Initial Pharmacologic Therapy of Heart Failure With Reduced Ejection Fraction in Adults - UpToDate PDF

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Terapia farmacológica inicial de insuficiencia cardíaca con

fracción de eyección reducida en adultos
Autor: Theo E Meyer, MD, PhD
Editor de sección: Stephen S Gottlieb, MD
Subdirector: Susan B Yeon, MD, JD, FACC
Todos los temas se actualizan a medida que hay nuevas pruebas disponibles y nuestro proceso de revisión por pares está completo.
Revisión de literatura actualizada hasta: junio de 2020. | Última actualización de este tema: 6 de mayo de 2020.
INTRODUCCIÓN
La insuficiencia cardíaca (IC) es un síndrome clínico común con síntomas causados por la capacidad
deteriorada de uno o ambos ventrículos para bombear a una presión normal debido a un trastorno cardíaco
estructural o funcional [ 1 ]. HF con fracción de eyección reducida (HFrEF) se define como HF con fracción de
eyección ventricular izquierda (LVEF) ≤40 por ciento.
Este tema presenta la terapia farmacológica inicial de HFrEF en pacientes no embarazadas [ 1-3 ].
Otros aspectos de la gestión de HFrEF se presentan por separado, incluidos:
● Una visión general de la gestión de HFrEF. (Ver "Descripción general del manejo de la insuficiencia
cardíaca con fracción de eyección reducida en adultos" ).
● Terapia farmacológica secundaria de insuficiencia cardíaca con fracción de eyección reducida. (Ver
"Terapia farmacológica secundaria en insuficiencia cardíaca con fracción de eyección reducida (HFrEF) en
adultos" .)
● Manejo de la insuficiencia cardíaca aguda. (Ver "Tratamiento de la insuficiencia cardíaca aguda

descompensada: componentes de la terapia" y "Tratamiento de la insuficiencia cardíaca aguda
descompensada: consideraciones generales" ).
● Manejo de pacientes embarazadas con IC. El tratamiento de HFrEF en el embarazo requiere atención a
preocupaciones específicas, incluidos los efectos de los medicamentos en el feto, y se discute por
separado. (Ver "Manejo de la insuficiencia cardíaca durante el embarazo" ).
TERAPIA INICIAL
https://www-uptodate-com.recursosenlinea.juanncorpas.edu.co:2443/contents/initial-pharmacologic-therapy-of-heart-failure-with-reduced-ejection-fra… 1/37
Los objetivos de la terapia para HFrEF incluyen la mejora de los síntomas y la supervivencia, así como atenuar
e invertir el impacto de la remodelación adversa en la geometría y la función del ventrículo izquierdo. Los
ensayos controlados aleatorios han demostrado que la terapia farmacológica inicial de HFrEF mejora estos
resultados clínicos y también retrasa o revierte el deterioro de la función miocárdica ( tabla 1 ) [ 1-3 ]:
● Las siguientes terapias iniciales se usan en combinación: diurético; bloqueador del sistema de
angiotensina (inhibidor del receptor de angiotensina-inhibidor de neprilisina [ARNI], inhibidor de la enzima
convertidora de angiotensina [ACE] o bloqueador del receptor de angiotensina II [ARB]); betabloqueante; e
hidralazina plus nitrate (used as an alternative to an angiotensin system blocker) have demonstrated
improved symptoms (including reduction in hospitalization for HF) and survival
● There is strong evidence that initial therapies used in combination (beta blocker and angiotensin system
blocker [ARNI or ACE inhibitor]) prolong survival. Reduction in mortality compared with placebo was
borderline significant for ARB therapy (used as an alternative to ARNI or ACE inhibitor) and for hydralazine
plus nitrate therapy (used as an alternative to an angiotensin system blocker).
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.
Approach — Pharmacologic therapy for HFrEF is initiated after screening for contraindications and
intolerances. (See 'Management of drug intolerances' below.)
For 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".)
Agents — Initial long-term management of each patient with HFrEF includes combined treatment with all
three of the following types of agents as tolerated (diuretic, a renin angiotensin system blocker [ARNI, ACE
inhibitor, or ARB; or alternate therapy with hydralazine plus nitrate], and a beta blocker), generally in the
following order (table 2):
● Diuretic therapy (typically with a loop diuretic) is used to relieve symptoms and signs of volume overload
(such as dyspnea and peripheral edema) while adverse effects are monitored. The use of diuretics in this
setting is discussed separately. (See "Use of diuretics in patients with heart failure".)
● Initial choice of angiotensin system blocker – A choice is made among the angiotensin system blockers
(angiotensin receptor-neprilysin inhibitor [ARNI], angiotensin converting enzyme [ACE] inhibitor, or single
agent angiotensin receptor blocker [ARB]); each patient should take only one of these agents at any given
time. 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), issues affecting access
(including cost, which is highest for ARNI), and risk of side effects (highest risk of hypotension with ARNI)
(table 3 and algorithm 1).
• ARNI – First, we determine whether the patient is a candidate for initial therapy with an ARNI.
Recommendations for use of the ARNI, sacubitril-valsartan, are likely to evolve with time as greater
data and experience with this drug grows. For patients with HFrEF with all three of the following
criteria, we recommend treatment with the sacubitril-valsartan (see 'Angiotensin receptor-neprilysin
inhibitor' below):
- Hemodynamic stability with systolic blood pressure (SBP) ≥100 mmHg (for at least six hours), no
increase in dose of intravenous diuretics in the preceding six hours, and no intravenous inotropes
in the preceding 24 hours [4]. ARNI therapy should be avoided if there is concern for hypotension
in the judgement of the clinician even if the SBP criterion is met. For example, the risk of
hypotension may be higher in patients who are very elderly (age >80 years) or frail.
- No history of angioedema. (See 'Angioedema' below.)
and
- The patient has access to medication (cost of medication or copay is not prohibitive for the
patient). If ongoing access to sacubitril-valsartan cannot be immediately achieved, then the patient
can be treated with an ACE inhibitor (or single ARB) and converted to sacubitril-valsartan as soon
as sustainable access to this medication can be secured at a reasonable cost for the patient.
• ACE inhibitor – For patients with HFrEF who are not candidates for ARNI therapy and have an SBP ≥
90 mmHg, lack symptomatic hypotension, and have no history of angioedema, we recommend an ACE
inhibitor.
• Single agent ARB – For patients with HFrEF with an SBP ≥90 mmHg who can take neither an ARNI
nor ACE inhibitor (eg, due to history of angioedema or cough), we recommend a single agent ARB.
This recommendation applies only when the ARNI or ACE inhibitor intolerance is not hyperkalemia or
worsening renal function.
The discussion here does not apply to pregnant patients; ACE inhibitors, ARNI, and ARBs are
contraindicated during pregnancy, as discussed separately. (See "Management of heart failure during
pregnancy".)
● Initiation and titration of angiotensin system blocker – The chosen angiotensin system blocker is
started generally at the time of or soon after initiation of diuretic therapy. However, angiotensin system
blocker initiation can be delayed if the patient has a large volume of fluid overload, requiring initial
aggressive diuresis. A low initial dose angiotensin system blocker is used to reduce the likelihood of
hypotension and worsening renal function (table 2).
If initial therapy is tolerated, the dose is then gradually increased at generally one-to two-week intervals to
target doses as tolerated in the outpatient setting. In a hospital setting, titration may be performed at one-to-
two-day intervals, as tolerated. Although the optimum dose is uncertain, the maximum tolerated dose up to
the target dose is recommended because these doses were used in successful trials [2,5,6]. In patients
with low risk of adverse response (adequate blood pressure, no hyponatremia, hyperkalemia, kidney
disease, or risk of intravascular depletion), higher doses can be started and the titration may progress more
quickly.
● If taking ACE inhibitor or single agent ARB, consider transition to ARNI – For patients with HFrEF who
are tolerating at least a moderate dose of ACE inhibitor (eg, lisinopril 7.5 or 10 mg daily) or single agent
ARB (eg, valsartan 40 mg twice daily) with SBP >100 mmHg and no symptomatic hypotension and who are
candidates for ARNI therapy (including no history of angioedema), transition to ARNI is indicated (algorithm
2). This involves discontinuation of the ACE-inhibitor (or single agent ARB) and starting sacubitril-valsartan.
For those taking an ACE-inhibitor, a 36-hour washout of ACE inhibitor must be strictly observed before
sacubitril-valsartan is started. For those taking a single agent ARB, sacubitril-valsartan is started in place of
the next dose of single agent ARB. (See 'Angiotensin receptor-neprilysin inhibitor' below.)
● If unable to tolerate any angiotensin system blocker – For patients with HFrEF who are unable to take
any angiotensin system blocker (ARNI, ACE inhibitor, or single agent ARB) due to hypotension, the cause
of hypotension should be assessed and managed. Volume status should be assessed to determine if
volume depletion is present and if diuretic therapy should be reduced or held. If hypotension persists in the
absence of volume depletion, consultation with an HF specialist is suggested.
For patients with HFrEF who are unable to take any angiotensin system blocker (ARNI, ACE inhibitor, or
single agent ARB) due to drug intolerance (eg, hyperkalemia) and who have a systolic blood pressure ≥90
mmHg, we suggest treatment with a combination of hydralazine plus an oral nitrate. (See 'Hydralazine plus
nitrate as alternative to angiotensin blocker' below.)
● Beta blocker – Beta blocker therapy is recommended for patients with HFrEF; therapy is initiated in
patients with no or minimal residual fluid retention. (See 'Beta blocker' below.)
Order of initiation and titration — Beta blocker therapy is generally introduced soon after initiation of
angiotensin system blocker (ARNI, ACE inhibitor, or single agent ARB) based upon clinical ACE inhibitor trials
that followed this approach as well as the anticipated time course of symptomatic benefit from these agents. An
ACE inhibitor, ARNI, or single agent ARB 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,
ARNI, or ARB may facilitate the subsequent initiation of beta blockers, which may transiently impair
hemodynamics and symptoms. On the other hand, randomized trials (eg, CIBIS III) suggest that eventual
outcomes may be similar if beta blockers are given first [7-9]. (See 'Beta blocker' below.)
As an example, we start with a low oral dose of an ACE inhibitor (eg, lisinopril 2.5 to 5 mg/day), ARNI (sacubitril-
valsartan 24 to 26 mg twice daily) or single agent ARB (eg, candesartan 4 to 8 mg/day or valsartan 40 mg bid),
increase to a moderate dose (eg, lisinopril 10 to 20 mg/day) as tolerated in approximately two weeks, and then
begin an initial dose of a beta blocker (eg, carvedilol 3.125 mg twice daily or metoprolol succinate 12.5 mg),
gradually uptitrate the beta blocker toward the highest tolerated dose up to the target maximal dose of beta
blocker. After the beta blocker titration is completed, the ACE inhibitor, ARNI, or single agent ARB titration is
completed.
Dosing and monitoring — As described above, each agent is started at a low initial dose and titrated to the
target dose as tolerated based upon experience from clinical trials (table 2) [1,2].
Limited data suggest that the optimum dose for ACE inhibitor, ARB and beta blocker may be lower for women
than men. An analysis of data from the prospective observational BIOSTAT-CHF study of patients with HFrEF
found that the dose of ACE inhibitor or ARB and beta blocker associated with lowest risk of death differed in
men compared to women [10]. In men, the lowest risk of death or hospitalization for HF occurred at 100 percent
of the target doses of ACE inhibitor or ARB and beta blocker; in women, there was an approximately 30 percent
reduction in risk of adverse events compared to no therapy at 50 percent of target doses, with no further
decrease in risk at higher dose levels. This difference persisted even after adjusting for body surface area.
Similar patterns of dose response in men and women were observed in the ASIAN-HF registry. Given the
available evidence, in treating women with HFrEF, we continue to titrate to target doses as tolerated.
Monitoring during pharmacologic treatment of HFrEF includes baseline and periodic clinical evaluation,
including evaluation of symptoms and signs of HF and screening for contraindications, adverse effects (eg,
hypotension), and drug interactions.
Monitoring for angiotensin system blocker therapy (ARNI, ACE inhibitor, or ARB) includes baseline and follow-
up blood tests (electrolytes [particularly serum potassium], blood urea nitrogen, and serum creatinine) at one to
two weeks (or one week and one month) following drug initiation or upward titration. Uptitration should be
continued only as tolerated and generally requires SBP ≥90 mmHg and absence of symptomatic hypotension.
After target dose (or the maximal tolerated subtarget dose) is attained, blood tests are checked periodically (eg,
every three to six months), depending on the patient's stability and baseline renal function. Close monitoring is
particularly important in patients with kidney disease or bilateral renal artery stenosis. (See "Renal effects of
ACE inhibitors in heart failure" and "Treatment of bilateral atherosclerotic renal artery stenosis or stenosis to a
solitary functioning kidney".)
Monitoring for beta blocker therapy includes baseline and follow-up assessment of heart rate (including baseline
electrocardiogram), symptoms and signs of HF (particularly evidence of volume overload) and bradycardia, and
other adverse effects. (See 'Dosing and cautions' below and "Major side effects of beta blockers".)
For patients treated with hydralazine, we suggest obtaining a baseline antinuclear antibody level prior to
initiation of hydralazine and periodically during prolonged therapy, given the risk of drug-induced lupus [11].
These studies are also indicated if the patient develops symptoms such as arthralgia, fever, chest pain, or
persistent malaise. The United States Food and Drug Administration labeling also recommends following the
complete blood count, but blood dyscrasias from hydralazine therapy are rare and patients with HFrEF often
have other indications to check blood counts, such as chronic anemia. (See "Drug-induced lupus", section on
'Diagnosis' and "Evaluation and management of anemia and iron deficiency in adults with heart failure".)
AGENTS INCLUDED IN INITIAL THERAPY
Combination therapy and individual agents — As described above, initial therapy of HFrEF includes
combination therapy with a diuretic to treat volume overload, one renin-angiotensin system blocker (ARNI, ACE
inhibitor, or ARB), and a beta blocker. If a patient is intolerant of all three of the angiotensin system blockers,
then hydralazine plus nitrate therapy is used as an alternative (along with beta blocker therapy). Dosing,
contraindications, and supporting evidence for each of these agents is presented here, except for diuretics
which are discussed separately. (See "Use of diuretics in patients with heart failure".)
Network meta-analyses have compared the efficacy of ACE inhibitors, beta blockers, single agent ARBs, MRAs,
ivabradine, and ARNI, and their combinations in patients with HFrEF [12,13]. However these results should be
interpreted with caution as limitations include use of study-level (not individual patient) data, use of only baseline
data on concomitant drug therapy, and pooling of data despite study differences with reliance on assumptions of
class effect and equivalent efficacy of drug doses. If >50 percent of trial patients received a concomitant drug,
the treatment was considered combination therapy (of study drug plus concomitant agent[s]).
● A network meta-analysis that included 57 randomized controlled trials published between 1987 and 2015
found that treatment with ARNI, ACE inhibitor, single agent ARB, beta blocker, and MRA and their
combinations significantly reduced mortality compared with placebo, except ARB monotherapy (and ARB
plus ACE inhibitor) for which nominal reductions in mortality were not statistically significant [12]. The
combination of ACE inhibitor plus beta blocker plus mineralocorticoid receptor antagonist (MRA) was
associated with a 56 percent reduction in mortality versus placebo (hazard ratio [HR] 0.44, 95% CI 0.26-
0.66). The combination of ARNI plus beta blocker plus MRA was associated with the greatest reduction in
mortality versus placebo (HR 0.37, 95% CI 0.19-0.65).
● Similar results for effects on mortality were observed in a network meta-analysis that included 58
randomized trials on treatment of HFrEF published between 1987 and 2017 [13]. This analysis also
examined nonfatal outcomes and found that the combination of ACE inhibitor plus beta blocker plus MRA
plus ivabradine and the combination of ARNI plus beta blocker plus MRA had the greatest effect in reducing
all-cause hospitalizations compared with placebo (HR 0.58, 95% CI 0.36-0.92 for both combinations). A
similar effect on all-cause hospitalization was seen with ACE inhibitor plus beta blocker plus MRA (HR 0.65,
95% CI 0.45-0.93). The combination of ACE inhibitor plus beta blocker was associated with reduced all-
cause hospitalization compared with placebo (HR 0.75, 95% CI 0.54-0.92) but the combination of single
agent ARB and beta blocker was associated with a statistically non-significant effect (HR 0.79, 95% CI
0.47-1.21).
Angiotensin receptor-neprilysin inhibitor
Dosing and cautions — The initial dose of sacubitril-valsartan is based upon whether the patient is already
taking an ACE inhibitor or ARB and at what dose (table 2).
As noted in the prescribing information for the sacubitril-valsartan combination tablet, the valsartan in this tablet
is more bioavailable than the valsartan in other marketed tablet formulations; 26, 51, and 103 mg of valsartan in
the combination tablet is equivalent to 40, 80, and 160 mg of valsartan in other marketed tablet formulations,
respectively [14].
Contraindications to the use of sacubitril-valsartan include pregnancy (given risk of fetal toxicity including fetal
death), history of angioedema (of any cause), and severe hepatic impairment (Child-Pugh C classification, given
lack of data in this population).
Sacubitril-valsartan should not be used concomitantly with the following drugs:
● ACE inhibitor (because of increased risk of angioedema). Do not administer within 36 hours of switching to
or from an ACE inhibitor.
● Aliskiren in patients with diabetes. Also, avoid use of sacubitril-valsartan with aliskiren in patients with
estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2.
● Another angiotensin II receptor blocker (ARB) (ie, avoid dual ARB therapy).
Impact on natriuretic peptide levels — During ARNI therapy, serum N-terminal proBNP (NT-proBNP) level
may be clinically helpful in monitoring HF, but B-type natriuretic peptide (BNP) levels are not. BNP is degraded
by neprilysin, so ARNI causes elevation of B-type natriuretic peptide (BNP) levels. Since N-terminal proBNP
(NT-proBNP) is not degraded by neprilysin, its levels are not increased by neprilysin inhibition.
Indeed, in the PARADIGM-HF trial, patients randomized to ARNI had higher BNP levels but lower NT-proBNP
levels at four weeks and eight months compared with those in the ACE inhibitor group [15]. Similarly, in the
PIONEER-HF trial, there were smaller reductions in BNP but greater reductions in NT-proBNP group (as
described above), in the patients treated with ARNI compared with those treated with ACE inhibitor [4]. (See
'Evidence' below.)
The role of natriuretic peptide measurement in diagnosis and monitoring of HF is discussed separately. (See
"Natriuretic peptide measurement in heart failure".)
Evidence — A randomized double-blind trial (PARADIGM-HF) in patients with HFrEF found that sacubitril-
valsartan reduced all-cause mortality as well as cardiovascular mortality and hospitalization for HF compared
with a proven dose of the ACE inhibitor enalapril [16]. In this trial, 8442 patients with an HFrEF (predominantly
New York Heart Association [NYHA] functional class II or III) were randomly assigned to receive either sacubitril-
valsartan (referred to as 200 mg twice daily, which is sacubitril 97 mg and valsartan 103 mg; ARB component
equivalent to 160 mg of valsartan twice daily) or enalapril (10 mg twice daily) following a run-in phase for
tolerability to enalapril and then to sacubitril-valsartan. At baseline, most patients in both treatment groups were
receiving recommended pharmacologic treatment for chronic HF (including over 90 percent receiving beta
blockers). The trial was stopped early after a median follow-up of 27 months because the prespecified boundary
for early termination for benefit was crossed.
● Sacubitril-valsartan reduced the risk of death compared with enalapril (17.0 versus 19.8 percent; HR 0.84;
95% CI 0.76-0.93). Sacubitril-valsartan versus enalapril reduced the risk of death from both progressive HF
and sudden cardiac death [17].
● Sacubitril-valsartan reduced the death from cardiovascular causes or hospitalization for HF (21.8 versus
26.5 percent; HR 0.80; 95% CI 0.73-0.87). Sacubitril-valsartan also reduced the risk of death from
cardiovascular causes (13.3 versus 16.5 percent; HR 0.80; 95% CI 0.71-0.89) and the risk of hospitalization
for HF (12.8 versus 15.6 percent; HR 0.79; 95% CI 0.71-0.89). Subjects randomized to ARNI therapy in the
PARADIGM-HF trial were also at reduced risk of 30- and 60-day all-cause readmission [18], and had higher
health-related quality of life as measured by the Kansas City Cardiomyopathy Questionnaire (KCCQ) [19],
including the physical and social domains [20]. Among patients with diabetes mellitus enrolled in the trial,
hemoglobin A1C levels were lower [21].
● The sacubitril-valsartan group had higher rates of hypotension and non-serious angioedema but lower rates
of renal impairment, hyperkalemia, and cough compared with the enalapril group.
Benefits of ARNI therapy were rapid, with a reduction of HF hospitalization evident within the first 30 days post-
randomization [15]. The benefits of ARNI therapy were consistent throughout the LVEF spectrum (range 5 to 42
percent; median 30 percent) among subjects enrolled in PARADIGM-HF [22], were independent of baseline
medical therapies or prior coronary revascularization [23], and were consistent across all baseline blood
pressures, including lower blood pressures [24].
The safety and efficacy of sacubitril-valsartan initiation during hospitalization for acute HF was evaluated in the
PIONEER-HF trial, in which 881 patients hospitalized with acute HF were randomly assigned to receive either
sacubitril-valsartan or enalapril following hemodynamic stabilization and followed for eight weeks [4]. The time-
averaged reduction in the NT-proBNP concentration was significantly greater in the sacubitril-valsartan group
than in the enalapril group (percent change in geometric mean of values at weeks 4 and 8 compared with
baseline, -46.7 percent versus -25.3 percent; ratio of change with sacubitril-valsartan versus enalapril, 0.71;
95% CI 0.63-0.81). The greater reduction in the NT-proBNP concentration with sacubitril-valsartan than with
enalapril was identified as early as week 1 (ratio of change, 0.76; 95% CI, 0.69 to 0.85). High-sensitivity troponin
T values also fell to a greater degree in those treated with sacubitril-valsartan (-36.6 versus -25.2 percent). In
exploratory analyses of clinical outcomes, while there was no significant difference in mortality, there was a
significant reduction in rehospitalization favoring sacubitril-valsartan versus enalapril (8 versus 13.8 percent, HR
0.56; 95% CI 0.37-0.84). Rates of worsening renal function, hyperkalemia, symptomatic hypotension, and
angioedema did not differ significantly between the two groups, although there was a higher frequency of
systolic blood pressure <100 mmHg at week 1 in the sacubitril-valsartan group (22.3 versus 13.3 percent). The
trial drug was discontinued prematurely in 19.6 percent in the sacubitril-valsartan group and in 20.3 percent in
the enalapril group. Thus, this trial demonstrated greater reduction of NT-proBNP and high-sensitivity troponin
with sacubitril-valsartan compared with enalapril with similar adverse outcomes. While not designed to test
clinical outcomes, exploratory analyses showed a significant reduction in rehospitalization for HF. Given these
findings combined with the findings from the PARADIGM trial, sacubitril-valsartan may be reasonably initiated as
a component of initial therapy for HFrEF (including during hospitalization for acute HF after hemodynamic
stabilization) or after the patient has tolerated two or more weeks of high dose ACE inhibitor (eg, enalapril 10
mg twice daily) or single agent ARB therapy. Criteria for hemodynamic stability in PIONEER-HF included
systolic blood pressure ≥100 mmHg, no intravenous vasodilators or increase in intravenous diuretics in the
preceding six hours, and no inotropes in preceding 24 hours.
ACE inhibitor
Dosing and cautions — Initial and target doses are listed in the table (table 2).
Contraindications to ACE inhibitor use include pregnancy (given risk of fetal toxicity including fetal death) and
history of angioedema (of any cause).
ACE inhibitor should not be used concomitantly with the following drugs:
• Sacubitril-valsartan (because of increased risk of angioedema). Do not administer within 36 hours of

switching to or from an ACE inhibitor.
• Aliskiren in patients with diabetes.
• In addition, concomitant use with an ARB is avoided given evidence of lack of clinical benefit from
combining ACE inhibitor and ARB therapy in this setting [25-27].
Patients with an ACE inhibitor-related cough can be switched to an ARNI or ARB. Cough has also been
observed as an adverse reaction to ARNI but the risk of ARNI-related cough in a patient with prior ACE inhibitor-
related cough is not known. Other side effects are discussed below. (See 'Management of drug intolerances'
below.)
Evidence — ACE inhibitors improve survival in patients with LV systolic dysfunction (LVEF ≤40 percent),
ranging from asymptomatic LV dysfunction [28] to moderate or severe HFrEF [29-32]. Although there has been
conflicting evidence on their effectiveness in black patients [33-37], the available evidence is not sufficient to
support a difference in ACE inhibitor use based on race.
ACE inhibitors are recommended to treat HFrEF dysfunction because multiple large, prospective, randomized
trials have demonstrated a significant reduction in mortality (table 1) [28-32,38] as well as alleviation of
symptoms and improvement in clinical status [39-41]. These benefits were summarized by a meta-analysis of
five trials (three starting during the first one to three weeks post-MI) involving 12,763 patients with LVEF ≤35
percent or <40 percent and/or clinical HF; approximately 20 percent of the subjects were taking a beta blocker.
ACE inhibition had the following benefits compared with placebo [32]:
● A lower total mortality (23 versus 27 percent for placebo, odds ratio [OR] 0.80, 95% CI 0.74-0.87). Most of
the mortality benefit was due to fewer deaths from progressive HF. This benefit of treatment was apparent
soon after the start of treatment and continued to increase after more than four years.
● A lower rate of readmission for HF (14 versus 19 percent, OR 0.67, 95% CI 0.61-0.74).
● A lower incidence of myocardial infarction (MI; 9 versus 11 percent, OR 0.79, 95% CI 0.70-0.89), but no
difference in stroke.
Angiotensin II receptor blocker
Dosing and cautions — Initial and target doses are listed in the table (table 2).
ARB therapy is contraindicated during pregnancy. An ARB should not be used with aliskiren in patients with
moderate-to-severe renal impairment (eGFR <60 mL/minute/1.73 m2). In addition, concomitant use with an ACE
inhibitor is avoided given evidence of lack of clinical benefit from combining ACE inhibitor and ARB therapy in
this setting [25-27].
Evidence — Benefits and harms of single agent ARB therapy for HFrEF were evaluated by a systematic
review that included nine randomized trials (including two unpublished studies) with a total of 4643 patients
comparing ARB therapy (without background ACE inhibitor therapy) to placebo [25]. ARBs nominally reduced
total mortality, although the result was of borderline statistical significance (relative risk [RR] 0.87, 95% CI 0.76-
1.00). An analysis limited to the seven fully reported trials found a smaller reduction in mortality that was again
of borderline statistical significance (RR 0.91, CI 0.79-1.04). Rates of total hospitalization were similar with ARB
and placebo (RR 1.00, 95% CI 0.92-1.08). To attain clinical benefits comparable to those observed with an ACE
inhibitor, it is important to select an appropriate ARB dose [42].
The CHARM-Alternative trial contributed most of the data for the comparison of ARB to placebo in this meta-
analysis. The trial enrolled 2028 patients with symptomatic HF and LVEF ≤40 percent who were not receiving
ACE inhibitor because of previous intolerance [43]. Patients were randomly assigned to candesartan or placebo.
The primary composite outcome of cardiovascular death or hospital admission for HF was reduced in the
candesartan group (33 versus 40 percent) at median 33.7-month follow-up (adjusted HR 0.70; 95% CI 0.60-
0.81). Each component of the primary outcome was also significantly reduced.
Pooled results of trials comparing ARBs with ACE inhibitors in patients with HFrEF showed no significant
difference in mortality with the point estimate only slightly favoring ACE inhibitor therapy (RR 1.05; 95% CI 0.91-
1.22) [25]. There were also no significant differences in stroke, MI, hospitalizations for HF, or total
hospitalizations. Drug withdrawals due to adverse effects were significantly less common with ARBs compared
with ACE inhibitors (RR 0.63, 95% CI 0.52-0.76).
Beta blocker
Dosing and cautions — Patients with HFrEF with no or minimal current evidence of volume overload should
be treated with one of the following three beta blockers with established clinical benefits in randomized trials:
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. Patients with low blood pressure may be less
likely to tolerate carvedilol because of its vasodilatory activity. Conversely, carvedilol may be preferred in
patients with higher blood pressure.
Beta blockers are commonly initiated soon after the patient has started an angiotensin system blocker (ACE
inhibitor, ARNI, or ARB). Among inpatients, initiation of therapy prior to hospital discharge improves beta-blocker
use without an increase in side effects or drug discontinuation [44]. (See 'Approach' above.)
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 begin at very low doses and the dose should be doubled at
intervals of two weeks or more until the target dose is reached or symptoms become limiting. Every effort should
be made to achieve the target dose since benefit appears to be dose-dependent [45] or related to the degree of
beta blockade [46-48], although a particular target heart rate goal is not of proven value [49]. However, even low
doses appear to be of benefit and should be used when higher doses are not tolerated [48]. Not uncommonly, a
dose that is not well tolerated during initial uptitration will be tolerated at a later time or with a slower rate of up
titration.
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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.
Contraindications to beta blocker therapy include the following (see "Major side effects of beta blockers"):
● Second- or third-degree atrioventricular (AV) block (in the absence of a pacemaker).
If patient has second- or third-degree AV block and a pacemaker is present, proceed with beta blocker
therapy. Indications for pacemaker implantation are discussed separately. (See "Second degree
atrioventricular block: Mobitz type I (Wenckebach block)" and "Second degree atrioventricular block: Mobitz
type II" and "Third degree (complete) atrioventricular block".)
If a patient with HFrEF becomes pacemaker dependent or is expected to become pacemaker dependent,
cardiac resynchronization therapy (CRT) is suggested. (See "Cardiac resynchronization therapy in heart
failure: Indications", section on 'Indications for referral for CRT'.)
● Heart rate <50 beats per minute (bpm; unless a pacemaker is present).
If the patient has a heart rate <50 bpm and a pacemaker is present, proceed with beta blocker therapy;
CRT is suggested since the patient is likely to become pacemaker dependent. (See "Cardiac
resynchronization therapy in heart failure: Indications", section on 'Indications for referral for CRT'.)
● Asthma is a relative contraindication. However, it is important to distinguish asthma from other conditions
such as symptoms caused by HF and chronic obstructive pulmonary disease (COPD). Chronic obstructive
pulmonary disease is not a contraindication. (See 'Lung disease' below.)
Beta blocker therapy should be used with caution in the following settings; a cardiology consultation is
suggested [3]:
● New York Heart Association (NYHA) class IV HF (table 4).
● Current or recent (<4 weeks ago) exacerbation of HF (including hospital admission for worsening HF). If a
patient has required recent intravenous inotropic therapy, beta blockade should only be initiated under the
guidance of an experienced HF specialist.
● Persisting signs of congestion and volume overload such as elevated jugular venous pressure, ascites,
marked peripheral edema.
● Systolic blood pressure <90 mmHg or symptomatic hypotension; consultation with an experienced HF
specialist is suggested.
● Heart rate <60 bpm.
Beta blockers with intrinsic sympathomimetic activity (such as pindolol and acebutolol) should be avoided in
patients with HFrEF.
Evidence — Randomized trials of specific beta blockers (carvedilol [50-53], sustained release metoprolol
succinate [54,55], and bisoprolol [56,57]) in patients with HFrEF have demonstrated reductions in mortality
(table 1) and hospitalization rates in patients with HFrEF with NYHA functional class II to III [50,54,57,58] and
probably NYHA functional class IV [52,57,59]. Symptomatic benefit (such as improvement in symptom scores,
NYHA functional class (table 4), and exercise tolerance) has been observed in randomized trials comparing
metoprolol CR/XL or carvedilol with placebo [53,59,60].
These benefits were illustrated by a meta-analysis that included 22 trials involving more than 10,000 patients
with an LVEF <35 to 45 percent, almost all of whom had NYHA functional class II or III HF and were also treated
with ACE inhibitors [58]. The following findings were noted:
● Beta blockers significantly reduced total mortality at one year (odds ratio [OR] 0.65, 95% CI 0.53-0.80) and
two years (OR 0.72, 95% CI 0.61-0.84). Assuming a mortality rate of 12 percent in the placebo group at
one year (derived from the three largest trials), beta blocker therapy saved 3.8 lives in the first year per 100
patients treated.
● Beta blockers also reduced hospitalization for HF (OR 0.64, 95% CI 0.53-0.79) with an absolute benefit of
four fewer hospitalizations in the first year per 100 patients treated.
Similar findings were noted in a meta-analysis limited to large randomized trials [61].
Limited data are available on the comparative efficacy of carvedilol, metoprolol succinate, and bisoprolol. A
meta-analysis compared the effects of vasodilating beta blockers, primarily carvedilol, with non-vasodilating beta
blocker (largely bisoprolol) using indirect evidence provided by trials comparing beta blocker with placebo [62].
Vasodilating beta blockers produced a greater survival benefit than nonvasodilating agents (45 versus 27
percent). This difference was primarily seen in patients with nonischemic cardiomyopathy. Indirect evidence
suggests that carvedilol may produce greater improvement in LVEF than metoprolol (combined short-acting and
extended-release forms) [63], but the clinical significance of this observation is uncertain.
A network meta-analysis of randomized trial data as well as observational data has suggested that the
beneficial effect of beta blocker therapy in HFrEF may be a class effect [64,65]. Observational data suggest that
some beta blockers other than those with proven benefit in randomized trials (eg, atenolol) may be beneficial in
HF. However, these observations are not sufficient to support a recommendation for use of beta blockers without
benefit established by randomized studies. In randomized trials, certain beta blockers (eg, metoprolol tartrate
and bucindolol) failed to improve overall mortality rates.
Evidence on beta blocker therapy in patients with atrial fibrillation and HFrEF is discussed below. (See 'Atrial
fibrillation' below.)
Hydralazine plus nitrate as alternative to angiotensin blocker
Dosing and cautions — Hydralazine plus nitrate may be administered as either a fixed-dose combination or
combined use of the two separate drugs (hydralazine and isosorbide dinitrate). Initial and target doses are
described in the table (table 2). Although direct evidence of efficacy is lacking, some clinicians prescribe
isosorbide mononitrate (30 to 120 mg daily) 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 [2].
Concomitant use of any form of nitrate with phosphodiesterase-5 inhibitors (eg, sildenafil, vardenafil, and
tadalafil) or with soluble guanylate cyclase stimulator (riociguat) is contraindicated. (See "Drugs that should be
avoided or used with caution in patients with heart failure", section on 'PDE-5 inhibitors'.)
A minority of patients taking hydralazine (estimated as 7 to 13 percent) develop a drug-induced lupus,

particularly with higher doses and longer duration of use. (See "Drug-induced lupus".)
Evidence — Hydralazine plus nitrate therapy may provide symptomatic and mortality benefit in selected
patients with HFrEF.
The earlier V-HeFT I and II trials found that the combination of hydralazine and isosorbide dinitrate produced a
modest reduction in mortality in patients with HF compared with placebo [66] and was less effective than ACE
inhibitors [29]. The V-HeFT I and II trials were performed in men with predominantly NYHA class II or III HF
(table 4) and LV enlargement or systolic dysfunction (LVEF <45 percent).
In the V-HeFT I, 642 men with HF were randomly assigned to placebo, prazosin (20 mg per day), or hydralazine
(titrated to 100 mg three times daily) plus isosorbide dinitrate (160 mg per day) added to a diuretic and digoxin
[66]. No patients were treated with a beta blocker or an ACE inhibitor. Mortality was not different between the
placebo and prazosin groups. With hydralazine plus isosorbide dinitrate, there was reduction in all-cause
mortality at two years (26 percent versus 34 percent with placebo) and there was a trend toward reduction in
mortality during the overall period of follow-up (mean 2.3 years). Post-hoc analysis found that black patients, but
not white patients, had a significant reduction in mortality with hydralazine plus isosorbide dinitrate compared
with placebo [33]. However, no significant interaction between race and treatment was found (p = 0.11).
The efficacy of ACE inhibitors compared with hydralazine and isosorbide dinitrate was evaluated in the V-HeFT
II trial of 804 men [29,67]. Patients were randomly assigned to receive enalapril (20 mg per day) or hydralazine
(300 mg per day) plus isosorbide dinitrate (160 mg per day). No patients were treated with a beta blocker. The
mortality rate was lower with enalapril (18 versus 25 percent with hydralazine/nitrate) at two years and there
was a trend toward reduction in mortality with enalapril during the overall period of follow-up (mean 2.5 years).
On post-hoc analysis, the mortality benefit with enalapril was seen only in white patients with hypertension [33].
However, no significant interaction between race and treatment was found (p = 0.09).
Use of hydralazine plus nitrate in addition to therapy with an ACE inhibitor, ARNI or ARB; a beta blocker, a
mineralocorticoid receptor antagonist (if indicated), and diuretic, is discussed separately. (See "Secondary
pharmacologic therapy in heart failure with reduced ejection fraction (HFrEF) in adults".)
DURATION OF THERAPY
Pharmacologic therapy for treatment of HFrEF (including angiotensin system blocker and beta blocker) is
generally continued indefinitely, even in patients with recovery of systolic function, although limited data are
available on the optimum duration of therapy and on the risk of drug withdrawal [68].
Diuretic therapy duration and withdrawal is discussed separately. (See "Use of diuretics in patients with heart
failure", section on 'Duration of therapy'.)
● Risk of drug withdrawal in patients with persistent LV systolic dysfunction:
• Angiotensin system blocker — The risk of worsening HF from withdrawal of angiotensin system
blocker was illustrated by a randomized controlled trial in patients treated with an ACE inhibitor [69].
After at least 10 weeks of quinapril therapy, 224 patients with NYHA functional class II or III HFrEF
were randomly assigned to continue quinapril or to receive placebo for 16 weeks. Compared with
patients continuing ACE inhibitor, patients withdrawn to placebo had worse NYHA functional class
(worsened in 18 versus 9 percent), exercise tolerance, symptoms of HF and quality of life. Progressive
worsening of HF began four to six weeks after ACE inhibitor withdrawal.
• Beta blocker withdrawal— Three small uncontrolled observational studies suggested high risk of
worsening HF after beta blocker withdrawal in patients with HFrEF with dilated cardiomyopathy [68]. In
the largest of these studies, long-term beta blocker therapy (mean duration greater than one year) in
26 patients was associated with improved NYHA class (3.3 to 1.8) and LVEF (25 to 41 percent) [70].
Subsequent beta blocker therapy withdrawal in 24 patients (mean observation time 7.7 months) was
associated with worsened NYHA class (1.8 to 2.8) and LVEF (41 to 32 percent) and there were four
deaths. Resumption of beta-blocker therapy in 12 patients was associated with improved NYHA class
(3.3 to 2.0) and LVEF (23 to 33 percent).
● Risk of drug withdrawal after recovery of LV systolic dysfunction — There is a risk of recurrent HF and
adverse remodeling after 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 [71]. During the initial six months, among
the 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 with 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.
MANAGEMENT OF DRUG INTOLERANCES
Patients with HFrEF are evaluated for contraindications and side effects of initial pharmacologic therapy prior to
and during drug therapy (table 3). (See "Major side effects of angiotensin-converting enzyme inhibitors and
angiotensin II receptor blockers", section on 'ACE inhibitors'.)
Hypotension — Hypotension that limits or prevents pharmacologic therapy for HFrEF should be evaluated and
appropriately treated. Since many patients with HFrEF have low blood pressures, we generally alter the drug
regimen only for symptoms or signs of hypoperfusion. A cardiologist should be consulted for patients who are
unable to initiate angiotensin system blocker or beta blocker or attain target doses of these drugs due to
hypotension.
A common cause of hypotension in this setting is hypovolemia (often secondary to diuretic therapy). When
the patient does not have volume overload, holding or reducing diuretic therapy may resolve hypotension.
Hypotension may be exacerbated or caused by angiotensin system blocker (ARNI, ACE inhibitor, or ARB),
beta blocker, or hydralazine plus nitrate therapy. If hypovolemia is not present, it may be necessary to
reduce the dose of one or more of these drugs or consider alternate agents within each drug class. The risk
of hypotension is higher with an ARNI than with an ACE inhibitor. So if ARNI therapy is discontinued due to
hypotension, substitution with a low dose of an ACE inhibitor (or a single agent ARB) is a potential option.
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.
Hyperkalemia — Hyperkalemia should be corrected and the cause(s) identified and addressed before initiating
or intensifying therapy with an ARNI, ACE inhibitor or ARB. Typically, a serum potassium >5.0 mEq/L should be
managed before starting or intensifying therapy, and a serum potassium >5.5 mEq/L (or >5.0 mEg/L with ECG
signs of hyperkalemia) should prompt reduction in dose or cessation of therapy. If a patient develops significant
hyperkalemia (serum K >5.5 mmol/L) on any angiotensin system blocker (ARNI, ACE inhibitor, or ARB) without
other contributing causes, intolerance of the other angiotensin system blockers may be inferred. (See "Causes
and evaluation of hyperkalemia in adults" and "Treatment and prevention of hyperkalemia in adults".)
Worsening renal function — Treatment with an ACE inhibitor, ARNI or ARB has a variable effect on the
glomerular filtration rate (GFR) in patients with HFrEF: some patients have no change in GFR, some have
worsening renal function and some have improved GFR. Measures to reduce the risk of worsening renal
function include avoiding concomitant nephrotoxic drugs (eg, nonsteroidal anti-inflammatory drugs [NSAIDs])
and avoidance of volume depletion (which may occur with excessive diuresis). Other potential causes of
worsening renal function (including bilateral renal artery stenosis or intrinsic kidney disease) should be
evaluated and treated. (See "Clinical manifestations and diagnosis of chronic kidney disease resulting from
atherosclerotic renal artery stenosis" and "Overview of the management of acute kidney injury (AKI) in adults".)
The use of ARNI, ACE inhibitor, or ARB in patients with kidney disease is discussed further below. (See
'Kidney disease' below.)
Worsening heart failure — Worsening symptoms and signs of HF develop in some patients on beta blocker
therapy. Volume overload should be treated prior to initiation of beta blocker therapy. If mild fluid overload
develops during beta blocker therapy, this should be promptly treated with increased diuretic therapy [1]. If
symptoms of fluid overload do not resolve with increased diuretic, the beta blocker dose should be reduced or
held. Management of beta blocker therapy in patients with acute decompensated HF is discussed separately.
(See "Treatment of acute decompensated heart failure: Components of therapy", section on 'Beta blocker'.)
Angioedema — A history of angioedema (of any cause, whether or not it is drug-related) is a contraindication
for ARNI or ACE inhibitor therapy.
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 HR
0.39; 95% CI 0.30-0.51) [72].
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.
SPECIAL POPULATIONS
Atrial fibrillation — Initial pharmacologic therapy for HFrEF in patients with atrial fibrillation is generally the
same as that for patients with HFrEF in sinus rhythm, including diuretic therapy, an angiotensin system blocker
(or hydralazine plus nitrate as an alternative), and a beta blocker.
Beta blockers are a primary therapy for rate control in patients with atrial fibrillation and HFrEF, although the
effect of beta blockers on mortality in patients with atrial fibrillation and HFrEF is uncertain. (See "The
management of atrial fibrillation in patients with heart failure".)
An individual patient data meta-analysis of randomized controlled trials of patients with HF (predominantly
HFrEF) found no significant reduction in mortality from beta blocker therapy in patients with atrial fibrillation and
HF, though this could reflect inadequate power [73]. The meta-analysis included 13,946 patients in sinus rhythm
and 3066 in atrial fibrillation. Beta blocker therapy improved mortality in patients in sinus rhythm (hazard ratio
[HR] 0.73, 95% CI 0.67-0.80) but the reduction in mortality was not significant in patients with atrial fibrillation
(HR 0.97, 95% CI 0.83-1.14). The interaction between baseline rhythm and clinical outcomes was statistically
significant.
On the other hand, an observational study based upon Danish nationwide registries of 205,174 patients with
nonvalvular atrial fibrillation (including 39,741 with HF) found that beta blocker therapy was associated with
reduced mortality in patients with atrial fibrillation and HF (HR 0.75, 95% CI 0.71-0.79), but effects of bias
cannot be excluded [74]. The percentage of patients with HFrEF could not be determined from registry data.
Lung disease — Recommendations for beta blocker therapy are more restrictive for patients with asthma than
for patients with chronic obstructive pulmonary disease (COPD). (See "Treatment of hypertension in asthma and
COPD", section on 'Beta blockers'.)
Patients with COPD may take beta-1 selective beta blockers (metoprolol succinate or bisoprolol) for HF. The
available evidence suggests that beta-1 selective beta blockers do not pose a safety risk in patients with COPD,
even when there is a bronchospastic component. In a systematic review and meta-analysis that included 20
randomized trials (11 studies of single dose of beta blocker and nine studies with treatment durations of 2 days
to 12 weeks), beta-1 selective beta blocker produced no change in forced expiratory volume (FEV1) or
respiratory symptoms compared with placebo and did not impair treatment response to beta-2 agonists [75]. A
subgroup analysis revealed no significant difference in results for patients with severe chronic airways
obstruction or a reversible obstructive component.
More limited data suggest that carvedilol (combined alpha and non-selective beta blockade) may be tolerated by
most patients with COPD, but is less well tolerated in patients with asthma [76].
Beta-blockers are relatively contraindicated in patients with asthma. Low doses of beta-1 selective beta blocker
(metoprolol succinate or bisoprolol) may be tried in patients with asthma who have HFrEF but close medical
supervision is required. A systematic review of randomized trials in patients with asthma acutely exposed to
beta-blocker therapy found increased risk of symptoms and declines in FEV1 and response to beta-2 agonist
therapy compared with placebo [77]. Beta-1 selective beta blockers were better tolerated than nonselective
agents but caused some worsening of symptoms and decline in FEV1. A dose response relationship was
demonstrated for selective beta blockers so a lower dose may mitigate the risk.
Kidney disease — While clinical trials of renin-angiotensin-aldosterone system (RAAS) antagonists in HF have
not specifically focused on patients with kidney disease, subgroup analyses of patients with and without chronic
kidney disease (CKD) as well as cohort studies have suggested that the beneficial effects of RAAS antagonism
on clinical outcomes extend to patients with concomitant CKD or early worsening renal function [78-80].
However, the risk of adverse events including hyperkalemia and worsening renal function during use of
angiotensin system inhibitors is elevated in patients with kidney disease [78,80,81], so close monitoring of
electrolytes and renal function is required during periods of drug initiation and uptitration, and periodic
monitoring is required throughout the duration of therapy [1] (table 3).
Management of HF in dialysis patients is discussed separately. (See "Overview of the management and
prevention of heart failure in dialysis patients".)
Bilateral renal artery stenosis — A patient with bilateral renal artery stenosis (or stenosis to a solitary
functioning kidney) can initiate treatment with an angiotensin system blocker (ARNI, ACE inhibitor, or single
agent ARB), but careful monitoring is required given the risk of decline in glomerular filtration rate (GFR). The
majority of patients with bilateral renal artery stenosis can likely tolerate an ARNI, ACE inhibitor, or single agent
ARB with only a small decline in GFR, although experience with an ARNI in this setting is lacking. (See
"Treatment of bilateral atherosclerotic renal artery stenosis or stenosis to a solitary functioning kidney", section
on 'Medical therapy'.)
Pregnancy — The treatment of HFrEF in pregnancy requires attention to specific concerns including the effects
of medications on the fetus, and is discussed separately. (See "Management of heart failure during pregnancy".)
COVID-19 — Standard indications for use of a renin angiotensin system inhibitor (eg, ARNI, ACE inhibitor, or
single-agent ARB) for treatment of HFrEF apply to patients with coronavirus disease 2019 (COVID-19).
Although there has been speculation that elevated ACE2 levels caused by renin-angiotensin-aldosterone
system inhibitors might impact susceptibility to SARS-CoV-2 because ACE2 is a receptor for this virus, there is
no evidence that treatment with these drugs worsens the clinical course of SARS-CoV-2 infection. (See
"Coronavirus disease 2019 (COVID-19): Issues related to kidney disease and hypertension", section on 'Renin
angiotensin system inhibitors'.)
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 therapy for heart failure with reduced ejection fraction (HFrEF) include improvement of
symptoms and reduction in mortality rate. Randomized controlled trials have shown that pharmacologic
therapy of HFrEF improves these clinical outcomes and also reverses or slows deterioration in myocardial
function (table 1) [1-3]. (See 'Initial therapy' above.)
● 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. (See 'Initial therapy' above.)
● Initial long-term management of each patient with HFrEF includes combined treatment with all three of the
following types of agents as tolerated, generally in the following order (see 'Approach' above):
• Diuretic therapy (typically with a loop diuretic) as needed to manage volume overload. The goal of
relieving signs and symptoms of volume overload (such as dyspnea and peripheral edema) should be
pursued while adverse effects are monitored. (See "Use of diuretics in patients with heart failure".)
• Angiotensin system blocker (angiotensin receptor-neprilysin inhibitor [ARNI], angiotensin converting

enzyme [ACE] inhibitor, or single agent angiotensin receptor blocker [ARB]) is started at an initial low
dose, generally at the time of or soon after initiation of diuretic therapy. The choice among the three
angiotensin system blockers is based upon the strength of evidence for efficacy in improving outcomes
(strongest for ARNI, intermediate for ACE inhibitor, and weakest for ARB), criteria for use, risk of
adverse effects (higher risk of hypotension with ARNI) (table 3), and access concerns (including cost,
which is highest for ARNI) (algorithm 1).
- For patients with NYHA class II or III HFrEF (left ventricular ejection fraction [LVEF] ≤40 percent)
with all of the following criteria, we recommend ARNI (sacubitril-valsartan) (Grade 1A). Criteria for
initiation include hemodynamic stability with systolic blood pressure (SBP) ≥100 mmHg, no history
of angioedema, and sustainable access to the medication. Sacubitril-valsartan may be initiated as
a component of initial therapy for HFrEF.
- For patients with HFrEF who do not meet criteria for use of ARNI and who have a systolic blood
pressure ≥90 mmHg and no history of angioedema, we recommend an ACE inhibitor compared
with no angiotensin system blocker (Grade 1A); we suggest an ACE inhibitor compared with a
single agent ARB (Grade 2C).
- For patients with HFrEF who do not meet criteria for use of ARNI or ACE inhibitor and who have a
systolic blood pressure ≥90 mmHg, we recommend a single agent ARB (Grade 1B). This
recommendation applies only when the ARNI or ACE inhibitor intolerance is not hyperkalemia or
worsening renal function.
- For patients with HFrEF who are unable to take any angiotensin system blocker (ARNI, ACE
inhibitor, or single agent ARB) due to hypotension, the cause of hypotension should be assessed
and managed. Volume status should be assessed to determine if volume depletion is present and
if diuretic therapy should be reduced or held. If hypotension persists, consultation with a heart
failure specialist is suggested.
• Alternative to angiotensin system blocker - For patients with HFrEF who cannot take an ARNI, ACE
inhibitor, or single agent ARB due to drug intolerance (eg, hyperkalemia) and who have a systolic blood
pressure ≥90 mmHg, we suggest treatment with a combination of hydralazine plus an oral nitrate
(Grade 2B). (See 'Hydralazine plus nitrate as alternative to angiotensin blocker' above.)
• Beta blocker — For patients with HFrEF, we recommend beta blocker therapy (Grade 1A). Beta
blocker therapy is initiated in patients with no or minimal residual fluid retention, generally soon after
initiation of an angiotensin system blocker. 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.)
● Each patient should take only one of the three angiotensin system blockers (ARNI, ACE inhibitor, or single
agent ARB) at a time. A 36-hour washout period is required when switching between an ACE inhibitor and
ARNI.
● Monitoring during pharmacologic treatment of HFrEF includes baseline and periodic clinical evaluation
including evaluation of symptoms and signs of HF and screening for contraindications, adverse effects (eg,
hypotension) and drug interactions. (See 'Dosing and monitoring' above and 'Management of drug
intolerances' above.)
● Pharmacologic therapy for treatment of HFrEF (including angiotensin system blocker and beta blocker) is
generally continued indefinitely, even in patients with recovery of systolic function, although limited data are
available on the optimum duration of therapy and on the risk of drug withdrawal. (See 'Duration of therapy'
above.)
ACKNOWLEDGMENTS
The UpToDate editorial staff would like to thank Wilson S Colucci, MD, Mark H Drazner, MD, MSc, and Marc A
Pfeffer, MD, PhD, for their contributions to previous versions of this topic review.
Use of UpToDate is subject to the Subscription and License Agreement.
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Topic 121086 Version 16.0
GRAPHICS
Demonstrated benefits of guideline-recommended heart failure therapies
Relative risk Number needed to

Guideline- reductions in pivotal treat for mortality Relative risk reduction
recommended therapy randomized clinical benefit (standardized in meta-analysis
trial(s) (%) to 12 m)
Angiotensin converting enzyme 17 77 20%

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

(carvedilol, bisoprolol,
extended release metoprolol
succinate)
Mineralocorticoid receptor 30 18 25%

antagonist
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 4.0
Initial pharmacologic therapy for heart failure with reduced ejection fraction
Target maximum Typical up

Type of therapy Drug Initial dose
dose titration interval*
Initial agents:
ACE inhibitor, ARNI, or ARB ¶
ACE inhibitor Any oral ACE inhibitor including the following:
Captopril 6.25 mg 3 times daily 50 mg 3 times/day Increase dose (eg,

double) at 1 to 2 week
intervals Δ
Enalapril 2.5 mg twice daily 10 to 20 mg twice daily Increase dose (eg,

double) dose at 1 to 2
week intervals Δ
Lisinopril 2.5 mg to 5 mg once 20 to 40 mg once daily Increase dose (eg,

daily double dose up to 10
mg increment as per
FDA approved labeling)
at 1 to 2 week
intervals Δ
Ramipril 1.25 mg once daily 10 mg once daily Increase dose (eg,

double) at 1 to 2 week
intervals Δ ◊
ARNI Sacubitril-valsartan 24/26 mg twice daily if 97/103 mg twice daily Double the dose at 2 to
1) patient not recently 4 week intervals Δ
taking an ACE inhibitor
or ARB, or 2) patient
has been taking a low
dose of ACE inhibitor
(≤10/day of enalapril or
equivalent) or ARB
(≤160 mg/day of
valsartan or
equivalent) §
49/51 mg twice daily if

patient has been taking
a moderate to high dose
ACE inhibitor (ie, >10
mg/day of enalapril or
equivalent) or ARB (ie,
>160 mg/day of
valsartan or equivalent)
ARB Prefer one of the ARBs in the key RCTS:
Candesartan 4 to 8 mg once daily 32 mg once daily Double the dose at 1 to

2-week intervals Δ
Valsartan 20 to 40 mg twice daily 160 mg twice daily Double the dose at 1 to

2-week intervals Δ
Some experts use the following ARB:
Losartan 25 to 50 mg once daily 150 mg once daily Double the dose at 1 to

2-week intervals Δ
Beta blocker Limited to one of the beta blockers in the key RCTs:
Carvedilol 3.125 mg twice daily For weight <85 kg: 25 Double the dose at 2-
mg twice daily week or greater
For weight >85 kg: 50 intervals
mg twice daily
Carvedilol CR 10 mg once daily 80 mg once daily Double the dose at 2-

week or greater
intervals
Metoprolol succinate 12.5 to 25 mg once 200 mg once daily Double the dose at 2-
extended release daily week or greater
(metoprolol CR/XL) intervals
Bisoprolol 1.25 mg once daily 10 mg once daily Double the dose at 2-

week or greater
intervals
Alternative agent (used in patients with intolerance of ACE inhibitor, ARNI, and ARB) ¥
Hydralazine plus Either fixed-dose combination or combined use of the two separate drugs
nitrate
Fixed-dose combination 20 mg isosorbide 40 mg isosorbide Double the dose in 2 to
dinitrate/37.5 mg dinitrate/75 mg 4 weeks
hydralazine 3 times hydralazine 3 times
daily daily
Combined use of 20 to 30 mg isosorbide 40 mg isosorbide Increase the dose in 2

isosorbide dinitrate and dinitrate 3 or 4 times dinitrate 3 times daily to 4 weeks
hydralazine daily and 25 to 50 mg and 100 mg hydralazine
hydralazine 3 or 4 times 3 times daily
daily
The drug doses presented here are those suggested for patients who do not require dose adjustments due to factors such as
comorbid illnesses, organ dysfunction, drug interactions, or other reasons. Consult a clinical drug reference, appropriate UpToDate
topic reviews, and/or other resources to confirm there are no clinically significant drug interactions and to determine the
appropriate dosing for a given patient.
ACE: angiotensin converting enzyme; ARB: angiotensin II receptor blocker; ARNI: angiotensin receptor-neprilysin inhibitor; CR: controlled
release; CR/XL: controlled release/extended release; HF: heart failure; HFrEF: heart failure with reduced ejection fraction (left ventricular
ejection fraction [LVEF] ≤40%); RCT: randomized controlled trials.
* These are general suggestions for time intervals and doses for outpatient titration. Titration should be continued only as tolerated. Slower
titration may be appropriate for individual patients. Down titration should be performed whenever indicated to manage patient intolerance
(eg, hypotension). Refer to UpToDate content on management of intolerances.
¶ Each patient should receive only one angiotensin system blocker (an ARNI, ACE inhibitor, or an ARB). When switching from an ACE
inhibitor to ARNI, a 36-hour washout period should be strictly observed given the risk of angioedema with combined used of these agents.
Δ Monitoring during drug titration includes periodic clinical evaluation, including screening for contraindications and adverse effects (eg,
hypotension), and checking blood tests (electrolytes, particularly serum potassium), blood urea nitrogen, and serum creatinine) obtained
one to two weeks following drug initiation or upward titration. Titration should be continued only as tolerated and generally requires a
systolic blood pressure ≥100 mmHg and no symptomatic hypotension.
◊ FDA-approved labeling specifies three-week intervals for HF post-myocardial infarction.
§ The lower starting dose (24/26 mg) is generally recommended in patients taking sacubitril-valsartan as a component of initial therapy for
HFrEF. However, some clinicians will use a higher starting dose (49 mg/51 mg orally twice daily) in hypertensive patients, provided hepatic
function is normal or only mildly impaired (Child-Pugh class A cirrhosis).
¥ This table describes use of hydralazine plus nitrate in patients who are unable to take ACE inhibitor, ARNI and ARB. Use of hydralazine
plus nitrate in addition to therapy with an ACE inhibitor, ARNI, or ARB is discussed in UpToDate content on secondary pharmacologic therapy
of HFrEF.
Management of intolerances to angiotensin converting enzyme inhibitor, angiotensin II

receptor blocker, or angiotensin receptor-neprilysin inhibitor in patients with heart failure
with reduced ejection fraction*
Intolerance Agent Timing Monitoring Response
Symptomatic ARNI, ACEI, Anytime, particularly Check BP with each If no congestion present, hold or reduce
hypotension or or ARB soon after initiation patient visit, diuretic.
severe and uptitration; may particularly with Check if other drugs with a hypotensive
asymptomatic improve with time changes in volume effect (eg, nitrates or calcium channel
hypotension status, diuretic blockers) can be discontinued.
(SBP <90 regimen, or drug If other measures are insufficient:
mmHg) doses.
Further evaluate and address cause of
hypotension.
Reduce dose of ARNI, ACEI or ARB.
It is rarely necessary to stop ACEI,
ARB, or ARNI; clinical deterioration
may occur following
discontinuation. **
Angioedema Δ ACEI or ARNI Most often starts Inform patients of Stop ACEI or ARNI.
during the first week risk of angioedema, Supportive care for angioedema.
to three months but including risk of Replace ACEI or ARNI with ARB, but
can occur after years potentially life- inform patient of risk of recurrent
of therapy threatening airway angioedema (up to 10%) that is ACEI-or
Episodic (even with obstruction. ARNI-related in first few weeks following
continued therapy) Ask about symptoms ACEI or ARNI discontinuation.
but frequency and at patient visits,
severity tend to particularly during
escalate the first three
months of therapy.
Persistent, ACEI or ARNI Usually begins within Ask about cough at Evaluate potential causes of cough (eg,
nonproductive one to two weeks of patient visits, worsening heart failure, lung disease).
cough initiation, but onset particularly during If cough is impairing quality of life (eg,
may be delayed by the first six months disturbing sleep) AND is related to ACEI
six months of therapy. or ARNI (recurs after ACEI or ARNI
withdrawal and rechallenge), stop ACEI
or ARNI and substitute with ARB.
Worsening renal ACEI, ARB, or Anytime, particularly Check baseline BUN, Initial steps:
function ARNI in the setting of serum creatinine, Avoid concomitant nephrotoxic drugs
volume depletion or and electrolytes. (eg, NSAIDs).
concomitant Recheck labs Evaluate and treat other potential
nephrotoxic drugs approximately one to causes of worsening renal function
two weeks after (eg, intrinsic kidney disease).
initiation or If no congestion is present, reduce or
uptitration. suspend diuretic therapy.
During stable May need to hold or stop
maintenance therapy, mineralocorticoid receptor antagonist.
recheck labs every
If increase in serum creatinine by >50%
three to six months
above baseline OR serum creatinine 3.1
(sooner if patient has
to 3.5 mg/dL (274 to 310 micromol/L)
clinical or laboratory
OR eGFR is 20 to 25 mL/minute/1.73
evidence of
m 2, decrease dose of ACEI or ARB or
instability).
ARNI by one-half and recheck labs. ◊
For worsening renal
If serum creatinine >3.5 mg/dL (310
function and/or
micromol/L) OR eGFR <20
hyperkalemia, check
mL/minute/1.73 m 2, stop ACEI, ARB, or
labs frequently and
ARNI ¶ and recheck labs. ◊
serially until
creatinine and
potassium have
decreased and
stabilized.
Hyperkalemia ACEI, ARB, or Anytime, particularly As above for Avoid K supplement (including K-
ARNI in the setting of worsening renal containing salt substitute) and retaining
worsening renal function. drugs (eg, triamterene, NSAIDs).
function or If K is ≤5.5 mmol/L and no ECG changes,
concomitant use of review drugs and diet for potential
agents that causes, including causes of worsening
supplement or retain renal function, and recheck labs ◊; ACEI,
potassium ARB, or ARNI dose may need to be
reduced.
If K is >5.5 mmol/L, or 5 to 5.5 mmol/L
with ECG changes, then temporarily stop
ACEI, ARB, or ARNI ¶, treat
hyperkalemia, review drugs and diet for
potential causes including causes of
worsening renal function, and recheck
labs. ◊ When reintroduced, ACEI, ARB, or
ARNI dose may need to be reduced.
Mineralocorticoid receptor antagonist
may need to be reduced or held.
Refer to UpToDate clinical review of
treatment and prevention of
hyperkalemia for additional details on
management.
SBP: systolic blood pressure; ACEI: angiotensin converting enzyme inhibitor; ARB: angiotensin II receptor blocker; ARNI: angiotensin
receptor-neprilysin inhibitor; BP: blood pressure; BUN: blood urea nitrogen; HFrEF: heart failure with reduced ejection fraction (left
ventricular ejection fraction <=40 percent); NSAIDs: nonsteroidal anti-inflammatory drugs; eGFR: estimated glomerular filtration rate; K:
potassium; ECG: electrocardiogram.
* The three drugs discussed here should generally not be used concomitantly. An ARNI should not be used with an ACEI (wait at least 36
hours when switching to or from ACE inhibitor). Avoid use of an ARNI with an ARB. Avoid use of an ARB with an ACEI, as there is limited
evidence of benefit from combined use of these drugs in this setting.
** The risk of hypotension is higher with an ARNI than with an ACEI (or an ARB). So if an ARNI is stopped due to hypotension, substitution
with a low dose of an ACEI (or ARB) is a potential option. After discontinuing ARNI, wait at least 36 hours before starting an ACEI.
¶ In this setting, some patients with hyperkalemia or renal insufficiency with ARNI may tolerate low dose ACEI or ARB. If ACEI, ARB, and
ARNI cannot be used for treatment of HFrEF due to hyperkalemia or renal insufficiency, we suggest treatment with a combination of
hydralazine plus nitrate.
Δ The risk of angioedema is particularly high in black patients.
◊ Serum creatinine, BUN, and serum potassium should be rechecked frequently (at least weekly) until levels have stabilized.
Adapted from: 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.
Choice of initial angiotensin system blocker (ARNI, ACE

inhibitor, or single agent ARB) in an adult with heart
failure with reduced ejection fraction
ACE inhibitor: angiotensin converting enzyme inhibitor; ARB: angiotensin II receptor

blocker; ARNI: angiotensin receptor-neprilysin inhibitor (sacubitril/valsartan); HFrEF:
heart failure with reduced ejection fraction (left ventricular ejection fraction ≤40%);
BNP: B-type natriuretic peptide; SBP: systolic blood pressure.
* Initiation of ARNI therapy is appropriate when these criteria are met only if the
patient will have ongoing access to this therapy (eg, cost or copay is not prohibitive
for the patient).
¶ Natriuretic thresholds for treatment of HFrEF with sacubitril/valsartan are as
follows:
For outpatients: B-type natriuretic peptide [BNP] level ≥150 pg/mL or N-
terminal proBNP [NT-proBNP] ≥600 pg/mL
For outpatients hospitalized for HF within the previous 12 months and BNP ≥100
pg/mL or NT-proBNP ≥400 pg/mL
For inpatients with acute HF: BNP level ≥400 pg/mL or NT-proBNP ≥1600 pg/mL
during current hospitalization
Δ Criteria for hemodynamic stability for ARNI therapy include SBP ≥100 mmHg (for
at least 6 hours), no increase in dose of intravenous diuretics in the preceding 6
hours, and no intravenous inotropes in the preceding 24 hours. ARNI therapy should
be avoided if there is concern for risk of hypotension in the judgement of the clinician
even if the SBP criterion is met. For example, the risk of hypotension may be higher
in patients who are very elderly (age >80 years) or frail.
◊ For patients with hypotension and/or worsening renal function, volume status
should be assessed to determine whether diuretic therapy should be reduced or held.
§ Refer to UpToDate content on management of hyperkalemia.
¥ Refer to UpToDate content on criteria for transition from ACE inhibitor or ARB to
ARNI therapy.
Continuing angiotensin system blockade using transition to angiotensin receptor-neprilysin

inhibitor therapy for adults with heart failure with reduced ejection
This algorithm is for use in patients who are already taking an angiotensin system blocker and is intended for use in conjunction
with additional UpToDate content on initial management of HFrEF in adults. Refer to UpToDate topics on pharmacologic management
of HFrEF in adults for additional details of our approach to treatment and the overall efficacy of these agents.
Initial long-term management of HFrEF includes combined treatment with diuretic therapy (as needed) plus an angiotensin system
blocker (ARNI, ACE inhibitor, or single agent ARB) and a beta blocker.
Each patient should take only ONE angiotensin system blocker at a time. If patient has a contraindication for all types of angiotensin
system blockers [eg, due to hyperkalemia], then hydralazine plus nitrate is an alternative therapy.
The decision to initiate ARNI depends upon factors including the patient's continuing access to medication and concerns (in the
judgement of the clinician) regarding the potential risk of hypotension.
ACE inhibitor: angiotensin converting enzyme inhibitor; ARB: angiotensin receptor blocker; ARNI: angiotensin receptor-neprilysin inhibitor
(sacubitril/valsartan); HF: heart failure; HFrEF: heart failure with reduced ejection fraction (left ventricular ejection fraction ≤ 40%); SBP:
systolic blood pressure.
* For patients with hypotension and/or worsening renal function, volume status should be assessed to determine whether diuretic therapy
should be reduced or held. Refer to UpToDate content on management of adverse effects of ACE inhibitors and ARBs.
¶ In this context, an example of a low dose ACE inhibitor is lisinopril 7.5 mg daily and an example of a low dose ARB is valsartan 40 mg twice
daily. History of angioedema (of any cause) is a contraindication for ARNI. ARNI therapy should be avoided if there is concern for hypotension in
the judgement of the clinician even if the SBP criterion is met. For example, the risk of hypotension may be higher in patients who are very
elderly (age >80 years) or frail.
Δ ARNI should be initiated only if the patient will have continuous access to medication (cost of medication or copay is not prohibitive for the
patient).
◊ It is reasonable to switch to ARNI in a patient with an ACE-inhibitor related cough, with the understanding that the risk of ARNI-related cough
in patients with prior ACE inhibitor-related cough is unknown.
§ The last dose of ACE inhibitor should precede the first dose of ARNI (sacubitril/valsartan) by at least 36 hours due to the risk of angioedema
with concurrent therapy.
¥ ACE-inhibitor related cough usually begins one to two weeks after instituting therapy but can be delayed up to six months. In a patient with an
ACE inhibitor-related cough, it is reasonable to try ARNI although data on the risk of ARNI-related cough in this setting is unknown.
‡ The patient should be warned that angioedema may recur weeks after discontinuation of the ACE inhibitor. Despite prior concerns about a
potential risk of angioedema with ARB therapy, an association between ARB therapy and angioedema has not be found.
† After discontinuation of ACE inhibitor, ACE-inhibitor related cough typically resolves within one week but can persist up to four weeks.
** A patient who develops hypotension with ACE inhibitor or ARB despite a euvolemic status may be at risk for developing hypotension with
hydralazine plus nitrate therapy.
NYHA and other classifications of cardiovascular disability
Canadian
NYHA functional Cardiovascular Society Specific activity
Class
classification [1] functional scale [3]
classification [2]
I Patients with cardiac disease Ordinary physical activity, such Patients can perform to
but without resulting as walking and climbing stairs, completion any activity
limitations of physical activity. does not cause angina. Angina requiring ≥7 metabolic
Ordinary physical activity does with strenuous or rapid equivalents (ie, can carry 24 lb
not cause undue fatigue, prolonged exertion at work or up 8 steps; do outdoor work
palpitation, dyspnea, or anginal recreation. [shovel snow, spade soil]; do
pain. recreational activities [skiing,
basketball, squash, handball,
jog/walk 5 mph]).
II Patients with cardiac disease Slight limitation of ordinary Patients can perform to
resulting in slight limitation of activity. Walking or climbing completion any activity
physical activity. They are stairs rapidly, walking uphill, requiring ≥5 metabolic
comfortable at rest. Ordinary walking or stair-climbing after equivalents (eg, have sexual
physical activity results in meals, in cold, in wind, or intercourse without stopping,
fatigue, palpitation, dyspnea, when under emotional stress, garden, rake, weed, roller
or anginal pain. or only during the few hours skate, dance foxtrot, walk at 4
after awakening. Walking more mph on level ground) but
than 2 blocks on the level and cannot and do not perform to
climbing more than 1 flight of completion activities requiring
ordinary stairs at a normal ≥7 metabolic equivalents.
pace and in normal conditions.
III Patients with cardiac disease Marked limitation of ordinary Patients can perform to
resulting in marked limitation physical activity. Walking 1 to 2 completion any activity
of physical activity. They are blocks on the level and requiring ≥2 metabolic
comfortable at rest. Less-than- climbing 1 flight in normal equivalents (eg, shower
ordinary physical activity conditions. without stopping, strip and
causes fatigue, palpitation, make bed, clean windows, walk
dyspnea, or anginal pain. 2.5 mph, bowl, play golf, dress
without stopping) but cannot
and do not perform to
completion any activities
requiring >5 metabolic
equivalents.
IV Patients with cardiac disease Inability to carry on any Patients cannot or do not
resulting in inability to carry on physical activity without perform to completion
any physical activity without discomfort. Anginal syndrome activities requiring >2
discomfort. Symptoms of may be present at rest. metabolic equivalents. Cannot
cardiac insufficiency or of the carry out activities listed above
anginal syndrome may be (specific activity scale III).
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.
Contributor Disclosures
Theo E Meyer, MD, PhD Grant/Research/Clinical Trial Support: CVRx [Heart failure]; DSMB [Heart failure]. Stephen S
Gottlieb, MD Grant/Research/Clinical Trial Support: Pfizer [Amyloidosis, Heart failure]; Cytokinetics [Heart failure]; Bristol-
Myers Squibb [Heart failure]; BTG International [Renal]. Consultant/Advisory Boards: Cytokinetics [Heart failure]. 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

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18/7/2020 Initial pharmacologic therapy of heart failure with reduced ejection fraction in adults - UpToDate

Reimpresión oficial de UpToDate ®

Terapia farmacológica inicial de insuficiencia cardíaca con

Otros aspectos de la gestión de HFrEF se presentan por separado, incluidos:

● Manejo de la insuficiencia cardíaca aguda. (Ver "Tratamiento de la insuficiencia cardíaca aguda

- No history of angioedema. (See 'Angioedema' below.)

AGENTS INCLUDED IN INITIAL THERAPY

Angiotensin receptor-neprilysin inhibitor

lack of data in this population).

Sacubitril-valsartan should not be used concomitantly with the following drugs:

• Sacubitril-valsartan (because of increased risk of angioedema). Do not administer within 36 hours of

• Aliskiren in patients with diabetes.

Angiotensin II receptor blocker

● Second- or third-degree atrioventricular (AV) block (in the absence of a pacemaker).

● New York Heart Association (NYHA) class IV HF (table 4).

● Heart rate <60 bpm.

Hydralazine plus nitrate as alternative to angiotensin blocker

A minority of patients taking hydralazine (estimated as 7 to 13 percent) develop a drug-induced lupus,

● Risk of drug withdrawal in patients with persistent LV systolic dysfunction:

MANAGEMENT OF DRUG INTOLERANCES

SOCIETY GUIDELINE LINKS

INFORMATION FOR PATIENTS

SUMMARY AND RECOMMENDATIONS

• Angiotensin system blocker (angiotensin receptor-neprilysin inhibitor [ARNI], angiotensin converting

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

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

14. http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/207620Orig1s000lbl.pdf (Accessed on July 22,

Topic 121086 Version 16.0

Demonstrated benefits of guideline-recommended heart failure therapies

Relative risk Number needed to

Angiotensin converting enzyme 17 77 20%

Beta-blocker therapy 34 28 31%

Mineralocorticoid receptor 30 18 25%

Hydralazine plus nitrate 43 21 Not available

Cardiac resynchronization 36 24 29/22%

Implantable cardioverter- 23 70 26%

Graphic 96488 Version 4.0

Target maximum Typical up

ACE inhibitor, ARNI, or ARB ¶

ACE inhibitor Any oral ACE inhibitor including the following:

Captopril 6.25 mg 3 times daily 50 mg 3 times/day Increase dose (eg,

Enalapril 2.5 mg twice daily 10 to 20 mg twice daily Increase dose (eg,

Lisinopril 2.5 mg to 5 mg once 20 to 40 mg once daily Increase dose (eg,

Ramipril 1.25 mg once daily 10 mg once daily Increase dose (eg,

49/51 mg twice daily if

ARB Prefer one of the ARBs in the key RCTS:

Candesartan 4 to 8 mg once daily 32 mg once daily Double the dose at 1 to

Valsartan 20 to 40 mg twice daily 160 mg twice daily Double the dose at 1 to

Some experts use the following ARB:

Losartan 25 to 50 mg once daily 150 mg once daily Double the dose at 1 to

Carvedilol CR 10 mg once daily 80 mg once daily Double the dose at 2-

Bisoprolol 1.25 mg once daily 10 mg once daily Double the dose at 2-

Combined use of 20 to 30 mg isosorbide 40 mg isosorbide Increase the dose in 2

Graphic 122656 Version 3.0

Management of intolerances to angiotensin converting enzyme inhibitor, angiotensin II

Intolerance Agent Timing Monitoring Response

Graphic 116261 Version 3.0

Choice of initial angiotensin system blocker (ARNI, ACE

ACE inhibitor: angiotensin converting enzyme inhibitor; ARB: angiotensin II receptor

Graphic 122393 Version 1.0

Continuing angiotensin system blockade using transition to angiotensin receptor-neprilysin

Graphic 122401 Version 1.0

NYHA and other classifications of cardiovascular disability