INTRODUCTION — Heart failure (HF) is a common clinical syndrome with symptoms caused by impaired ability of one or both ventricles to pump at a normal pressure due to a structural or functional cardiac disorder [1]. HF with reduced ejection fraction (HFrEF) is defined as HF with left ventricular ejection fraction (LVEF) ≤40 percent.
This topic presents the initial pharmacologic therapy of HFrEF in nonpregnant patients [1-3]. (Related Pathway(s): Heart failure: Initial pharmacologic therapy and dose titration for compensated heart failure with reduced ejection fraction (HFrEF).)
Other aspects of management of HFrEF are presented separately including:
●An overview of management of HFrEF. (See "Overview of the management of heart failure with reduced ejection fraction in adults".)
●Secondary pharmacologic therapy of heart failure with reduced ejection fraction. (See "Secondary pharmacologic therapy in heart failure with reduced ejection fraction (HFrEF) in adults".)
●Management of acute heart failure. (See "Treatment of acute decompensated heart failure: Specific therapies" and "Treatment of acute decompensated heart failure: General considerations".)
●Management of pregnant patients with HF. 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".)
INITIAL THERAPY — The goals of HFrEF therapy are to reduce symptom severity, decrease the risk of mortality and morbidity, and attenuate or possibly reverse the process of adverse remodeling of the LV. Randomized controlled trials have shown that initial pharmacologic therapy of HFrEF improves these clinical outcomes and also slows or reverses deterioration in LV chamber and myocardial function (table 1) [1-3]:
●The following initial therapies used in combination: diuretic; angiotensin system blocker (angiotensin receptor-neprilysin inhibitor [ARNI], angiotensin converting enzyme [ACE] inhibitor, or angiotensin II receptor blocker [ARB]); beta blocker; and isosorbide dinitrate-hydralazine (used as an alternative to an angiotensin system blocker) have demonstrated improved symptoms (including a 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 isosorbide dinitrate-hydralazine 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.) (Related Pathway(s): Heart failure: Initial pharmacologic therapy and dose titration for compensated heart failure with reduced ejection fraction (HFrEF).)
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: Specific therapies".)
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 isosorbide dinitrate-hydralazine], 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 renin-angiotensin system blocker – A choice is made among the renin-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 (most robust for ARNI), 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 the 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 >80 years old 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 ≥100 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 ≥100 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 renin-angiotensin system blocker – The chosen renin-angiotensin system blocker is generally started 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 that requires aggressive diuresis. We use a low initial dose of an angiotensin system blocker to reduce the likelihood of hypotension and worsening kidney function; for the target dose, we use the doses targeted in randomized trials (table 2) [2,5,6].
In the outpatient setting, the initial dose is gradually increased every two weeks as tolerated.
In the hospital setting, higher initial doses may be used and doses may be increased more rapidly if the patient is observed after each dose increase and is at low risk of an adverse response [4]. Factors that increase the risk of an adverse response include:
•Systolic blood pressure <100 mmHg
•Electrolyte abnormalities (eg, hyponatremia, hyperkalemia)
•Acute or chronic kidney disease and risk factors for acute kidney injury (eg, contrast)
•Ongoing large volume diuresis
•Polypharmacy
•Advanced age
●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 ARNI. 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, ARNI 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 ≥100 mmHg, we suggest treatment with a combination of hydralazine plus an oral nitrate. (See 'Isosorbide dinitrate-hydralazine 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 females than males. 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 males compared to females [10]. In males, 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 females, 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 males and females were observed in the ASIAN-HF registry. Given the available evidence, in treating females 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 renin-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 ≥100 mmHg and absence of symptomatic hypotension. After target dose (or the maximal tolerated 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 antinuclear antibody levels if there is any clinical suggestion of lupus, 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 US 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
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 [12].
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 pro-BNP (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 BNP levels. Since 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 [13]. 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 — In stable patients with New York Heart Association (NYHA) class II to III HF, sacubitril-valsartan reduced the risk of mortality or rehospitalization, while among less stable patients who started sacubitril-valsartan while hospitalized, sacubitril-valsartan may reduce the risk of rehospitalization:
●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 [14]. In this trial, 8442 patients with an HFrEF (predominantly 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; hazard ratio [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 [15].
•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 [16], and had higher health-related quality of life as measured by the Kansas City Cardiomyopathy Questionnaire (KCCQ) [17], including the physical and social domains [18]. Among patients with diabetes mellitus enrolled in the trial, hemoglobin A1C levels were lower [19].
•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 [13]. 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 [20], were independent of baseline medical therapies or prior coronary revascularization [21], and were consistent across all baseline blood pressures, including lower blood pressures [22].
●In the PIONEER-HF trial, 881 patients hospitalized with acute HF were randomly assigned to receive either sacubitril-valsartan or enalapril following hemodynamic stabilization and were then observed for 8 weeks for changes in NT-proBNP (the primary outcome) and the occurrence of clinical events (secondary outcomes) [4]. Most (90 percent) of the patients enrolled had NYHA class II or III heart HF symptoms. Patients treated with sacubitril-valsartan had a larger decrease in NT-proBNP levels (-47 versus -24 percent; ratio of changes between groups 0.71, 95% CI 0.63-0.81). The two groups had a similar risk of mortality, and the sacubitril-valsartan group had a reduction in the risk of rehospitalization (8 versus 14 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. Thus, treatment with sacubitril-valsartan before hospital discharge demonstrated greater reduction of NT-proBNP and a possible reduction in the risk of rehospitalization.
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 [23-25].
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 [26] to moderate or severe HFrEF [27-30]. Although there has been conflicting evidence on their effectiveness in Black patients [31-35], 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) [26-30,36] as well as alleviation of symptoms and improvement in clinical status [37-39]. 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 [30]:
●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 [23-25].
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 [23]. 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 [40].
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 [41]. 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) [23]. 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 [42]. (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 the benefit appears to be dose-dependent [43] or related to the degree of beta blockade [44-46], although a particular target heart rate goal is not of proven value [47]. However, even low doses appear to be of benefit and should be used when higher doses are not tolerated [46]. 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 uptitration.
Patients should weigh themselves 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 and choice of system", 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 and choice of system", 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]:
●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.
●Heart rate <60 bpm, especially when beta blockers are used with amiodarone.
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 [48-51], sustained release metoprolol succinate [52,53], and bisoprolol [54,55]) 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 [48,52,55,56] and probably NYHA functional class IV [50,55,57]. 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 [51,57,58].
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 [56]. 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 [59].
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 [60]. 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) [61], 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 [62,63]. 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.)
Isosorbide dinitrate-hydralazine as alternative to angiotensin blocker
Dosing and cautions — Isosorbide dinitrate-hydralazine may be administered as either a fixed-dose combination or combined use of the two separate drugs (isosorbide dinitrate and hydralazine). Initial and target doses are described in the table (table 2). We do not recommend replacing isosorbide dinitrate with another nitrate; there are no studies that describe the safety or efficacy of nitrate substitution, and guidelines do not suggest this approach [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 — Isosorbide dinitrate-hydralazine 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 [64] and was less effective than ACE inhibitors [27]. The V-HeFT I and II trials were performed in males 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 males 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 [64]. 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 [31]. 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 males [27,65]. 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 [31]. However, no significant interaction between race and treatment was found (p = 0.09).
Use of isosorbide dinitrate-hydralazine 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 [66].
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 [67]. 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 [66]. 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) [68]. 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 [69]. 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). If 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 isosorbide dinitrate-hydralazine 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 "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 rare 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: Specific therapies", section on 'Approach to long-term therapy in hospitalized patients'.)
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 a patient develops or has had angioedema, regardless of the cause, ACE inhibitors or ARNI should be discontinued indefinitely and neither an ACE inhibitor nor ARNI should be used thereafter. In patients with HFrEF who require ongoing therapy, we generally replace the ACE inhibitor or ARNI with an ARB. Despite prior concerns about a potential risk of angioedema with ARB therapy, an association between ARB therapy and angioedema has not been found. From a pharmacologic perspective, angioedema is caused by ACE inhibitors and ARNI largely because these agents block the degradation of bradykinin; in contrast, ARBs do not interfere with bradykinin metabolism. A nationwide cohort study found that among 5507 patients with prior ACE-inhibitor-induced angioedema, the incidence of angioedema was significantly lower in patients treated with ARBs than in those treated with other antihypertensive agents (beta blockers, calcium channel blockers, or thiazides; adjusted hazard ratio 0.39, 95% CI 0.30-0.51) [70].
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 isosorbide dinitrate-hydralazine 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 [71]. 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.
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 [72]. 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 [73].
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 [74]. 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 [75-77]. 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 [75,77,78], 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 "COVID-19: Issues related to acute kidney injury, glomerular 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 prescription drug prices in the United States (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●Goals of therapy – 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.)
●Approach to initial therapy – 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 (related Pathway(s): Heart failure: Initial pharmacologic therapy and dose titration for compensated heart failure with reduced ejection fraction (HFrEF)) (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 – Either an 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), 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).
-Initial therapy with an ARNI – 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. (See 'Angiotensin receptor-neprilysin inhibitor' above.)
-Patients who cannot take an ARNI – For patients with HFrEF who do not meet criteria for use of ARNI and who have a systolic blood pressure ≥100 mmHg and no history of angioedema, we recommend an ACE inhibitor or ARB (Grade 1A). (See 'ACE inhibitor' above.)
-Patients who cannot tolerate ACE inhibitor – For patients with HFrEF who have angioedema or cough from ACE inhibitor and who have a systolic blood pressure ≥100 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. (See 'Angiotensin II receptor blocker' above.)
-Patients who cannot take a RAAS inhibitor – 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 ≥100 mmHg, we suggest treatment with a combination of hydralazine plus an oral nitrate (Grade 2B). (See 'Isosorbide dinitrate-hydralazine 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.)
●Dosing and monitoring – 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.)
●Management of drug intolerances – Patients with HFrEF are evaluated for contraindications and side effects of initial pharmacologic therapy prior to and during drug therapy. (See 'Management of drug intolerances' above.) Common intolerances include:
•Hypotension (see 'Hypotension' above)
•Hyperkalemia (see 'Hyperkalemia' above)
•Worsening renal function (see 'Worsening renal function' above)
•Worsening heart failure (see 'Worsening heart failure' above)
•Angioedema (see 'Angioedema' above)
●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. (See 'Duration of therapy' above.)
●Special populations – Patients who require an alternative approach to initial therapy for HFrEF include patients with:
•Atrial fibrillation (see 'Atrial fibrillation' above)
•Lung disease (see 'Lung disease' above)
•Kidney disease (see 'Kidney disease' above)
•Bilateral renal artery stenosis (see 'Bilateral renal artery stenosis' above)
•Pregnancy (see 'Pregnancy' above)
ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges Wilson S Colucci, MD, Mark H Drazner, MD, MSc, and Marc A Pfeffer, MD, PhD, who contributed to earlier versions of this topic review.
