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treatment_of_heart_failure

Treatment of Heart Failure

By the end of the self study you should be able to:

1. Define the concepts of preload, myocardial contractility and afterload as determinants of

left ventricular performance.
2. Explain the difference between systolic dysfunction and diastolic dysfunction in
congestive heart failure.
3. Explain the rational for the use of diuretics, inotropic agents & vasodilators in the
treatment of systolic heart failure.
4. Explain the beneficial effects of ACE inhibitors (ARBs), aldosterone antagonists and beta
blockers on the heart in patients with systolic heart failure.
5. Explain the rationale for using calcium channel blockers and beta-adrenergic blockers in
the treatment of diastolic heart failure.
6. Explain the beneficial effects of furosemide and nitroglycerin in treating acute pulmonary
edema

Drugs:

 Diuretics: furosemide, torsemide

 Positive inotropes: digoxin, dobutamine, dopamine
 Vasodilators: nitrates (nitroglycerin, isosorbide dinitrate), nitroprusside, nesiritide,
hydralazine
 ACE Inhibitors: captopril, enalapril, ramipril
 ARBs: losartan, valsartan
 Aldosterone Antagonists: spironolactone
 Beta blockers: metoprolol, carvedilol
 Calcium Channel Blockers: diltiazem, verapamil
 Morphine (for acute treatment of associated pulmonary edema)
 Drug Class with Therapeutic Promise:
o Neprilysin Inhibitors: sacubitril, LCZ696 (sacubitril + valsartan)

Abbreviations:

 ARB - Angiotensin Receptor Blocker

 ACE – Angiotensin Converting Enzyme
 CHF – Congestive Heart Failure
INTRODUCTION

Heart failure is a pathophysiologic state in which an abnormally 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, while maintaining normal filling pressures. This
condition is often, but not necessarily, caused by an abnormality in myocardial contraction
(myocardial failure). Myocardial failure can result from primary myocardial disease
(cardiomyopathies), ischemia (coronary insufficiency due to atherosclerosis), or long-standing
hemodynamic overload (hypertension, valvular heart disease). Heart failure in the absence of
myocardial failure can result from acute hemodynamic overload (i.e., hypertensive crisis, rupture
of mitral or aortic valve leaflet), or impairment of ventricular filling (i.e., constrictive
pericarditis, pericardial tamponade). It is now recognized that patients with congestive heart
failure may suffer from systolic dysfunction, diastolic dysfunction or both. While the clinical
manifestations may be similar, the therapeutic approach to treatment of these two subtypes of
heart failure is fundamentally different.

 In systolic dysfunction the patient will manifest a reduced ejection fraction (less than
45%) due to pump failure, usually associated with ventricular dilatation and
cardiomegaly.

 Patients with diastolic dysfunction, on the other hand, have ejection fractions greater
than 50%. In these patients, cardiac output is reduced due to a “stiff heart” that does not
allow for adequate ventricular filling during diastole.

A detailed description of the clinical manifestations and types of heart failure is beyond the
scope of this discussion. However, in order to understand the rationale for the treatment of heart
failure, some basic points will be highlighted.

Consequences of Heart Failure: The inability of the heart to meet the metabolic demands of
peripheral tissues results in tissue hypoperfusion and inadequate delivery of oxygen. These
result in a widening of the A-V oxygen difference (normal 3.5-5.0 ml per 100 ml at rest), and,
clinically, in the symptoms of fatigue and weakness, particularly with physical effort.

Heart failure also results in pulmonary and systemic venous hypertension. Pulmonary venous
hypertension leads to pulmonary congestion, and, if severe enough, to pulmonary edema (i.e.,
when the pulmonary capillary hydrostatic pressure exceeds a critical level of 25-40 mm Hg,
according to the Starling law of capillary-interstitial fluid exchange). Clinically, this results in
decreased lung compliance and increased work of breathing leading to dyspnea (respiratory
distress).

Systemic venous hypertension is responsible for the development of congestive hepatomegaly,

and peripheral edema, as well as fluid accumulation in the thoracic and abdominal cavities
(hydrothorax, ascitis).

REVIEW OF COMPENSATORY MECHANISMS IN HEART FAILURE

To compensate for the presence of heart failure, the body attempts to compensate for the
decreased cardiac output by the following four mechanisms:

1. The Frank-Starling Mechanism. At any given inotropic state, myocardial performance

(stroke volume) is dependent on myocardial end-diastolic fiber length (this is referred to
as the preload, and is usually equated with left-ventricular end-diastolic volume or
pressure – or venous pressure) (Figure 1). The normal heart, and the heart in the early
stages of heart failure, operates in the ascending limb of the Starling curve.
2. Sympathetic Stimulation. Cardiac output is the product of heart rate and stroke volume.
Thus, an increase in sympathetic tone, resulting in an increase in heart rate & contractility
are a first-line compensatory mechanism in heart failure (Figure 2). Patients in congestive
heart failure commonly have marked elevations in the rate of norepinephrine excretion in
the urine.
3. Renin-Angiotensin-Aldosterone System. The major determinants of filling pressure are
blood volume and venous capacity. In the presence of heart failure, effective filling of the
systemic arterial tree is reduced, and this results in hemodynamic and hormonal
adjustments that lead to sodium and water retention, mainly due to renal hypoperfusion
and increased aldosterone and ADH secretion (Figure 2). The resulting increase in blood
volume increases venous return and filling pressure (preload), so that stroke volume can
be improved. The symptoms of pulmonary and systemic venous hypertension described
previously are in part a consequence of this compensatory mechanism.
4. Hypertrophy. With long-standing hemodynamic overload (i.e., pulmonary or systemic
hypertension), and after an initial period of dilatation, the failing heart attempts to
compensate by increasing the ventricular muscle mass (the size of the myocardial fibers
increases). However, if overloading is not corrected, this is followed by irreversible
dilatation of the heart (Figure 2).
 Figure 1. The
Frank-Starling relationship for a normal heart & in systolic heart failure. Within normal
physiological limits, increases in the End-Diastolic Ventricular Pressure (or Preload) result in
stretching of the relaxed myocardium, producing a more optimal alignment of actin & myosin
filaments at the end of diastole. Because of this increase in alignment, electrical stimulation
during systole results in a stronger contraction & an increased stroke volume. In systolic failure,
the slope of this relationship is greatly reduced & the curve is shifted to the right.
Figure 2. Schematic diagram showing different compensatory mechanisms that become
activated to maintain mean arterial blood pressure during heart failure. Many of the signs and
symptoms of congestive heart failure result from activation of these compensatory mechanisms.
(Adapted from Maron & Rocco, 2011).

Normally, these compensatory mechanisms are reserved for times of cardiovascular stress, such
as during exercise (they comprise the normal cardiac functional reserve). During heart failure
these compensatory mechanisms are required even during periods of mild stress, or even at rest,
and exercise tolerance is diminished. If these compensatory mechanisms are insufficient to
maintain normal cardiac output, the patient is said to be in a condition of uncompensated CHF.
Under these conditions, the kidneys will continue to retain fluid until cardiac output is either
elevated to the point where there is adequate renal blood flow or the patient drowns in their own
fluid (e.g. due to pulmonary edema), whichever comes first.

ACUTE vs CHRONIC HEART FAILURE

In the case of acute heart failure (e.g. immediately after a myocardial infarction) the activation of
the sympathetic and angiotensin-renin-aldosterone system collaborate to support the circulation
(Figures 2 & 3) by increasing myocardial contractility, supporting mean arterial pressure, and
venous return. Thus over the short term, these compensatory mechanisms are beneficial in
supporting the circulation.

However, when heart failure progresses into a chronic situation, the continual unrelenting
stimulation of heart tissue by neurohumoral mediators (norepinephrine, angiotensin II,
aldosterone), as well as the presence of hypertrophy and continued sustained pressure or
volume loading result in “remodeling” of the heart. Changes associated with remodeling
include abnormal changes in gene expression, increased cardiac myocyte apoptosis, and
other intracellular changes that lead to changes in the shape of the heart, and its
performance as a pump.

Ventricular Remodeling:

When myocardial ischemia in the left ventricle occurs for as little as 45-60 minutes, myocardium
becomes irreversibly damaged (infarcted). When an infarction is transmural, the left ventricle
often undergoes a process called remodeling. This adaptive response occurs at both the cellular
level (from changes in apoptosis, gene expression, fibroblast & myocyte hypertrophy) to the
whole-organ level (changes in the shape & size of the left ventricle that affect ventricular
performance – e.g. progressive chamber dilation & loss of contractile function). These changes
are believed to be triggered by increased wall stress & chronically elevated stimulation of
the heart by elevated angiotensin II, catecholamines and aldosterone.

Eugene Braunwald & the “Discovery” of Vasodilator Treatment for Heart Failure

In the 1960’s, digitalis and diuretics were the mainstay of the conventional treatment for heart
failure. However, it was generally appreciated that digoxin did not always produce an optimal
hemodynamic response in patients with coronary artery disease, and excessive use of diruretics
could lead to electrolyte imbalances, hypovolemia, low cardiac output & shock.

In 1964 John Ross & Eugene Braunwald published an important paper in Circulation describing
a new method of evaluating the performance of the left ventricle when the resistance to
ventricular ejection was increased in patients with & without evidence of systolic heart failure.
They gave patients graded infusions of angiotensin while simultaneously measuring cardiac
output by the indicator dilution method. In normal patients there was an increase in ventricular
stroke “work” with increased arterial resistance, so that stroke volume was maintained constant.
However, in severely depressed hearts, stroke volume decreased with any increase in aortic
pressure. Surprisingly, the potential therapeutic implications of this new concept was initially
poorly understood. For many years, no one asked the question “if an increase in resistance to
ventricular ejection worsens ventricular performance, wouldn’t a reduction in arterial resistance
improve performance?”

References:
  Ross J & Braunwald E (1964) Circulation 29:739-749.
 Perret C & Enrico JF (2003) Intensive Care Med 2003 29:364-7.

AFTERLOAD

The load or tension that the left ventricle must exert with each stroke in order to eject the
volume of blood contained within it is referred to as the ventricular afterload (i.e., the load
encountered when the ventricular muscle attempts to shorten during ejection). In the absence of
aortic valvular disease, afterload is related to total peripheral resistance (TPR).

Additional Contributors to Afterload:

Ventricular radius is an additional determinant of afterload (from LaPlace's law ✘). A failing
heart that has become dilated, and has a larger radius, has to do additional work to eject the same
volume of blood. Other contributors to afterload include the compliance of large arteries (how
much they can stretch during ejection), total peripheral vascular resistance, blood viscosity and
intra-arterial volume. However, in the absence of aortic valvular disease, systemic arteriolar
resistance is the most important factor regulating afterload, and is also the most susceptible
to pharmacologic interventions.

✘
LaPlace’s law: It explains why a dilated heart requires more energy to pump the same amount
of blood as compared to a heart of normal size. Trust me, we won’t ask you to explain it. LaPlace
Eqn: T = ( P x R ) / M. (T: wall tension; P: pressure difference across the wall; R: radius of the
cylinder; M: wall thickness).

As discovered by Ross & Braunwald, when the left ventricle is normal, a change in afterload or
aortic impedance does not affect the left ventricular stroke volume significantly (Figure 3)
because the heart is working at a high level of efficiency. However, in hearts suffering from
systolic failure stroke volume is often critically dependent on outflow resistance. In systolic
heart failure, an increase in outflow resistance will result in a decrease in stroke volume. This is
because a weakened left ventricle is not strong enough to eject its volume of blood into the aorta
when pushing against a high resistance. The more severe the degree of heart failure, the greater
the stroke volume will decrease as the outflow resistance increases (notice the different curves in
Figure 3 reflecting different degrees of severity of myocardial dysfunction). Conversely, in
systolic heart failure a reduction in outflow resistance will commonly result in an increase in
stroke volume (Figure 3). (Q: What could cause a decrease in outflow resistance?)
Figure 3. The relationship between ventricular outflow resistance & stroke volume in patients
with systolic failure. An increase in ventricular outflow resistance, a principle determinant of
afterload, has little effect on stroke volume in normal hearts. In contrast, in patients with systolic
failure, an increase in afterload is often accompanied by a sharp decline in stroke volume,
because the weakened ventricle cannot eject blood against the resistance. With more severe
failure, this curve becomes steeper. Because of this relationship, drugs that reduce arterial
resistance (arterial vasodilators) can result in increases in stroke volume in patients with systolic
heart failure (Adapted from Goodman & Gilman’s 11th Ed.

OVERVIEW OF THE MODERN DAY THERAPY OF CHF

Treatment Algorithm for Systolic CHF

 Figure 4.
Treatment algorithm for systolic CHF (depressed ejection fraction). The patient's fluid retention
should be treated before starting an ACE inhibitor (or an ARB if the patient is ACE-intolerant).
Beta blockers should be started after the fluid retention has been treated and/or the dose of the
ACE inhibitor has been titrated. Patients that remain symptomatic can be given a triple therapy
consisting of an ARB, aldosterone antagonist (e.g. spironolactone), and digoxin. Digoxin is also
indicated in patients with both systolic failure and chronic atrial fibrillation. Addition of a fixed-
dose combination of hydralazine/isosorbide dinitrate to an ACE inhibitor and beta blocker is
recommended in African-American patients with NYHA class II–IV heart failure. Device
therapy should be considered in addition to drug therapy in appropriate patients, as indicated.
ACE: angiotensin-converting enzyme; ARB: angiotensin receptor blocker; NYHA: New York
Heart Association; CRT: cardiac resynchronization therapy; ICD: implantable cardiac
defibrillator. (Adapted from Mann & Chakinala, 2012).

REST, DIURETICS

If the patient has signs of edema, they are managed with dietary sodium restriction, diuretics,
and in some cases, fluid restriction. These interventions will decrease preload (filling pressure)
and relieve the symptoms of pulmonary and systemic venous hypertension. Cardiac output may
in fact decrease after diuretic therapy (the Frank-Starling curve does not shift, but the point
defining the relationship between preload & stroke volume moves left down along the same
curve, due to the reduction in preload) (Figure 1). The majority of patients with heart failure will
require chronic administration of a loop diuretic to maintain an appropriate volume status.
(Other diuretics, such as thiazide diuretics have a more restricted role in the treatment of CHF,
and are primarily used in the treatment of hypertension). In some situations the patient may also
need to be placed at rest (e.g. bed rest) in addition to conventional drug therapy, to help reduce
the workload of the heart.
DRUGS THAT REVERSE CARDIAC REMODELING

Current treatment of congestive heart failure commonly includes the inclusion of three major
drug classes to prevent or reverse remodeling and its associated harmful effects (Figure 5):

 ACE inhibitors or ARBs (angiotensin II receptor blockers)

 Beta blockers
 Aldosterone antagonists (e.g. spironolactone)

Figure 5. Pathophysiological mechanisms of heart failure & major sites of drug action. Heart
failure is accompanied by compensatory neurohumoral responses including activation of the
sympathetic nervous system & rennin-angiotensin-aldosterone systems. Although these
responses initially help to maintain cardiovascular function by increasing ventricular preload &
arterial blood pressure, over time they contribute to the progression of myocardial failure.
Increased ventricular afterload, due to systemic vasoconstriction & chamber dilation, causes a
depression in systolic function. In addition, increased arterial resistance (afterload) & the direct
effects of angiotensin, aldosterone & norepinephrine on the ventricular myocardium cause
pathological remodeling characterized by progressive chamber dilation & loss of contractile
function. The figure illustrates several mechanisms that appear to play important roles in the
pathophysiology of heart failure, and the sites of action of drug therapies that have been shown
to be of clinical value. Adapted from Maron & Rocco, 2011).

SPECIFIC DRUGS USED TO TREAT CHF

ANGIOTENSIN-CONVERTING ENZYME (ACE) INHIBITORS

Data from numerous clinical trials involving over 100,000 patients support the use of ACE
inhibitors for the treatment of heart failure of any level of severity. Three examples of ACE
inhibitors are CAPTOPRIL, ENALAPRIL & LISINOPRIL. ACE inhibitors reduce angiotensin
II and aldosterone levels & reduce sympathetic nervous system activity. They are more potent
arterial than venous dilators. Left ventricular filling pressure and volume are reduced in
association with decreased total peripheral resistance. Cardiac output increases and natriuresis is
also observed. Blood pressure may decrease significantly after the first few doses and patients
should be monitored closely. These agents are now considered an effective alternative to digitalis
in patients with mild or moderate heart failure that are also receiving diuretic therapy. The
CONSENSUS Study (1987) demonstrated a 40% reduction in mortality after 6 months in
patients with severe heart failure randomized to enalapril rather than placebo. These results were
extended to patients with mild to moderate heart failure in the SOLVD trial which reported a
16% reduction in mortality with enalapril vs. placebo. Enalapril was also found to significantly
reduce the development of ventricular remodeling in the SOLVD trial (Figure 6).

Common side-effects for ACE inhibitors include hypotension, hyperkalemia, angioedema

(potentially lethal) & cough (- believed to be caused by decreased breakdown of bradykinin –
most common in women & affects one’s quality of life). Hyperkalemia is caused by inhibiting
the formation of aldosterone (a potassium ‘wasting’ hormone).
Figure 6. ACE Inhibitors significantly reduce the development of cardiac remodeling in patients
with systolic heart failure. Graph shows the effect of enalapril on left ventricular dysfunction in
patients with an ejection fraction of <0.35 (systolic failure)(SOLVD trial). Enalapril significantly
reduced LV hypertrophy during a 12 month period of drug therapy. It also had similar beneficial
effects to significantly reduce LV dilatation & end-systolic volume (not shown). Adapted from
Greenburg et al. (1995).

SPIRONOLACTONE

The aldosterone antagonist spironolactone has also been shown to be highly effective in treating
congestive heart failure. There is growing evidence that aldosterone may mediate some of the
major harmful effects of the activated rennin-angiotensin-aldosterone system, including
myocardial remodeling & fibrosis, as well as sodium retention. The RALES trial compared 25
mg spironolactone daily vs. placebo in patients with advanced heart failure (e.g. class IV) that
were already receiving an ACE inhibitor & diuretics. Adding spironolactone produced a 30%
reduction in mortality as well as similar improvements in other clinical end points (Figure 7). Its
effectiveness in milder forms of heart failure has not been established.
Figure 7. Spironolactone increases the chances of survival by 30% in patients with congestive
heart failure. It also produced a significant improvement in NYHA CHF class status in 41% of
patients on spironolactone vs. 33% given placebo (P<0.001). The curves represent a Kaplan-
Meier Analysis of the Probability of Survival among Patients in the Placebo Group and Patients
in the Spironolactone Group. (Pitt et al, 1999).

BETA BLOCKERS

Drugs like metoprolol, carvedilol and bisoprolol are now also part of the drug regimen used to
treat patients with chronic heart failure due to dilated cardiomyopathy (systolic dysfunction).
Several trials have documented a survival benefit for patients on long-term beta-blockers. An
increase in ejection fraction between 2 and 4 months after initiation of therapy is seen
consistently with beta blockers used in patients with systolic heart failure (Figure 8). Carvedilol
therapy (Figure 9) in the US Carvedilol Trial was associated with a 65% reduction in mortality.
In general, beta blocker therapy is initiated at very low doses (generally 1/10th of the final target
dose), and then the dose is increased slowly over the course of weeks, under close supervision.
Figure 8. Time dependent effects of metoprolol on left ventricular ejection fraction in patients
with systolic heart failure. The initial low dose of metoprolol caused an immediate depression in
ejection fraction on day 1 due to the drugs direct negative inotropic effect. However, over time &
despite an upwards titration of metoprolol to full therapeutic levels, ejection fraction returned to
baseline after 1 month, and by 3 months the ejection fraction was significantly higher than at
baseline. In the group given standard therapy, ejection fraction did not change significantly.
Adapted from Hall et al. (1995).
Figure 9. Dose-dependent effect of carvedilol on ejection fraction. In the US Carvedilol Trials
Program, a subgroup of patients was randomized to placebo or carvedilol at different dosage
levels. After 6 months of treatment the ejection fraction increased significantly with all 3 doses
of carvedilol, but not with placebo. The increase in ejection fraction was strongly dose
dependent. These data emphasize the importance of titrating doses of beta blockers to the target
or highest tolerated dose. Adapted from Bristow et al (1996).

DIGOXIN

Digoxin is used in patients with moderate to severe heart failure that are not adequately
controlled with other medications, and in patients with both systolic heart failure and atrial
fibrillation where it has beneficial effects for both increasing the force of contraction, and
controlling the ventricular rate by increasing vagal tone. However, in other clinical situations the
use of digoxin has been largely supplanted by therapies that have been more clearly documented
to provide a mortality benefit, and a better safety profile (e.g. ACE inhibitors & beta blockers).
Dobutamine, a beta-1 selective agonist (administered by i.v. infusion) is also sometimes used for
temporary inotropic support in a hospital setting.
VASODILATORS

As a result of the chronically activated compensatory mechanisms described above (increased

sympathetic tone, elevated angiotensin & aldosterone levels) total peripheral vascular
resistance is increased in heart failure, so that the failing heart is in fact confronted with an
increased afterload.

It is on this basis that specific vasodilator agents are sometimes used in the therapy of congestive
heart failure, in order to reduce afterload. Examples of such agents include:

 Isosorbide dinitrate (nitrates)

 Hydralazine
 Neseritide

Vasodilator drugs are also used in the treatment of acute heart failure due to sudden
hemodynamic overload of the left ventricle, such as in rupture of a papillary muscle, mitral or
aortic valve leaflet. In these conditions, a reduction in aortic impedance increases “forward” flow
and decreases regurgitant flow due to mitral or aortic insufficiency.

HYDRALAZINE + ISOSORBIDE DINITRATE vs ALPHA BLOCKERS

Although a number of different types of direct vasodilators (e.g. prazosin, phentolamine,

hydralazine, nitrates) may improve symptoms in heart failure acutely, of the drugs within this
class, only the hydralazine-isosorbide dinitrate combination has been shown to improve
survival in prospective randomized trials. Hydralazine is a directly acting arterial vasodilator.
Nitrates are drugs that behave as nitric oxide donors, which cause selective venous dilation at
low doses, and some degree of arterial dilation at higher doses.

In the Veterans Administration Cooperative Vasodilator-Heart Failure II Trial (V-HeFT II), the
hydralazine-nitrate combination was superior to placebo, whereas the alpha-receptor
blocker prazosin was found to be no better than placebo in reducing mortality/death (Cohn et
al., 1987; 1991). One major limitation of hydralazine is that it produces a reversible drug-
induced lupus syndrome in ~10% of patients.

COMBINATION OF VASODILATORS AND INOTROPIC AGENTS

In a hospital setting, a simultaneous administration of i.v. sodium nitroprusside and

dopamine has been found useful in the treatment of severe congestive heart failure.
Nitroprusside (discussed later) is a nitric oxide donar that spontaneously releases NO, which
causes equal dilation of both the venous and arterial circulation. Dopamine, at appropriate
moderate doses, causes both renal vasodilation (acting at specific dopamine receptors) and
increases myocardial contractility (by stimulation of beta-1 receptors). Thus, when afterload
reduction is combined with inotropic stimulation, a greater increase in cardiac output can be
achieved in patients with heart failure. Dobutamine is another effective inotropic agent given by
i.v. infusion (2.5-10 mg/kg/minute), also acting on cardiac beta-1 receptors. Dobutamine does
not stimulate dopamine receptors.
Other combinations of vasodilators (e.g. ACE inhibitors) and positive inotropes (e.g. short term
treatment with dobutamine, or chronic therapy with digoxin) can also yield similar results – i.e.
additive increases in cardiac output (Figure 10).

Figure 10. Hemodynamic responses to different drug therapies in heart failure. Positive inotropic
agents (digoxin, dobutamine) move patients to a higher ventricular function curve. Vasodilators
(ACE inhibitors, nitroprusside) also move patients to improved ventricular function curves while
reducing cardiac filling pressure. Diuretics improve the symptoms of congestive heart failure by
moving patients to a lower cardiac filling pressure along the same ventricular function curve.
Combinations of drugs often will yield additive effects on hemodynamics. (Adapted from Maron
& Rocco, 2011).

VASODILATORS PRIMARILY USED ACUTELY (IN A HOSPITAL SETTING)

Alpha Blockers
PHENTOLAMINE. A reversible nonselective alpha blocker that has a predominant effect on
the arteriolar vascular bed. In the presence of heart failure, the main effect is reduction of
afterload and increased cardiac output. Reflex tachycardia is a predominant side effect with
this drug. Phentolamine must be given by im or iv injection or infusion (not orally).

PRAZOSIN. An alpha-adrenergic receptor blocker with selectivity for the post-synaptic alpha-1
receptor. Tachycardia is not as prominent a side-effect compared with phentolamine due to
selective blockade of post-synaptic alpha receptors (the pre-synaptic alpha-2 receptor is not
blocked, and when stimulated by synaptic norepinephrine, will decrease further presynaptic
release of norepinephrine from the nerve terminal.) Another advantage of prazosin is that it is
effective orally, and its action is sustained for 4-6 hours. Side-effects of prazosin include
syncope, usually after the initial doses, and most likely related to the venous pooling effect. This
can be minimized by starting with low doses (i.e., 1 mg) and by slowly increasing the dose until
the desired effects are obtained.

Nitrates & Nitric Oxide Donars

NITRATES. Nitroglycerin and isosorbide dinitrate are the most commonly used drugs in this
category. Nitroglycerin has a greater dilator effect on the venous than the arterial bed. At
low to moderate therapeutic concentrations, the predominant hemodynamic action of nitrates is a
reduction in venous return and filling pressure (i.e., preload is reduced). There is some effect to
reduce afterload as well, but this effect is relatively small at low to moderate doses. Nitroglycerin
can be given sublingually, with rapid onset but short duration of action (about 30 minutes).
Nitroglycerin can be given as an intravenous infusion for continuous effects. Sustained
hemodynamic effects can also be obtained with nitroglycerin ointment (2% ointment - 0.4 inch
of extruded ointment applied over a 36 square inch area of the patient's back, covered by a plastic
wrap). Hemodynamic actions are sustained for 4-6 hours after cutaneous administration.
Isosorbide dinitrate is given sublingually or orally, with hemodynamic actions lasting 4-6
hours. The effects are essentially the same as those described for nitroglycerin.

SODIUM NITROPRUSSIDE. A very potent, short-acting vasodilator. It directly dilates both

arterial and venous smooth muscle. It can therefore produce a combination of reduced arterial
impedance and venous pooling. The latter effect will decrease filling pressure (preload) and can
improve the symptoms of pulmonary congestion. However, if heart failure is mild, cardiac output
will decrease as a result of decreased preload, and, due to the ensuing hypotension, a reflex
tachycardia will develop. In severe heart failure, afterload reduction results in the increase in
cardiac output and heart rate may actually decrease, in spite of a reduction in mean arterial
pressure. Sodium nitroprusside is given by continuous intravenous infusion in doses that can
range from 15 to 400 μg per minute, depending on individual patient response. Nitroprusside is
useful in the in-hospital therapy of severe chronic congestive heart failure, and also in acute
heart failure due to mitral or aortic regurgitation.

WARNING: Nitroprusside can cause cyanide poisoning

Nitroprusside is a complex of iron, cyanide groups, and a nitroso moiety. It is rapidly

metabolized (resulting in its very short half life). If it is given for too long or at “too high” an iv
infusion rate, an accumulation of cyanide results. This can in turn result in metabolic acidosis,
arrhythmias & death. (Sounds like something you would only hear about on House MD?)
Administration of sodium thiosulfate as a sulfur donar facilitates the metabolism of cyanide.
Hydroxocobalamin also combines with cyanide to form a nontoxic product.

SOME CAUTIONARY NOTES: All vasodilator agents, and in particular those given by
intravenous infusion, can result in extreme hypotension. This is particularly undesirable in
patients with coronary artery disease. Thus, careful monitoring is mandatory when vasodilator
therapy is used in heart failure, so that an adequate balance is reached between afterload
reduction and proper perfusion pressure to vital organs. Vasodilator therapy with sodium
nitroprusside has been combined with intra-aortic balloon pumping in patients with left
ventricular failure due to acute myocardial infarction, thus providing afterload reduction and
adequate coronary perfusion.

NEWER DRUG CLASSES UNDER INVESTIGATION

Neseritide

Neseritide is a parenterally administered recombinant form of human brain naturetic peptide

(BNP) that has been approved by the FDA for treatment of dyspnea due to CHF.
Physiologically BNP is secreted by ventricular myocytes in response to stretch, and circulating
levels of BNP correlate with the severity of heart failure. In the setting of CHF, the effects of
BNP counteract the effects of angiotensin & norepinephrine by producing vasodilation,
naturesis & diuresis. Despite its promise, a recent clinical trial with neseritide showed no change
in the rate of death & rehospitalization. It is currently not recommended for routine use in the
broad population of patietns with acute heart failure (O'Connor et al, 2011; Chen et al, 2013).

Neprilysin inhibitors

Neprilysin is an endogenous metalloprotease/endopeptidase that is abundantly expressed in

multiple tissues, including the kidney & lung. It degrades several different peptides, including
several vasoactive peptides including natriuretic peptides, bradykinin & adrenomedullin
(McMurray et al, 2014; Wikipedia). Inhibition of neprilysin increases the levels of these
substrates, which in patients with heart failure, counteracts the over-activation of pathways
involved in promoting vasoconstriction, sodium retention and remodeling (McMurray et al,
2014).

 The results of an initial clinical trial suggested that treatment with the combination of a
neprilysin inhibitor plus an experimental angiotensin receptor blocker (LCZ696) was
superior to enalapril in reducing the risks of death and hospitalization for heart
failure (McMurray et al, 2014).

More recently, a drug combination of sacubitril + valsartan (Entresto ®) was found to produce
clinical effects superior to that of valsartan alone:

 In patients with class II-IV HF & reduced EF, compared to valsartan monotherapy,
the drug combination of sacubitril + valsartan (Entresto ®) produced a significantly
 greater reduction of: a) first hospitalization for worsening of heart failure, b) death
from CV causes & c) death from CV causes. It also slowed the progression of HF
(Colucci & Pheffer, 2015; Med Lett Drugs Ther, 2015).

DIASTOLIC Vs SYSTOLIC HEART FAILURE

Recent estimates indicate that over 50% of all patients with congestive heart failure have
diastolic dysfunction vs. systolic dysfunction. In these patients, the heart (e.g. due to fibrosis)
is unable to relax & fill with blood during diastole, as compared to an inability to eject blood
during systole. Patients with significant diastolic dysfunction that results in signs of heart failure
will have a normal ejection fraction (>50%) in contrast to patients with systolic heart failure
who have a reduced ejection fraction (which various sources have defined as EF values less than
anywhere from 40-50%) (Jessup & Brozena, 2003; Zile et al, 2012). In clinical practice the
diagnosis of diastolic heart failure is typically based on the finding of a normal or near normal
(or “preserved”) ejection fraction (an average EF for a healthy adult is 60-70%, with a range of
50-55% being 2 standard deviations below the mean).

Diastolic failure is frequently also referred to as “Heart Failure with Preserved Ejection
Fraction” (Zile et al, 2012). The major differences in characteristics between systolic & diastolic
failure are summarized below (Jessup & Brozena, 2003; Ziles et al, 2012):

Patient Characteristics in Diastolic & Systolic Heart Failure

Diastolic HF Systolic HF
normal EF (> 50%) reduced EF (< 40%)
concentric remodeling or hypertrophy chamber dilation & eccentric remodeling
frequently elderly all ages, typically 50-70 yr
frequently female more often male
4th heart sound 3rd heart sound

Diastolic Heart Failure Characteristics

 ↓LV compliance (relaxation)

 ↑Cardiomyocyte resting tension
 ↑Collagen deposition

Causes of Diastolic Dysfunction

 Myocardial ischemia (due to coronary artery disease)

o ischemia slows myocyte relaxation, causing persistent actin-myosin cross-
bridges & muscle tension to persist during diastole
 Chronic hypertension → LV concentric hypertrophy with increased ischemia
o inadequate coronary artery growth vs muscle mass
o increased atherosclerosis due to hypertension
 valvular aortic stenosis
 hypertrophic cardiomyopathy
DRUGS USED TO TREAT DIASTOLIC DYSFUNCTION

The treatment of diastolic heart failure is currently based upon a consensus of expert opinion,
rather than on the results of clinical trials. Hence treatment remains empiric, rather than based
upon clinical trials. The current recommendations for treatment of diastolic heart failure were
included in the 2013 American College of Cardiology Foundation / American Heart Association
(ACC/AHA) Heart Failure guidelines (Yancy et al, 2013).

With the goal of improving diastolic filling, recommended treatments include the use of beta-
blockers (propranolol, metoprolol) or calcium channel blockers (verapamil, diltiazem). As
summarized in the table below, these drugs increase ventricular relaxation and increase
diastolic filling time, as well as reduce blood pressure & reduce oxygen demand, effects that are
beneficial in treating diastolic failure.

ACE inhibitors and diuretics are also used in treating diastolic failure. ACE inhibitors can
reduce myocardial interstitial collagen deposition & fibrosis, thereby increasing ventricular
compliance. Diuretics are useful in reducing excessive volume, although they should be used
cautiously because diastolic filling is already compromised in these patients.

Interestingly, a recent 3 year clinical trial concluded that spironolactone was no better than
placebo in the treatment of HF with a preserved ejection fraction (Pitt et al, 2014).

Treatment Goals (Empirical) for Diastolic HF

 REDUCE HYPERTENSTION: normalize blood pressure

o thiazide diuretics
o beta blockers
o calcium channel blockers
o ACE inhibitor or ARBs
 RATE CONTROL: ↑diastolic interval to increase diastolic filling
o calcium channel blockers
o beta blockers
o radiofrequency ablation of the AV node & ventricular pacing
 REDUCE EDEMA: control blood volume (edema is not helpful)
o low salt diet
o diuretic (furosemide or thiazide)
o ACE inhibitor or ARB
 REDUCE MYOCARDIAL ISCHEMIA: reduce the “oxygen demand” vs “oxygen
supply” ratio
o medical management with nitrates, beta blockers & calcium channel blockers
o percutaneous coronary intervention (angioplasty, stents)
o coronary artery bypass surgery
 INCREASE DIASTOIC RELAXATION: in diastolic HF the heart can't fill properly
because the wall is stiff
o calcium channel blockers
o beta blockers
TREATING CARDIOGENIC PULMONARY EDEMA

Acute pulmonary edema, leading to severe hypoxemia, acidosis and death, can be the result of
left ventricular failure. Dyspnea (difficulty breathing) is a very prominent symptom, and the
patients frequently present with elevated arterial pressure and peripheral vascular resistance.
Treatment is directed at:

 improving oxygenation
 decreasing pulmonary vascular congestion
 decreasing the feeling of dyspnea

Treatments to achieve these goals include (Johnson, 2009; Colucci 2014):

 Supplemental oxygen - early intervention with noninvasive mask ventilation decreases

the need for intubation, and reduces morbidity and mortality.
 Nitroglycerin infusion - a first line treatment to reduce both preload and afterload.
Infusions should be administered early.
 Furosemide (or another loop diuretic) - to produce diruesis & venodilation. In
addition to diuresis due to its effect on the kidney, furosemide also produces a preload-
reducing venodilator effect (inhibited by aspirin) that can be observed within minutes,
long before the onset of diuresis is observed (Wiemer et al, 1994; Jhund et al, 2001).
 Morphine sulfate - is sometimes used for its venodilator effect (to reduce preload), and
to decrease anxiety. However, high doses should be avoided because they can mask chest
pain (resulting in a misdiagnosis of evolving chest pain), produce histamine release,
hypotension and respiratory depression.

The use of digitalis glycosides is typically not advocated since the above measures are usually
effective and the peripheral vasoconstriction induced by digitalis is potentially deleterious
(increased afterload in the presence of severe heart failure). If necessary, digoxin therapy can be
started after the patient is compensated by reduction in pulmonary congestion and oxygenation
has improved.

References:

 Bristow MR, Gilbert EM et al (1996): Carvedilol produces dose-related improvements in

left ventricular function and survival in subjects with chronic heart failure. Circulation
94:2807-2816.
 Chen HH et al (2013): Low-dose dopamine or low-dose nesiritide in acute heart failure
with renal dysfunction. The ROSE acute heart failure randomized trial. JAMA
310(23):2533-2543.
 Cohn JN, Archibald D et al (1987): Cooperative Study Group. Effects of vasodilator
therapy on peak oxygen consumption in heart failure: V-HeFT. Circulation 76:Suppl
IV:IV-443 (abstract).
 Cohn JN, Johnson G et al (1991): A comparison of enalapril with hydralazine-isosorbide
dinitrate in the treatment of chronic congestive heart failure. N Engl J Med 325:303-310.
  Colucci WS (2014): Treatment of acute decompensated heart failure: components of
therapy. In: UpToDate. Basow, DS (Ed), UpToDate, Waltham, MA. Cited 10/15/14.
 Colucci WS, Pfeffer, MA (2015): Use of angiotensin II receptor blocker and neprilysin
inhibitor in heart failure with reduced ejection fraction. In: In: UpToDate, Basow, DS
(Ed), Waltham, MA. Cited 9/11/15
 Greenberg B, Quinones MA, et al (1995): Effects of long-term enalapril therapy on
cardiac structure and function in patients with left ventricular dysfunction: results of the
SOLVD echocardiography substudy. Circulation. 91:2573-81.
 Hall SA, Cigarroa CG et al (1995):Time course of improvement in left ventricular
function, mass and geometry in patients with congestive heart failure treated with beta-
adrenergic blockade. J Am Coll Cardiol 25(5):1154-61
 Jessup M, Brozena S (2003): Heart failure. N Engl J Med 348:2007-13.
 Jhund PS et al (2001): Aspirin inhibits the acute venodilator response to furosemide in
patients with chronic heart failure. J Am Coll Cardiol 37(5):1234-1236.
 Johnson JM (2009): Management of acute cardiogenic pulmonary edema. A literature
review. Adv Emerg Nursing J 31(1):36-43.
 Mann DL, Chakinala M (2012): Heart failure and Cor Pulmonale (Chapter 234). In:
Harrison's Internal Medicine. 18e. McGraw-Hill.
 Maron BA, Rocco TP (2011): Pharmacotherapy of Congestive Heart Failure (Chapter
28). In: Goodman & Gilman's The Pharmacological Basis of Therapeutics. 11th Edition.
Brunton LL (Editor). McGraw Hill
 McMurray JJV et al (2014): Angiotensin-neprilysin inhibition versus enalapril in heart
failure. N Engl J Med 371:993-1004.
 O'Connor CM et al (2011): Effect of nesiritide in patients with acute decompensated
heart failure. N Engl J Med 365:32-43.
 Pitt B, Zannad F et al (1999): The effect of spironolactone on morbidity and mortality in
patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators.
N Engl J Med 341:709-17.
 Pitt B et al (2014): Spironolactone for heart failure with preserved ejection fraction. N
Engl J Med 370:1383-1392.
 The Medical Letter on Drugs and Therapeutics (2015): Sacubitril/Valsartan (Entresto) for
Heart Failure. 57 (1474):107-109.
 Wiemer G et al (1994): Furosemide enhances the release of endothelial kinins, nitric
oxide and prostacyclin. J Pharmacol Exp Ther 27(3):1611-1615.
 Yancy CW et al (2013): ACC/AHA guideline for the management of heart failure: a
report of the American College of Cardiology Foundation/American Heart Association
Task Force on Practice Guidelines. J Am Coll Cardiol 62(16): e147-239.
doi:10.1016/j.jacc.2013.05.019
 Zile MR, Gaasch WH (2014): Treatment and prognosis of diastolic heart failure. In:
UpToDate, Basow, DS (Ed), UpToDate, Waltham, MA. Cited 9/29/15.
 Zile MR, Wexler L, Gaasch WH (2012): Pathophysiology of diastolic heart failure. In:
UpToDate, Basow, DS (Ed), UpToDate, Waltham, MA. Cited 12/6/12.

treatment_of_heart_failure.txt · Last modified: 2015/11/10 10:23 by cclarks

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