Christopher Gans MDNovember 25 t h, 2013cpgans@uic.edu

DRUG TREATMENT OF HEART FAILURE

Epidemiology of Heart Failure (HF) – Why is this important?

Definition of Heart Failure – Systolic versus DiastolicPathophysiology of Heart Failure – What are we

treating? The importance of volume and contractility

Drug Therapies for Acute HF Indications, mechanisms and monitoring

Drug Therapies for Chronic HF Indications, mechanisms and monitoring

OBJECTIVES

EPIDEMIOLOGY OF HEART FAILURE

Cardiovascular Disease remains the #1 killer in the US

Advancements in the last 20 years have resulted in a curtailing of the number of patients with CAD and more importantly, more people surviving AMIs.

This has resulted in more patients living with ventricular dysfunction and more HF patients. Currently over 500,000 patients but projected to double in the next 20 years!

Despite technological advancements, the prognosis for HF patients remains grim, with mortality close to 50% at 5 years from diagnosis1.

One in nine death certificates lists HF as one of the causes1.

EPIDEMIOLOGY

1. Heart Disease and Stroke Statistics - 2013 Update. Circulation. 2013; 127: e6-e245

Inability to produce adequate cardiac output to meet the metabolic requirements of the body.

Can result from impairment of either phase of ventricular function: Systolic HF or HF with reduced Ejection Fraction (HFrEF) Diastolic HF or HF with preserved Ejection Fraction (HFpEF)

Systolic HF (HFrEF) will be our focus today, but be aware that HFpEF is increasing in incidence, and has no proven drug therapies for improving morbidity or mortality

HFrEF is the syndrome, while cardiomyopathy refers to the ventricular dysfunction. It results from a multitude of cardiac diseases including: CAD, hypertension, valvular disease, arrhythmias, toxins including alcohol and congenital abnormalities.

DEFINITION OF HEART FAILURE

Heart Fai lure is a cl inical syndrome, characterized by: Major criteria:

Paroxysmal nocturnal dyspnea Neck vein distention Rales Radiographic cardiomegaly (increasing heart size on chest radiography) Acute pulmonary edema S3 gallop Increased central venous pressure (>16 cm H2O at right atrium) Hepatojugular reflux Weight loss >4.5 kg in 5 days in response to treatment

Minor criteria: Bilateral ankle edema Nocturnal cough Dyspnea on ordinary exertion Hepatomegaly Pleural eff usion Decrease in vital capacity by one third from maximum recorded Tachycardia (heart rate>120 beats/min.)

DEFINITION OF HEART FAILURE

Determinants of Cardiac Output:

PATHOPHYSIOLOGY OF HF

Heart Rate Determined by sympathetic tone (b receptors) and vagal

innervation (baroreceptor reflex).

Stroke Volume – infl uenced by contractility, afterload and preload Contractility is the ability to generate pressure and is inherent

to the myocardium, can be increased by sympathetic tone (b receptors) as well as ionotropic drugs (b agonists).

Afterload is the resistance to flow which the ventricle must overcome to generate forward flow. Don’t confuse this with arterial blood pressure, as it depends on peripheral vascular resistance as well as aortic impedance.

Preload is the amount of myocardial distention at the start of contraction. It can be influenced by venous return and overall plasma volume, and it’s relation to contractility can be plotted as the Starling curve.

PATHOPHYSIOLOGY OF HF

In normal ventricles, increasing preload results in a mild increase in stroke volume.

In failing ventricles, increasing preload will not increase stroke volume but will increase end diastolic pressure, leading to higher left atrial pressures and more resistance to flow from the pulmonary circuit.

PATHOPHYSIOLOGY OF HF

PATHOPHYSIOLOGY OF HF

PATHOPHYSIOLOGY OF HF

Decreased Contractility

Decreased Stroke Volume

Increased volume/preload means higher LVEDP

Narrower pulse pressure

The decreased contractility and stroke volume lead to a decrease in cardiac output.

The decreased pressure at the carotid sinus leads to increased sympathetic discharge in an attempt to increase heart rate, afterload and contractility.

Decreased renal perfusion leads to activation of the RAAS in an attempt to increase plasma volume.

PATHOPHYSIOLOGY OF HF

That’s a great compensatory mechanism, but the SNS and RAAS don’t know that the ventricle is failing.

Increasing afterload and preload only lead to more LV dilation and a decrease in stroke volume, further decrease in cardiac output and so on and so on…

PATHOPHYSIOLOGY OF HF

Try to think of HFrEF with two major components of pathophysiology: Decreased contractility leading to poor stroke volume.

Medications can influence contractility directly (ionotropes) or indirectly (vasodilators, ACE inhibitors, ARBs, b blockers)

Increased plasma volume contributing to poor stroke volume via increased preload, but also leading to increased filling pressures and many of the symptoms of ‘congestion’ including dyspnea, edema and orthopnea. This component is largely treated with diuretics.

As you’ll see both of these components need to be treated successfully in both the acute and chronic patients.

PATHOPHYSIOLOGY OF HF

Acute HF therapies should be tailored to the patient’s individual hemodynamic parameters, by assessing both volume status and perfusion.

Cold v. Warm (perfusion) Wet v. Dry (congestion)Treat decreased perfusion with ionotropes and vasodilators Treat congestion with diuretics and vasodilators

DRUG THERAPY FOR ACUTE HF

Stevenson L W Eur J Heart Fail 2005;7:323-331

Increasing contractility can be performed with ionotropic agents, typically those that act as b agonists. Dobutamine – a selective b1 agonist can increase cardiac

contractility by increasing cAMP. a1 and b2 activation in the vasculature are offset, so it results in only small changes in blood pressure and can produce vasodilation at low doses. Dobutamine can be useful in patients with poor perfusion but increased vascular resistance. (Cold and wet)

Dopamine – at low doses stimulates D1 receptors in the renal vasculature to increase renal blood flow to augment diuresis, but at higher doses also stimulates b and a receptors to increase contractility. Dopamine can be useful in HF patients with decreased perfusion who are hypotensive. (Wet and cold or warm with hypotension)

Both of these agents are additive with other sympathomimetics, and can increase myocardial oxygen consumption, so watch out for angina or arrhythmias such as ventricular tachcyardias.

DRUG THERAPY FOR ACUTE HF

Bipyridines – Milrinone acts as a PDE-3 inhibitor, and can increase contractility by increasing inward calcium fl ux. They also act as vasodilators by increasing cAMP in smooth muscles. Toxicity includes bone marrow toxicity and hepatic dysfunction as well as arrhythmias, and studies in the US have shown a small increase in mortality associated with these subjects for only a minimal increase in effi cacy compared to dobutamine. Controversy still exists about the role of milrinone in acute HF treatment, but some smaller studies suggest it may be useful in patients chronically treated with b blockers.

Natriuretic peptides – Nesiritide is a recombinant natriuretic peptide, theoretically used to augment renal sodium excretion. It has never been shown to change in hospital mortality and is incredibly expensive. It has been shown to be associated with worsening hypotension.

DRUG THERAPY FOR ACUTE HF

Vasodilators can improve hemodynamics acutely by reducing venous tone and reducing preload or by reducing arterial tone and reducing afterload. They have been shown to increase diuresis in acute HF but never been shown to have an eff ect on short term morbidity or mortality. Nitroglycerin acts primarily as a venodilator by increasing

cGMP in smooth muscle, resulting in reduced venous return and reduced preload. Caution in use with patients demonstrating isolated right heart failure as too much preload reduction can lead to hemodynamic collapse.

Nitroprusside is an obligate NO donor, and acts as a both a venodilator and arterial dilator. Very useful in patients with increased PVR and volume overload, but cannot be used in patients with renal dysfunction.

DRUG THERAPY FOR ACUTE HF

Diuretics work to increase renal sodium excretion (natriuresis) with accompanying water (diuresis). This can result in decreased preload and ventricular fi lling pressures, improving both hemodynamics as well as symptoms. Since the goal is to create diuresis, loop diuretics such as furosemide are the most useful acutely. Furosemide – Blocks sodium resorption in the thick ascending

loop, resulting in a loss of hypertonic renal medulla and thus abolishing the osmotic gradient for water resorption. This results in increased excretion of water and salt.

Bumetanide and torsemide have similar MOAs, but increased oral bioavailability and half lifes respectively.

Thiazide diuretics block sodium resorption in the distal convoluted tubule, and will not aff ect the renal medulla, resulting in generally less water excretion. They are not used clinically for the management of HF.

DRUG THERAPY FOR ACUTE HF

Acute HF Summary Base your therapy on the patient’s hemodynamics, and

make sure to address perfusion as well as congestion. Do use loop diuretics to treat congestion. Do use vasodilators in congested patients, particularly if

not responding to diuretics alone. Do use ionotropes to treat poor perfusion, but watch out for

arrhythmias and angina. Don’t use thiazide diuretics to treat HF. Don’t use nesiritide to treat acute HF without exhausting

other therapies first. Don’t use milrinone unless patients are not responding to

dobutamine (normotensive) or dopamine (hypotensive).

DRUG THERAPY FOR ACUTE HF

Class Mechanism Effects Utility Kinetics/Toxicities

Loop DiureticsFurosemideTorsemideBumetanide

Inhibit Na resorption in thick loop of Henle

Increase sodium and water excretionDecrease preload and LVEDPReduce pulmonary and peripheral edema

Congestive symptoms

Oral and IV, duration 4-6 hours, watch for orthostatic hypotension, hypokalemia, ototoxicity at high doses

IonotropesDobutamineDopamine

b receptor agonism Increase contractilityDobutamine is relatively BP neutral Dopamine increases BP/PVR

Decreased perfusion

IV only, last minutes, watch for arrhythmias and angina

IonotropesMilrinone

Inhibits PDE-3 – increasing intracellular calcium

Increased contractility

Decreased perfusion

IV only, lasts minutes, watch for arrhythmias and angina

VasodilatorsNitroglycerinNitroprusside

NO mediated – increased cGMP in smooth muscles

NTG reduces venous tone and return resulting in decreased preloadNTP also reduces arterial tone and reduces afterload

Improved stroke volume in congested patients

IV form useful for acute HF, last only minutes, watch for hypotensionNo NTP in renal failure

VasodilatorsNesiritide

Recombinant BNP Augments diuresis No proven benefit

IV only in the US, watch for hypotension

DRUG THERAPY FOR ACUTE HF

Chronic HF implies that the patient is somewhat well compensated, and the goal shifts to maintaining an appropriate volume status while attempting to prevent further destabilization of ventricular function. Goals of therapy for chronic HF focus on reducing symptoms and improving morbidity and mortality.

Ionotropes are not used in chronic HF, except for severe HF which can sometimes be ionotrope dependent. This a bad prognostic sign and is associated with increased mortality.

Most drugs for chronic HF aim to break the vicious cycle of neurohormonal activation and decreased cardiac output.

Diuretics for chronic HF are the same, but now with an emphasis on maintaining volume balance rather than total diuresis.

DRUG THERAPY FOR CHRONIC HF

ACE inhibitorsAngiotensin receptor

blockersb BlockersDigoxinAldosterone antagonistsHydralazine and nitrates

DRUG THERAPY FOR CHRONIC HF

ACE inhibitorsAngiotensin receptor

blockersb BlockersDigoxinAldosterone antagonistsHydralazine and nitrates

DRUG THERAPY FOR CHRONIC HF

ACE inhibitors block the conversion of angiotensin to angiotensin I I , resulting in a decrease in sodium retention amongst other benefi ts.

ACE inhibitors also delay the degradation of bradykinin, which acts as a vasodilator.

ACE inhibitors have been shown to reduce ventricular remodeling, the dilatation of the ventricle in response to volume and pressure overload.

DRUG THERAPY FOR CHRONIC HF

HOPE trial. NEJM 342:145-153 1/20/2000

ACE inhibitors have been shown to reduce mortality in HF, and should be used in every HF patient without a contraindication.

Less than 1% of patients treated with an ACE inhibitor can develop an angioedema reaction.

ACE inhibitors appear to have a class eff ect in HF.

DRUG THERAPY FOR CHRONIC HF

CHARM trial. Circulation. 2004; 110: 2180-2183

Patients who can’t tolerate ACE inhibitors can be treated with angiotensin receptor blockers (ARBs).

Similar eff ect with less vasodilation, they have also been shown to decrease mortality.

Both ACE-I’s and ARBs can cause potassium retention and decreased renal perfusion, so monitor for hyperkalemia and azotemia.

DRUG THERAPY FOR CHRONIC HF

b blockers are typically thought of as negative ionotropes and may seem counterintuitive in HF, but some b blockers have been shown to decrease morbidity and mortality when used in conjunction with ACE/ARBs.

This eff ect is likely due to blunting of sympathetic activation on the myocardium, thus reducing eventual fi brosis and apoptosis.

b blockers also have an antiarrhythmic eff ect, decrease renin secretion, and decrease myocardial oxygen consumption.

Only three B blockers have been shown to be benefi cial in chronic HF, carvedilol, metoprolol succinate and bisoprolol.

Nebivolol is approved in Europe for HF, but in the US only for hypertension.

Start at a low dose and monitor for bradycardia.

DRUG THERAPY FOR CHRONIC HF

MERIT-HF. JAMA. 2000;283(10):1295-1302COPERNICUS trial. AJC. Vol 93, Issue 9 No 1, 6 May 2004, Pages 35–39

It is important to diff erentiate the use of b blockers during the chronic phase versus the acute phase.

In acutely decompensated HF, b blockers are relatively contraindicated as cardiac output is dependent on heart rate and b blockade can lead to hemodynamic instability and shock.

b blockers should be initiated once the patients are euvolemic, well compensated and being prepared for discharge.

Patients admitted with ADHF can usually be continued on their stable dose of b blockers, but titration is only in euvolemic patients.

DRUG THERAPY FOR CHRONIC HF

RALES. N Engl J Med 1999; 341:709-717

Aldosterone release is stimulated by angiotensin II, but can also be prompted by ACTH, serum potassium levels and sympathetic tone.

Adding aldosterone receptor blockade to ACE/ARB and b blocker therapy has been shown to reduce mortality in patients with symptomatic HF, particularly post-MI.

Has been shown to reduce ventricular remodeling, probably by preventing fibrosis in both the ventricle and arteries.

Aldosterone normally stimulates potassium excretion, so antagonism usually blocks sodium resorption without a concomitant loss of potassium.

Spironolactone can cause gynecomastia, but eplerenone has a much smaller incidence of this side eff ect.

DRUG THERAPY FOR CHRONIC HF

AA-HEFT. N Engl J Med 2004; 351:2049-2057

Hydralazine and isosorbide dinitrate are arterial and venodilators respectively.

When used concomitantly, they act to reduce both afterload and preload.

Mortality benefit has only been shown in African Americans, and was modest compared to ACE inhibitors and b blockers.

It should be used in symptomatic patients on ACE/ARB and b blocker therapy, but dosing regimen limits its utility, as both these medications are taken orally every 8 hours.

DRUG THERAPY FOR CHRONIC HF

Digoxin is a cardiac glycoside, extracted from the foxglove plant.

It acts as an inhibitor of the Na/K ATPase, resulting in increased intracellular sodium and decreased calcium expulsion by the Na/Ca exchanger.

In net, this results in increased intracellular calcium and increased contracti l ity.

DRUG THERAPY FOR CHRONIC HF

[Na]i

While this is good for a mild increase in cardiac contractility, it aff ects all cardiac tissues including the sinus and AV nodes.

As dosage approaches toxic levels, increased intracellular calcium can trigger spontaneous release of stores in the SR, leading to membrane depolarizations known as ‘delayed afterdepolarizations’. This can lead to bigeminy or even alternating bundle branch tachycardias.

DRUG THERAPY FOR CHRONIC HF

More commonly, digoxin exerts autonomic eff ects by sensitizing baroreceptors and vagal stimulation.

This results in decreased sinus node automaticity, increased conduction velocity and increased refractory period in the AV node. This can be particularly useful in rate control for SVTs.

While it is said that digoxin toxicity can cause any arrhythmia, pathognomonic rhythms include atrial tachycardia with AV block, alternating bundle branch block VT or accelertaed junctional rhythm.

Patients with hypokalemia, hypercalcemia and impaired renal function are at the highest risk for digoxin toxicity.

DRUG THERAPY FOR CHRONIC HF

DIG trial. N Engl J Med 1997; 336: 525-533.

Digoxin has been used for centuries to treat heart failure, as well as a host of other cardiac maladies.

Today, its use is limited to HF and rate control of SVTs. At therapeutic levels, it is easily overrun by the sympathetic system, so never use it as your sole agent.

In HF, studies have shown a trend toward improved survival on digoxin, but not statistically significant. It has been shown to reduce symptoms and improve QOL. Many suggest that digoxin’s small therapeutic window (serum levels of 0.8-1.0 ng/ml) contributes largely to its lack of findings in trials.

If toxic, administer potassium, hold calcium and administer digoxin antibodies.

DRUG THERAPY FOR CHRONIC HF

DRUG THERAPY FOR HF

ACE inhibitors – fi rst line in all patients with HF, with or without symptoms, class IA. These are the cornerstone of HF therapy.

ARBs – class IA for patients who can’t tolerate ACE inhibitors or reasonable to add if symptomatic patients can’t tolerate aldosterone antagonism.

b blockers – IA for all symptomatic patients and asymptomatic patients with CAD

Aldosterone antagonists – IA for patients symptomatic on ACE/ bB or in HF patients post MI

Vasodilators (hydralazine/nitrate) – IA in African American patients still symptomatic on ACE/ bB

Digoxin – IIaB in symptomatic patients on ACE/ bB

DRUG THERAPY FOR CHRONIC HF

First Line

Second Line

DRUG THERAPY FOR CHRONIC HF

Class Mechanism Effects Utility Kinetics/Toxicities

ACE inhibitorsLisinoprilEnalaprilCaptoprilRamiprilOthers

Blocks conversion of angiotensin to angiotensin II. Blocks degradation of bradykinin.

Decreased sodium retention.Vasodilation via bradykinin.Alters gene expression and reduces ventricular remodeling.

All HF patients

Oral, clinically useful doses last 12-24h. Monitor serum potassium, some patients develop cough or angioedema (rare).

Angiotensin Receptor BlockersLosartanValsartanOthers

Blocks effects of angiotensin II at receptor.

Similar to ACE inhibitors, less convincing evidence for reduction of remodeling.

HF patients intolerant to ACE inhibitor

Oral, clinically useful doses last 6-8h. Monitor serum potassium, some patients develop cough or angioedema (rare).

Beta Receptor AntagonistsCarvedilolMetoprolol SuccinateBisoprolol

Block beta-adrenergic receptor. Blunts myocardial response to SNS.

Reduced myocardial oxygen consumptionAV nodal block reduces heart rateDecreased ionotropyDecreased myocardial apoptosis, fibrosis,

All HF patients with symptoms.

Oral, lasts 10-12h, monitor for bradycardia, AV block.

DRUG THERAPY FOR CHRONIC HF

Class Mechanism Effects Utility Kinetics/Toxicities

Aldosterone receptor antagonistsSprionolactoneEplerenone

Blocks effect of aldosterone at receptor.

Increased salt and water excretion.Reduces ventricular remodeling.

HF patients symptomatic on ACE/bB

Oral, lasts 24-48h. Monitor serum potassium, some patients develop gynecomastia (spiro only, reversible with d/c).

VasodilatorsHydralazine and Isosorbide Dinitrate

Increases cGMP, donates NO.

Arterial and venous dilation to reduce preload and afterload.

African American HF patients symptomatic on ACE/bB

Oral, lasts 8-12h, requires q8h dosing.

Cardiac GlycosidesDigoxin

Blocks Na/K ATPase leading to increased i[Ca]

Increased myocardial contraction, decreases AV nodal conduction/sinus rate.

HF patients symptomatic on ACE/bB

Oral, lasts 36-40h, renal excreted, monitor for arrhythmia. Narrow therapeutic window.

Drugs to Avoid in HF patients: Non-dihydropyridine CCBs, particularly verapamil but also

diltiazem Peripherally active NSAIDs Class IA antiarrhythmic medications particularly flecainide Dronaderone

DRUG THERAPY FOR CHRONIC HF

Feel free to contact me with any questions or for further reading at cpgans@uic.edu

Want to try a case?

QUESTIONS?