Sem 3 Lect 2 Fármaco en Icc Con Fe Baja

7/8/2019 Pharmacologic therapy of heart failure with reduced ejection fraction - UpToDate
Official reprint from UpToDate®

www.uptodate.com ©2019 UpToDate, Inc. and/or its affiliates. All Rights Reserved.
Pharmacologic therapy of heart failure with reduced

ejection fraction
Author: Stephen S Gottlieb, MD
Section Editor: Sharon A Hunt, MD
Deputy Editor: Susan B Yeon, MD, JD, FACC
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Jul 2019. | This topic last updated: May 10, 2019.
INTRODUCTION
Heart failure (HF) is a common clinical syndrome resulting from any structural or functional cardiac
disorder that impairs the ability of the ventricle to fill with or eject blood. HF may be caused by
disease of the myocardium, pericardium, endocardium, heart valves, vessels, or by metabolic
disorders [1]. HF due to left ventricular dysfunction is categorized according to left ventricular
ejection fraction (LVEF) into HF with reduced ejection fraction (with LVEF ≤40 percent, known as
HFrEF; also referred to as systolic HF), HF with preserved ejection fraction (with LVEF ≥50
percent; known as HFpEF; also referred to as diastolic HF), and HF with mid-range ejection
fraction (with LVEF 41 to 49 percent; known as HFmrEF).
Pharmacologic therapy of HFrEF will be presented here [1-3]. An overview of the management of
HFrEF, the management of acute HF, drugs that should be avoided or used with caution in
patients with HF, management of HF during pregnancy, the management of refractory HF, and
therapy of HFpEF (diastolic HF) are discussed separately. (See "Overview of the therapy of heart
failure with reduced ejection fraction" and "Treatment of acute decompensated heart failure:
General considerations" and "Treatment of acute decompensated heart failure: Components of
therapy" and "Drugs that should be avoided or used with caution in patients with heart failure" and
"Management of heart failure during pregnancy" and "Management of refractory heart failure with
reduced ejection fraction" and "Treatment and prognosis of heart failure with preserved ejection
fraction".)
GOALS OF THERAPY
https://www.uptodate.com/contents/pharmacologic-therapy-of-heart-failure-with-reduced-ejection-fraction/print?search=BETABLOQUEDORES E… 1/32
The goals of pharmacologic therapy of HFrEF are to improve symptoms (including risk of
hospitalization), slow or reverse deterioration in myocardial function, and reduce mortality (table 1)
[1-3]:
● Improvement in symptoms can be achieved by diuretics, beta blockers, angiotensin

converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), angiotensin
receptor-neprilysin inhibitor (ARNI), hydralazine plus nitrate, digoxin, and aldosterone
antagonists.
● Prolongation of patient survival has been documented with beta blockers, ACE inhibitors,
ARNI, hydralazine plus nitrate, and aldosterone antagonists.
While the initial goal is to alleviate symptoms, drug therapy should be titrated as tolerated to target
ranges for optimum clinical benefit. The benefits observed from aggressive monitoring strategies
suggest that treatment beyond clinical congestion may improve outcomes. Additional
pharmacologic therapy is directed at management of contributing and associated conditions. (See
"Overview of the therapy of heart failure with reduced ejection fraction", section on 'Manage
contributing and associated conditions'.)
OUR APPROACH
We recommend the following approach to long-term pharmacologic therapy in patients with

HFrEF. In patients who present with acute HF, long-term therapy is begun following initial
stabilization as described separately. (See "Treatment of acute decompensated heart failure:
General considerations" and "Treatment of acute decompensated heart failure: Components of
therapy".)
The data supporting these summary recommendations are discussed in detail in the appropriate
topic reviews on individual pharmacologic agents. Although the use of evidence-based HF
therapies has improved due in part to efforts such as the American Heart Association "Get With
the Guidelines" program, the underutilization of evidence-based HF therapies continues to
contribute to substantial excess mortality [4].
We recommend the following sequence of pharmacologic therapy for patients with HFrEF (left
ventricular ejection fraction [LVEF] ≤40 percent), with allowance for variations depending upon
clinical response and presence of contraindications.
Initial therapy:
● Loop diuretics are introduced first in patients in volume overload. Diuresis to relieve signs and
symptoms of volume overload is pursued while adverse effects are monitored. (See 'Diuretic'
below.)
● Patients with HFrEF should be treated with an ACE inhibitor, ARNI, or ARB. For patients who
can take neither an ARNI nor ACE inhibitor (eg, due to hypotension with ARNI therapy and
cough with ACE inhibitor therapy), a single agent ARB is an alternative. One of these three
drugs is typically initiated during or after the optimization of diuretic therapy. The choice
among these agents is based upon considerations of efficacy in improving outcomes
(strongest for ARNI, intermediate for ACE inhibitor, and weakest for ARB), risk of side effects,
and access (including cost, which is highest for ARNI). These drugs are usually started at low
doses and then titrated to goals based upon trial data. (See 'ACE inhibitor, ARNI, or ARB'
below.)
● Beta blockers are initiated after the patient is stable on ACE inhibitor (or ARB), beginning at
low doses with titration to target doses as tolerated. (See 'Beta blocker' below.)
The following drugs are indicated in selected patients:
● For patients who can take neither an ACE inhibitor, nor ARNI, nor ARB, we suggest a
combination of hydralazine plus isosorbide dinitrate as an alternative. (See 'Hydralazine plus
nitrate' below.)
● For patients with LVEF ≤35 percent in sinus rhythm with a resting heart rate ≥70 beats per
minute (bpm) and who are either on a maximum tolerated dose of beta blocker or have
contraindication to beta blocker use, we suggest ivabradine. (See 'Ivabradine' below.)
● For patients who can be monitored for adequate renal function and a normal plasma
potassium concentration, and have symptomatic HF and an LVEF <35 percent, we suggest
addition of an mineralocorticoid receptor antagonist (MRA; spironolactone or eplerenone). An
MRA is also recommended for patients who are post-ST elevation myocardial infarction with
an LVEF ≤40 percent, are already receiving therapeutic doses of ACE inhibitor, and have
either symptomatic HF or diabetes mellitus. MRA therapy is limited to patients with baseline
serum potassium <5 mEq/L and estimated glomerular filtration rate >30 mL/min per 1.73 m2.
(See 'Mineralocorticoid receptor antagonist' below.)
● For patients (particularly black patients) who have persistent symptoms despite therapy with
an ACE inhibitor (or ARNI or single agent ARB) and beta blocker, we suggest the addition of
the combination of hydralazine and a nitrate. (See 'Hydralazine plus nitrate' below.)
● For most patients with HFrEF, we suggest not routinely using digoxin. We reserve the use of
digoxin for patients with HFrEF who continue to have NYHA functional class III and IV
symptoms (table 2) despite optimal therapy; some experts also require an LVEF <25 percent.
(See 'Digoxin' below.)
INITIAL THERAPY
Diuretic — For patients with HFrEF and volume overload, we recommend diuretic therapy,
typically with a loop diuretic [1]. The goal of relieving signs and symptoms of volume overload
(such as dyspnea and peripheral edema) should be pursued while adverse effects are monitored.
Improvement in symptoms can occur within hours to days. In comparison, the clinical effects of
digoxin, angiotensin converting enzyme (ACE) inhibitors, and beta blockers may require weeks or
months to become fully apparent. (See "Use of diuretics in patients with heart failure".)
The most commonly used loop diuretic for the treatment of HF is furosemide, but some patients
respond better to bumetanide or torsemide because of superior and more predictable absorption.
The usual starting dose in outpatients with HF is 20 to 40 mg of furosemide or its equivalent; the
maximum suggested total daily dose of furosemide is 400 mg (though some use higher doses).
Subsequent dosing is determined by the diuretic response. In patients who are volume
overloaded, a reasonable goal is weight reduction of 1.0 kg/day. If a patient does not respond, the
diuretic dose should initially be increased to find the single effective dose, rather than giving the
same dose twice a day. (See "Use of diuretics in patients with heart failure", section on 'Chronic
therapy'.)
Intravenous diuretics (either as a bolus or a continuous infusion) are more potent than their
equivalent oral doses, and may be required for unstable or severe disease. Thiazide diuretics can
be added for a synergistic effect. (See "Use of diuretics in patients with heart failure".)
The fall in intracardiac filling pressure that results from diuretic-induced fluid removal may lower
the cardiac output via the Frank-Starling relationship. This effect occurs when the rate of diuresis
exceeds the rate of fluid mobilization from tissues, and may occur despite persistent peripheral
edema and/or ascites. An otherwise unexplained fall in blood pressure or rise in blood urea
nitrogen and serum creatinine should be viewed as a sign of a potentially important reduction in
cardiac output. Further diuresis should be performed at a slower rate and only with careful
monitoring for signs and symptoms attributable to hypoperfusion. (See "Use of diuretics in patients
with heart failure".)
Over the long term, diuretic therapy should be maintained to prevent recurrent edema. In many
cases, this adjustment can be facilitated by having the patient record his or her weight each day
and allowing him or her to make changes in dose if the weight increases or decreases beyond a
specified range.
Although data on diuretic efficacy are very limited, a meta-analysis of a few small trials found that
diuretics were associated with reduction in mortality as well as reduced admission for worsening
HF [5]. However, diuretic therapy requires careful monitoring given observational data showing an
association between non-potassium-sparing diuretics and arrhythmic death. (See "Use of diuretics
in patients with heart failure", section on 'Efficacy and safety'.)
Appropriate diuretic usage can also affect the success of other drugs given for the treatment of HF.
Inappropriately low doses will result in fluid retention, which can diminish the response to ACE
inhibitors and angiotensin receptor blockers (ARBs) and increase the risk of decompensation with
the use of beta blockers. Conversely, excessive diuresis will lead to volume contraction, which can
increase the risk of hypotension and renal insufficiency with ACE inhibitors, ARBs, and beta
blockers.
ACE inhibitor, ARNI, or ARB — Treatment of patients with HFrEF should include treatment with
an ACE inhibitor, angiotensin receptor-neprilysin inhibitor (ARNI), or ARB. For selected patients
who can take neither an ARNI nor ACE inhibitor (eg, due to hypotension with ARNI therapy and
cough with ACE inhibitor therapy), a single agent ARB is an alternative. However, ACE inhibitor,
ARNI, or ARB should not be combined, and a 36 hours washout after ACE inhibitor
discontinuation is required before initiating ARNI.
The choice among these agents is based upon considerations of efficacy in improving outcomes
(strongest for ARNI, intermediate for ACE inhibitor, and weakest for ARB), risk of side effects
(higher risk of hypotension with ARNI), and access (including cost, which is highest for ARNI).
Patients with history of angioedema should take an ARB rather than an ACE inhibitor or ARNI.
Patients with an ACE-inhibitor-related cough can be switched to an ARNI or ARB. ARB and ARNI
intolerance can be presumed in patients who develop hyperkalemia or renal insufficiency on ACE
inhibitor therapy.
If none of these three agents is tolerated, the combination of hydralazine plus nitrate is a potential
alternative therapy. (See 'Hydralazine plus nitrate' below.)
ACE inhibitor — When an ACE inhibitor is selected, low initial doses (eg, 2.5 to 5 mg of
lisinopril once daily, 2.5 mg of enalapril twice daily) will reduce the likelihood of hypotension and
azotemia [6]. If initial therapy is tolerated, the dose is then gradually increased at one- to two-week
intervals to, if tolerated, a target dose of 20 mg twice daily of enalapril or up to 40 mg/day of
lisinopril or quinapril. These relatively high doses are recommended because they were used in
the successful trials [1]. Although there is uncertainty if these doses are much more beneficial than
lower doses, maximum dose therapy, if tolerated, is still recommended [1,7,8]. If the target doses
cannot be administered or are poorly tolerated, the tolerated lower doses should be used. (See
"Use of angiotensin converting enzyme inhibitors in heart failure with reduced ejection fraction",
section on 'Effect of dose'.)
In hospitalized patients, the dose of ACE inhibitor may be titrated at one- to two-day intervals.
While therapy may be initiated with captopril in patients in whom there is concern about blood
pressure reduction, we prefer once-per-day agents such as lisinopril for convenience in long-term
therapy in these patients, who typically receive multiple medications. Blood should be obtained in
all patients one to two weeks after starting or changing a dose and periodically thereafter to
assess the plasma potassium concentration and renal function.
ACE inhibitors improve survival in patients with left ventricular systolic dysfunction (left ventricular
EF [LVEF] ≤40 percent), ranging from asymptomatic left ventricular dysfunction [9] to moderate or
severe HFrEF (figure 1A-C) [10-13]. Although some concern has been raised concerning their
effectiveness in black patients, the available evidence is not sufficient to support a difference in
ACE inhibitor use based on race. (See "Use of angiotensin converting enzyme inhibitors in heart
failure with reduced ejection fraction".)
Angiotensin receptor-neprilysin inhibitor (ARNI) — The following recommendations for use

of the ARNI sacubitril-valsartan are likely to evolve with time as greater data and experience with
this drug develop (see "Use of angiotensin receptor-neprilysin inhibitor in heart failure with
reduced ejection fraction", section on 'Indication'):
For patients with NYHA class II or III HFrEF (LVEF ≤40 percent) with all of the following criteria,
we recommend treatment with sacubitril-valsartan.
Criteria for initiation include
● Current or prior elevated natriuretic peptide level
• For outpatients: B-type natriuretic peptide [BNP] level ≥150 pg/mL or N-terminal proBNP
[NT-proBNP] ≥600 pg/mL; or, if the patient was been hospitalized for HF within the
previous 12 months and BNP ≥100 pg/mL or NT-proBNP ≥400 pg/mL
• For patients hospitalized with acute HF: BNP level ≥400 pg/mL or NT-proBNP ≥1600
pg/mL during current hospitalization
● Systolic blood pressure (SBP) ≥100 mmHg
● Estimated glomerular filtration rate ≥30 mL/min/1.73 m2
and
● No history of angioedema (See "Use of angiotensin receptor-neprilysin inhibitor in heart

failure with reduced ejection fraction", section on 'Contraindications'.)
In patients with established HFrEF who are tolerating target dose ACE-inhibitor (eg, enalapril 10
mg bid) or single agent ARB, sacubitril-valsartan should be started and the ACE-inhibitor (or single
agent ARB) should be discontinued. For those on ACE-inhibitor, a 36-hour washout of ACE
inhibitor is required before sacubitril-valsartan is started. (See "Use of angiotensin receptor-
neprilysin inhibitor in heart failure with reduced ejection fraction", section on 'Contraindications'.)
Sacubitril-valsartan may also be initiated as a component of initial therapy for HFrEF (including
during hospitalization for acute HF after hemodynamic stabilization). In this context, hemodynamic
stability is defined as a systolic blood pressure (SBP) ≥100 mmHg for the preceding six hours, no
intravenous vasodilators and no increase in dose of intravenous diuretics in the preceding six
hours, and no intravenous inotropes in the preceding 24 hours [14]. (See "Use of angiotensin
receptor-neprilysin inhibitor in heart failure with reduced ejection fraction", section on 'Evidence'.)
For patients with new diagnosis of NYHA class II to IV HFrEF (left ventricular ejection fraction
[LVEF] ≤40 percent), we use either an ACE inhibitor (or single agent ARB) or ARNI as a
component of initial medical therapy. (See "Treatment of acute decompensated heart failure:
Components of therapy", section on 'ACE inhibitor, ARNI, or ARB'.)
In-hospital initiation of sacubitril-valsartan is contingent upon ensuring that the patient will have
continued access to the drug in the outpatient setting after discharge. If outpatient access to
sacubitril-valsartan cannot be achieved, then the patient can be discharged on ACE inhibitor (or
single ARB) and converted to sacubitril-valsartan as soon as sustainable outpatient access to this
medication can be secured at a reasonable cost for the patient.
Angiotensin II receptor blocker (ARB) — As discussed below, for patients with HFrEF (LVEF
≤40 percent) with current or prior symptoms of HF who are ACE inhibitor or ARNI intolerant due to
angioedema, we recommend a single agent ARB as an alternative. This recommendation applies
only when the ACE inhibitor intolerance is not hyperkalemia or renal insufficiency [15].
Routine combined use of both an ARB and an ACE inhibitor should be avoided. (See "Use of
angiotensin II receptor blocker in heart failure with reduced ejection fraction", section on 'Addition
of ARB to ACE inhibitor does not improve survival'.)
Angioedema due to ACE inhibitor or ARNI — When a patient treated with an ACE inhibitor or
ARNI develops angioedema for the first time, it can generally be assumed to be due to the ACE
inhibitor or neprilysin inhibitor, provided there are no additional symptoms or signs, such as
urticaria or bronchospasm, to suggest that the angioedema might be part of an allergic reaction,
since ACE inhibitors and ARNI cause isolated angioedema (meaning not associated with allergic
symptoms). Referral to an allergist may be helpful for evaluation if the diagnosis of angioedema is
unclear or when there may be other causes for the patient's symptoms and for management (of
symptoms and future risk), particularly when symptoms are life-threatening. (See "An overview of
angioedema: Clinical features, diagnosis, and management" and "An overview of angioedema:
Pathogenesis and causes" and "ACE inhibitor-induced angioedema".)
Angioedema due to ACE inhibitor or ARNI is mediated largely by bradykinin, and acute treatment
involves discontinuing the drug and carefully monitoring the airway (if that is the affected area)
until the episode is clearly resolving. There are no pharmacologic therapies with proven efficacy in
ACE-inhibitor-induced angioedema, although some treatments for other bradykinin-mediated
forms of angioedema may be used in severe cases. (See "ACE inhibitor-induced angioedema",
section on 'Therapies of unproven efficacy'.)
If angioedema is likely caused by an ACE inhibitor or ARNI, the causative drug should be
discontinued indefinitely and neither an ACE inhibitor nor ARNI should be used thereafter. In
patients with HFrEF who require ongoing therapy, we generally replace the ACE inhibitor or ARNI
with an ARB. Despite prior concerns about a potential risk of angioedema with ARB therapy, an
association between ARB therapy and angioedema has not been found. From a pharmacologic
perspective, angioedema is caused by ACE inhibitors and ARNI largely because these agents
block the degradation of bradykinin; in contrast, ARBs do not interfere with bradykinin metabolism.
A nationwide cohort study found that among 5507 patients with prior ACE-inhibitor-induced
angioedema, the incidence of angioedema was significantly lower in patients treated with ARBs
than in those treated with other antihypertensive agents (beta blockers, calcium channel blockers,
or thiazides) (adjusted hazard ratio 0.39; 95% CI 0.30-0.51) [16].
Since patients with angioedema are at risk for recurrent episodes even after the offending drug is
discontinued, it is important to avoid incorrectly attributing recurrent angioedema to an ARB
started as replacement therapy. We explain to patients that they could have a recurrence of
angioedema related to the discontinued drug or another medical condition, particularly during the
first month after discontinuation (but up to six months after) and review with them how to proceed
if this should occur. This is particularly important in patients with a past episode of severe
angioedema affecting the airway and consultation with an allergist may be helpful in managing
these patients. Patients with past severe angioedema affecting the airway should be counseled to
proceed immediately to the emergency department for monitoring if another angioedema episode
develops. In our experience, this occurs rarely and subsequent episodes are generally
significantly less severe. The potential benefit of ARB therapy in a patient with HFrEF generally far
exceeds the risk of falsely attributing recurrent angioedema to such therapy. Another approach is
to wait an interval of time (eg, four weeks) after an ACE inhibitor or ARNI is discontinued before
starting an ARB. However, this is only appropriate if the patient is deemed likely to safely go
without the medication for this period of time.
Beta blocker — Patients with HFrEF with no or minimal current evidence of fluid retention should
be treated with one of the following three beta blockers: carvedilol (immediate release or extended
release), extended release metoprolol succinate, or bisoprolol. For carvedilol, the immediate
release preparation was used in clinical trials demonstrating a mortality benefit but the extended
release preparation may be used as an alternative. Among inpatients, initiation of therapy prior to
hospital discharge improves beta-blocker use without an increase in side effects or drug
discontinuation [17]. If a patient has required recent intravenous inotropic therapy, beta blockade
should only be initiated under the guidance of an experienced HF center. As discussed above, we
recommend that patients initiate and at least partially titrate up ACE inhibitor therapy prior to
initiation of a beta blocker.
The patient should be informed that beta blockers may lead to an increase in symptoms for one to
two weeks before any improvement is noted. Therapy should be begun at very low doses and
the dose doubled at intervals of two weeks or more until the target dose is reached or symptoms
become limiting [18]. Initial and target doses are:
● For carvedilol immediate release, 3.125 mg twice daily initially and 25 to 50 mg twice daily
ultimately (the higher dose can be used in subjects over 85 kg). For carvedilol extended
release, 10 mg once daily initially and 80 mg once daily ultimately.
● For extended-release metoprolol (metoprolol succinate), 12.5 mg daily in patients with New
York Heart Association (NYHA) class III or IV symptoms or 25 mg daily in patients with NYHA
II symptoms, and ultimately 200 mg/day.
● For bisoprolol, 1.25 mg once daily initially and 5 to 10 mg once daily ultimately.
Every effort should be made to achieve the target dose since benefit appears to be dose-
dependent. The proportion of patients who reach the target dose is higher in clinical trials than in
the general population. However, although not optimal, even low doses appear to be of benefit
and should be used when higher doses are not tolerated [19]. Not uncommonly, a dose that is not
well tolerated during initial up-titration will be tolerated at a later time or with a slower rate of up-
titration. What may be most important is the degree of beta blockade [19]. However, aiming for a
particular resting heart rate or a particular reduction in heart rate is not of proven value [20].
The patient should weigh himself or herself daily and call the physician if there has been a 1 to 1.5
kg weight gain. Weight gain alone may be treated with diuretics, but resistant edema or more
severe decompensation may require dose reduction or cessation (possibly transient) of the beta
blocker. (See "Use of beta blockers in heart failure with reduced ejection fraction".)
Although data about the duration of beta blocker therapy in HF are lacking, it has been suggested
that patients who are doing well should not have the beta blocker withdrawn, since clinical
deterioration and sudden death or death from progressive HF have been observed after
withdrawal.
At least certain beta blockers, particularly carvedilol, metoprolol succinate, and bisoprolol, improve
overall and event-free survival in patients with NYHA class II to III HF [21-23] and probably in
class IV HF [24,25]. Beta blockers with intrinsic sympathomimetic activity (such as pindolol and
acebutolol) should be avoided [21]. The magnitude of benefit was illustrated in a meta-analysis
that included 22 trials involving more than 10,000 patients [21]. Compared to placebo, beta
blockers significantly reduced mortality at one year (odds ratio 0.65) and two years (odds ratio
0.72). During the first year, it was estimated that beta blocker therapy saved 3.8 lives per 100
patients treated and was associated with four fewer hospitalizations per 100 patients treated.
ACE inhibitors/ARNI or beta blockers first — In patients with new diagnosis of HFrEF, we
initiate ACE inhibitor or ARNI therapy prior to beta blocker therapy based upon clinical ACE
inhibitor trials that followed this approach. Randomized trials (eg, CIBIS III) suggest that eventual
outcomes may be similar if beta blockers are given first [26-28]. The approach we recommend is
based upon practical considerations related to differences in time to benefit and the importance of
attaining target dose for these two drug classes:
● An ACE inhibitor or ARNI provides rapid hemodynamic benefit and will not exacerbate HF in
the short run [1]. The rapid improvement in hemodynamics and renal function that can occur
with an ACE inhibitor or ARNI may facilitate the subsequent initiation of beta blockers, which
may transiently impair hemodynamics and symptoms. (See "Use of angiotensin converting
enzyme inhibitors in heart failure with reduced ejection fraction", section on 'Effect of dose'.)
● The hemodynamic benefits of beta blockers are delayed (and there may be a transient
worsening in cardiac function when therapy is initiated), but the long-term improvements in
LVEF and survival are dose dependent in patients who can tolerate the target dose (figure 2)
[29]. However, patients who cannot tolerate the target dose may derive similar benefit as
those who can, if they attain the same degree of beta blockade, as assessed from the
reduction in heart rate [19]. These observations suggest that some patients have higher
sensitivity to beta blockers.
Given these considerations, we start with a low oral dose of an ACE inhibitor (eg, lisinopril 2.5 to 5
mg/day) or ARNI (24 mg of sacubitril with 26 mg of valsartan twice daily), increase to a moderate
dose (eg, lisinopril 15 to 20 mg/day or 49 mg of sacubitril with 51 mg of valsartan twice daily) at
one- to two-week intervals, and then begin a beta blocker, gradually increasing toward the target
dose or, if this cannot be achieved, the highest tolerated dose. When the beta blocker titration is
completed, the ACE inhibitor or ARNI titration is completed.
In patients with low risk of adverse response to ACE inhibitors (adequate blood pressure, no
hyponatremia, hyperkalemia, or risk of intravascular depletion), higher doses of the ACE inhibitor
can be started and the titration can be quicker.
Complications that develop during dose titration of the beta blocker should be treated. For
example, the diuretic dose should be increased for fluid overload [1]. Hypotension rarely limits
metoprolol succinate titration, but may occur with carvedilol due to its additional vasodilator
activity. If hypotension limits carvedilol titration, one should consider a change to metoprolol
succinate. Since many patients with HFrEF have low blood pressures, we generally alter the
regimen only for symptoms or signs of underperfusion. A cardiologist should be consulted for
patients who have difficulty attaining target doses.
ADDITIONAL THERAPY
The following drugs are indicated in selected patients identified by their response to initial therapy
described above.
Mineralocorticoid receptor antagonist — We recommend mineralocorticoid receptor antagonist

(MRA; spironolactone or eplerenone) therapy (in addition to angiotensin converting enzyme [ACE]
inhibitor or angiotensin II receptor blocker [ARB] or angiotensin receptor-neprilysin inhibitor and
beta blocker therapy) in patients who have New York Heart Association (NYHA) functional class II
https://www.uptodate.com/contents/pharmacologic-therapy-of-heart-failure-with-reduced-ejection-fraction/print?search=BETABLOQUEDORES … 10/32
HF and an left ventricular ejection fraction (LVEF) ≤30 percent, or NYHA functional class III to IV
HF and an LVEF <35 percent, who can be carefully monitored for serum potassium and renal
function. We also recommend MRA therapy for patients post-ST elevation myocardial infarction
who are already receiving therapeutic doses of ACE inhibitor, have an LVEF ≤40 percent, and
have either symptomatic HF or diabetes mellitus, who can be carefully monitored for serum
potassium and renal function. MRA therapy is limited to patients with baseline serum potassium
<5.0 mEq/L, and estimated glomerular filtration rate (eGFR) should be >30 mL/min per 1.73 m2.
(See "Use of mineralocorticoid receptor antagonists in heart failure with reduced ejection fraction",
section on 'Our approach'.)
Spironolactone and eplerenone, which compete with aldosterone for the mineralocorticoid
receptor, prolong survival in selected patients with HFrEF as demonstrated in randomized
controlled trials [30-32] (See "Use of mineralocorticoid receptor antagonists in heart failure with
reduced ejection fraction".)
Although eplerenone is associated with fewer endocrine side effects than spironolactone (1 versus
10 percent in the respective trials), this advantage must be weighed against the marked difference
in cost between the two drugs. It is reasonable to begin with spironolactone (12.5 or 25 mg/day
titrated to 50 mg/day) and switch to eplerenone (25 mg/day and after four weeks titrated to 50
mg/day) if endocrine side effects occur. The endocrine side effects of spironolactone result from
nonselective binding to androgen and progesterone receptors; eplerenone has greater specificity
for the mineralocorticoid receptor and therefore has a lower incidence of endocrine side effects
such as gynecomastia. (See "Use of mineralocorticoid receptor antagonists in heart failure with
reduced ejection fraction".)
To the degree that blockade of a deleterious effect of aldosterone on the heart is important, a
similar benefit would not be expected with other potassium-sparing diuretics (such as amiloride).
It is essential that serum potassium and creatinine be rechecked within one week (eg, the 2013
American College of Cardiology/American Heart Association guidelines suggest within two to
three days and again at seven days) after starting spironolactone or eplerenone and periodically
thereafter (at least monthly for the first three months and after subsequently every three months)
[1]. Patients with poor renal function are particularly at risk for hyperkalemia. Renal dysfunction,
which is an important risk factor for hyperkalemia in this setting, may be underestimated by the
serum creatinine concentration, especially in elderly and other patients with reduced lean body
mass in whom creatinine production is reduced. Patients receiving diuretics with accompanying
potassium supplements and patients with diabetes mellitus are also at risk of hyperkalemia when
taking an MRA.
A specific approach to minimizing the risk of hyperkalemia has been proposed (table 3) [33]. (See
"Use of mineralocorticoid receptor antagonists in heart failure with reduced ejection fraction",
section on 'Risk of hyperkalemia' and "Assessment of kidney function", section on 'Estimation

equations'.)
Ivabradine — We suggest also using ivabradine (a selective sinus node inhibitor) for patients with
chronic HFrEF (with LVEF ≤35 percent) in sinus rhythm with a resting heart rate ≥70 bpm and who
are either on a maximum tolerated dose of beta blocker or have contraindication to beta blocker
use. Concurrent treatment should include ACE inhibitor (or ARB), and a mineralocorticoid receptor
blocker (if potassium can be appropriately monitored). (See "Use of ivabradine in heart failure with
reduced ejection fraction", section on 'Selection of candidates for ivabradine therapy'.)
Ivabradine reduces the risk of hospitalization by lowering heart rate in patients with chronic HFrEF
with sinus heart rate ≥70 bpm. (See "Use of ivabradine in heart failure with reduced ejection
fraction", section on 'Evidence'.)
Hydralazine plus nitrate — In black patients, we recommend the addition of hydralazine plus oral
nitrate therapy for patients with persistent NYHA class III to IV HF and LVEF <40 percent despite
optimal therapy including a beta blocker, ACE inhibitor (or ARB), aldosterone antagonist (if
indicated), and diuretics. Although the evidence of benefit is stronger in black patients, the addition
of hydralazine plus oral nitrate may be considered in non-black patients who have persistent
NYHA class II to IV HF despite optimal conventional therapy, particularly those with low output
syndromes, hypertension, or mitral regurgitation.
We suggest treatment with a combination of hydralazine plus nitrate in patients (of any race) with
HFrEF who can take neither an ACE inhibitor nor an ARNI, nor an ARB due to drug intolerance
(including hyperkalemia, hypotension, or worsening renal insufficiency). ARB intolerance can be
presumed in patients who develop hyperkalemia or renal insufficiency on ACE inhibitor therapy.
However, for patients with HFrEF who are unable to take an ACE inhibitor (or ARNI) due to
angioedema, an ARB is the preferred alternative. (See 'Angiotensin II receptor blocker (ARB)'
above.)
Starting doses of hydralazine 25 mg three times daily and isosorbide dinitrate 20 mg three times
daily are recommended. Uptitration of dose should be considered every two to four weeks. The
dose should not be increased if symptomatic hypotension develops. The target dose is
hydralazine 75 mg three times daily and isosorbide dinitrate (40 mg three times daily).
Although direct evidence of efficacy is lacking, isosorbide mononitrate (30 to 120 mg daily) may be
used in place of isosorbide dinitrate to improve compliance. The use of isosorbide mononitrate in
this setting is not included in the 2017 ACC/AHA/HFSA HF guideline update [34].
Hydralazine plus nitrate therapy may provide symptomatic and mortality benefit in selected
patients with HFrEF. Data supporting the efficacy of hydralazine plus nitrates in patients with
HFrEF are discussed separately. (See "Hydralazine plus nitrate therapy in patients with heart
Digoxin — For most patients with HFrEF, we suggest not routinely using digoxin. In treating
HFrEF, we reserve used of digoxin for patients with HFrEF on optimal evidence-based therapy
with NYHA functional class III and IV (table 2); some experts also require an LVEF <25 percent.
(See "Use of digoxin in heart failure with reduced ejection fraction", section on 'Our approach'.)
Digoxin dose is individualized based upon renal function, ideal body weight, and concomitant
medications that may affect digoxin levels. A common strategy is to use standard initial dosing
(particularly for individuals with ideal body weight, 61 to 80 kg) as follows:
● 0.125 mg per day for individuals with a creatinine clearance ≥30 mL/min.
● 0.0625 per day (which can be given as 0.125 mg every other day) for individuals with a
creatinine clearance <30 mL/min.
A nomogram may be helpful in determining an initial dose based upon ideal body weight and
renal function, particularly for patients with small or large body size and/or renal dysfunction
(table 4).
For patients with HFrEF, the target serum digoxin level for maximal efficacy and minimal risk of
toxicity is between 0.5 and 0.8 ng/mL. Higher serum levels should be avoided since they are
associated with an increased risk of toxicity without evidence of enhanced efficacy. Consensus is
lacking on the role of monitoring serum digoxin levels in patients treated with digoxin for HFrEF.
Some experts do not routinely measure digoxin levels if low doses are used and there is no
clinical evidence of toxicity. Alternatively, some experts routinely check a digoxin level after steady
state is reached (which is 7 to 10 days for most patients and up to three weeks in patients with
severe renal impairment).
Digoxin is not indicated as primary therapy for the stabilization of patients with acutely
decompensated HF. Such patients should first receive appropriate treatment for acute HF, usually
including intravenous medications. Digoxin may be initiated after stabilization and prior to
discharge as part of a long-term treatment strategy to reduce risk of rehospitalization.
Digoxin is given to patients with HFrEF to control symptoms (such as fatigue, dyspnea, and
exercise intolerance) and, in patients with atrial fibrillation, to control the ventricular rate. As
demonstrated in the DIG trial, digoxin therapy was associated with a significant reduction in
hospitalization for HF but no benefit in terms of overall mortality [35]. (See "Use of digoxin in heart
As noted above, in patients with sinus rates >70 bpm despite maximally-tolerated beta blockers,
ivabradine may be used to decrease the risk of hospitalization. (See 'Ivabradine' above.)
For patients with chronic HFrEF and atrial fibrillation requiring rate control, we recommend beta
blockers as initial therapy, since they are recommended in such patients for general HF treatment.
However, beta blockers may need to be initiated at lower doses with careful titration in patients
with severe left ventricular systolic dysfunction. If a second agent is necessary to achieve
adequate rate control, we suggest adding digoxin.
N-3 polyunsaturated fatty acids — Recommendations for fish oil and omega-3 fatty acids
consumption (including recommendations based on evidence in patients with HF) are discussed
separately. (See "Fish oil and marine omega-3 fatty acids", section on 'Heart failure'.)
OTHER DRUGS
Antithrombotic therapy — For patients in sinus rhythm with left ventricular systolic dysfunction
(with or without HF) without acute left ventricular thrombus, coronary artery disease, or other
indication for antithrombotic therapy, we recommend not administering antiplatelet or
anticoagulant therapy. However, many patients with HFrEF have indications for antiplatelet or
anticoagulant therapy. These issues are discussed separately. (See "Antithrombotic therapy in
patients with heart failure".)
Statins — Use of statin therapy in patients with HF is discussed separately. (See "Statin therapy
in patients with heart failure".)
Calcium channel blockers — There is no direct role for calcium channel blockers in the
management of HFrEF. Some initial studies suggested a possible deleterious effect of calcium
channel blockers in patients with HF, while later trials with vasoselective calcium channel blockers
amlodipine and felodipine showed no effect on mortality [36]. Amlodipine and felodipine appear to
be safe in patients with HFrEF and can be used if treatment with a calcium channel blocker is
necessary for another indication, such as angina or hypertension. (See "Calcium channel blockers
in heart failure with reduced ejection fraction".)
DURATION OF THERAPY
Pharmacologic therapy for treatment of HFrEF is generally continued indefinitely, as tolerated,

although limited data on the optimum duration of therapy are available.
There is a risk of recurrent adverse remodeling and HF with withdrawal of treatment for HFrEF
even in patients with recovery of LV systolic function. This risk was illustrated by an open-label,
pilot trial in 51 asymptomatic patients with prior dilated cardiomyopathy in whom LVEF had
improved from <40 percent to ≥50 percent; 25 patients were randomly assigned to treatment
withdrawal and 26 to continued treatment [37]. During the initial six months, among the treatment
withdrawal group, 11 (44 percent) met the primary endpoint of relapse (reduction in LVEF of more
than 10 percent and to less than 50 percent, an increase in LV end diastolic volume by more than
10 percent and to greater than the normal range, a two-fold rise in NT-proBNP level and to more
than 400 ng/L, or clinical evidence of HF), compared to none of those assigned to continue
treatment. After six months, 25 of the 26 patients initially assigned to continue therapy switched to
withdraw therapy; during the subsequent six months, nine patients (36 percent) met the primary
endpoint of relapse.
Predictors of durable recovery of ventricular systolic function have not been established.
DRUGS TO AVOID
A variety of drugs should be avoided or used with caution in patients with heart failure. This issue
is presented separately. (See "Drugs that should be avoided or used with caution in patients with
heart failure".)
MANAGEMENT DURING PREGNANCY
The treatment of HFrEF in pregnancy requires attention to specific concerns about the effects of
medications on the fetus and the mother, and is discussed separately. (See "Management of heart
failure during pregnancy".)
SOCIETY GUIDELINE LINKS
Links to society and government-sponsored guidelines from selected countries and regions
around the world are provided separately. (See "Society guideline links: Heart failure in adults".)
INFORMATION FOR PATIENTS
UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics."
The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading
level, and they answer the four or five key questions a patient might have about a given condition.
These articles are best for patients who want a general overview and who prefer short, easy-to-
read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and
more detailed. These articles are written at the 10th to 12th grade reading level and are best for
patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or
e-mail these topics to your patients. (You can also locate patient education articles on a variety of
subjects by searching on "patient info" and the keyword(s) of interest.)
● Basics topics (see "Patient education: Heart failure (The Basics)" and "Patient education:
Medicines for heart failure with reduced ejection fraction (The Basics)" and "Patient
education: Coping with high drug prices (The Basics)" and "Patient education: Heart failure
and atrial fibrillation (The Basics)" and "Patient education: Heart failure with reduced ejection
fraction (The Basics)")
● Beyond the Basics topics (see "Patient education: Heart failure (Beyond the Basics)" and
"Patient education: Coping with high drug prices (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
● The goals of pharmacologic therapy of heart failure with reduced ejection fraction (HFrEF; left
ventricular ejection fraction [LVEF] ≤40 percent) are to improve symptoms (including risk of
hospitalization), slow or reverse deterioration in myocardial function, and reduce mortality
(table 1). (See 'Goals of therapy' above.)
• Improvement in symptoms can be achieved by diuretics, beta blockers, angiotensin

converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), angiotensin
receptor-neprilysin inhibitor (ARNI), hydralazine plus nitrate, digoxin, and aldosterone
antagonists.
• Prolongation of patient survival has been documented with beta blockers, ACE inhibitors,
ARNI, hydralazine plus nitrate, and aldosterone antagonists.
● In patients who present with acute HF, long-term combination therapy is begun following
hemodynamic stabilization. (See "Treatment of acute decompensated heart failure:
Components of therapy".)
● Treatment of HFrEF is accomplished via appropriate combinations of the following agents

(see 'Our approach' above):
● Initial therapy: Initial therapy for HFrEF includes combination therapy with a diuretic therapy
(as required to treat volume overload); an ACE inhibitor, ARNI, or ARB; and a beta blocker.
• Patients with HFrEF and volume overload, require diuretic therapy. (See 'Diuretic' above.)
• Patients with HFrEF should be treated with an ACE inhibitor, ARNI, or ARB.
The choice among these agents is based upon considerations of strength of evidence for
efficacy in improving outcomes (strongest for ARNI, intermediate for ACE inhibitor, and
weakest for ARB), meeting criteria for use and risk of side effects (higher risk of
hypotension with ARNI), and access (including cost, which is highest for ARNI).
- In patients with a history of angioedema should not take an ACE inhibitor or ARNI,
and an ARB is preferred.
- Patients with an ACE inhibitor-related cough can be switched to an ARNI or ARB.
- ARNI and ARB intolerance can be presumed in patients who develop hyperkalemia
or renal insufficiency on ACE inhibitor therapy.
- If none of these three agents is tolerated, the combination of hydralazine plus nitrate
is a potential alternative therapy. (See 'Hydralazine plus nitrate' above.)
• Routine concomitant use of an ACE inhibitor and ARB should be avoided. (See
'Angiotensin II receptor blocker (ARB)' above and "Use of angiotensin II receptor blocker
in heart failure with reduced ejection fraction", section on 'Addition of ARB to ACE
inhibitor does not improve survival'.)
• An ACE inhibitor should not be used concomitantly with an ARNI. A 36-hour washout
period is required when switching between these drugs. (See 'ACE inhibitor, ARNI, or
ARB' above and "Use of angiotensin receptor-neprilysin inhibitor in heart failure with
reduced ejection fraction", section on 'Contraindications'.)
• For patients with current or prior HF and an LVEF ≤40 percent, we recommend therapy
with a beta blocker (Grade 1A). We believe that clinicians should choose one of the beta
blockers of proven benefit (including reduction in all-cause mortality) in randomized trials
(ie, carvedilol, extended-release metoprolol succinate, or bisoprolol). (See 'Beta blocker'
above.)
● Additional therapy:
• For patients with chronic stable HF with LVEF ≤35 percent, in sinus rhythm with a resting
heart rate ≥70 beats per minute, and who either are on a maximum tolerated dose of a
beta blocker or have a contraindication to beta blocker use, we suggest treatment with
ivabradine (Grade 2B). (See 'Ivabradine' above and "Use of ivabradine in heart failure
with reduced ejection fraction", section on 'Selection of candidates for ivabradine
therapy'.)
• For patients who can be monitored for preserved renal function and a normal plasma
potassium concentration and meet one of the following criteria, we recommend the
addition of a mineralocorticoid receptor antagonist (MRA; spironolactone or, if not
tolerated, eplerenone): NYHA functional class II HF and an LVEF ≤30 percent; NYHA
functional class III to IV HF and an LVEF <35 percent (table 2); or post-ST elevation
myocardial infarction, already receiving therapeutic doses of ACE inhibitor, an LVEF ≤40
percent, and either symptomatic HF or diabetes mellitus (Grade 1A). Given the relative
cost differences, we suggest spironolactone rather than eplerenone for initial therapy,
with switch to eplerenone if endocrine side effects occur (Grade 2B). (See
'Mineralocorticoid receptor antagonist' above.)
• For black patients with persistent moderate to severe HF symptoms and LVEF <40
despite optimal therapy including a beta blocker, ACE inhibitor (or ARB), MRA (if
indicated), and other diuretics, we recommend the addition of the combination of
hydralazine and an oral nitrate (Grade 1A). (See 'Hydralazine plus nitrate' above.)
• For patients with HFrEF who can take neither an ACE inhibitor nor an ARB due to drug
intolerance, hypotension, or renal insufficiency, we suggest hydralazine plus a nitrate
(Grade 2B). (See 'Hydralazine plus nitrate' above.)
• For select non-black patients with LVEF <40, particularly those with low output
syndromes, hypertension, or mitral regurgitation with persistent symptoms (despite
optimal therapy including a beta blocker, ACE inhibitor [or ARB], aldosterone antagonist
[if indicated], and other diuretics), we suggest the addition of the combination of
hydralazine and an oral nitrate (Grade 2B). (See 'Hydralazine plus nitrate' above.)
• For most patients with HFrEF, we suggest not routinely using digoxin (Grade 2B). We
reserve use of digoxin for patients with HFrEF who continue to have NYHA functional
class III and IV symptoms (table 2) despite optimal therapy; some experts also require a
left ventricular ejection fraction <25 percent. (See 'Digoxin' above.)
ACKNOWLEDGMENT
The UpToDate editorial staff would like to thank Dr. Wilson S. Colucci for his contributions as
author to previous versions of this topic review.
Use of UpToDate is subject to the Subscription and License Agreement.
REFERENCES
1. Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of
heart failure: executive summary: a report of the American College of Cardiology
Foundation/American Heart Association Task Force on practice guidelines. Circulation 2013;
128:1810.
2. WRITING COMMITTEE MEMBERS, Yancy CW, Jessup M, et al. 2016 ACC/AHA/HFSA

Focused Update on New Pharmacological Therapy for Heart Failure: An Update of the 2013
ACCF/AHA Guideline for the Management of Heart Failure: A Report of the American
College of Cardiology/American Heart Association Task Force on Clinical Practice
Guidelines and the Heart Failure Society of America. Circulation 2016; 134:e282.
3. Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC Guidelines for the diagnosis and
treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment
of acute and chronic heart failure of the European Society of Cardiology (ESC)Developed
with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J
2016; 37:2129.
4. Fonarow GC, Yancy CW, Hernandez AF, et al. Potential impact of optimal implementation of
evidence-based heart failure therapies on mortality. Am Heart J 2011; 161:1024.
5. Faris R, Flather MD, Purcell H, et al. Diuretics for heart failure. Cochrane Database Syst Rev
2006; :CD003838.
6. Kostis JB, Shelton BJ, Yusuf S, et al. Tolerability of enalapril initiation by patients with left
ventricular dysfunction: results of the medication challenge phase of the Studies of Left
Ventricular Dysfunction. Am Heart J 1994; 128:358.
7. Packer M, Poole-Wilson PA, Armstrong PW, et al. Comparative effects of low and high doses
of the angiotensin-converting enzyme inhibitor, lisinopril, on morbidity and mortality in
chronic heart failure. ATLAS Study Group. Circulation 1999; 100:2312.
8. Delahaye F, de Gevigney G. Is the optimal dose of angiotensin-converting enzyme inhibitors

in patients with congestive heart failure definitely established? J Am Coll Cardiol 2000;
36:2096.
9. SOLVD Investigators, Yusuf S, Pitt B, et al. Effect of enalapril on mortality and the
development of heart failure in asymptomatic patients with reduced left ventricular ejection
fractions. N Engl J Med 1992; 327:685.
10. Cohn JN, Johnson G, Ziesche S, et al. A comparison of enalapril with hydralazine-isosorbide
dinitrate in the treatment of chronic congestive heart failure. N Engl J Med 1991; 325:303.
11. CONSENSUS Trial Study Group. Effects of enalapril on mortality in severe congestive heart
failure. Results of the Cooperative North Scandinavian Enalapril Survival Study
(CONSENSUS). N Engl J Med 1987; 316:1429.
12. SOLVD Investigators, Yusuf S, Pitt B, et al. Effect of enalapril on survival in patients with
reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med 1991;
325:293.
13. Flather MD, Yusuf S, Køber L, et al. Long-term ACE-inhibitor therapy in patients with heart
failure or left-ventricular dysfunction: a systematic overview of data from individual patients.
ACE-Inhibitor Myocardial Infarction Collaborative Group. Lancet 2000; 355:1575.
14. Velazquez EJ, Morrow DA, DeVore AD, et al. Angiotensin-Neprilysin Inhibition in Acute
Decompensated Heart Failure. N Engl J Med 2019; 380:539.
15. Heart Failure Society of America, Lindenfeld J, Albert NM, et al. HFSA 2010 Comprehensive
Heart Failure Practice Guideline. J Card Fail 2010; 16:e1.
16. Rasmussen ER, Pottegård A, Bygum A, et al. Angiotensin II receptor blockers are safe in
patients with prior angioedema related to angiotensin-converting enzyme inhibitors - a
nationwide registry-based cohort study. J Intern Med 2019; 285:553.
17. Gattis WA, O'Connor CM, Gallup DS, et al. Predischarge initiation of carvedilol in patients
hospitalized for decompensated heart failure: results of the Initiation Management
Predischarge: Process for Assessment of Carvedilol Therapy in Heart Failure (IMPACT-HF)
trial. J Am Coll Cardiol 2004; 43:1534.
18. Eichhorn EJ, Bristow MR. Practical guidelines for initiation of beta-adrenergic blockade in
patients with chronic heart failure. Am J Cardiol 1997; 79:794.
19. Wikstrand J, Hjalmarson A, Waagstein F, et al. Dose of metoprolol CR/XL and clinical
outcomes in patients with heart failure: analysis of the experience in metoprolol CR/XL
randomized intervention trial in chronic heart failure (MERIT-HF). J Am Coll Cardiol 2002;
40:491.
20. Gullestad L, Wikstrand J, Deedwania P, et al. What resting heart rate should one aim for
when treating patients with heart failure with a beta-blocker? Experiences from the
Metoprolol Controlled Release/Extended Release Randomized Intervention Trial in Chronic
Heart Failure (MERIT-HF). J Am Coll Cardiol 2005; 45:252.
21. Brophy JM, Joseph L, Rouleau JL. Beta-blockers in congestive heart failure. A Bayesian
meta-analysis. Ann Intern Med 2001; 134:550.
22. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised
Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet 1999; 353:2001.
23. Packer M, Bristow MR, Cohn JN, et al. The effect of carvedilol on morbidity and mortality in
patients with chronic heart failure. U.S. Carvedilol Heart Failure Study Group. N Engl J Med
1996; 334:1349.
24. Goldstein S, Fagerberg B, Hjalmarson A, et al. Metoprolol controlled release/extended

release in patients with severe heart failure: analysis of the experience in the MERIT-HF
study. J Am Coll Cardiol 2001; 38:932.
25. Packer M, Coats AJ, Fowler MB, et al. Effect of carvedilol on survival in severe chronic heart
failure. N Engl J Med 2001; 344:1651.
26. Willenheimer R, van Veldhuisen DJ, Silke B, et al. Effect on survival and hospitalization of
initiating treatment for chronic heart failure with bisoprolol followed by enalapril, as compared
with the opposite sequence: results of the randomized Cardiac Insufficiency Bisoprolol Study
(CIBIS) III. Circulation 2005; 112:2426.
27. Sliwa K, Norton GR, Kone N, et al. Impact of initiating carvedilol before angiotensin-
converting enzyme inhibitor therapy on cardiac function in newly diagnosed heart failure. J
Am Coll Cardiol 2004; 44:1825.
28. Fang JC. Angiotensin-converting enzyme inhibitors or beta-blockers in heart failure: does it
matter who goes first? Circulation 2005; 112:2380.
29. Bristow MR, Gilbert EM, Abraham WT, et al. Carvedilol produces dose-related improvements
in left ventricular function and survival in subjects with chronic heart failure. MOCHA
Investigators. Circulation 1996; 94:2807.
30. Zannad F, McMurray JJ, Krum H, et al. Eplerenone in patients with systolic heart failure and
mild symptoms. N Engl J Med 2011; 364:11.
31. Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone on morbidity and mortality in
patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N
Engl J Med 1999; 341:709.
32. Pitt B, White H, Nicolau J, et al. Eplerenone reduces mortality 30 days after randomization
following acute myocardial infarction in patients with left ventricular systolic dysfunction and
heart failure. J Am Coll Cardiol 2005; 46:425.
33. Palmer BF. Managing hyperkalemia caused by inhibitors of the renin-angiotensin-

aldosterone system. N Engl J Med 2004; 351:585.
34. Yancy CW, Jessup M, Bozkurt B, et al. 2017 ACC/AHA/HFSA Focused Update of the 2013
ACCF/AHA Guideline for the Management of Heart Failure: A Report of the American
College of Cardiology/American Heart Association Task Force on Clinical Practice
Guidelines and the Heart Failure Society of America. J Am Coll Cardiol 2017; 70:776.
35. Digitalis Investigation Group. The effect of digoxin on mortality and morbidity in patients with
heart failure. N Engl J Med 1997; 336:525.
36. Cohn JN, Ziesche S, Smith R, et al. Effect of the calcium antagonist felodipine as
supplementary vasodilator therapy in patients with chronic heart failure treated with enalapril:
V-HeFT III. Vasodilator-Heart Failure Trial (V-HeFT) Study Group. Circulation 1997; 96:856.
37. Halliday BP, Wassall R, Lota AS, et al. Withdrawal of pharmacological treatment for heart
failure in patients with recovered dilated cardiomyopathy (TRED-HF): an open-label, pilot,
randomised trial. Lancet 2019; 393:61.
Topic 105338 Version 22.0
GRAPHICS
Demonstrated benefits of guideline-recommended heart failure therapies
Relative risk
Number needed to
Guideline- reductions in Relative risk
treat for mortality
recommended pivotal randomized reduction in meta-
benefit (standardized
therapy clinical trial(s) analysis
to 12 m)
(%)
Angiotensin converting 17 77 20%

enzyme inhibitor OR
angiotensin II receptor
blocker
Beta-blocker therapy 34 28 31%

(carvedilol, bisoprolol,
extended release
metoprolol succinate)
Aldosterone antagonist 30 18 25%
Hydralazine plus nitrate 43 21 Not available
Cardiac resynchronization 36 24 29/22%

therapy
Implantable cardioverter- 23 70 26%

defibrillator
Original figure modified for this publication. Fonarow GC, Yancy CW, Hernandez AF, et al. Potential impact of optimal
implementation of evidence-based heart failure therapies on mortality. Am Heart J 2011; 161:1024. Table used with the
permission of Elsevier Inc. All rights reserved.
Graphic 96488 Version 3.0
NYHA and other classifications of cardiovascular disability
Canadian
NYNA functional Cardiovascular Specific activity
Class
classification [1] Society functional scale [3]
classification [2]
I Patients with cardiac Ordinary physical activity, Patients can perform to

disease but without such as walking and completion any activity
resulting limitations of climbing stairs, does not requiring ≥7 metabolic
physical activity. Ordinary cause angina. Angina with equivalents (ie, can carry
physical activity does not strenuous or rapid 24 lb up 8 steps; do
cause undue fatigue, prolonged exertion at work outdoor work [shovel
palpitation, dyspnea, or or recreation. snow, spade soil]; do
anginal pain. recreational activities
[skiing, basketball,
squash, handball, jog/walk
5 mph]).
II Patients with cardiac Slight limitation of Patients can perform to

disease resulting in slight ordinary activity. Walking completion any activity
limitation of physical or climbing stairs rapidly, requiring ≥5 metabolic
activity. They are walking uphill, walking or equivalents (eg, have
comfortable at rest. stair-climbing after meals, sexual intercourse without
Ordinary physical activity in cold, in wind, or when stopping, garden, rake,
results in fatigue, under emotional stress, or weed, roller skate, dance
palpitation, dyspnea, or only during the few hours fox trot, walk at 4 mph on
anginal pain. after awakening. Walking level ground), but cannot
more than 2 blocks on the and do not perform to
level and climbing more completion activities
than 1 flight of ordinary requiring ≥7 metabolic
stairs at a normal pace equivalents.
and in normal conditions.
III Patients with cardiac Marked limitation of Patients can perform to

disease resulting in ordinary physical activity. completion any activity
marked limitation of Walking 1 to 2 blocks on requiring ≥2 metabolic
physical activity. They are the level and climbing 1 equivalents (eg, shower
comfortable at rest. Less- flight in normal conditions. without stopping, strip and
than-ordinary physical make bed, clean windows,
activity causes fatigue, walk 2.5 mph, bowl, play
palpitation, dyspnea, or golf, dress without
anginal pain. stopping) but cannot and
do not perform to
completion any activities
requiring >5 metabolic
equivalents.
IV Patients with cardiac Inability to carry on any Patients cannot or do not

disease resulting in physical activity without perform to completion
inability to carry on any discomfort. Anginal activities requiring >2
physical activity without syndrome may be present metabolic equivalents.
discomfort. Symptoms of at rest. Cannot carry out activities
cardiac insufficiency or of listed above (specific
the anginal syndrome may activity scale III).
be present even at rest. If
any physical activity is
undertaken, discomfort is
increased.
NYHA: New York Heart Association.
References:
1. The Criteria Committee of the New York Heart Association. Nomenclature and Criteria for Diagnosis of Diseases of
the Heart and Great Vessels, 9 th ed, Little, Brown & Co, Boston, 1994. p.253.
2. Campeau L. Grading of angina pectoris. Circulation 1976; 54:522.
3. Goldman L, Hashimoto B, Cook EF, Loscalzo A. Comparative reproducibility and validity of systems for assessing
cardiovascular functional class: Advantages of a new specific activity scale. Circulation 1981; 64:1227.
Enalapril improves outcome in asymptomatic LV

dysfunction
In the SOLVD prevention trial of 4228 patients (83 percent post-MI) with
asymptomatic left ventricular dysfunction, prophylactic administration of
enalapril reduced the probability of death or heart failure (p<0.001).
ACE: angiotensin-converting enzyme; LV: left ventricular; MI: myocardial infarction.
Data from: The SOLVD Investigators. Effect of enalapril on mortality and the
development of heart failure in asymptomatic patients with reduced left ventricular
ejection fractions. N Engl J Med 1992; 327:685.
ACE inhibitor improves survival in moderate HF
Enalapril, compared with placebo, decreases patient mortality in NYHA classes II

and III heart failure (p = 0.0036).
ACE: angiotensin-converting enzyme; HF: heart failure; NYHA: New York Heart
Association.
Data from: The SOLVD Investigators. Effect of enalapril on survival in patients with
reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med
1991; 325:293.
ACE inhibitor improves survival in advanced HF
Decreased mortality in patients with advanced NYHA class III or IV heart failure
after treatment with enalapril compared to placebo (p = 0.003).
Data from: The CONSENSUS Trial Study Group, N Engl J Med 1987; 316:1429.
Dose-related increase in LVEF with carvedilol in nonischemic

cardiomyopathy
Change in left ventricular ejection fraction (LVEF) among patients with dilated
cardiomyopathy after the administration of carvedilol. There is a dose-related increase in
LVEF in those with nonischemic cardiomyopathy; no such dose relationship is seen in
patients with ischemic cardiomyopathy.
Data from Bristow MR, Gilbert EM, Abraham WT, et al. Circulation 1996; 94:2807.
Approach to patients at risk for hyperkalemia caused by inhibitors of the renin-

angiotensin-aldosterone system
Estimate glomerular filtration rate to assess specific risk of hyperkalemia
Discontinue nonsteroidal anti-inflammatory drugs and other drugs that interfere with renal potassium excretion
Inquire about use of herbal preparations
Prescribe a low-potassium diet
Inquire about use of potassium-containing salt substitutes
Prescribe thiazide or loop diuretics to increase potassium excretion
Prescribe sodium bicarbonate to correct metabolic acidosis if present
When initiating ACE inhibitor, angiotensin receptor blocker, or aldosterone receptor blocker therapy, use low doses
Measure plasma potassium concentration one week after initiating therapy or after increasing dose of these agents
If plasma potassium increases to ≤5.5 mmol/liter, decrease dose of drug and, if combination therapy is being given,
discontinue one agent
In plasma potassium increases to >5.5 mmol/liter despite above measures, discontinue these agents
ACE: angiotensin converting enzyme.
Adapted from: Palmer BF. Managing hyperkalemia caused by inhibitors of the renin- angiotensin-aldosterone system. N
Engl J Med 2004; 351:585.
Initial digoxin maintenance dose for adult patients with heart failure targeting a
serum concentration of 0.5 to 0.9 nmol/L
Creatinine clearance Digoxin oral dose per day

Ideal body weight (kg)*
(mL/minute) ¶ (mg)
45 to 50 ≤60 0.0625 Δ
>60 0.125
51 to 60 ≤45 0.0625 Δ
46 to 110 0.125
>110 0.25
61 to 70 ≤35 0.0625 Δ
36 to 110 0.125
>110 0.25
71 to 80 ≤20 0.0625 Δ
21 to 80 0.125
>80 0.25
81 to 90 ≤10 0.0625 Δ
11 to 70 0.125
>70 0.25
Patients with unstable renal function or stage 5 renal disease requiring renal replacement therapy, pregnant
patients, and patients who were receiving medications known to significantly interact with digoxin (ie,
amiodarone, quinidine, verapamil, or macrolide antibiotics) were excluded from the population in which this
nomogram was validated. For adjustment of initial dose based upon response and serum digoxin concentration at
steady state (ie, after 7 to 10 days or more of daily use), refer to the topic review.
* A calculator to determine ideal body weight (method of Devine) is available in UpToDate.

¶ A calculator to estimate creatinine clearance according to Cockcroft and Gault equation is available in UpToDate.
Δ 0.0625 mg daily dose can be given as 0.125 mg every other day.
Sources:
1. Bauman JL, DiDomenico RJ, Viana M, Fitch M. A method of determining the dose of digoxin for heart failure in the
modern era. Arch Intern Med 2006; 166:2539.
2. DiDomenico RJ, Bress AP, Na-Thalang K, et al. Use of a simplified nomogram to individualize digoxin dosing versus
standard dosing practices in patients with heart failure. Pharmacotherapy 2014.
Contributor Disclosures
Stephen S Gottlieb, MD Grant/Research/Clinical Trial Support: Pfizer [Amyloidosis (Tafamidis), Heart
failure (Omecamtiv mecarbil)]; Cytokinetics [Heart failure (Omecamtiv mecarbil)]; Bristol-Myers Squibb [Heart
failure (BMS-986231)]; BTG International [Renal (Digoxin antibodies)]. Consultant/Advisory Boards:
Cytokinetics [Heart failure (Omecamtiv mecarbil)]. Sharon A Hunt, MD Nothing to disclose Susan B Yeon,
MD, JD, FACC Nothing to disclose
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are
addressed by vetting through a multi-level review process, and through requirements for references to be
provided to support the content. Appropriately referenced content is required of all authors and must conform
to UpToDate standards of evidence.
Conflict of interest policy

Sem 3 Lect 2 Fármaco en Icc Con Fe Baja

Caricato da

Informazioni sul documento

Copyright

Formati disponibili

Condividi questo documento

Condividi o incorpora il documento

Opzioni di condivisione

Hai trovato utile questo documento?

Questo contenuto è inappropriato?

Copyright:

Formati disponibili

Sem 3 Lect 2 Fármaco en Icc Con Fe Baja

Caricato da

Copyright:

Formati disponibili

7/8/2019 Pharmacologic therapy of heart failure with reduced ejection fraction - UpToDate

Official reprint from UpToDate®

Pharmacologic therapy of heart failure with reduced

● Improvement in symptoms can be achieved by diuretics, beta blockers, angiotensin

We recommend the following approach to long-term pharmacologic therapy in patients with

The following drugs are indicated in selected patients:

Angiotensin receptor-neprilysin inhibitor (ARNI) — The following recommendations for use

Criteria for initiation include

● Current or prior elevated natriuretic peptide level

● Systolic blood pressure (SBP) ≥100 mmHg

● Estimated glomerular filtration rate ≥30 mL/min/1.73 m2

● No history of angioedema (See "Use of angiotensin receptor-neprilysin inhibitor in heart

Mineralocorticoid receptor antagonist — We recommend mineralocorticoid receptor antagonist

section on 'Risk of hyperkalemia' and "Assessment of kidney function", section on 'Estimation

Pharmacologic therapy for treatment of HFrEF is generally continued indefinitely, as tolerated,

MANAGEMENT DURING PREGNANCY

SOCIETY GUIDELINE LINKS

INFORMATION FOR PATIENTS

SUMMARY AND RECOMMENDATIONS

• Improvement in symptoms can be achieved by diuretics, beta blockers, angiotensin

● Treatment of HFrEF is accomplished via appropriate combinations of the following agents

- Patients with an ACE inhibitor-related cough can be switched to an ARNI or ARB.

Use of UpToDate is subject to the Subscription and License Agreement.

2. WRITING COMMITTEE MEMBERS, Yancy CW, Jessup M, et al. 2016 ACC/AHA/HFSA

8. Delahaye F, de Gevigney G. Is the optimal dose of angiotensin-converting enzyme inhibitors

24. Goldstein S, Fagerberg B, Hjalmarson A, et al. Metoprolol controlled release/extended

33. Palmer BF. Managing hyperkalemia caused by inhibitors of the renin-angiotensin-

randomised trial. Lancet 2019; 393:61.

Topic 105338 Version 22.0

Demonstrated benefits of guideline-recommended heart failure therapies

Angiotensin converting 17 77 20%

Beta-blocker therapy 34 28 31%

Aldosterone antagonist 30 18 25%

Hydralazine plus nitrate 43 21 Not available

Cardiac resynchronization 36 24 29/22%

Implantable cardioverter- 23 70 26%

Graphic 96488 Version 3.0

NYHA and other classifications of cardiovascular disability

I Patients with cardiac Ordinary physical activity, Patients can perform to

II Patients with cardiac Slight limitation of Patients can perform to

III Patients with cardiac Marked limitation of Patients can perform to

IV Patients with cardiac Inability to carry on any Patients cannot or do not

NYHA: New York Heart Association.

Graphic 52683 Version 16.0

Enalapril improves outcome in asymptomatic LV

ACE: angiotensin-converting enzyme; LV: left ventricular; MI: myocardial infarction.

Graphic 75136 Version 5.0

ACE inhibitor improves survival in moderate HF

Enalapril, compared with placebo, decreases patient mortality in NYHA classes II

Graphic 70015 Version 3.0

ACE inhibitor improves survival in advanced HF

Graphic 62325 Version 1.0

Dose-related increase in LVEF with carvedilol in nonischemic

Graphic 57443 Version 3.0

Approach to patients at risk for hyperkalemia caused by inhibitors of the renin-

Estimate glomerular filtration rate to assess specific risk of hyperkalemia

Inquire about use of herbal preparations

Prescribe a low-potassium diet

Inquire about use of potassium-containing salt substitutes

Prescribe thiazide or loop diuretics to increase potassium excretion

Prescribe sodium bicarbonate to correct metabolic acidosis if present

ACE: angiotensin converting enzyme.

Graphic 67783 Version 6.0

Creatinine clearance Digoxin oral dose per day