Heart Failure

Heart failure (HF) is a progressive clinical syndrome caused by inability of the heart
to pump sufficient blood to meet the body’s metabolic needs. HF can result from any
disorder that affects the ability of the heart to contract (systolic dysfunction) and/or
relax (diastolic dysfunction). HF with reduced systolic function (ie, reduced left
ventricular ejection fraction, LVEF) is referred to as HF with reduced ejection
fraction (HFrEF). Preserved LV systolic function (ie, normal LVEF) with presumed
diastolic dysfunction is termed HF with preserved ejection fraction (HFpEF).

PATHOPHYSIOLOGY
Causes of systolic dysfunction (decreased contractility) are reduced muscle mass (eg,
myocardial infarction [MI]), dilated cardiomyopathies, and ventricular hypertrophy.
Ventricular hypertrophy can be caused by pressure overload (eg, systemic or
pulmonary hypertension and aortic or pulmonic valve stenosis) or volume overload
(eg, valvular regurgitation, shunts, and high-output states).
Causes of diastolic dysfunction (restriction in ventricular filling) are increased
ventricular stiffness, ventricular hypertrophy, infiltrative myocardial diseases,
myocardial ischemia and MI, mitral or tricuspid valve stenosis, and pericardial
disease (eg, pericarditis and pericardial tamponade).
The leading causes of HF are coronary artery disease and hypertension.
Regardless of the index event, decreased cardiac output results in activation of
compensatory responses to maintain circulation: (1) tachycardia and increased
contractility through sympathetic nervous system activation; (2) the Frank–Starling
mechanism, whereby increased preload (through sodium and water retention)
increases stroke volume; (3) vasoconstriction; and (4) ventricular hypertrophy and
remodeling. Although these compensatory mechanisms initially maintain cardiac
function, they are responsible for the symptoms of HF and contribute to disease
progression.
In the neurohormonal model of HF, an initiating event (eg, acute MI) leads to
decreased cardiac output; the HF state then becomes a systemic disease whose
progression is mediated largely by neurohormones and autocrine/paracrine factors
that drive myocyte injury, oxidative stress, inflammation, and extracellular matrix
remodeling. These substances include angiotensin II, norepinephrine, aldosterone,
natriuretic peptides, and arginine vasopressin.
Common precipitating factors that may cause a previously compensated HF patient
to decompensate include myocardial ischemia and MI, atrial fibrillation, pulmonary
infections, nonadherence with diet or drug therapy, and inappropriate medication use.
Drugs may precipitate or exacerbate HF through negative inotropic effects, direct
cardiotoxicity, or increased sodium and water retention.

CLINICAL PRESENTATION

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 Patient presentation may range from asymptomatic to cardiogenic shock.
Primary symptoms are dyspnea (especially on exertion) and fatigue, which lead to
exercise intolerance. Other pulmonary symptoms include orthopnea, paroxysmal
nocturnal dyspnea, tachypnea, and cough.
Fluid overload can result in pulmonary congestion and peripheral edema.
Nonspecific symptoms may include fatigue, nocturia, hemoptysis, abdominal pain,
anorexia, nausea, bloating, ascites, poor appetite or early satiety, mental status
changes, and weight gain.
Physical examination findings may include pulmonary crackles, S3 gallop, cool
extremities, Cheyne–Stokes respiration, tachycardia, narrow pulse pressure,
cardiomegaly, symptoms of pulmonary edema (extreme breathlessness and anxiety,
sometimes with coughing and pink, frothy sputum), peripheral edema, jugular venous
distention, hepatojugular reflux, and hepatomegaly.

DIAGNOSIS
Consider diagnosis of HF in patients with characteristic signs and symptoms. A
complete history and physical examination with appropriate laboratory testing are
essential in evaluating patients with suspected HF.
Laboratory tests for identifying disorders that may cause or worsen HF include
complete blood cell count; serum electrolytes (including calcium and magnesium);
renal, hepatic, and thyroid function tests; urinalysis; lipid profile; and A1C. B-type
natriuretic peptide (BNP) will generally be greater than 100 pg/mL.
Ventricular hypertrophy can be demonstrated on chest radiograph or
electrocardiogram (ECG). Chest radiograph may also show pleural effusions or
pulmonary edema.
Echocardiogram can identify abnormalities of the pericardium, myocardium, or heart
valves and quantify LVEF to determine if systolic or diastolic dysfunction is present.
The New York Heart Association Functional Classification System is intended
primarily to classify symptoms according to the physician’s subjective evaluation.
Functional class (FC)-I patients have no limitation of physical activity, FC-II patients
have slight limitation, FC-III patients have marked limitation, and FC-IV patients are
unable to carry on physical activity without discomfort.
The American College of Cardiology/American Heart Association (ACC/AHA)
staging system provides a more comprehensive framework for evaluating,
preventing, and treating HF (see further discussion below).

TREATMENT OF CHRONIC HEART FAILURE

Goals of Treatment: Improve quality of life, relieve or reduce symptoms, prevent or
minimize hospitalizations, slow disease progression, and prolong survival.

GENERAL APPROACH
The first step is to determine the etiology or precipitating factors. Treatment of
underlying disorders (eg, hyperthyroidism) may obviate the need for treating HF.
Nonpharmacologic interventions include cardiac rehabilitation and restriction of fluid

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intake (maximum 2 L/day from all sources) and dietary sodium (<2–3 g of
sodium/day). Drugs that aggravate HF should be discontinued if possible.
ACC/AHA Stage A: These are patients at high risk for developing heart failure. The
emphasis is on identifying and modifying risk factors to prevent development of
structural heart disease and subsequent HF. Strategies include smoking cessation and
control of hypertension, diabetes mellitus, and dyslipidemia. Although treatment
must be individualized, angiotensin-converting enzyme (ACE) inhibitors or
angiotensin receptor blockers (ARBs) are recommended for HF prevention in
patients with multiple vascular risk factors.
ACC/AHA Stage B: In these patients with structural heart disease but no HF signs
or symptoms, treatment is targeted at minimizing additional injury and preventing or
slowing the remodeling process. In addition to treatment measures outlined for stage
A, patients with reduced LVEF should receive an ACE inhibitor (or ARB) and a β-
blocker to prevent development of HF, regardless of whether they have had an MI.
Patients with a previous MI and reduced LVEF should also receive an ACE inhibitor
or ARB, evidence-based β-blockers, and a statin.
ACC/AHA Stage C: These patients have structural heart disease and previous or
current HF symptoms and include both HFrEF and HFpEF. In addition to treatments
for stages A and B, patients with HFrEF should be treated with guideline-directed
medical therapy (GDMT) that includes an ACE inhibitor or ARB and an evidence-
based β-blocker (Fig. 9–1). Loop diuretics, aldosterone antagonists, and hydralazine–
isosorbide dinitrate (ISDN) are also used routinely. Digoxin, ivabradine, and
sacubitril/valsartan can be considered in select patients. Other general measures
include moderate sodium restriction, daily weight measurement, immunization
against influenza and pneumococcus, modest physical activity, and avoidance of
medications that can exacerbate HF.

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a
If not already receiving this therapy for previous MI, LV dysfunction, or other indication.
bIf NYHA class II-IV symptoms, estimated creatinine clearance >30 mL/min, and K+ <5.0 mEq/L.
c
Indication is to reduce hospitalization.
dNot included in current guidelines.
(ACEI, angiotensin-converting enzyme inhibitor; ARA, aldosterone receptor antagonist; ARB,
angiotensin receptor blocker; bpm, beats per minute; GDMT, guideline-directed medical therapy;
HTN, hypertension; ISDN, isosorbide dinitrate; LV, left ventricular; MI, myocardial infarction.)

FIGURE 9–1. Guideline-directed treatment algorithms for patients with

ACC/AHA stage C heart failure with reduced ejection fraction. (Adapted
from Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/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 2013;62:e147–239.)

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 ACC/AHA Stage D HFrEF: These are patients with persistent HF symptoms
despite maximally tolerated GDMT. They should be considered for specialized
interventions, including mechanical circulatory support, continuous IV positive
inotropic therapy, cardiac transplantation, or hospice care (when no additional
treatments are appropriate). Restriction of sodium and fluid intake may be beneficial.
High doses of diuretics, combination therapy with a loop and thiazide diuretic, or
mechanical fluid removal methods such as ultrafiltration may be required. Patients
may be less tolerant to ACE inhibitors and β-blockers, so low starting doses, slow
upward dose titration, and close monitoring are essential.
Management of HFpEF: Treatment includes controlling heart rate (HR) and blood
pressure (BP), alleviating causes of myocardial ischemia, reducing volume, and
restoring and maintaining sinus rhythm in patients with atrial fibrillation. Many of
the drugs are the same as those used to treat HFrEF (eg, β-blockers and diuretics), but
the rationale and dosing may be different. Calcium channel blockers (eg, diltiazem,
amlodipine, and verapamil) may be useful in HFpEF but have little utility in treating
HFrEF.

PHARMACOLOGIC THERAPY

Drug Therapies for Routine Use in Stage C HFrEF (Fig. 9–1)

DIURETICS
Compensatory mechanisms in HF stimulate excessive sodium and water retention,
often leading to systemic and pulmonary congestion. Consequently, diuretic therapy
(in addition to sodium restriction) is recommended for all patients with clinical
evidence of fluid retention. However, because they do not alter disease progression or
prolong survival, diuretics are not required for patients without fluid retention. In
patients with HFpEF, diuretic treatment should be initiated at low doses to avoid
hypotension and fatigue.
Thiazide diuretics (eg, hydrochlorothiazide) are relatively weak and are
infrequently used alone in HF. However, thiazides or the thiazide-like diuretic
metolazone can be used in combination with a loop diuretic to promote very
effective diuresis. Thiazides may be preferred over loop diuretics in patients with
only mild fluid retention and elevated BP because of their more persistent
antihypertensive effects.
Loop diuretics (furosemide, bumetanide, and torsemide) are usually necessary to
restore and maintain euvolemia in HF. In addition to acting in the thick ascending
limb of the loop of Henle, they induce a prostaglandin-mediated increase in renal
blood flow that contributes to their natriuretic effect. Unlike thiazides, loop diuretics
maintain their effectiveness in the presence of impaired renal function, although
higher doses may be necessary. See Table 9–1 for initial doses and usual dose
ranges.
TABLE 9–1 Drug Dosing Table

Brand Special Population

Drug Name Initial Dose Usual Range Dose

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Loop Diuretics
Furosemide Lasix 20–40 mg once or 20–160 mg once or Clcr 20–50 mL/min:
twice daily twice daily 160 mg once or
twice daily
Clcr<20 mL/min: 400
mg daily
Bumetanide Bumex 0.5–1.0 mg once or 1–2 mg once or Clcr 20–50 mL/min: 2
twice daily twice daily mg once or twice
daily
Clcr<20 mL/min: 8–10
mg daily
Torsemide Demadex 10–20 mg once daily 10–80 mg once daily Clcr 20–50 mL/min: 40
mg once daily
Clcr<20 mL/min: 200
mg daily
ACE Inhibitors
Captopril Capoten 6.25 mg three times 50 mg three times
daily dailya
Enalapril Vasotec 2.5 mg twice daily 10–20 mg twice
dailya
Lisinopril Zestril, 2.5–5 mg once daily 20–40 mg once
Prinivil dailya
Quinapril Accupril 5 mg twice daily 20–40 mg twice daily
Ramipril Altace 1.25–2.5 mg 5 mg twice dailya
Fosinopril Monopril 5–10 mg once daily 40 mg once daily
Trandolapril Mavik 0.5–1 mg once daily 4 mg once dailya

Perindopril Aceon 2 mg once daily 8–16 mg once daily

Angiotensin Receptor Blockers
Candesartan Atacand 4 mg once daily 32 mg once dailya
Valsartan Diovan 20–40 mg twice daily 160 mg twice dailya

Losartan Cozaar 25–50 mg once daily 150 mg once dailya

Beta-Blockers
Bisoprolol Zebeta 1.25 mg once daily 10 mg once dailya
Carvedilol Coreg 3.125 mg twice daily 25 mg twice dailya Target dose for
patients weighing
>85 kg is 50 mg
twice daily
Carvedilol Coreg CR 10 mg once daily 80 mg once daily
phosphate
Metoprolol Toprol-XL 12.5–25 mg once 200 mg once dailya
succinate CR/XL daily
Aldosterone Antagonists
Spironolactone Aldactone eGFR ≥50 25–50 mg once eGFR 30–49
mL/min/1.73m2: dailya mL/min/1.73m2:
12.5–25 mg once 12.5 mg once daily

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 daily or every other day
Eplerenone Inspra eGFR ≥50 50 mg once dailya eGFR 30–49
mL/min/1.73m2: mL/min/1.73m2: 25
25 mg once daily mg every other day
Other
Hydralazine- Bidil Hydralazine 37.5 mg Hydralazine 75 mg
Isosorbide three times daily three times dailya
Dinitrate Isosorbide dinitrate Isosorbide dinitrate
20 mg three times 40 mg three times
daily dailya
Digoxin Lanoxin 0.125–0.25 mg once 0.125–0.25 mg once Reduce dose in
daily daily elderly, patients
with low lean body
mass, and patients
with impaired renal
function
Ivabradine Corlanor 5 mg twice daily 5–7.5 mg twice daily Avoid if resting heart
rate <60 BPM
before treatment
Sacubitril/valsartan Entresto 49/51 mg 97/103 mg For patients taking a
sacubitril/valsartan sacubitril/valsartan low dose of or not
twice daily twice dailya taking an ACEI or
ARB or if eGFR is
<30 mL/min/1.73m2,
the starting dose is
24/26 mg
sacubitril/valsartan
twice daily
aRegimens
proven in large clinical trials to reduce mortality.
ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; Clcr, creatinine
clearance; eGFR,estimated glomerular filtration rate; HFrEF, heart failure with reduced ejection
fraction.
(Data from Brater DC. Pharmacology of diuretics. Am J Med Sci 2000;319:38-50; Yancy CW, Jessup
M, Bozkurt B, et al. 2013 ACCF/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 2013;62:e147–e239.)

ANGIOTENSIN-CONVERTING ENZYME INHIBITORS

ACE inhibitors decrease angiotensin II and aldosterone, attenuating many of their
deleterious effects, including reducing ventricular remodeling, myocardial fibrosis,
myocyte apoptosis, cardiac hypertrophy, norepinephrine release, vasoconstriction,
and sodium and water retention.
Clinical trials have documented favorable effects of ACE inhibitors on symptoms,
NYHA functional classification, clinical status, HF progression, hospitalizations, and
quality of life. ACE inhibitors improve survival by 20% to 30% compared with
placebo. All patients with HFrEF should receive ACE inhibitors unless
contraindications are present. Post-MI patients without HF symptoms or reduced
LVEF (Stage B) should also receive ACE inhibitors to prevent development of HF
and to reduce mortality.
Therapy should be started with low doses followed by gradual titration as tolerated to

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 target doses to minimize the risk of hypotension and renal insufficiency (Table 9–1).
Renal function and serum potassium should be evaluated at baseline and within 1 to 2
weeks after the start of therapy with periodic assessments thereafter. Initiation of β-
blocker therapy should not be delayed while the ACE inhibitor is titrated to the target
dose because low–intermediate ACE inhibitor doses are equally effective as higher
doses for improving symptoms and survival.
ANGIOTENSIN RECEPTOR BLOCKERS
The ARBs block the angiotensin II receptor subtype AT1, preventing the deleterious
effects of angiotensin II, regardless of its origin. Because they do not affect the ACE
enzyme, ARBs do not affect bradykinin, which is linked to ACE inhibitor cough and
angioedema.
Although ACE inhibitors remain first-line therapy in patients with Stage C HFrEF,
current guidelines recommend use of ARBs in patients unable to tolerate (usually due
to cough) ACE inhibitors. Combined use of ACE inhibitors, ARBs, and aldosterone
antagonists is not recommended because of an increased risk of renal dysfunction and
hyperkalemia. Current guidelines recommend that addition of an ARB can be
considered in patients with HFrEF who remain symptomatic despite treatment with
an ACE inhibitor and a β-blocker if an aldosterone antagonist cannot be used.
Although a number of ARBs are available, only candesartan, losartan, and valsartan
are recommended because efficacy has been demonstrated in clinical trials. As with
ACE inhibitors, initial doses should be low with titration to targets achieved in
clinical trials (see Table 9–1).
Assess BP, renal function, and serum potassium within 1 to 2 weeks after therapy
initiation and dose increases, with these endpoints used to guide subsequent dose
changes. It is not necessary to reach target ARB doses before adding a β-blocker.
Caution should be exercised when ARBs are used in patients with angioedema from
ACE inhibitors because cross reactivity has been reported. ARBs are not alternatives
in patients with hypotension, hyperkalemia, or renal insufficiency due to ACE
inhibitors because they are just as likely to cause these adverse effects.
β-BLOCKERS
There is overwhelming clinical trial evidence that certain β-blockers slow disease
progression, decrease hospitalizations, and reduce mortality in patients with systolic
HF.
The ACC/AHA guidelines recommend use of β-blockers in all stable patients with
HF and a reduced LVEF in the absence of contraindications or a clear history of β-
blocker intolerance. Patients should receive a β-blocker even if symptoms are mild or
well controlled with ACE inhibitor and diuretic therapy. It is not essential that ACE
inhibitor doses be optimized before a β-blocker is started because the addition of a β-
blocker is likely to be of greater benefit than an increase in ACE inhibitor dose.
β-Blockers are also recommended for asymptomatic patients with a reduced LVEF
(stage B) to decrease the risk of progression to HF.
Initiate β-blockers in stable patients who have no or minimal evidence of fluid
overload. Because of their negative inotropic effects, start β-blockers in very low
doses with slow upward dose titration to avoid symptomatic worsening or acute

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 decompensation. Titrate to target doses when possible to provide maximal survival
benefits.
Carvedilol, metoprolol succinate (CR/XL), and bisoprolol are the only β-blockers
shown to reduce mortality in large HF trials. Because bisoprolol is not available in
the necessary starting dose of 1.25 mg, the choice is typically limited to either
carvedilol or metoprolol succinate. Initial and target doses are those associated with
reductions in mortality in placebo-controlled clinical trials (see Table 9–1).
Doses should be doubled no more often than every 2 weeks, as tolerated, until the
target dose or the maximally tolerated dose is reached. Patients should understand
that dose up-titration is a long, gradual process and that achieving the target dose is
important to maximize benefits. Further, the response to therapy may be delayed, and
HF symptoms may actually worsen during the initiation period.
ALDOSTERONE ANTAGONISTS
Spironolactone and eplerenone block the mineralocorticoid receptor, the target site
for aldosterone. In the kidney, aldosterone antagonists inhibit sodium reabsorption
and potassium excretion. However, diuretic effects are minimal, suggesting that their
therapeutic benefits result from other actions. In the heart, aldosterone antagonists
inhibit cardiac extracellular matrix and collagen deposition, thereby attenuating
cardiac fibrosis and ventricular remodeling. Aldosterone antagonists also attenuate
the systemic proinflammatory state, atherogenesis, and oxidative stress caused by
aldosterone.
Based on clinical trial results demonstrating reduced mortality, low-dose aldosterone
antagonists may be appropriate for: (1) patients with mild to moderately severe
HFrEF (NYHA class II–IV) who are receiving standard therapy, and (2) those with
LV dysfunction and either acute HF or diabetes early after MI.
Aldosterone antagonists must be used cautiously and with careful monitoring of renal
function and potassium concentration. They should be avoided in patients with renal
impairment, recent worsening of renal function, serum potassium greater than 5
mEq/L, or a history of severe hyperkalemia. Spironolactone also interacts with
androgen and progesterone receptors, which may lead to gynecomastia, impotence,
and menstrual irregularities in some patients.
Initial doses should be low, and doses should be limited to those associated with
beneficial effects to decrease the risk for hyperkalemia (see Table 9–1).

Drugs to Consider for Select Patients with HFrEF

NITRATES AND HYDRALAZINE
Nitrates (eg, ISDN) and hydralazine have complementary hemodynamic actions.
Nitrates are primarily venodilators, producing reductions in preload. Hydralazine is a
direct arterial vasodilator that reduces systemic vascular resistance (SVR) and
increases stroke volume and cardiac output. The mechanism for the beneficial effects
of hydralazine/ISDN in HF remains uncertain but is likely related to normalization of
the increased oxidative stress and reduced nitric oxide signaling that contributes to
HF progression.
Guidelines recommend addition of hydralazine/ISDN to self-described African

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 Americans with HFrEF and NYHA class III–IV symptoms treated with ACE
inhibitors and β-blockers. The combination can also be useful in patients unable to
tolerate either an ACE inhibitor or ARB because of renal insufficiency,
hyperkalemia, or possibly hypotension.
Obstacles to successful therapy with this drug combination include the need for
frequent dosing (ie, three times daily with the fixed-dose combination product), high
frequency of adverse effects (eg, headache, dizziness, and GI distress), and increased
cost for the fixed-dose combination product.
ARB/NEPRILYSIN INHIBITOR (ARNI)
Valsartan/sacubitril is an angiotensin receptor/neprilysin inhibitor approved for
treatment of HFrEF. The drug product is a crystalline complex composed of both
drugs. Neprilysin is one of the enzymes that break down endogenous natriuretic
peptides. The peptides are beneficial because they cause vasodilation, increased
glomerular filtration, natriuresis, and diuresis. Sacubitril is a neprilysin inhibitor
prodrug that is cleaved into its active form, which inhibits neprilysin thereby
promoting vasodilation through a different mechanism than the ARB. Combination
with valsartan negates the elevated levels of AT2 that would result from use of
neprilysin alone.
The combination product is indicated to reduce the risk of cardiovascular death and
hospitalization for HF in patients with NYHA Class II–IV HF and reduced LVEF.
When titrated to a target dose of 200 mg (sacubitril 97 mg/valsartan 103 mg) twice
daily, the combination reduced the combined endpoint of cardiovascular death and
hospitalization for HF by 20% compared to enalapril 10 mg twice daily in patients
with symptomatic HF and reduced LVEF. Its use will likely be incorporated into
future HF guidelines.
IVABRADINE
Ivabradine blocks the If current in the sinoatrial node that is responsible for
controlling heart rate, thereby slowing spontaneous depolarization of the sinus node
and resulting in a dose-dependent slowing of the heart rate.
It is indicated to reduce the risk of hospitalization for worsening HF in patients with
LVEF ≤ 35% who are in sinus rhythm with resting heart rate ≥ 70 bpm and either are
on maximally tolerated doses of β-blockers or have a contraindication to β-blocker
use. The most common adverse effects are bradycardia, atrial fibrillation, and visual
disturbances.
DIGOXIN
Although digoxin has positive inotropic effects, its benefits in HF are related to its
neurohormonal effects. Digoxin improves cardiac function, quality of life, exercise
tolerance, and HF symptoms in patients with HFrEF but does not improve survival.
Based on available data, digoxin is not considered a first-line agent in HF, but a trial
may be considered in conjunction with GDMT including ACE inhibitors, β-blockers,
and diuretics in patients with symptomatic HFrEF to improve symptoms and reduce
hospitalizations. Digoxin may also be considered to help control ventricular response
rate in patients with HFrEF and supraventricular arrhythmias, although β-blockers

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 are generally more effective rate control agents, especially during exercise.
In the absence of digoxin toxicity or serious adverse effects, digoxin should be
continued in most patients. Digoxin withdrawal may be considered for asymptomatic
patients who have significant improvement in systolic function with optimal ACE
inhibitor and β-blocker treatment.
The target serum digoxin concentration for most patients is 0.5 to 0.9 ng/mL (0.6–1.2
nmol/L). Most patients with normal renal function can achieve this level with a dose
of 0.125 mg/day. Patients with decreased renal function, the elderly, or those
receiving interacting drugs (eg, amiodarone) should receive 0.125 mg every other
day.

TREATMENT OF ACUTE DECOMPENSATED HEART FAILURE

GENERAL APPROACH
Acute decompensated heart failure (ADHF) involves patients with new or worsening
signs or symptoms (often resulting from volume overload and/or low cardiac output)
requiring medical intervention, such as emergency department visit or
hospitalization.
Goals of Treatment: The overall goal is to relieve symptoms while optimizing
volume status and cardiac output so the patient can be discharged in a stable
compensated state on oral drug therapy.
Hospitalization should be considered based on clinical findings. Most patients may
be admitted to a monitored unit or general medical floor. Admission to an intensive
care unit (ICU) may be required if the patient experiences hemodynamic instability
requiring frequent monitoring of vital signs, invasive hemodynamic monitoring, or
rapid titration of IV medications with close monitoring.
History and physical exam should focus on potential etiologies of ADHF; presence of
precipitating factors (eg, arrhythmias, hypertension, myocardial infarction, anemia,
and thyroid disorders); onset, duration, and severity of symptoms; and a careful
medication history. Laboratory tests that may be obtained include BNP or N-terminal
pro-BNP, thyroid function tests, complete blood count, cardiac enzymes, and routine
serum chemistries.
Ascertain hemodynamic status to guide initial therapy. Patients may be categorized
into one of four hemodynamic subsets based on volume status (euvolemic or “dry” vs
volume overloaded or “wet”) and cardiac output (adequate cardiac output or “warm”
vs hypoperfusion or “cold”) (Fig. 9–2).

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 (IV, intravenous; MCS, mechanical circulatory support; PAC, pulmonary artery catheter; PCWP,
pulmonary capillary wedge pressure; SBP, systolic BP.)

FIGURE 9–2. General management algorithm for acute decompensated

heart failure based on clinical presentation. Patients may be categorized
into a hemodynamic subset based on signs and symptoms or invasive
hemodynamic monitoring. Adjunct strategies for overcoming diuretic
resistance include increasing the dose of loop diuretic; switching to a
continuous infusion; adding a diuretic with an alternative mechanism of
action, an IV vasodilator, or an IV inotrope; and in select patients,
ultrafiltration or a vasopressin antagonist.

Reserve invasive hemodynamic monitoring for patients who are refractory to initial
therapy, whose volume status is unclear, or who have significant hypotension or
worsening renal function despite appropriate initial therapy.
Address and correct reversible or treatable causes of decompensation.
Assess medications being taken prior to admission and determine whether adjustment
or discontinuation is required.
If fluid retention is evident on physical exam, pursue aggressive diuresis, often with
IV diuretics.
In the absence of cardiogenic shock or symptomatic hypotension, strive to continue
all GDMT for HF. β-blockers may be temporarily held or dose-reduced if recent
changes are responsible for acute decompensation. Other GDMT (ACE inhibitors,
ARBs, neprilysin inhibitors, and aldosterone antagonists) may also need to be
temporarily held in the presence of renal dysfunction, with close monitoring of serum
potassium. Most patients may continue to receive digoxin at doses targeting a trough
serum concentration of 0.5 to 0.9 ng/mL (0.6–1.2 nmol/L).

PHARMACOTHERAPY OF ACUTE DECOMPENSATED HEART

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FAILURE

Diuretics
IV loop diuretics, including furosemide, bumetanide, and torsemide, are used for
ADHF, with furosemide being the most widely studied and used agent.
Bolus administration reduces preload by functional venodilation within 5 to 15
minutes and later (>20 min) via sodium and water excretion, thereby improving
pulmonary congestion. However, acute reductions in venous return may severely
compromise effective preload in patients with significant diastolic dysfunction or
intravascular depletion.
Because diuretics can cause excessive preload reduction, they must be used
judiciously to obtain the desired improvement in congestive symptoms while
avoiding a reduction in cardiac output, symptomatic hypotension, or worsening renal
function.
Diuretic resistance may be overcome by administering larger IV bolus doses or
continuous IV infusions of loop diuretics. Diuresis may also be improved by adding a
second diuretic with a different mechanism of action (eg, combining a loop diuretic
with a distal tubule blocker such as metolazone or hydrochlorothiazide). The loop
diuretic–thiazide combination should generally be reserved for inpatients who can be
monitored closely for development of severe electrolyte and intravascular volume
depletion. In the outpatient setting, very low doses of the thiazide-type diuretic or
infrequent administration (eg, 1–3 times weekly) are recommended.

Vasodilators
Venodilators reduce preload by increasing venous capacitance, improving symptoms
of pulmonary congestion in patients with high ventricular filling pressures. Arterial
vasodilators reduce afterload and cause a reflex increase in cardiac output, which
may promote diuresis via improved renal perfusion. Mixed vasodilators act on both
arterial resistance and venous capacitance vessels, reducing congestive symptoms
while increasing cardiac output.
NITROGLYCERIN
IV nitroglycerin is often preferred for preload reduction in ADHF, especially in
patients with pulmonary congestion. It reduces preload and pulmonary capillary
wedge pressure (PCWP) via functional venodilation and mild arterial vasodilation. In
higher doses, nitroglycerin displays potent coronary vasodilating properties and
beneficial effects on myocardial oxygen demand and supply, making it the
vasodilator of choice for patients with severe HF and ischemic heart disease.
Initiate nitroglycerin at 5 to 10 mcg/min (0.1 mcg/kg/min) and increase every 5 to 10
minutes as necessary and tolerated. Maintenance doses usually range from 35 to 200
mcg/min (0.5–3 mcg/kg/min). Hypotension and an excessive decrease in PCWP are
important dose-limiting side effects. Tolerance to the hemodynamic effects may
develop over 12 to 72 hours of continuous administration.
NESIRITIDE

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 Nesiritide is a recombinant form of endogenous BNP, which is secreted by the
myocardium in response to volume overload. Nesiritide mimics the vasodilatory and
natriuretic actions of BNP, resulting in venous and arterial vasodilation; increased
cardiac output; natriuresis and diuresis; and decreased cardiac filling pressures,
sympathetic nervous system activity, and renin–angiotensin–aldosterone system
activity. In contrast to nitroglycerin or dobutamine, tolerance to its pharmacologic
effects does not develop.
Evidence from clinical trials indicates a limited role for nesiritide beyond relief of
congestive symptoms in patients with acute dyspnea. Its use for management of
ADHF has declined because it produces marginal improvement in clinical outcomes
and is substantially more expensive than other IV vasodilators.
NITROPRUSSIDE
Sodium nitroprusside is a mixed arteriovenous vasodilator that acts directly on
vascular smooth muscle to increase cardiac index and decrease venous pressure to a
similar degree as dobutamine and milrinone despite having no direct inotropic
activity. However, nitroprusside generally produces greater decreases in PCWP,
SVR, and BP.
Hypotension is an important dose-limiting adverse effect of nitroprusside, and its use
should be primarily reserved for patients with elevated SVR. Close monitoring is
required because even modest heart rate increases can have adverse consequences in
patients with underlying ischemic heart disease or resting tachycardia.
Nitroprusside is effective in the short-term management of severe HF in a variety of
settings (eg, acute MI, valvular regurgitation, after coronary bypass surgery, and
ADHF). Generally, it does not worsen, and may improve, the balance between
myocardial oxygen demand and supply. However, an excessive decrease in systemic
arterial pressure can decrease coronary perfusion and worsen ischemia.
Nitroprusside has a rapid onset and a duration of action less than 10 minutes,
necessitating continuous IV infusions. Initiate therapy with a low dose (0.1–0.2
mcg/kg/min) to avoid excessive hypotension, and increase by small increments (0.1–
0.2 mcg/kg/min) every 5 to 10 minutes as tolerated. Usual effective doses range from
0.5 to 3 mcg/kg/min. Taper nitroprusside slowly when stopping therapy because of
possible rebound after abrupt withdrawal. Nitroprusside-induced cyanide and
thiocyanate toxicity are unlikely when doses less than 3 mcg/kg/min are administered
for less than 3 days, except in patients with significant renal impairment (ie, serum
creatinine > 3 mg/dL [>265 μmol/L]).

Vasopressin Antagonists
The vasopressin receptor antagonists currently available affect one or two arginine
vasopressin (AVP; antidiuretic hormone) receptors, V1A or V2. Stimulation of V1A
receptors (located in vascular smooth muscle cells and myocardium) results in
vasoconstriction, myocyte hypertrophy, coronary vasoconstriction, and positive
inotropic effects. V2 receptors are located in renal tubules, where they regulate water
reabsorption.
Tolvaptan selectively binds to and inhibits the V2 receptor. It is an oral agent

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 indicated for hypervolemic and euvolemic hyponatremia in patients with
syndrome of inappropriate antidiuretic hormone (SIADH), cirrhosis, and HF.
Tolvaptan is typically initiated at 15 mg orally daily and then titrated to 30 or 60
mg daily as needed to resolve hyponatremia. It is a substrate of cytochrome P450-
3A4 and is contraindicated with potent inhibitors of this enzyme. The most
common side effects are dry mouth, thirst, urinary frequency, constipation, and
hyperglycemia.
Conivaptan nonselectively inhibits both the V1A and V2 receptors. It is an IV
agent indicated for hypervolemic and euvolemic hyponatremia due to a variety of
causes; however, it is not indicated for hyponatremia associated with HF.
Monitor patients closely to avoid an excessively rapid rise in serum sodium that
could cause hypotension or hypovolemia; discontinue therapy if that occurs. Therapy
may be restarted at a lower dose if hyponatremia recurs or persists and/or these side
effects resolve.
The role of vasopressin receptor antagonists in the long-term management of HF is
unclear. In clinical trials, tolvaptan improved hyponatremia, diuresis, and
signs/symptoms of congestion. However, one study failed to demonstrate
improvement in global clinical status at discharge or a reduction in 2-year all-cause
mortality, cardiovascular mortality, or HF rehospitalization.

Inotropes
Low cardiac output in ADHF may worsen renal perfusion, resulting in resistance to
diuretic therapy. IV inotropes may improve peripheral hypoperfusion and diuresis by
improving central hemodynamics. However, because of their adverse effect profile
they should generally be reserved for patients not responding to other modalities or
those with clear evidence of low cardiac output.
Guidelines recommend that inotropes be considered only as a temporizing measure
for maintaining end-organ perfusion in patients with cardiogenic shock or evidence
of severely depressed cardiac output and low systolic BP (ie, ineligible for IV
vasodilators) until definitive therapy can be initiated, as a “bridge” for patients with
advanced HF who are eligible for mechanical circulatory support (MCS) or cardiac
transplantation, or for palliation of symptoms in patients with advanced HF who are
not eligible for MCS or cardiac transplantation.
Dobutamine and milrinone produce similar hemodynamic effects, but dobutamine is
usually associated with more pronounced increases in heart rate.
DOBUTAMINE
Dobutamine is a β1- and β2-receptor agonist with some α1-agonist effects. It does
not result in norepinephrine release from nerve terminals, so the positive inotropic
effects are attributed to effects on β1-receptors. Stimulation of cardiac β1-receptors
does not generally produce a significant increase in heart rate. Modest peripheral β2-
receptor-mediated vasodilation tends to offset minor α1-receptor-mediated
vasoconstriction; the net vascular effect is usually vasodilation.
The initial dose for ADHF is 1 to 2 mcg/kg/min, titrated by 1 to 2 mcg/kg/min every
10 to 20 minutes to a maximum of 20 mcg/kg/min on the basis of clinical and

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 hemodynamic responses.
Cardiac index is increased because of inotropic stimulation, arterial vasodilation, and
a variable increase in heart rate. It causes relatively little change in mean arterial
pressure compared with the more consistent increases observed with dopamine.
Although attenuation of dobutamine’s hemodynamic effects may occur with
prolonged administration, the dobutamine dose should be tapered rather than abruptly
discontinued.
MILRINONE
Milrinone inhibits phosphodiesterase III and produces positive inotropic and arterial
and venous vasodilating effects (an inodilator). It has supplanted use of amrinone,
which has a higher rate of thrombocytopenia.
During IV administration, milrinone increases stroke volume and cardiac output with
minimal change in heart rate. However, the venodilating effects may predominate,
leading to decreased BP and a reflex tachycardia. Milrinone also lowers pulmonary
PCWP by venodilation and is particularly useful in patients with a low cardiac index
and elevated LV filling pressure. However, this decrease in preload can be hazardous
for patients without excessive filling pressure, thus blunting the improvement in
cardiac output.
Use milrinone cautiously in severely hypotensive HF patients because it does not
increase, and may even decrease, arterial BP.
Most patients are started on a continuous IV infusion of 0.1 to 0.3 mcg/kg/min,
titrated to a maximum of 0.75 mcg/kg/min. A loading dose of 50 mcg/kg over 10
minutes can be given if rapid hemodynamic changes are required, but it should
generally be avoided because of the risk of hypotension.
The most notable adverse events are arrhythmia, hypotension, and, rarely,
thrombocytopenia. Measure the platelet count before and during therapy.
DOPAMINE
Dopamine should generally be avoided in ADHF, but its pharmacologic actions may
be preferable to dobutamine or milrinone in patients with marked systemic
hypotension or cardiogenic shock in the face of elevated ventricular filling pressures,
where dopamine in doses greater than 5 mcg/kg/min may be necessary to raise
central aortic pressure.
Dopamine produces dose-dependent hemodynamic effects because of its relative
affinity for α1-, β1-, β2-, and D1- (vascular dopaminergic) receptors. Positive
inotropic effects mediated primarily by β1-receptors become more prominent with
doses of 2 to 5 mcg/kg/min. At doses between 5 and 10 mcg/kg/min, chronotropic
and α1-mediated vasoconstricting effects become more prominent.
Evidence supporting use of low-dose dopamine (2–5 mcg/kg/min) to enhance
diuresis is controversial. Most studies indicate little if any improvement in urine
output, renal protection, or symptom relief, but increased rates of tachycardia. Thus,
it may not provide any advantage over traditional inotropes in this setting.

MECHANICAL CIRCULATORY SUPPORT

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 For patients with refractory ADHF, temporary MCS may be considered for
hemodynamic stabilization until the underlying etiology of cardiac dysfunction
resolves or has been corrected (“bridge to recovery”) or until evaluation for definitive
therapy (eg, durable MCS or cardiac transplantation) can be completed (“bridge to
decision”).
Because of its invasive nature and potential complications, MCS should be reserved
for patients refractory to maximally tolerated pharmacologic therapy.
IV vasodilators and inotropes may be used with temporary MCS to maximize
hemodynamic and clinical benefits or facilitate device removal.
Systemic anticoagulant therapy is generally required to prevent device thrombosis,
regardless of the method selected.
The intraaortic balloon pump (IABP) is most commonly employed due to ease of
use; however, it only increases cardiac output by about 1 L/min. It may be
particularly useful for patients with myocardial ischemia complicated by cardiogenic
shock, but it has not been shown to improve mortality in this setting.
Ventricular assist devices (VADs) are surgically implanted and assist, or in some
cases replace, the pumping functions of the right and/or left ventricles. Compared to
an IABP, VADs confer greater hemodynamic improvements but no differences in
long-term survival.
Extracorporeal membrane oxygenation (ECMO) may be venoarterial or
venovenous in nature. In venoarterial ECMO, deoxygenated blood is transported
from the venous circulation to an extracorporeal oxygenator and returned as
oxygenated blood to the arterial circulation. Venovenous ECMO consists of only
extracorporeal oxygenation; hemodynamic support is provided by native cardiac
function. Venoarterial ECMO is more commonly employed in the management of
ADHF.

SURGICAL THERAPY
Orthotopic cardiac transplantation is the best therapeutic option for patients with
irreversible advanced HF, as 10-year survival rates approach 60% in patients
transplanted after 2001.

EVALUATION OF THERAPEUTIC OUTCOMES

CHRONIC HEART FAILURE
Ask patients about the presence and severity of symptoms and how symptoms affect
daily activities.
Evaluate efficacy of diuretic treatment by disappearance of the signs and symptoms
of excess fluid retention. Physical examination should focus on body weight, extent
of jugular venous distention, presence of hepatojugular reflux, and presence and
severity of pulmonary congestion (rales, dyspnea on exertion, orthopnea, and
paroxysmal nocturnal dyspnea) and peripheral edema.
Other outcomes are improvement in exercise tolerance and fatigue, decreased
nocturia, and a decrease in heart rate.
Monitor BP to ensure that symptomatic hypotension does not develop as a result of

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 drug therapy.
Body weight is a sensitive marker of fluid loss or retention, and patients should
weigh themselves daily and report changes to their healthcare provider so that
adjustments can be made in diuretic doses.
Symptoms may worsen initially on β-blocker therapy, and it may take weeks to
months before patients notice symptomatic improvement.
Routine monitoring of serum electrolytes and renal function is mandatory in patients
with HF.

ACUTE DECOMPENSATED HEART FAILURE

Initial stabilization requires adequate arterial oxygen saturation, cardiac index, and
BP. Functional end-organ perfusion may be assessed by mental status, renal function
sufficient to prevent metabolic complications, hepatic function adequate to maintain
synthetic and excretory functions, stable heart rate and rhythm, absence of ongoing
myocardial ischemia or MI, skeletal muscle and skin blood flow sufficient to prevent
ischemic injury, and normal arterial pH (7.34–7.47) and serum lactate concentration.
These goals are most often achieved with a cardiac index greater than 2.2 L/min/m2,
mean arterial BP greater than 60 mm Hg, and PCWP 15 mm Hg or greater.
Daily monitoring should include weight, strict fluid intake and output measurements,
and HF signs/symptoms to assess the efficacy of drug therapy. Monitoring for
electrolyte depletion, symptomatic hypotension, and renal dysfunction should be
performed frequently. Vital signs should be assessed frequently throughout the day.
Patients should not be discharged until optimal volume status is achieved and the
patient is successfully transitioned from IV to oral diuretics, GDMT is stable, and IV
inotropes and vasodilators have been discontinued for at least 24 hours.

____________
See Chapter 14, Chronic Heart Failure, authored by Robert B. Parker, Jean M. Nappi,
and Larisa H. Cavallari, and Chapter 15, Acute Decompensated Heart Failure,
authored by Jo E. Rodgers and Brent N. Reed, for a more detailed discussion of this
topic.

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CHAPTER

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