Secondary pharmacologic therapy for heart failure with reduced ejection fraction

INTRODUCTION — Heart failure (HF) is a common clinical syndrome with symptoms caused by the inability 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 a left ventricular ejection fraction (LVEF) ≤40 percent.

This topic will review therapies for patients with HFrEF who have mild to moderate symptoms of HF despite initial pharmacologic therapy with a renin-angiotensin system inhibitor, beta blocker, mineralocorticoid receptor antagonist, and sodium-glucose co-transporter 2 inhibitor or who cannot take one or more of these agents due to intolerances.

Other aspects of HFrEF management are presented separately:

●Overview of management of HFrEF. (See "Overview of the management of heart failure with reduced ejection fraction in adults".)

●Primary pharmacologic therapy of HFrEF. (See "Primary pharmacologic therapy for heart failure with reduced ejection fraction".)

●Cardiac resynchronization therapy. (See "Cardiac resynchronization therapy in heart failure: Indications and choice of system" and "Cardiac resynchronization therapy in atrial fibrillation".)

●Management of arrhythmias and risk of sudden cardiac arrest (eg, implantable cardioverter-defibrillator devices). (See "The management of atrial fibrillation in patients with heart failure" and "Ventricular arrhythmias: Overview in patients with heart failure and cardiomyopathy" and "Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF" and "Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy".)

●Management of pregnant patients with HF. (See "Management of heart failure during pregnancy".)

●Management of HF in patients receiving dialysis. (See "Management of heart failure in patients on dialysis".)

●Management of acute HF. (See "Treatment of acute decompensated heart failure: Specific therapies" and "Treatment of acute decompensated heart failure: General considerations".)

INABILITY TO TAKE PRIMARY PHARMACOLOGIC THERAPY

Initial approach — In patients with HFrEF who cannot tolerate optimal pharmacologic therapy, the first step in management is to manage the causes of intolerance and, if appropriate, change the therapeutic regimen (eg, reduce diuretic dose, change spironolactone to eplerenone) to allow for optimal use (eg, agents, dose) of the primary pharmacologic therapies for HFrEF (table 1). Common intolerances and approaches to optimal primary therapy for HFrEF are discussed separately. (See "Primary pharmacologic therapy for heart failure with reduced ejection fraction".)

Renin-angiotensin/neprilysin blocker intolerance — In patients with HFrEF who have persistent New York Heart Association (NYHA) class II to III symptoms and who cannot tolerate low-dose therapy with sacubitril-valsartan, an angiotensin converting enzyme (ACE) inhibitor, or an angiotensin II receptor blocker (ARB) despite changes to the medical regimen and other appropriate therapies for HFrEF (eg, cardiac resynchronization), we suggest therapy with hydralazine plus isosorbide dinitrate rather than another vasodilator or no vasodilator (algorithm 1 and table 2).

●Choice of drug – Isosorbide dinitrate-hydralazine may be administered as either a fixed-dose combination or combined use of the two separate drugs (ie, isosorbide dinitrate plus hydralazine). Initial and target doses are described in the table (table 2).

We consider a combination of generic hydralazine hydrochloride plus isosorbide dinitrate a reasonable substitute for the fixed-dose combination tablet. The fixed-dose combination tablet is more expensive but more convenient than dosing the two drugs individually. 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 [1].

●Initial and subsequent dosing – We favor starting with a low dose of isosorbide dinitrate plus hydralazine to enhance tolerance and reduce common adverse effects such as headache, dizziness, and hypotension. In the A-HeFT trial, headache occurred in 48 percent of patients taking this drug combination (significantly greater than 19 percent in the placebo group) and dizziness occurred in 29 percent (versus 12 percent in the placebo group). If symptomatic hypotension occurs, reduce the doses of isosorbide dinitrate and hydralazine and, if possible, continue any primary therapies for HFrEF (such as beta blocker, ACE inhibitor or ARB, and mineralocorticoid receptor antagonist [MRA] therapy) without change.

Prior to initiation of therapy, clinicians prescribing isosorbide dinitrate-hydralazine therapy should be aware of and counsel patients on the side effects and schedule of administration, which are barriers to adherence. In one study, the adherence to isosorbide dinitrate plus hydralazine was approximately 7 percent [2].

●Cautions – Concomitant use of any form of nitrate with phosphodiesterase-5 inhibitors (eg, sildenafil, vardenafil, and tadalafil) or with soluble guanylate cyclase stimulator (riociguat, vericiguat) is contraindicated. (See "Drugs that should be avoided or used with caution in patients with heart failure", section on 'PDE-5 inhibitors'.)

Patients taking hydralazine may rarely develop drug-induced lupus or vasculitis. In trials, arthralgia leading to discontinuation or dose reduction occurred in 5 to 10 percent of patients, and 2 to 3 percent of patients had sustained elevations in antinuclear antibody titers [3]. The presence of clinical manifestations of drug-induced lupus or vasculitis should trigger an immediate evaluation. (See "Drug-induced lupus" and "Clinical spectrum of antineutrophil cytoplasmic autoantibodies", section on 'Hydralazine'.)

Other adverse effects of isosorbide dinitrate plus hydralazine therapy are nausea and vomiting, sinus congestion, and tachycardia [4].

●Evidence – The role of isosorbide dinitrate plus hydralazine in modern HFrEF pharmacotherapy is controversial. The trials that evaluated the effect of isosorbide dinitrate plus hydralazine were conducted prior to the era of modern HF pharmacotherapy. In aggregate, these trials suggest that isosorbide dinitrate plus hydralazine is less effective than an ACE inhibitor as monotherapy and more effective than placebo when added to a regimen of an ACE inhibitor, beta blocker, and spironolactone.

•In the V-HeFT I trial, 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 [5]. 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, all-cause mortality was lower at two years (26 percent versus 34 percent with placebo, p<0.028). A 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 [6]. 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 [7,8]. 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 isosorbide dinitrate plus hydralazine) at two years. A post-hoc analysis found that the mortality benefit with enalapril was seen only in White patients with hypertension and high renin levels [6]. However, no significant interaction between race and treatment was found (p = 0.09).

•In the African-American Heart Failure trial (A-HeFT), 1050 patients with HF were randomly assigned to receive either placebo or a fixed-dose combination of hydralazine (37.5 to 75 mg orally three times daily) plus isosorbide dinitrate (20 to 40 mg orally three times daily) [9,10]. Nearly all patients had NYHA class III symptoms, with only 0.2 percent of patients in NYHA class II and 4 percent of patients in NYHA class IV (table 3) [9]. Inclusion criteria included a baseline LVEF ≤35 or <45 percent with an LV end-diastolic diameter of >6.5 cm or >2.9 cm/m² body surface area. Nearly all patients were receiving an angiotensin system blocker, over half were receiving a beta blocker, and spironolactone use was 39 percent. While enrollment was restricted to people who self-identified as Black, we interpret the study’s results as applicable to all people with HFrEF.

The A-HeFT trial was terminated early because of a significantly lower mortality rate in the isosorbide dinitrate-hydralazine arm (6.2 versus 10.2 percent with placebo at a mean of 10 months). Hydralazine-isosorbide dinitrate therapy was also associated with a significantly lower rate of hospitalizations (ie, first hospitalization, recurrent hospitalizations for HF, all-cause hospitalizations) and significant improvement in quality of life [9-11].

Primary therapies without alternatives — For patients who cannot tolerate MRAs or a sodium-glucose co-transporter 2 inhibitor, there are no alternative therapies. While the physiologic effect of ivabradine on heart rate is similar to the effect of beta blockers, we do not consider ivabradine a substitute for beta blockade. Further details on this trial are described elsewhere in this topic. (See 'Ivabridine' below.)

APPROACH TO PERSISTENT SYMPTOMS

Optimize primary therapies — In patients with HFrEF who have persistent class II to III symptoms, the first step in management is to optimize all therapies appropriate for HFrEF including:

●Pharmacologic therapies for HFrEF. (See "Primary pharmacologic therapy for heart failure with reduced ejection fraction".)

●Cardiac resynchronization therapy. (See "Cardiac resynchronization therapy in heart failure: Indications and choice of system".)

●Iron replacement for patients with iron deficiency. (See "Evaluation and management of anemia and iron deficiency in adults with heart failure".)

●Intervention for moderate to severe mitral valve regurgitation.

Add isosorbide dinitrate plus hydralazine in select patients — In patients with HFrEF who have persistent NYHA class II to III symptoms despite optimal therapy with primary therapies for HFrEF and who are at low risk of hypotension (eg, hypertensive, systolic pressure >110 mmHg), we suggest additional therapy with isosorbide dinitrate plus hydralazine rather than no additional therapy (table 2).

In patients who take multiple vasodilator agents but who remain hypertensive (eg, systolic pressure >135 mmHg), we typically add amlodipine.

As an add-on therapy, professional societies give isosorbide dinitrate plus hydralazine a grade 2A recommendation [1,12]. Professional societies provide a 1A recommendation for the treatment of hypertension in patients with HFrEF, and the European guidelines similarly recommend use of hydralazine or amlodipine for the treatment of hypertension in patients with HFrEF [1,12].

In our experience, many patients with HF symptoms and reduced systolic function may have fewer symptoms and a lower risk of hospitalization with additional vasodilator therapy. In addition, there are indirect data that therapy with hydralazine plus isosorbide dinitrate is associated with a reduced risk of HF hospitalization. (See 'Renin-angiotensin/neprilysin blocker intolerance' above.)

Optional therapies — In patients with HFrEF who have persistent NYHA class II or III symptoms despite an optimal regimen of primary medical therapy for HFrEF, maximal vasodilator therapy (eg, isosorbide dinitrate plus hydralazine), and use of other therapies appropriate for HFrEF (eg, cardiac resynchronization therapy, iron supplementation), additional options for therapy include ivabradine, vericiguat, or digoxin (table 2). Optimal medical therapy (eg, primary pharmacologic therapies, maximal vasodilator therapy) without additional pharmacologic therapy is also a reasonable option.

The patient's risk of drug toxicity, drug-drug interactions, cost of therapy, and monitoring requirements typically determine which agents are feasible for use. Addition of one of these agents should not prevent treatment with one of the primary drugs for the treatment of HFrEF.

Our approach differs from professional guidelines, which give a 2A recommendation for ivabradine and digoxin [1,12].

For ivabradine and vericiguat, the evidence for efficacy is restricted to specific patient groups (resistant HR >70 or recent worsening HF, respectively). For each of these add-on therapies (ivabradine, vericiguat, digoxin), efficacy is less than that of the primary therapies for HFrEF based on indirect evidence, and there are no direct comparison of these agents to each other to guide selection of a specific secondary therapy for HFrEF.

The options for additional therapy include:

Ivabridine — In patients with HFrEF with a sinus heart rate ≥70 beats per minute (bpm) and whose heart rates are not determined by a pacemaker, ivabradine may be added to the medical regimen (table 2). Ivabradine therapy is most appropriate for patients who are adherent to an optimized beta blocker regimen and who do not have evidence of decompensated HF.

Professional guidelines give a 2A recommendation for the use of ivabradine to reduce the risk of hospitalization [1,12].

●Dosing and monitoring – Initial and target doses of ivabradine are included in the table (table 2) . For patients who take a beta blocker, the beta blocker is continued at the maximum tolerated dose when ivabradine is added.

Monitoring for ivabradine 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.

●Cautions and adverse effects – Symptomatic bradycardia, visual side effects (phosphenes, which is transient enhanced brightness in a restricted area of the visual field), and atrial fibrillation can occur with concomitant ivabradine therapy.

Patients should have no or minimal evidence of volume overload or Stage D HF at the time of initiation of ivabradine.

●Evidence – The SHIFT trial included 6558 patients with HFrEF with an LVEF ≤35 percent and a sinus heart rate of ≥70 bpm who were treated with a beta blocker if tolerated [13]. After a median follow up of 24 months, patients assigned to receive ivabradine had similar rates of all-cause mortality (16 versus 17 percent in the control group; hazard ratio [HR] 0.9, 95% CI 0.8-1.04), a lower risk of all-cause hospitalization (38 versus 42 percent; HR 0.89, 95% CI 0.82-0.96), and a lower risk of HF hospitalization (16 versus 21 percent; HR 0.74, 95% CI 0.66-0.83) when compared with patients assigned to receive placebo.

However, among patients who were taking a beta blocker (90 percent of the trial participants), only 23 percent received target beta blocker doses and only 56 percent of patients received ≥50 percent of the target dose of beta blocker. Thus, the trial may not have adequately tested the hypothesis that ivabradine provided benefit for patients treated with optimum beta blocker therapies [14].

In patients taking ivabradine, bradycardia and phosphenes were more common in the ivabradine group than in the placebo group (5 versus 1 percent and 3 versus 1 percent, respectively) in the SHIFT study.

Two meta-analyses identified an increased risk of atrial fibrillation with ivabradine therapy (relative risk [RR] 1.15, 95% CI 1.07-1.24 and RR 1.24, 95% CI 1.08-1.42) [15,16].

Vericiguat — In patients with HFrEF who are optimally treated with primary therapies for HFrEF and vasodilator therapy, vericiguat can be added to the existing regimen (table 2). The clinical experience with vericiguat is limited to patients who had HF decompensation in the last six months (ie, hospitalization or use of intravenous diuretics).

●Dosing and cautions – Vericiguat is an oral soluble guanylate cyclase stimulator with vasodilatory effects. The initial dose of vericiguat is 2.5 mg once daily administered with food. This dose can be increased in two-week intervals to 5 mg once daily and then to a target maintenance dose of 10 mg once daily, as tolerated based upon blood pressure and clinical symptoms. Dose reduction is not required for patients with mild to moderate kidney function impairment. Vericiguat therapy does not require additional laboratory monitoring.

Vericiguat is not recommended for use in patients who are receiving a long-acting nitrate or a phosphodiesterase-5 inhibitor due to the potential for hypotension. Vericiguat is contraindicated in pregnancy and is not recommended for use in those who are breast-feeding.

●Evidence – The Vericiguat Global Study in Subjects with Heart Failure with Reduced Ejection Fraction (VICTORIA) trial included 5050 patients with chronic HF (NYHA functional class II, III, or IV), LVEF <45 percent (86 percent with LVEF <40 percent), recently elevated natriuretic peptide level, and worsening HF defined as hospitalization for HF within six months or need for intravenous diuretics within three months. Patients were randomly assigned to vericiguat (target dose 10 mg once daily) or placebo [17]. During a median of 10.8 months of treatment, there was a nonsignificant reduction in death from any cause with vericiguat (16.4 versus 17.5 percent; HR 0.93, 95% CI 0.81-1.06) and a nonsignificant reduction in the rate of first hospitalization for HF with vericiguat (27.4 versus 29.6 percent; HR 0.90, 95% CI 0.81-1.00). There were similar rates of symptomatic hypotension (9.1 versus 7.9 percent) and syncope (4.0 versus 3.5 percent) with vericiguat compared with placebo.

Digoxin — Digoxin therapy is rarely used in modern practice due to its narrow therapeutic window and unclear efficacy. In patients with HFrEF who are optimally treated with primary therapies for HFrEF and vasodilator therapy and who have a low risk of digoxin toxicity (eg, moderate or less severe kidney disease, ability to adhere to periodic monitoring), digoxin can be added to the existing medical regimen (table 2). We start with a low dose, obtain frequent monitoring, and if complications or toxicity occur, we cease therapy.

In patients who are already taking digoxin without signs of toxicity, we typically continue digoxin.

Professional society guidelines give a 2A recommendation for the use of digoxin to reduce hospitalizations [1,12].

●Cautions – Digoxin is contraindicated in patients with significant sinus or atrioventricular (AV) block unless treated with a permanent pacemaker. We suggest avoiding digoxin in the setting of acute kidney injury, severe chronic kidney disease, labile electrolyte concentrations (eg, hypokalemia, hypercalcemia, hypomagnesemia), therapy with other AV nodal blockers, or other drugs that utilize the p-glycoprotein efflux transporter system (table 4).

Digoxin can be used in patients at risk of hypotension; in most patients, it increases or has no effect on blood pressure.

The use of digoxin during pregnancy and in patients with amyloidosis is discussed separately. In patients with amyloidosis, we avoid use of digoxin. (See "Treatment with digoxin: Initial dosing, monitoring, and dose modification", section on 'Digoxin in pregnancy' and "Treatment with digoxin: Initial dosing, monitoring, and dose modification", section on 'Digoxin in patients with amyloidosis'.)

●Dosing and monitoring – In patients with HFrEF, we do not use a loading dose. The initial maintenance dose of digoxin is based on body size and kidney function (table 5) and ranges between 0.0625 to 0.25 mg daily. For patients with HF, the target serum digoxin level for maximal efficacy and minimal risk of toxicity is between 0.5 and 0.8 ng/mL (0.64 to 1.0 nmol/L) (figure 1) [18,19]. Further details on initiation of digoxin are discussed separately. (See "Treatment with digoxin: Initial dosing, monitoring, and dose modification", section on 'Initiation of therapy'.)

If initiating digoxin therapy in patients with normal or mild kidney dysfunction, we typically measure a digoxin level after one to six weeks of therapy depending on the degree of kidney dysfunction. For patients with moderate to severe kidney dysfunction or who are at higher risk of digoxin toxicity (eg, electrolyte abnormalities), digoxin should only be used after careful consideration of alternative approaches and with careful monitoring of the digoxin level. We measure a digoxin level within one week after the first dose and periodically. Digoxin levels should be measured prior to the dose or at least six hours after the last dose.

During the maintenance phase of digoxin therapy, we measure a digoxin level approximately every six months and if clinical status changes occur, such as a decline in kidney function, change in electrolyte levels, or introduction of a drug with a potential interaction with digoxin (table 4).

●Toxicity – The approach to patients with digoxin toxicity is presented separately. (See "Digitalis (cardiac glycoside) poisoning" and "Cardiac arrhythmias due to digoxin toxicity" and "Dosing regimen for digoxin-specific antibody (Fab) fragments in patients with digoxin toxicity".)

●Evidence – While a body of data has indicated that digoxin can provide clinical benefits in patients with HFrEF, its use remains controversial [20]. Its efficacy in the presence of modern pharmacologic and device therapies has not been rigorously evaluated, and it has a narrow therapeutic window (ie, the risk of adverse events increases at relatively low serum levels). Clinical trials have found that digoxin reduces HF hospitalization but not all-cause mortality in patients with HFrEF [21-29]. There are conflicting reports on the effect of digoxin on quality of life, but in aggregate, digoxin has the potential to improve or stabilize symptoms of HF [22,25,27,30-33]. Trials of digoxin withdrawal suggest worsening symptoms. The trials include:

•The efficacy of digoxin was evaluated in the Digitalis Investigation Group (DIG) trial [29]. In a trial that included 6800 patients with LVEF <45 percent, NYHA class II to IV HF, the risk of mortality was similar between patients randomly assigned to digoxin or to placebo (approximately 11 percent per year) and a decrease in hospitalization that was predominantly driven by a decrease in HF hospitalization (26.8 versus 34.7 percent). Hospitalization for suspected digoxin toxicity was higher in the digoxin group (2 versus 0.9 percent in the placebo group).

In subgroup analyses, there was a significant reduction in the combined endpoint of death from HF and hospitalization for worsening HF (figure 2). Patients assigned to digoxin therapy had a small decrease in mortality rate from worsening HF that did not reach statistical significance (11.6 versus 13.2 percent for placebo) and a significant increase in non-HF cardiac deaths, which included death from arrhythmia (15 versus 13 percent).

•Two randomized controlled trials (PROVED and RADIANCE) examined the effects of digoxin withdrawal in patients with stable HF treated with either diuretics and digoxin (PROVED) or diuretics, ACE inhibitors, and digoxin (RADIANCE) [27,28]. These studies randomly assigned patients to continuation of digoxin therapy versus placebo after an eight-week single-blinded stabilization phase. In both trials, digoxin withdrawal resulted in clinical deterioration:

-In PROVED, patients withdrawn from digoxin showed worsened maximal exercise capacity, increased incidence of treatment failures, lower ejection fractions, increased body weight, and higher heart rate [27]. Deterioration occurred even in patients with mild disease [34].

-In RADIANCE, worsening of HF symptoms was more likely to occur in the group withdrawn from digoxin for 12 weeks (27 versus 5 percent in those continuing to take digoxin; RR 5.9) [28]. A deterioration in quality of life was also observed.

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".)

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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

●Inability to take primary pharmacologic therapy

•Initial approach – In patients with heart failure with reduced ejection fraction (HFrEF) who cannot take optimal pharmacologic therapy, the first step in management is to manage the causes of intolerance and, if appropriate, change the therapeutic regimen (eg, reduce diuretic dose, change spironolactone to eplerenone) to allow for use of the primary pharmacologic therapies for HFrEF (table 1). Common intolerances and the approaches to optimal primary therapy for HFrEF are discussed separately. (See "Primary pharmacologic therapy for heart failure with reduced ejection fraction".)

•Renin-angiotensin/neprilysin blocker intolerance – In patients with HFrEF who have persistent New York Heart Association (NYHA) class II to III symptoms and who cannot tolerate low-dose therapy with sacubitril-valsartan, an angiotensin converting enzyme (ACE) inhibitor, or an angiotensin II receptor blocker (ARB) despite changes to the medical regimen, we suggest therapy with hydralazine plus isosorbide dinitrate rather than another vasodilator or no vasodilator (algorithm 1 and table 2) (Grade 2C).

•Primary therapies without alternatives – For patients who cannot tolerate mineralocorticoid receptor antagonists (MRAs) or a sodium-glucose co-transporter 2 inhibitor, there are no alternative therapies. While the physiologic effect of ivabradine on heart rate is similar to the effect of beta blockers, we do not consider ivabradine a substitute for beta blockade. Further details on this trial are described elsewhere in this topic. (See 'Ivabridine' above.)

●Approach to persistent symptoms – In patients with HFrEF who have persistent class II to III symptoms despite optimal therapy with the primary pharmacologic therapies for HFrEF. After optimizing four-drug therapy, there are few studies to guide therapy, and treatment is individualized to the patient's clinical status and ability to take a complex drug regimen (eg, adherence, cost). Our approach is as follows:

•Optimize primary therapies – In patients with HFrEF who have persistent class II to III symptoms, the first step in management is to optimize all therapies appropriate for HFrEF, including:

-Pharmacologic therapies for HFrEF (table 1). (See "Primary pharmacologic therapy for heart failure with reduced ejection fraction".)

-Cardiac resynchronization therapy. (See "Cardiac resynchronization therapy in heart failure: Indications and choice of system".)

-Iron replacement for patients with iron deficiency. (See "Evaluation and management of anemia and iron deficiency in adults with heart failure".)

-Intervention for moderate to severe mitral valve regurgitation. (See "Chronic secondary mitral regurgitation: General management and prognosis".)

•Add a vasodilator in select patients – In patients who are at low risk of hypotension (eg, hypertensive, systolic pressure >110 mmHg), we suggest additional therapy with isosorbide dinitrate plus hydralazine rather than no additional therapy (table 2) (Grade 2C). In patients in whom compliance with isosorbide dinitrate is likely to be low, hydralazine alone or amlodipine are reasonable therapeutic options. (See 'Add isosorbide dinitrate plus hydralazine in select patients' above.)

•Optional therapies – In patients with HFrEF who have persistent NYHA class II or III symptoms despite an optimal regimen of primary medical therapy for HFrEF and maximal vasodilator therapy (eg, isosorbide dinitrate plus hydralazine), additional options for therapy include ivabradine, vericiguat, or digoxin (table 2). Optimal medical therapy (eg, primary pharmacologic therapies, maximal vasodilator therapy) without additional pharmacologic therapy is also a reasonable option. (See 'Optional therapies' above.)

-Ivabradine – In patients with HFrEF with a sinus heart rate ≥70 beats per minute (bpm) despite maximal beta blocker therapy and whose heart rate is not determined by a pacemaker, ivabradine may be added to the medical regimen (table 2). Ivabradine therapy is most appropriate for patients who are adherent to an optimized beta blocker regimen and who do not have evidence of decompensated HF. (See 'Ivabridine' above.)

-Vericiguat – In patients with HFrEF who are optimally treated with primary therapies for HFrEF and vasodilator therapy, vericiguat can be added to the existing regimen (table 2). The clinical experience with vericiguat is too limited to provide characteristics of patients who are most likely to benefit from this therapy versus other secondary therapies for HFrEF. (See 'Vericiguat' above.)

-Digoxin – Digoxin is rarely used in patients with HFrEF who are optimally treated with primary therapies for HFrEF due to its narrow therapeutic window and unclear efficacy. In patients who will undergo a trial of digoxin therapy, we start with a low dose, frequent monitoring, and, if complications or toxicity occur, we cease therapy (table 2). (See 'Digoxin' above.)

In patients who are already taking digoxin without signs of toxicity, we typically continue digoxin unless its ongoing use interferes with use of any of the primary therapies for the treatment of HFrEF (eg, concomitant beta blocker use).

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Marc A Pfeffer, MD, PhD, who contributed to earlier versions of this topic review.