Pharmacotherapy of Heart Failure

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Pharmacotherapy of Heart Failure

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Pharmacotherapy of Heart Failure:

Pharmacotherapy of Heart Failure Dr. Ashutosh Tiwari PG Resident, IInd Year Pharmacology Department SAIMS Indore 14/02/2015

Contents:

Contents Introduction Definition Epidemiology Signs and symptoms Pathophysiology Pharmacotherapy Classification of HF Management Guidelines for HF Recent advances Newer drug targets Conclusion

Introduction:

Introduction Considerable advances have been made in management of heart failure over the past few decades. In outpatient-based clinical trials, mortality has more than halved in people with established systolic chronic heart failure; moreover, admissions have fallen and patients’ quality of life has risen. Nevertheless , heart failure remains a major public- health issue, with high prevalence and poor outcomes. Management of this condition includes appropriate non- pharmacological strategies, use of drugs (particularly those that inhibit key activated neurohormonal systems), and implantation of devices in appropriate patients. Surgery and transplantation are also options for selected individuals with highly advanced disease .

Heart Failure:

Heart Failure The inability of the heart to pump sufficient blood to meet the needs of the tissues for oxygen and nutrients

Symptoms :

Symptoms

Definition:

Definition HF is a complex clinical syndrome that results from any structural or functional impairment of ventricular filling or ejection of blood.

Definition:

Definition Heart failure with reduced ejection fraction ( HF r EF ) EF (%) ≤40 Also referred to as systolic HF coronary artery disease (CAD) with antecedent myocardial infarction (MI) is a major cause of HFrEF

Definition:

Definition Heart failure with preserved ejection fraction ( HF p EF ) EF (%) ≥50 Also referred to as diastolic HF Hypertension, obesity, CAD, diabetes mellitus, and hyperlipidemia are important cause of HFpEF

Epidemiology:

Epidemiology The lifetime risk of developing HF is 20% for Americans ≥40 years of age. HF incidence: >650 000 new HF cases diagnosed annually HF incidence increases with age, rising from approximately 20 per 1000 individuals 65 to 69 years of age to >80 per 1000 individuals among those ≥85 years of age. Mortality rates for HF remain approximately 50% within 5 years of diagnosis The total cost of HF care in the United States exceeds $30 billion annually, with over half of these costs spent on hospitalizations .

Signs and symptoms:

Signs and symptoms Left-Sided Heart Failure: Results from LV dysfunction Blood backs up into Left atrium Pulmonary congestion and edema

Signs and symptoms:

Signs and symptoms Right -Sided Failure: Results from diseased right ventricle Blood backs up into right atrium and venous circulation

Biomarkers in HF:

Biomarkers in HF Natriuretic Peptides: BNP (B-type natriuretic peptide) or NT - proBNP (N-terminal pro-B-type natriuretic peptide) generated by cardiomyocytes in response to myocardial stretch useful to support clinical decision making regarding the diagnosis of HF, especially in the setting of clinical uncertainty useful for establishing prognosis or disease severity in chronic HF

Pathophysiology of HF:

Pathophysiology of HF In order to maintain normal cardiac output, several compensatory mechanisms play a role: Compensatory enlargement in the form of cardiac hypertrophy , cardiac dilatation, or both. Tachycardia (i.e. increased heart rate) due to activation of neurohumoral system e.g. release of norepinephrine and atrial natrouretic peptide, activation of renin-angiotensin aldosterone mechanism.

Pharmacotherapy of HF:

Pharmacotherapy of HF

Goals of Pharmacotherapy:

Goals of Pharmacotherapy Relief of congestion/low cardiac output symptoms & restoration of cardiac performance : Inotropic drugs-digoxin, dobutamine,amrinone / milrinone . Diuretics : furosemide, thiazides. Vasodilators: ACE inhibitors/AT1 antagonist, hydralazine, nitrate. Beta blockers: metoprolol,bisprolol, carvedilol Arrest/reversal of disease progression & prolongation of survival ACE inhibitors/ AT1 antagonist (ARBs). Beta-blockers Aldosterone antagonist-spironolactone

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

Mechanism of action: Cardiac Glycosides:

Mechanism of action: Cardiac Glycosides Act by inhibiting Na + K + ATPase of cardiac cells  increased intracellular Na decreased extrusion of Ca by Na + Ca 2+ exchanger  increased intracellular Ca  increased contractility  increased CO  decreases pulmonary congestion & systemic venous pressure & hence compensatory sympathetic overactivity is withdrawn Decreases heart rate by direct & indirect actions  ↓ myocardial O2 demand

Mechanism of action: ACE Inhibitors:

Mechanism of action: ACE Inhibitors inhibits generation of Angiotensin II , which is a potent vasoconstrictor , causes aldosterone secretion  Na & water retention & causes cardiac hypertrophy & remodeling (by collagen deposition & fibrosis) Inhibits degradation of Bradykinin (potent vasodilator, cough, angioedema)

Mechanism of action: Diuretics:

Mechanism of action: Diuretics Heart failure  accumulation of fluid in lungs & peripheral organs  congestive symptoms Diuretics  promote Na & water excretion  ↓ ECF vol  ↓ preload  reduce symptoms

Mechanism of action: Inotropes:

Mechanism of action: Inotropes Dobutamine & Dopamine: acts via β 1 receptor  increase cardiac contractility  increase CO Milrinone  inhibit phosphodiesterase III  ↑ cAMP in heart & blood vessels  ↑ myocardial contractility & vasodilatation

HF: Classification:

HF: Classification ACCF/AHA (American College of Cardiology Foundation/ American Heart Association) stages of HF NYHA (New York Heart Association) functional classification of HF ACCF /AHA stages of HF emphasize the development and progression of disease whereas NYHA classes focus on exercise capacity and symptomatic status of the disease

HF: Classification:

HF: Classification

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Goals of HF management: Stage A: modifying risk factors Stage B: treating structural heart disease Stage C & D: reducing morbidity and mortality

Stage A: Recommendations :

Stage A: Recommendations Class I Hypertension and lipid disorders should be controlled to lower the risk of HF. Other conditions that may lead to or contribute to HF, such as obesity, diabetes mellitus, tobacco use, and known cardiotoxic agents, should be controlled or avoided.

Stage A: Recommendations :

Stage A: Recommendations Diuretic-based antihypertensive therapy has repeatedly been shown to prevent HF in a wide range of patients; ACE inhibitors, ARBs, and beta blockers are also effective. Data are less clear for calcium antagonists and alpha blockers in reducing the risk for incident HF. Treatment of hyperlipidemia with statins reduces the likelihood of HF in at-risk patients

Stage B: Recommendations :

Stage B: Recommendations ACE inhibitors and Beta blockers should be used in all patients with a reduced EF to prevent HF In patients with MI or history of MI and reduced EF, ACE inhibitors or ARBs and beta blockers should be used to prevent HF In patients with MI, statins should be used to prevent HF Blood pressure should be controlled to prevent symptomatic HF Nondihydropyridine calcium channel blockers may be harmful in patients with low LVEF

Stage C HFrEF recomendations:

Stage C HFrEF recomendations NYHA Class I: ACEI or ARB and Beta Blocker NYHA Class II,III,IV for volume overload: add Loop diuretics for persistently symptomatic : add vasodilators (hydralazine and isosorbide dinitrate ) LVEF ≤35 %, estimated creatinine >30 mL/min and K+ <5.0 mEq / dL : add Aldosterone Antagonist Calcium channel blockers are not recommended as routine treatment in HFrEF

Diuretics: recommendations:

Diuretics: recommendations Diuretics should be prescribed to all patients who have evidence of or prior history of, fluid retention. Diuretics should generally be combined with an ACE inhibitor , beta blocker, and aldosterone antagonist. Loop diuretics have emerged as the preferred diuretic agents for use in most patients with HF. Thiazide diuretics may be considered in hypertensive patients with HF and mild fluid retention because they confer more persistent antihypertensive effects.

Diuretics: recommendations:

Diuretics: recommendations Diuretics increase urinary sodium excretion and decrease physical signs of fluid retention in patients with HF Diuretics are the only drugs used for the treatment of HF that can adequately control the fluid retention of HF. The most commonly used loop diuretic for the treatment of HF is furosemide, but some patients respond more favorably to other agents in this category (e.g., bumetanide , torsemide ) because of their increased oral bioavailability

Diuretics: recommendations:

Diuretics: recommendations Patients may become unresponsive to high doses of diuretic drugs if they consume large amounts of dietary sodium or are taking agents that can block the effects of diuretics (e.g., nonsteroidal anti-inflammatory drugs [NSAIDs] , or have a significant impairment of renal function or perfusion Diuretic resistance can generally be overcome by the intravenous administration of diuretics or combination of different diuretic classes (e.g., metolazone with a loop diuretic)

Diuretics: recommendations:

Diuretics: recommendations Adverse effects: electrolyte and fluid depletion, hypotension and azotemia depletion of potassium and magnesium, which can predispose patients to serious cardiac arrhythmias

ACE Inhibitors: recommendations:

ACE Inhibitors: recommendations ACE inhibitors are recommended in patients with HFrEF and current or prior symptoms, to reduce morbidity and mortality The benefits of ACE inhibition were seen in patients with mild, moderate, or severe symptoms of HF and in patients with or without CAD.

ACE Inhibitors: recommendations:

ACE Inhibitors: recommendations Contraindications H/O life-threatening adverse reactions (i.e., angioedema) during previous medication exposure pregnancy systolic blood pressure <80 mm Hg markedly increased serum levels of creatinine (>3 mg/ dL ) bilateral renal artery stenosis elevated levels of serum potassium (>5.0 mEq /L).

ARB: recommendations:

ARB: recommendations ARBs are recommended in patients with HFrEF with current or prior symptoms who are ACE inhibitor intolerant (cough, angioedema), to reduce morbidity and mortality ARBs were developed with the rationale that a) angiotensin II production continues in the presence of ACE inhibition , driven through alternative enzyme pathways and b ) interference with the renin-angiotensin system without inhibition of kininase would produce all of the benefits of ACE inhibitors while minimizing the risk of adverse reactions to them. However , it is now known that some of the benefits of ACE inhibitors may be related to the accumulation of kinins rather than to the suppression of angiotensin II formation, whereas some of the adverse effects of ACE inhibitors in HF are related to the suppression of angiotensin II formation.

Beta Blockers: Recommendations:

Beta Blockers: Recommendations Use of 1 of the 3 beta blockers proven to reduce mortality (e.g., bisoprolol , carvedilol , and sustained-release metoprolol succinate) is recommended for all patients with current or prior symptoms of HFrEF , to reduce morbidity and mortality Like ACE inhibitors, beta blockers can reduce the risk of death and the combined risk of death or hospitalization

Beta Blockers: Recommendations:

Beta Blockers: Recommendations Adverse effects: fluid retention and worsening HF; fatigue; bradycardia or heart block; and hypotension. if the bradycardia is accompanied by dizziness or lightheadedness or if second- or third-degree heart block occurs, the dose of the beta blocker should be decreased Abrupt withdrawal of treatment with a beta blocker can lead to clinical deterioration and should be avoided

Aldosterone receptor antagonists: Recommendations:

Aldosterone receptor antagonists: Recommendations Aldosterone receptor antagonists (Spironolactone, Eplerenone ) are recommended in patients with NYHA class II–IV HF and who have LVEF of 35% or less, to reduce morbidity and mortality. Aldosterone receptor antagonists are recommended to reduce morbidity and mortality following an acute MI in patients who have LVEF of 40% or less who develop symptoms of HF or who have a history of diabetes mellitus

Aldosterone receptor antagonists: Recommendations:

Aldosterone receptor antagonists: Recommendations To minimize the risk of life- threatening hyperkalemia, patients should have initial serum creatinine <2.5 mg/ dL and serum potassium <5.0 mEq /L without a history of severe hyperkalemia.

Hydralazine & Isosorbide dinitrate: recommendations:

Hydralazine & Isosorbide dinitrate : recommendations The combination of hydralazine and isosorbide dinitrate is recommended to reduce morbidity and mortality for patients with NYHA class III–IV HFrEF who remain symptomatic despite concomitant use of ACE inhibitors, beta blockers, and aldosterone antagonists. Adverse effects include headache, dizziness, and gastrointestinal complaints .

Digoxin: recommendaton:

Digoxin: recommendaton Digoxin can be beneficial in patients with HFrEF , to decrease hospitalizations for HF treatment with digoxin for 1 to 3 months can improve symptoms, HRQOL (Health R elated Quality of Life), and exercise tolerance in patients with mild to moderate HF treatment with digoxin for 2 to 5 years had no effect on mortality but modestly reduced the combined risk of death and hospitalization Digoxin can be used only in patients who remain symptomatic despite therapy with the neurohormonal antagonists or in patients with AF

Digoxin: recommendaton:

Digoxin: recommendaton A dverse effects: cardiac arrhythmias (e.g., ectopic and re-entrant cardiac rhythms and heart block), gastrointestinal symptoms (e.g., anorexia, nausea, and vomiiting ), and neurological complaints (e.g., visual disturbances, disorientation, and confusion) . Overt digoxin toxicity is commonly associated with serum digoxin levels >2 ng / mL. However, toxicity may also occur with lower digoxin levels, especially if hypokalemia, hypomagnesemia , or hypothyroidism coexists

Stage D recommendations:

Stage D recommendations Intravenous inotropic support (Dopamine, Dobutamine , Milrinone ) to maintain systemic perfusion and preserve end-organ performance . C hronic oral inotrope treatment increases mortality, mostly related to arrhythmic events. Inotropes should be considered only in such patients HF who are refractory to other therapies, with systolic dysfunction,and who have low cardiac index and evidence of systemic hypoperfusion and/or congestion

Anticoagulation: Recommendations :

Anticoagulation: Recommendations Patients with chronic HF with permanent/persistent/ paroxysmal AF and an additional risk factor for cardioembolic stroke (history of hypertension, diabetes mellitus , previous stroke or transient ischemic attack, or ‡75 years of age) should receive chronic anticoagulant therapy The selection of ananticoagulant agent ( warfarin,dabigatran , apixaban , or rivaroxaban ) should be individualized on the basis of risk factors, cost, tolerability, patient preference, potential for drug interactions, and other clinical characteristics.

Statins: recommendation:

Statins: recommendation Statins are not beneficial as adjunctive therapy when prescribed solely for the diagnosis of HF in the absence of other indications for their use Originally designed to lower cholesterol in patients with cardiovascular disease, statins are increasingly recognized for their favorable effects on inflammation, oxidative stress, and vascular performance. However, 2 large RCTs have demonstrated that rosuvastatin has neutral effects on long-term outcomes in patients with chronic HFrEF At present, statin therapy should not be prescribed primarily for the treatment of HF to improve clinical outcomes.

Omega-3 Fatty Acids: Recommendation :

Omega -3 Fatty Acids: Recommendation Omega -3 polyunsaturated fatty acid (PUFA) supplementation is reasonable to use as adjunctive therapy in patients with NYHA class II–IV symptoms and HFrEF or HFpEF , to reduce mortality and cardiovascular hospitalizations Trials in primary and secondary prevention of coronary heart disease showed that omega-3 PUFA supplementation results in a 10% to 20% risk reduction in fatal and nonfatal cardiovascular events.

Nutritional Supplements and Hormonal Therapies :

Nutritional Supplements and Hormonal Therapies Several nutritional supplements (e.g., coenzyme Q10, carnitine , taurine , and antioxidants) and hormonal therapies (e.g., growth hormone or thyroid hormone) have been proposed for the treatment of HF No clinical trials have demonstrated improved survival rates with use of nutritional or hormonal therapy, with the exception of omega-3 fatty acid supplementation

Device Therapy for HF:

Device Therapy for HF Implantable cardioverter -defibrillator Cardiac resynchronization therapy Mechanical Circulatory Support Cardiac Transplantation

Non-pharmacological Management:

Non-pharmacological Management Sodium Restriction to 2g/day Risk Factor Management Exercise Decreases mortality Decreases hospitalizations Multidisciplinary, Disease-Management Approach Aspirin, beta-blocker, Nitrates, ACE-I, Statin, Exercise, Smoking Cessation, Dietary

Recent Advances in the management of HF:

Recent Advances in the management of HF

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On August 30, 2014 at the European Society of Cardiology congress and published simultaneously in the New England Journal of Medicine, Novartis revealed that its investigational heart failure medicine, LCZ696, was superior to ACE-inhibitor enalapril on key endpoints in the largest heart failure study ever done PARADIGM-HF is a randomized, double-blind, phase III study evaluating the efficacy and safety profile of LCZ696 versus enalapril (a widely studied ACE inhibitor) in 8,442 patients with HF-REF. The trial was stopped early, according to prespecified rules, because the boundary for an overwhelming benefit with LCZ696 had been crossed.

LCZ696:

LCZ696 LCZ696, represents one of the most important cardiology advances of the last decade It acts to enhance the protective neurohormonal systems of the heart (NP system) while simultaneously suppressing the harmful system (the RAAS ) reduced the risk of death from cardiovascular causes by 20% (p=0.00004) reduced heart failure hospitalizations by 21% (p=0.00004 ) reduced the risk of all-cause mortality by 16% (p=0.0005) Overall there was a 20% risk reduction on the primary endpoint, a composite measure of CV death or heart failure hospitalization (p=0.0000002)

LCZ696 :

LCZ696 LCZ696 is an ARNI (Angiotensin Receptor Neprilysin Inhibitor ) It harnesses the body's natural defences against heart failure, simultaneously acting to enhance the levels of natriuretic and other endogenous vasoactive peptides, while also inhibiting the renin- angiotensin-aldosterone system (RAAS). Neprilysin , a neutral endopeptidase , degrades several endogenous vasoactive peptides, including natriuretic peptides, bradykinin , and adrenomedullin . Inhibition of neprilysin increases the levels of these substances, countering the neurohormonal overactivation that contributes to vasoconstriction, sodium retention, and mal- adaptive remodeling.

LCZ696 :

LCZ696 Combined inhibition of the renin–angiotensin system and neprilysin had effects that were superior to those of either approach alone in experimental studies but in clinical trials, the combined inhibition of ACE and neprilysin was associated with serious angioedema due to inhibition of enzymes responsible for degradation of bradykinin . LCZ696, which consists of the neprilysin inhibitor sacubitril (AHU377) and the ARB valsartan , was designed to minimize the risk of serious angioedema as it does not inhibit ACE .

New targets in clinical development for acute heart failure :

New targets in clinical development for acute heart failure

New targets in clinical development for chronic heart failure :

New targets in clinical development for chronic heart failure

Activation of SERCA2a :

Activation of SERCA2a In patients with heart failure, there is decreased calcium content in the sarcoplasmic reticulum , which is partly due to the diminished sarcoplasmic reticulum calcium adenosine triphosphatase isoform 2a (SERCA2a) pump activity. Istaroxime is a molecule that has the unprecedented ability to increase the SERCA2a pump activity and cause myocardial relaxation. It also causes inhibition of Na+/K+-ATPase

Cardiac myosin ATPase activation :

Cardiac myosin ATPase activation During myocardial contraction, the myosin head works as an independent force generator if it is bound tightly to actin. However, the majority of myosin heads are not tightly bound to actin in the physiological state. This can be changed by omecamtiv mecarbil , which increases the number of myosin heads that are in force-generating configuration to get tightly bound to actin that leads to enhanced cardiac contraction.

Relaxin:

Relaxin Relaxin hormone, besides being produced by the corpus luteum and placenta, is also produced by the failing myocardium. It acts on a G-protein coupled receptor named RXFP1 that is produced in the vasculature , heart and the kidneys. As a result, cAMP & nitric oxide production is increased Serelaxin ( human recombinant relaxin ) causes greater vasodilation and improved vessel compliance

Natriuretic peptides :

Natriuretic peptides ANP is mainly produced in atrial myocytes . The main stimulant for ANP release is atrial wall stretch resulting from increased intravascular volume ANP has vasodilatory , natriuretic, diuretic, and kaliuretic properties. Carperitide is a recombinant ANP for the treatment of acute heart failure syndrome Urodilatin is a modified form of pro-ANP that is synthesized and secreted from the distal convoluted tubules in the kidney and regulates renal sodium reabsorption and water homeostasis Ularitide is a synthetically derived form of urodilatin

Ryanodine receptor stabilizers :

Ryanodine receptor stabilizers The ryanodine receptors that are present in the sarcoplasmic reticulum of the heart cause release of calcium on activation. Under resting conditions, the ryanodine receptor channel is maintained in a closed state by a protein calstabin -2. JTV519 is a drug that can potentiate the binding of calstabin to ryanodine, and thus help it to retain its closed state S44121 is a ryanodine receptor stabilizer, studied in patients with heart failure who are at increased risk for ventricular arrhythmia.

Neuregulins :

Neuregulins The neuregulins are proteins that belong to the epidermal growth factor family of ligands that bring about their effects through ErbB tyrosine kinase receptors. reduced ErbB signaling in the failing myocardium increases its chance of cell death and rapid worsening of heart failure Recombinant NRG-1β has been evaluated in several animal models of cardiac failure and found to improve the structural and functional indices for ventricular remodeling recombinant neuregulin-1 improved the LVEF and reduced the LV remodeling by decreasing EDV and ESV

Sarcoplasmic reticulum calcium ATPase 2A gene therapy :

Sarcoplasmic reticulum calcium ATPase 2A gene therapy The enzyme SERCA2a catalyzes the adenosine triphosphate- dependent movement of calcium ions into the sarcoplasmic reticulum from the cytosol Increase of calcium levels by augmenting SERCA2a activity will improve cardiac function. Istaroxime causes overexpression of SERCA2a in the cardiomyocytes of the failing heart in order to improve the contraction velocity gene transfer using adenovirus as a vector for delivery of SERCA2a complementary DNA is being studied

NEED FOR NEWER THERAPIES:

NEED FOR NEWER THERAPIES Available drugs treat only symptomatically Even the available drugs do not control symptoms effectively Associated side effects are more Needed life long treatment HF is associated with high morbidity and mortality

Conclusion:

Conclusion Despite advances in management of heart failure, the condition remains a major public-health issue, with high prevalence, poor clinical outcomes, and large health-care costs. Risk factors are well known and, thus, preventive strategies should have a positive effect on disease burden. Emerging strategies for heart failure management include individualisation of treatment, novel approaches to diagnosis and tracking of therapeutic response, pharmacological agents aimed at new targets, and cell-based and gene-based methods for cardiac regeneration .

Conclusion :

Conclusion Agents directly acting on remodeling process may even reverse current pathological condition of heart failure . The newer therapeutics may be potential candidates in future for heart as there is increase in understanding of pathophysiology of heart failure.

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