIC RESONANCE IMAGING) Recommended if Other Imaging Techniques not Provided Diagnostic Answer INVASIVE INVESTIGATION Elucidating the Cause and Prognostic Informations Coronary Angiography : in CAD’s Patients Haemodynamic Monitoring : To Assess Diagnostic and Treatment of HF Endomyocardial Biopsy : in Patients with Unexplained HF NATRIURETIC PEPTIDES Cardiac Function ↓↓ (LV Function ↓↓) → ↑↑ Plasma Natriuretic Peptide Concentration (Diagnostic Blood Use for HF) Natriuretic Peptide ↑↑ : Greatest Risk of CV Events Natriuretic Peptide ↓↓ : Improve Outcome in Patients with Treatment Identify Pts. With Asymptomatic LV Dysfunction (MI, CAD) ALGORITHM FOR THE DIAGNOSIS OF THE HF (ESC, 2001) Suspected Heart Failure Because of symptoms and signs Assess Presence of Cardiac Disease by ECG, X-Ray or NatriureticPeptides (Where Available) If Normal Heart Failure Unlikely Tests Abnormal Imaging by Echocardiography (Nuclear Angiography or MRI Where Available) If Normal Heart Failure Unlikely Tests Abnormal Assess Etiology, Degree, Precipitating Factors and Type of Cardiac Dysfunction Choose Therapy Additional Diagnosis Tests Where Appropriate (e.g. Coronary Angiography) Treatment of C H F Aims of Treatment 1. Prevention a) Prevention and/or controlling of diseases leading to cardiac dysfunction and heart failure b) Prevention of progression to heart failure once cardiac dysfunction is established 2. Morbidity Maintenance or improvement in quality of life 3. Mortality Increased duration of life Guidelines for the diagnosis and treatment of chronic heart failure European Heart Journal (2001) 22, 1527-1560 ACC/AHA & EUROPE (ESC) 2001 GUIDELINES FOR THE MANAGEMENT OF HEART FAILURE ACE-inhibitor → Use as first line therapy → Should be up titrated to the dosages shown in the large clinical trial, and not titrated based on symptomatic improvement DIURETIC → to control fluid overload Β-BLOCKER → For all patients with stable mild-severe HF on standard treatment ACC/AHA & EUROPE (ESC) 2001 GUIDELINES FOR THE MANAGEMENT OF HEART FAILURE Aldosteron Receptor Antagonis → in advance HF ( NYHA III-IV ) DIGOXIN → in AF (atrial fibrillation) → May be added for symptom relief ARB → Considered in patients not tolerate ACEinhibitors and not on β - blocker Management Outline Establish that the patient has HF. Ascertain presenting features: pulmonary oedema, exertional breathlessness, fatigue, peripheral oedema Assess severity of symptoms Determine aetiology of heart failure Identify precipitating and exacerbating factors Identify concomitant diseases Estimate prognosis Anticipate complications Counsel patient and relatives Choose appropriate management Monitor progress and manage accordingly Guidelines for the diagnosis and treatment of chronic heart failure European Heart Journal (2001) 22, 1527-1560 TREATMENT Correction of aggravating factors Pregnancy Arrhythmias (AF) Infections Hyperthyroidism Thromboembolism Endocarditis Obesity Hypertension Physical activity Dietary excess MEDICATIONS Treatment options Non-pharmacological management General advice and measures Exercise and exercise training Pharmacological therapy Angiotensin-converting enzyme (ACE) inhibitors Diuretics Beta-adrenoceptor antagonists Aldosterone receptor antagonists Angiotensin receptor antagonists Cardiac glycosides Vasodilator agents (nitrates/hydralazine) Positive inotropic agents Anticoagulation Antiarrhythmic agents Oxygen Devices and surgery Revascularization (catheter interventions and surgery), other forms of surgery Pacemakers Implantable cardioverter defibrillators (ICD) Heart transplantation, ventricular assist devices, artificial heart Ultrafiltration, haemodialysis Guidelines for the diagnosis and treatment of chronic heart failure European Heart Journal (2001) 22, 1527-1560 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. 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 Pharmacological therapy Stages in the evolution of HF and recommended therapy by stage • • • • • • Stage A Stage B Pts with : • Hypertension • CAD • DM • Cardiotoxins • FHx CM Pts with : • Previous MI • LV systolic dysfunction • Asymptomatic Valvular disease Struct. Heart Disease THERAPY Treat Hypertension Stop smoking Treat lipid disorders Encourage regular exercise Stop alcohol & drug use ACE inhibition THERAPY • All measures under stage A • ACE inhibitor • Beta-blockers Stage C Stage D Pts with : Develop Symp.of HF • Struct. HD Refract. • Shortness of Symp.of breath and fatigue, HF at rest reduce exercise tolerance THERAPY • All measures under stage A • Drugs for routine use: • diuretic • ACE inhibitor • Beta-blockers • digitalis • • • • Pts who have marked symptoms at rest despite maximal medical therapy. THERAPY All measures under stage A,B and C Mechanical assist device Heart transplantation Continuous IV inotrphic infusions for palliation ACC/AHA Guidelines for the Evaluation and Management of Chronic Heart Failure in the Adult 2001 1. ACE INHIBITOR Angiotensin-converting enzyme inhibitors Recommended as first-line therapy. Should be uptitrated to the dosages shown to be effective in the large, controlled trials, and not titrated based on symptomatic improvement. Moderate renal insufficiency and a relatively low blood pressure (serum creatinine 250 µmol.l-1 and systolic BP 90 mmHg) are not contraindications. Absolute contraindications: bilateral renal artery stenosis and angioedema. Guidelines for the diagnosis and treatment of chronic heart failure European Heart Journal (2001) 22, 1527-1560 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 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 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 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) ACE-Inhibitors in Asymptomatic Heart Failure Development of symptomatic HF Hospitalization of HF SAVE & TRACE Study Guidelines for the diagnosis and treatment of chronic heart failure European Heart Journal (2001) 22, 1527-1560 ACE-Inhibitors in Symptomatic Heart Failure All patients symptomatic Heart Failure should receive ACE-I. A) No fluid retention, ACE-I should be given first. B) With fluid retention, ACE-I + Diuretic ACE-I : A) improves survival and symptoms. B) reduces hospitalization. Guidelines for the diagnosis and treatment of chronic heart failure European Heart Journal (2001) 22, 1527-1560 ACE INHIBITORS USED TO TREAT HEART FAILURE DRUG DOSE RANGE (mg)FREQUENCY TARGET DOSE FOR SURVIVAL BENEFIT* Captopril 6.25 – 150 Three times daily 50 mg three times daily Enalapril 2.5 – 20 Twice daily 10 mg twice daily Lisinopril 2.5 – 40 Daily Ramipril2.5 – 10 Once or twice daily 5 mg twice daily Quinapril 5 – 20 Twice daily Zofenopril† 30 mg twice daily Trandolapril† 4 mg daily Imidapril HCl 5 – 10 Once daily 10 mg daily * Target doses are those associated with increased survival in clinical trials † This drug is not approved in the United States 2. DIURETICS Diuretics Essential for symptomatic treatment when fluid overload is present and manifest. Always be administered in combination with ACE inhibitors if possible. Guidelines for the diagnosis and treatment of chronic heart failure European Heart Journal (2001) 22, 1527-1560 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 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) DIURETICS ADVERSE REACTIONS K-SPARING DIURETICS Changes in electrolytes: Na+, K+, acidosis Musculoskeletal: Cramps, weakness Cutaneous allergic reactions : Rash, pruritis 3. ALDOSTERONE INHIBITORS 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 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 receptor antagonists - spironolactone Recommended in advanced HF (NYHA III-IV), in addition to ACE inhibition and diuretics to improve survival and morbidity Guidelines for the diagnosis and treatment of chronic heart failure European Heart Journal (2001) 22, 1527-1560 Aldosterone receptor antagonists - spironolactone The RALES mortality trial Low dose spironolactone (12.5–50 mg) on top of an ACE inhibitor and a loop diuretic improved survival of patients in advanced heart failure (NYHA class III or IV). 4. ß-Blockers Start Low Go Slow Activation and Blockade of Neurohumoral System in CHF RAA System SNS System Angiotensin II Noradrenalin ACE-I β-Blocker Hypertrophy, apoptosis, ischaemia, arrhytmia, remodeling, fibrosis ADRENERGIC ACTIVATION ↑ CNS Sympathetic Outflow ↑ Sympathetic activity to kidneys & blood vessels ↑ Cardiac Sympathetic activity β1-receptors β2-receptors a1-receptors Mycocyte hypertrophy & death, dilatation, ischaemia & arrhytmia’s Vasoconstriction Sodium Retention Packer, AHA 2000 Why add-on β-blocker, if HF patient is already stable on standard therapy with ACE-I, diuretics ± digoxin ? Benefits of “Add-on” β-Blocker Short-term : 1. Improvement of symptoms (LVEF ↑) 2. Improvement of NYHA class 3. Improvement of daily activities 4. Reduction of hospitalization rate & length of hospital stay (financial & psychological burden) Long-term : 1. Slowing the progression of CHF 2. Increase of survival rate Beta-adrenoceptor antagonists Recommended for the treatment of all pts with stable, mild, moderate and severe heart failure on standard treatment, unless there is a contraindication. Patients with LV systolic dysfunction, with or without symptomatic HF, following an AMI long-term betablockade is recommended in addition to ACE inhibitor. Guidelines for the diagnosis and treatment of chronic heart failure European Heart Journal (2001) 22, 1527-1560 PHARMACOLOGICAL PROPERTIES OF β-BLOCKING AGENT FOR HF a- β1BLOKADE β2BLOKADE BLOKADE ISA ANCILLARY EFFECTS Carvedilol +++ +++ +++ - +++ Metoprolol +++ - - - - Bisoprolol +++ - - - - AGENT ISA: intrinsic sympathetic activity THE RECOMMENDED PROCEDURE FOR STARTING β-BLOCKER 1. Patient should be on standard therapy (ACE inhibitor +/- diuretic) 2. Patient in stable conditions No iv inotropic therapy Without signs of marked fluid retention 3. Start initial low doses and titrate to maintenance dose (the dose may be doubled every 1 – 2 weeks) (ESC.Guidelines for HF, 2001) DOSES OF β-BLOCKER β BLOCKER FIRST DOSE TARGET DOSE TITRATION PERIOD Bisoprolol 1.25 mg 10 mg Weeks – Month Metoprolol Tartrate 5 mg 150 mg Weeks – Month Metoprolol Succinate 12.5 mg 200 mg Weeks – Month Carvedilol 2 x 3.125 mg 2 x 25 mg Weeks – Month (European Heart Journal, vol. 22, Sept. 2001) CONTRAINDICATIONS OF β-BLOCKER IN PATIENT H F Asthma Bronchial Severe Bronchial Desease Symptomatic Bradycardia and Hypotension INTOLERANCE OF β-BLOCKER Symptomatic Bradycardia Worsening HF Hypotension How to Handle Intolerance SYMPTOMATIC BRADYCARDIA Check Blood Digoxin and/or reduce other AV nodus inhibiting drugs Reduces β-Blocker dose or if necessary stop it Consider implantation of pacemaker How to Handle Intolerance WORSENING HF Increase dose of Diuretics Reduces β-Blocker dose or if necessary stop it If indicated, give inotropic drugs or nitroprusside or nitroglycerin How to Handle Intolerance HYPOTENSION Reduces ACE-I or vasodilator Take β-Blocker : After meal At different time than ACE-I Reduces dose or if necessary stop it 5. Angiotensin II receptor antagonists 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 AT1 RECEPTOR BLOCKERS DRUGS Losartan Valsartan Irbersartan Candesartan Competitive and selective blocking of AT1 receptors Angiotensin II receptor antagonists ARBs could be considered in patients who do not tolerate ACE inhibitors for symptomatic treatment. It is unclear whether ARBs are as effective as ACE inhibitors for mortality reduction. In combination with ACE inhibition, ARBs may improve heart failure symptoms and reduce hospitalizations for worsening heart failure. Guidelines for the diagnosis and treatment of chronic heart failure European Heart Journal (2001) 22, 1527-1560 6. Cardiac glycosides DIGOXIN Na-K ATPase Na+ K+ K+ Na+ Na-Ca Exchange Na+ Myofilaments Ca++ Ca++ CONTRACTILITY 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 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 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 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 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 Cardiac glycosides indicated in atrial fibrillation and any degree of symptomatic heart failure. A combination of digoxin and beta-blockade appears superior than either agent alone. In sinus rhythm, digoxin is recommended to improve the clinical status of patients with persisting heart failure despite ACE inhibitor and diuretic treatment. Guidelines for the diagnosis and treatment of chronic heart failure European Heart Journal (2001) 22, 1527-1560 Cardiac glycosides DIG trial Long-term digoxin did not improve survival. The primary benefit and indication for digoxin in heart failure is to reduce symptoms and improve clinical status decrease the risk of hospitalization for heart failure without an impact on survival. 7. Vasodilator agents Vasodilator agents in chronic heart failure No specific role for vasodilators in the treatment of HF Used as adjunctive therapy for angina or concomitant hypertension. In case of intolerance to ACE inhibitors ARBs are preferred to the combination hydralazine–nitrates. HYDRALAZINE-ISOSORBIDE DINITRATE Hydralazine (up to 300 mg) in combination with ISDN (up to 160 mg) without ACE inhibition may have some beneficial effect on mortality, but not on hospitalization for HF. Nitrates may be used for the treatment of concomitant angina or relief of acute dyspnoea. Guidelines for the diagnosis and treatment of chronic heart failure European Heart Journal (2001) 22, 1527-1560 8. Positive inotropic therapy 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 CarbuterolFenoterol Salbutamol SalmefamolQuinterenol Mixed Dopamine 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 POSITIVE INOTROPES CONCLUSIONS May increase mortality Safer in lower doses Use only in refractory CHF NOT for use as chronic therapy Positive inotropic therapy Commonly used to limit severe episodes of HF or as a bridge to heart transplantation in end-stage HF. Repeated or prolonged treatment with oral inotropic agents increases mortality. Currently, insuffcient data are available to recommend dopaminergic agents for heart failure treatment. Guidelines for the diagnosis and treatment of chronic heart failure European Heart Journal (2001) 22, 1527-1560 Positive inotropic therapy POSITIVE INOTROPHIC AGENTS Dobutamin Milrinone Levosimendan DOPAMINERGIC AGENTS Ibopamine is not recommended for the treatment of chronic HF due to systolic LV dysfunction. Intravenous dopamine is used for the sort-term correction of haemodynamic disturbances of severe episodes of worsening HF. Guidelines for the diagnosis and treatment of chronic heart failure European Heart Journal (2001) 22, 1527-1560 9. Antiarrhythmics ANTIARRHYTHMICS Sustained VT, with/without symptoms - ß Blockers - Amiodarone Sudden death from VF - Consider implantable defibrillator 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 Antiarrhythmics No indication for the use of antiarrhythmic agents in HF Indications for antiarrhythmic drug therapy include AF (rarely flutter), non-sustained or sustained VT. CLASS I ANTIARRHYTHMICS should be avoided CLASS II ANTIARRHYTHMICS Beta-blockers reduce sudden death in heart failure CLASS III ANTIARRHYTHMICS Amiodarone is the only antiarrhythmic drug without clinically relevant negative inotropic effects. Guidelines for the diagnosis and treatment of chronic heart failure European Heart Journal (2001) 22, 1527-1560 10. Anticoagulation 11. Antiplatelet Drugs 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 Anticoagulation Recommendation 1. All pts with HF and AF should be treated with warfarin unless contraindicated. 2. Patients with LVEF 35% or less. HFSA Guidelines for Management of Patients With Heart Failure Caused by Left Ventricular Systolic Dysfunction - Pharmacological Approaches 2000 Antiplatelet Drugs Recommendation There is insufficient evidence concerning the potential negative therapeutic interaction between ASA and ACE inhibitors. Antiplatelet agent for pts with HF who have underlying CAD. HFSA Guidelines for Management of Patients With Heart Failure Caused by Left Ventricular Systolic Dysfunction - Pharmacological Approaches 2000 A Chronic heart failure — choice of pharmacological therapy LV systolic dysfunction ACE inhibitor Diuretic Beta-blocker Aldosterone Antagonist Asymptomatic LV dysfunction Indicated Not indicated Post MI Not indicated Symptomatic HF (NYHA II) Indicated Indicated if Fluid retention Indicated Not indicated Worsening HF (NYHA III-IV) Indicated Indicated comb. diuretic Indicated End-stage HF (NYHA IV) Indicated Indicated comb. diuretic Indicated Indicated Indicated Guidelines for the diagnosis and treatment of chronic heart failure European Heart Journal (2001) 22, 1527-1560 B Chronic heart failure — choice of pharmacological therapy LV systolic dysfunction Angiotensin II receptor antagonists Asymptomatic LV dysfunction Not indicated Symptomatic HF (NYHA II) Worsening HF (NYHA III-IV) End-stage HF (NYHA IV) Vasodilator (hydralazine/ Potassium -sparing Cardiac glycosides isosorbide diuretic dinitrate) With AF Not indicated (a) when AF If ACE inhibitors If ACE inhibitors and angiotensin are not tolerated (b) when improved from more severe II antagonists and not on betaare not HF in sinus blockade tolerated rhythm If ACE inhibitors If ACE inhibitors and angiotensin are not tolerated indicated II antagonists and not on betaare not blockade tolerated If ACE inhibitors If ACE inhibitors and angiotensin are not tolerated indicated II antagonists and not on betaare not blockade tolerated Not indicated If persisting hypokalaemia If persisting hypokalaemia If persisting hypokalaemia Guidelines for the diagnosis and treatment of chronic heart failure European Heart Journal (2001) 22, 1527-1560 Intervention Surgical Revascularization Non Surgical Pts with heart failure of ischaemic origin revascularization symtomatic improvement. A strong negative correlation of operative mortality and LVEF, a low LVEF (<25%) was associated with increased operative mortality. Advance HF symptoms (NYHA IV) resulted in a greater mortality rate. Off pump coronary revascularization may lower the surgical risk for HF. Heart Transplantation is an accepted mode of treatment for end-stage HF. Guidelines for the diagnosis and treatment of chronic heart failure European Heart Journal (2001) 22, 1527-1560 Care and Follow-up Recommended components of programs use a team approach vigilant follow-up, first follow-up within 10 days of discharge discharge planning increased access to health care optimizing medical therapy with guidelines intense education and counselling inpatient and outpatient strategies address barriers to compliance early attention to signs and symptoms flexible diuretic regimen Guidelines for the diagnosis and treatment of chronic heart failure European Heart Journal (2001) 22, 1527-1560 Future treatment Neurohormonal modulation 1. 2. 3. 4. 5. 6. 7. Sympathetic nervous system The RAA system Atrial and brain natriuretic peptides Arginin vasopressin Endothelin Growth hormone Calcitonin gene related peptide Cardiac reparation: fixing the heart with cells, new vessels and genes (1) Cell based interventions Aims: to repopulate fibrous scars with new contractile cells 1. Multiplication of residual myocytes (forcing the cells to enter mytotic cycle) 2. Transforming fibrablasts in the scar 3. Implanting exogenous contractiles cells (foetal cardiomyocites, skeletal myoblasts, stem cells) Eur Heart J 2002;4: D73-81 CON’T (2) Angiogenesis Aims: to provides new blood supply to the diseased heart 1. Administration of angiogenic growth factors VEGF, basic FGF 2. Problems: nature of compound , dose, route, and adverse events (abnormal blood vessels, proliferative retinopathy, etc) Eur Heart J 2002;4: D73-81 CON’T(3) Gene therapy Aims: to improve the function of the failing heart 1. Gene manipulation of 3 majors areas: Ca handling, beta-adenergic signalling and apoptosis 2. Inducing expression of silent genes Safety problems: control of targeted protein expression, inflammation, autoimmunity and oncogenesis (basically irreversible) Eur Heart J 2002;4: D73-81 Resume Pharmacological Treatment : I. Asymptomatic Systolic LV dysfunction : • • II. ACE Inhibitor -Blocker (in CAD) Symptomatic Systolic LV dysfunction A. No fluid retention ACE Inhibitor -Blocker If ischaemia (+) nitrate / revascularization B. Fluid retention Diuretic ACE Inhibitor (ARBs if not tolerated) -Blocker ± Digitalis Resume III. Worsening HF Standard treatment : ACE Inhibitor, -Blocker Diuretic : doses + loop diuretic Low dose spironolactone Digitalis Consider : » Revascularization » Valve surgery » Heart transplant IV. End-stage HF Intermittent inotrophic support Circulatory support (IABP, Ventr.Assist Devices) Haemofiltration on dialysis briddging to heart transplantation Conclusion Management of HF must be starting from the earlier stage (AHA/ACC stage A). Treatment at each stage can reduce morbidity and mortality. Before initiating therapy : Established the correct diagnose. Consider management outline. Conclusion Non pharmacolgical intervention are helpfull in : improving quality of life reducing readmission lowering cost. Organize multi-disciplinary care : HF clinic, HF nurse specialist, pts telemonitoring. Health care system. To optimize HF management Treatment should be according to the Guidelines, intensive education, and behavioral change efforts. THANK YOU Have a nice study !!!