Heart failure (ESC,2016)

Transcription

1 Heart failure (ESC,2016) structural or functional cardiac disorder impaired ability of the ventricule to fill with or eject blood clinical syndrome: shortness of breath fatigue fluid retention limitation of exercise tolerance pulmonary congestion, peripheral edema HF a clinical syndrome: symptoms typical of HF fatigue, shortness of breath, peripheral edema + signs typical of HF tachycardia, tachypnoe, pulmonary rales, raised jugular venous pressure, peripheral edema, hepatomegaly + objective evidence of a structural or functional abnormality of the heart at rest cardiomegaly, third heart sound, cardiac murmurs, abnormality on the echocardiogram, raised BNP ESC,2012 CAUSES OF HEART FAILURE Myocardial diseases: - coronary heart disease (2/3) - systemic hypertension - kardiomyopathy - myocarditis (rheumatic, viral) - infiltrative diseases (amyloidosis) Drugs beta-blockers, calcium antagonists, cytotoxic agents, anthiarrhythmics, Toxins alcohol, medications, cocaine Endocrine diabetes mellitus, hypo/hyperthyroidism, Cushing syndrome, adrenal insuff., excessive growth hormone Anemia/hypoxia HEART FAILURE: HF and a reduced EF (HF-REF) - SYSTOLIC HF HF and a precerved EF (HF-PEF) - DIASTOLIC HF SYSTOLIC HEART FAILURE (HF-REF) an impairment of myocardial contractility weakened systolic contraction: reduction in stroke volume (SV), and cardiac output (CO), inadequate ventricular emptying, cardiac dilatation and often elevation of ventricular diastolic pressure EF </= 35%; in advanced HF 20% EF = SV/ left end-diastolic volume (LEDV) In diastolic heart failure (HF-PEF) the principal abnormality is: impaired relaxation and filling which leads to of the ventricle, an elevation of ventricular diastolic pressure at any given diastolic volume EF normal (35-50%), SV and CO reduced 1

2 preload forces acting on the venous side of the circulation to affect myocardial wall tension. venous return LVEDV- left ventricular end diastolic volume LVEDP left ventricular end diastolic pressure preload - venous distention or decreased venous volume preload - venous constriction or increased venous volume afterload is the tension developed in the ventricular wall as contraction (systole) occurs It relates to intraventricular pressure, ventricular diameter, and wall thickness Afterload is regulated by: the resistance or impedance which the ventricle must pump during ejection and is chiefly determined by arterial blood pressure. afterload - hypertension, atherosclerotic disease or a narrow aortic valve afterload - hypotonia Terminology related to the timecourse of heart failure (ESC,2016): NEW ONSET first presentation acute or slow onset TRANSIENT recurrent or episodic CHRONIC patients who have had HF for some time persistent stable, worsening or decompensated Na AND WATER RETENTION BLOOD VOLUME VENOCONSTRICTION PRELOAD SVR - AFTERLOAD Heart failure MYOCYTE DAMAGE LV SYSTOLIC DYSFUNCTION CARDIAC OUTPUT LV END DIASTOLIC PRESS. COMPENSATORY RESPONSES RAA, SNS VENTRICULAR HYPERTROPHY Clinical manifestation of heart failure Chronic HF: 1. increased RAA system activity 2. increased sympathetic system activity 3. cardiac hypertrophy 4. high mortality rate 2

3 RELIEF OF SYMPTOMS in hospitalized patients iv diuretics, positive inotropic agents (dopamine, dobutamine, amrinone) and vasodilatators (sodium nitroprusside, NT) in ambulatory patients - oral diuretics, digitalis and vasodilatators (ACE-I) GOALS OF THE THERAPY slow or prevent the progression of myocardial remodeling, prevent hospital admission ACE-I and/or ARBs beta receptors antagonists aldosterone antagonists Drugs for the management of heart failure 1. Diuretics 2. Aldosterone receptor antagonists 3. Vasodilatators: ACE-I ARBs organic nitrate direct acting (hydralazine, minoxidil) 3. -adrenergic receptor antagonists 4. Iwabradine 5. Cardiac glycosides 6. -adrenergic receptor agonists - dopamine, dobutamine 7. Phosphodiesteraze inhibitors (Bipyridines) 8. Natriuretic peptide POSITIVE INOTROPIC AGENTS CARDIAC GLYCOSIDES Cardiac glycosides slow the ventricular rate reduce hospitalizations have no effects on mortality should be used in conjunction with diuretics, an ACE -I, and a beta-blocker 3

4 Chemistry: All of the cardiac glycosides combine a steroid nucleus to a lactone ring Mechanism of action: Inhibition of Na + K + -ATPase Cardiac effects of glycosides: Cardiac effects of glycosides: mechanical effects increased intensity of the interaction of the actin and myosin filaments of the cardiac sarcomere POSITIVE INOTROPIC EFFECT electrical effects: POSITIVE BATMOTROPIC EFFECT a. the decrease in action potential duration - K + conductance caused by intracellular Ca ++ level b. reduced resting membrane potential (less negative) a result of inhibition of the Na + pump and reduced intracellular K + concentration c. delayed afterdepolarizations (ectopic beat, bigeminy) overloading of the intracellular Ca ++ stores and oscillation in the free intracellular Ca ++ concentration Cardiac effects of glycosides: NEGATIVE CHROMOTROPIC AND DROMOTROPIC EFFECTS a. cardioselective parasympathomimetic effects (lower portion of the dose range) especially at atrial and atrioventricular nodal tissue b. sympathetic activity - toxic levels of glycosides Effects at Therapeutic Dosage Sinus node Rate Rate Effects at toxic dosage Atrial node Refractory period Refractory period, arrhythmias A-v node Purkinje system, ventricular muscle ECG Conduction velocity, refractory period Slight refractory period QT interval, PR interval Refractory period, arrhythmias Extrasystoles, tachycardia, fibrillation Tachycardia, fibrillation, arrest at extremely high dosage 4

5 Positive hemodynamic and neurohormonal effects are observed at lower serum digoxin levels than those needed to induce a positive inotropic effect - reduced sympathetic tone inhibition of Na/KATP-ase in vagal afferent fibres sensitizes cardiac baroreceptors to reduce sympathetic outflow from CNS - stimulated parasympathetic response - Na renal tubular reabsorption renin release Effects on other organs of cardiac glycosides: a. Decrease in vascular tone b. GI tract anorexia, nausea, vomiting, diarrhea (direct effects and stimulation of chemoreceptor trigger zone in CNS) c. CNS vagal and chemoreceptor zone stimulation; disorientation, hallucinations (especially in the elderly), visual disturbances (aberrations of color perception), agitation and convulsions d. Gynecomastia (peripheral estrogenic action or hypothalamic stimulation) Digoxin Digitoxin Ouabain Lipid solubility medium high low Oral availability (percentage absorbed) Half-life in body (hours) Plasma protein binding (percentage bound) Percentage metabolized Volume of distribution (L/kg) 75 (Eubacterium lentum) > >90 0 <20 > Clinical uses of digitalis: - symptomatic HFrEF with sinus rhythm (NYHA class II-IV, STAGE C) - HF with atrial fibrillation (NYHA class I-IV, STAGE A-D) to slow a rapid ventricular rate when other therapeutic options cannot be pursued Digoxin (ESC, 2016) - may be considered TO REDUCE THE RISK of HF hospitalization in patients with an EF 40% and persisting symptoms (NYHA II IV) despite treatment with a beta-blocker, ACE-I (or ARB), and an MRA (or ARB) Contraindication: 1. Second or third-degree heart block 2. arrhythmias associated with pre-excitation syndrome (increased probability of conduction of arrhythmic atrial impulses through the alternative rapidly conducting atrioventricular pathway) 3. hypertrophic cardiomyopathy 4. previous evidence of digoxin intolerance 5

6 Practical Use of Digitalis in HF Serum therapeutic level ng/ml older recommendation ng/ml DAILY DOSE: to 0.25 mg low doses (0.125 mg daily or every other day) should be used if the patient: is over 70 years old, has impaired renal function, has a low lean body mass there is no reason to use loading doses of digoxin to initiate therapy in patients with HF Practical Use of Digitalis in HF Risks of treatment the major side effects include: a.cardiac arrhythmias (e.g., ectopic and re-entrant cardiac rhythms and heart block), b.gi symptoms (e.g., anorexia, nausea, and vomiting), c. neurological complaints (e.g., visual disturbances, disorientation, and confusion). d. digitalis toxicity is commonly associated with serum digoxin levels >2 ng/ml but may occur with lower digoxin levels, especially if hypokalemia, hypomagnesemia, or hypothyroidism co-exist Practical Use of Digitalis in HF Risks of treatment INTERACTIONS: 1. POTASSIUM A. hyperkalemia: reduces the enzyme-inhibiting actions of glycosides; inhibits abnormal cardiac automaticity (moderate increased extracellular K reduces the effect of digitalis) B. hypokalemia: facilitates action of cardiac glycosides 2. CALCIUM - hyperkalcemia - the overloading of intracellular calcium stores, risk factor for arrhythmias 3. MAGNESIUM - hypomagnesemia - risk factor for arrhythmias 4. concomitant use of: quinidine, verapamil, spironolactone, flecainide, propafenone, or amiodarone can increase serum digoxin concentration DOPAMINE DOBUTAMINE PDE-I - MILRINONE, ENOXIMONE LEVOSIMENDAN Inotropic agents CLINICAL INDICATIONS: AHF decompensated chronic HF RISK OF USE: increased oxygen demand - myocardial ischemia, arrhythmias Other positive inotropic drugs used in heart failure DOPAMINE: inotropic, chronotropic and vasoactive properties dose dependent 0.5-2(3)ug/kg/min dopaminergic receptors renal blood flow 2(3) 5 ug/kg/min stimulation of beta-1 receptors inotropic effect, chronotropic effect CO 5-10 ug/kg/min stimulation of beta-1 and alpha-1 receptors vasoactive effect unpredictable >(10)15-20 ug/kg/min activation of alpha-1 receptors SVR Onset of action within minutes Hemodynamic response variable among patients 6

7 Other positive inotropic drugs used in heart failure DOBUTAMINE: agent with predominant direct beta-1 agonist effects and weak beta-2 and alpha-1 effects Infusion rate μg/kg/min compared to dopamine equal or grater inotropic action - PCWP and SVR with increasing doses - less chronotropic at lower infusion rates - preferred in patients with CO, normal or moderately PCWP and moderate or severe hypotension Other positive inotropic drugs used in heart failure drugs that inhibit phosphodiesterases PDE-Is (inodilators) selective (III) milrinone, enoximone inotropic, peripheral vasodilating effect; maintain their effects even during concomitant beta-blocker therapy Clinical indications: - peripheral hypoperfusion, refractory to diuretics and vasodilators at optimal doses, and preserved systemic blood pressure; - may be preferred to dobutamine in patients on concomitant beta-blocker therapy and/or with an inadequate response to dobutamine Other positive inotropic drugs used in heart failure drugs that inhibit phosphodiesterases TOXICITY: milrinone arrhythmias, less toxic to bone marrow and liver Other positive inotropic drugs used in heart failure levosimendan - calcium sensitizer, binds to troponin-c in cardiomyocytes; - mild PDE inhibitory action; - significant vasodilating action via ATPsensitive action; indication - patints with decomensated chronic HF; alternative for patients on beta-blocker therapy Repeated or prolonged use of positive inotropes increases mortality in patients with HF (especially phosphodiesterase inhibitors) Na and water retention hallmark of HF Diuretics: reduce extracellular fluid volume reduce ventricular filling pressure (preload) improve exercise capacity but do not improve survival rate (exception aldosterone antagonists) Diuretics used in the therapy of HF: Thiazides Loop diuretics Potassium sparing diuretics 7

8 Practical Use of Diuretic Therapy Diuretics should be prescribed to all patient: - who have evidence of fluid retention DIURETICS SHOULD GENERALLY BE COMBINED WITH AN ACE- I AND A BETA-BLOCKER (AND USUALLY DIGOXIN) Clinical use of diuretics in patients with HF CHOICE OF THERAPY: mild heart failure thiazides moderate heart failure loop diuretic - furosemide severe heart failure loop diuretic furosemide iv bumetanide po, combination of loop diuretcs and thiazides hypokalemia - potassium-sparing diuretics ADEQUATE MONITORING OF DAILY WEIGHTS, BLOOD PRESSURE, AND BLOOD ELECTROLYTE LEVELS (K, NA, MG) SIDE EFFECTS: hypokalemia/hyperkalemia, hyponatremia, hypomagnesemia, hyperuricemia, acid-base equilibrium disturbances Mineralocorticoid/aldosterone receptor antagonists (MRAs) HF aldosterone level 20x higher than normal Monotherapy with diuretics may cause increased neuro-hormonal activation due to volume depletion and progress heart failure Mechanism Na and water retention K and Mg loss Reduced myocardial NE uptake Reduced baroreceptor sensitivity Myocardial fibrosis, fibroblast proliferation Alteration in Na channel expression Patophysiological effect Edema, cardiac filling pressure Arrythmogenesis and risk for sudden cardiac death Potentation of NE effects: myocardial remodeling and arrythmogenesis Reduced parasymphatetic activity and risk of sudden cardiac death Remodeling and ventricular dysfunction Increased excitability and contractility of cardiac myocytes Mineralocorticoid/aldosterone receptor antagonists (MRAs) SPIRONOLACTONE, EPLERENONE ARE RECOMMENDED for all patients with persisting symptoms (NYHA II IV) and an EF 35%, DESPITE treatment with an ACE-I/ARB and a beta-blocker, to reduce the risk of HF hospitalization and the risk of premature death Mineralocorticoid/aldosterone receptor antagonists (MRAs) Contraindications: serum K concentration > 5.0mmol/L serum creatinine >2.5mg/dL concomitant potassium sparing diuretic or potassium supplements combination of ACE-I and ARB 8

9 Beta-Adrenergic Receptor Blockers long-term activation of the sympathetic nervous system: peripheral vasoconstriction and impairing sodium excretion by the kidneys increase in ventricular volumes and pressure NE RAA cardiac hypertrophy the ability of the coronary arteries to supply blood to the thickened ventricular wall, leading to myocardial ischemia Beta-Adrenergic Receptor Blockers activation of the sympathetic nervous system arrhythmias increased the automaticity of cardiac cells, increased triggered activity in the heart, promotion of the development of hypokalemia Beta-Adrenergic Receptor Blockers Proposed mechanisms of action in patients with heart failure: 1. improvement in left ventricular structure and function 2. decrease in chamber size 3. increase in ejection fraction 4. decrease in malignant ventricular arrhythmias 5. reduction of oxidative stress in the mycoradium Practical Use of Beta-Blockers A beta-blocker is recommended, in addition to an ACE-I/ARB FOR ALL PATIENTS WITH AN EF 40% to reduce the risk of HF hospitalization and the risk of premature death Practical Use of Beta-Blockers beta-blockers should not be used in patients: (1) hospitalized in an intensive care unit, (2) with evidence of fluid overload or volume depletion, (3) required recent treatment with an intravenous positive inotropic agent, (4) with reactive airways disease (5) with symptomatic bradycardia or advanced heart block (unless treated with a pacemaker) Practical Use of Beta-Blockers CONTINUATION OF BETA-BLOCKER TREATMENT DURING AN EPISODE OF DECOMPENSATION: is safe, although dose reduction may be necessary TEMPORARY DISCONTINUATION is advised in shocked or severely hypoperfused patients RE-INSTITUTION OF TREATMENT should be attempted before discharge 9

10 Betablocker Practical Use of Beta-Blockers First dose [mg] Increment s [mg/day] Bisoprolol , 3.75, 5, 7.5, 10 Metoprolol succinate CR 12.5/25 25, 50, 100, 200 Carvedilol , 12.5, 25, 50 Target dose [mg/day] Titration period 10 Weeksmonths 200 Weeksmonths 50 Weeksmonths Nebivolol , 5, Weeksmonths Beta-Adrenergic Receptor Blockers POTENTIAL ADVERSE EFFECTS 1. SYMPTOMATIC HYPOTENSION 2. WORSENING HF 3. EXCESSIVE BRADYCARDIA IVABRADINE IVABRADINE drug that inhibits the If channel in the sinus node Its only known pharmacological effect is TO SLOW THE HEART RATE in patients in sinus rhythm (it does not slow the ventricular rate in AF) IVABRADINE Should be considered to reduce the risk of HF hospitalization in patients in sinus rhythm with an EF 35%, a heart rate 70 b.p.m., and persisting symptoms (NYHA II IV) despite treatment with an evidence-based dose of beta-blocker (or maximum tolerated dose below that), ACE-I(or ARB), and an MRA (or ARB) IVABRADINE May be considered to reduce the risk of HF hospitalization in patients in sinus rhythm with an EF 35% and a heart rate 70 b.p.m. who are unable to tolerate a beta-blocker. Patients should also receive an ACE-I(ARB) and an MRA (or ARB) Drugs Hydralazine Nitrates ACE-I, ARBs Site of dilating action Arterioles Veins and venules Both arterioles and veins 10

11 ACE Inhibitors Effect of ACE Inhibitors in the Management of HF ACE-I can: alleviate symptoms, improve clinical status, reduce the risk of death as well as the combined risk of death or hospitalization Effects of ACE inhibition Veno- and arteriodilation blood pressure - afterload and systolic wall stress venous return to heart (venodilation) preload increased cardiac output, and heart rate increased renal blood flow increased natriuresis increased exercise tolerance improvement in ventricular geometry (changes in preload and afterload, prevention of the growth effects of angiotensin II, decrease aldosteron induced cardiac fibrosis) Selection of patients: An ACE inhibitor is recommended, in addition to a beta-blocker, for all patients with an EF 40% to reduce the risk of HF hospitalization and the risk of premature death. asymptomatic patients to delay the development of HF to reduce the risk of myocardial infarction to reduce the risk of sudden death symptomatic patients to improve survival, symptoms, functional capacity ACE Inhibitors Contraindications: 1. pregnancy 2. hypotension 3. history of angioedema 4. bilateral renal stenosis or stenosis of the artery to a single remaining kidney, others severe kidney s diseases 5. hyperkaliemia, K>5,0mmol/l 6. Serum creatinine >2.5mg/dl (220umol/l) Adverse effects Angiotensin Receptor Blockers ATII *hypotonia *worsening of renal function *hyperkalemia bradykinin ^cough ^angioedema ARBs bind to AT 1 receptors and inhibit biological effects of angiotensin II Differences between ACE-I and ARBs ARBs reduce activation of AT 1 more effectively than do ACE-I (ACE-Is do not inhibit the alternative angiotensin II generating pathway) ARBs indirectly activate AT 2 receptors increasing angiotensin II level ARBs do not increase ACE substrats (bradykinin) 11

12 Angiotensin Receptor Blockers ARNI = angiotensin receptor neprilysin inhibitor Recommendations Concerning ARBs: to reduce the risk of HF hospitalization and the risk of premature death 1. in patients with an EF 40%AND UNABLE TO TOLERATE AN ACE-I because of cough (patients should also receive a beta-blocker and an MRA) 2. n patients with an EF 40% and persisting symptoms (NYHAII IV) DESPITE treatment with an ACE-I and a beta-blocker who are unable to tolerate an MRA ARBs are as likely as ACE-I to produce hypotension, worsening renal function, and hyperkalemia. ARNI = angiotensin receptor neprilysin inhibitor Sacubitril/valsartan recommended as a replacement for an ACE-I to further reduce the risk of HF hospitalization and death in ambulatory patients with HFrEF who remain symptomatic despite optimal treatment with an ACE-I, a beta-blocker and an MRA ARNI = angiotensin receptor neprilysin inhibitor contraindicated with concomitant use of ACE inhibitors. Do not administer within 36 hours of switching from or to an ACE inhibitor. Common adverse effects: Hypotension, hyperkalemia, cough, dizziness and renal failure/acute renal failure Hydralazine and Isosorbide Dinitrate to reduce the risk of HF hospitalization and risk of premature death in patients with an EF 45% and dilated LV (or EF 35%): 1. AN ALTERNATIVE TO AN ACE-I/ARB WHEN ARE NOT TOLERATED, patients should also receive a betablocker and an MRA. 2. AS ADD-ON THERAPY TO AN ACE-I/ARB in patients with persisting symptoms (NYHA II IV) despite treatment with a beta-blocker, ACE-I (or ARB), and an MRA (or ARB). Hydralazine and Isosorbide Dinitrate POTENTIAL ADVERSE EFFECTS: symptomatic hypotension arthralgia/muscle pain, joint pain or swelling, pericarditis, rash or fever drug-induced lupuslike syndrome 12

13 Vasodilators in AHF Nitroprusside arterial vasodilation, PCWP by venodilation NTG - preload Hydralazine direct acting smooth muscles relaxant with significant arteriolar dilating effect with no effect on the venous system Vasodilators in AHF Nesiritide recombinant form of human brain natriuretic peptide (BNP) mixed arterial and venous dilation, Na excretion, suppression of deleterious effects of RAA, SNS PCWP, SVR, CO as a result of decrease in afterload Clinical use AHF with fluid overload Ca 2+ channel antagonists The use of amlodipine or felodipine may be considered in patients requiring: - additional control of blood pressure or afterload reduction or - if other vasodilators are contraindicated or poorly tolerated verapamil and diltiazem may be useful in the treatment of diastolic heart failure (by slowing HR may facilitate diastolic relaxation and lower diastolic filling pressures) Omega-3 polyunsaturated fatty acids An n-3 PUFAf preparation may be considered to reduce the risk of death and the risk of cardiovascular hospitalization in patients treated with an ACE inhibitor (or ARB), beta-blocker, and an MRA (or ARB). EBM IIB Anticoagulant and antiplatelet drugs in HF Anticoagulation therapy is recommended for patients: who have atrial fibrillation Aspirin therapy: patients with CAD related HF alternative antiplatelet agents ticlopidine, clopidogrel (do not interfere with prostaglandins metabolism) Antiarrhytmic drugs in HF Antyarrhythmic drugs - negative inotropic, proarrhythmic properties It is not recommended to use antyarrhythmic drugs in patients with heart failure Exception - amiodarone (agent with additional beta-adrenergic suppressing properties) 13

14 Newer agents in HF Renin inhibitors ALISKIREN Direct renin inhibitor Currently evaluated in 2 RCTs presently not recommended as an alternative to an ACE-I or ARB *HF is a disease associated with high morbidity and mortality *ACE-Is (ARBs), beta-blockers and aldosterone antagonists improve morbidity and mortality in HF patients *diuretics, ivabradine, digoxin, nitrates/hydralazine improve symptoms *basic treatment should include advice regarding the condition, salt and water balance, and the importance of exercices 14