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 and/or functional cardiac disorder [1]. HF with reduced ejection fraction (known as HFrEF) is defined as HF with a left ventricular ejection fraction (LVEF) ≤40 percent.
Secondary pharmacologic therapy of HFrEF in nonpregnant patients is presented here [1-3]. Each patient with HFrEF receiving continued optimal initial pharmacologic therapy is evaluated to determine whether there is an indication for adding one or more secondary pharmacologic agents (mineralocorticoid receptor antagonist, sodium-glucose cotransporter 2 inhibitor, ivabradine, hydralazine plus nitrate, and digoxin).
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".)
This includes:
•Initial pharmacologic therapy of HFrEF. (See "Initial pharmacologic therapy of heart failure with reduced ejection fraction in adults".)
•Cardiac resynchronization therapy, if indicated. (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. (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. The treatment of HF during 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".)
●Management of HF in dialysis patients is discussed separately. (See "Overview of the management and prevention of heart failure in dialysis patients" and "Management and prevention of heart failure in dialysis patients: Specific measures".)
●Management of acute HF. (See "Treatment of acute decompensated heart failure: Specific therapies" and "Treatment of acute decompensated heart failure: General considerations".)
GOALS OF THERAPY — The goals of HFrEF therapy are to improve survival and quality of life. Randomized trials have shown that initial and secondary pharmacologic therapy of HFrEF improves these clinical outcomes and also slows or reverses deterioration in myocardial function (table 1) [1-3]:
●Improvement in symptoms including reduction in hospitalization for HF has been demonstrated with the following secondary therapies: mineralocorticoid receptor antagonist (MRA), sodium-glucose cotransporter 2 (SGLT2) inhibitor (eg, dapagliflozin, empagliflozin), vericiguat, hydralazine plus nitrate, ivabradine, and digoxin.
●Prolongation of patient survival has been documented with the following secondary therapies: MRA, SGLT2 inhibitor, and hydralazine plus nitrate.
While the initial goal is to alleviate symptoms, drug therapy should ultimately be titrated as tolerated to target ranges for optimum clinical benefit. The benefits observed from aggressive monitoring strategies suggest that treatment beyond clinical congestion improves outcomes.
APPROACH TO SECONDARY THERAPY — We recommend the following sequential approach to secondary, long-term pharmacologic therapy in patients with HFrEF. Secondary pharmacologic agents are used as indicated in addition to continued initial pharmacologic therapy. While additional therapies may confer added benefits in HFrEF, increasing the number of medications for HFrEF treatment may increase the likelihood of adverse drug-related events and reduce adherence to treatment.
Long-term initial pharmacologic therapy for HFrEF includes a diuretic (as needed to treat volume overload), a renin-angiotensin system antagonist (an angiotensin receptor-neprilysin inhibitor [ARNI], angiotensin converting enzyme [ACE] inhibitor, or single agent angiotensin receptor blocker [ARB]), and a beta blocker. If a patient is unable to take any of the renin angiotensin system antagonists due to contraindications, the combination of hydralazine plus an oral nitrate is an alternative. Thus, initial therapy for each patient with HFrEF generally includes three types of drugs. (See "Initial pharmacologic therapy of heart failure with reduced ejection fraction in adults".)
Secondary pharmacologic therapy for HFrEF is added to optimal initial pharmacologic therapy for patients who meet specific criteria. Each patient with HFrEF may take none, one, or multiple of the secondary agents, depending upon the patient's characteristics (related Pathway(s): Heart failure: Secondary pharmacologic therapy in adults with compensated chronic heart failure with reduced ejection fraction (HFrEF)):
●Add MRA if indicated – For patients receiving initial pharmacologic therapy for HFrEF, the next step is to add a mineralocorticoid receptor antagonist (MRA) if the patient has an indication. The following are two partially overlapping indications for MRA therapy. MRA use is limited to patients whose serum potassium and renal function can be carefully monitored and who have baseline serum potassium <5 mEq/L; an estimated glomerular filtration rate (eGFR) ≥30 mL/min per 1.73 m2 is also generally required. (See 'Mineralocorticoid receptor antagonist' below.)
•For patients with persistent symptoms on initial therapy – For patients with HFrEF who have symptomatic HF (New York Heart Association [NYHA] class II, III, or IV (table 2)) and an LVEF ≤35 percent on optimal initial pharmacologic therapy, we recommend addition of an MRA.
•For patients post-myocardial infarction with LVEF ≤40 percent – For patients post myocardial infarction (MI) with an LVEF ≤40 percent who are already receiving a renin angiotensin system inhibitor and have either symptomatic HF or diabetes mellitus (DM), we recommend the addition of an MRA.
Given the relative costs, we suggest spironolactone rather than eplerenone for initial MRA therapy and switching to eplerenone only if endocrine side effects occur.
●If symptoms persist on initial therapy plus MRA (if indicated), add one or more additional agents, as indicated – For patients with persistent symptoms on optimal initial therapy plus MRA (if indicated), the options for additional drug therapy are an SGLT2 inhibitor (choice of agent described in this section), vericiguat, ivabradine, hydralazine plus nitrate, and digoxin. The choice of which drug to add next is based upon evidence of efficacy, criteria for use, contraindications, risks of adverse drug effects and patient compliance. For most patients in this setting, we suggest next adding an SGLT2 inhibitor.
Assessment of persistent symptoms of HF including the potential role of natriuretic peptide (B-type natriuretic peptide [BNP] or N-terminal proBNP) testing, is discussed separately. (See "Determining the etiology and severity of heart failure or cardiomyopathy" and "Natriuretic peptide measurement in heart failure", section on 'Chronic HF'.)
Randomized trials in patients with HFrEF with persistent symptoms despite optimal initial therapy have demonstrated a mortality benefit with the addition of SGLT2 inhibitor or hydralazine plus nitrate. Randomized trials in appropriately selected patients with HFrEF have shown that addition of ivabradine or digoxin reduces hospitalization for HF. Data directly comparing these secondary agents are lacking. (See 'Evidence on SGLT2 inhibitors' below and 'Evidence on hydralazine plus nitrate' below and 'Evidence on ivabradine' below and 'Evidence on digoxin' below.)
•SGLT2 inhibitor – An SGLT2 inhibitor is a treatment option for patients with HFrEF with type 2 DM (dapagliflozin, empagliflozin, canagliflozin, or ertugliflozin) or without type 2 DM (dapagliflozin or empagliflozin). For patients with HFrEF and concurrent type 2 DM, an SGLT2 inhibitor may also be used as a component of therapy to treat hyperglycemia and to reduce the progression of diabetic kidney disease. (See "Sodium-glucose co-transporter 2 inhibitors for the treatment of hyperglycemia in type 2 diabetes mellitus" and "Treatment of diabetic kidney disease", section on 'Type 2 diabetes: Treat with additional kidney-protective therapy'.)
SGLT2 inhibitors are contraindicated in patients with type 1 DM, type 2 DM with risk factors for ketoacidosis, or severely impaired or rapidly declining kidney function. Additional contraindications are described below (See 'Contraindications and precautions' below.)
•Vericiguat – Vericiguat is an additional therapy for patients who have NYHA Class II to IV HF, LVEF <45 percent, and were either hospitalized in the last six months or received outpatient intravenous diuretic therapy. Vericiguat can be used after optimizing therapy with a renin-angiotensin system antagonist, neprilysin inhibitor, beta blocker, MRA, and SGLT2 inhibitor. (See 'Vericiguat' below.)
•Hydralazine plus nitrate – The combination of hydralazine plus nitrate is an alternative or additional add-on therapy for patients with persistent symptoms on initial therapy plus MRA (if indicated). This drug combination may be particularly helpful for patients with persistent hypertension despite compliance with other drug therapies for HFrEF. Use of this drug is limited by generally poor adherence, likely caused by inconvenient dosing (large number of tablets and frequency of administration) and the high rate of adverse reactions. (See 'Hydralazine plus nitrate' below.)
•Ivabradine – Ivabradine is indicated for patients with an LVEF ≤35 percent in sinus rhythm with a resting heart rate ≥70 beats per minute despite a maximum tolerated dose of beta blocker or with contraindications to beta blockers. For patients able to take a beta blocker, the beta blocker is continued at the maximum tolerated dose when ivabradine is added. (See 'Ivabradine' below.)
•Digoxin – Digoxin is an additional add-on therapy for patients with HFrEF who continue to have NYHA functional class III and IV symptoms despite optimal initial therapy plus all other indicated secondary pharmacologic therapies and cardiac resynchronization therapy (if indicated); some experts also require an LVEF <25 percent. (See 'Digoxin' below.)
SECONDARY AGENTS — As described above, each patient on initial therapy may or may not be a candidate for one or more of the following secondary agents. Dosing, contraindications, monitoring, and supporting evidence for each of the secondary agents is presented here. Monitoring during pharmacologic treatment of HFrEF includes baseline and periodic clinical evaluation, including evaluation of symptoms and signs of HF and assessment for incident contraindications, adverse effects (eg, hypotension), and drug interactions. Indications for the secondary agents are described above. (See 'Approach to secondary therapy' above.)
Mineralocorticoid receptor antagonist — Indications for mineralocorticoid receptor antagonist (MRA) therapy for HFrEF are described above. (See 'Approach to secondary therapy' above.)
Choice of agent — For patients with HFrEF who are candidates for MRA therapy, one of the two available MRAs (spironolactone or eplerenone) should be chosen; these two agents should not be used together. Although eplerenone is associated with fewer endocrine side effects than spironolactone (1 versus 10 percent in the respective trials), this advantage must be weighed against the marked difference in cost between the two drugs.
It is reasonable to begin with spironolactone and switch to eplerenone if endocrine side effects occur. (See 'Dosing and cautions' below.)
Dosing and cautions
●Dosing – Initial and target doses for spironolactone and eplerenone are included in the table (table 3). The dose of spironolactone or eplerenone should be reduced if serum potassium levels rise. Serum creatinine must also be monitored, as rises may limit dose titration. As in the EPHESUS and EMPHASIS-HF trials, if the serum potassium level is 5.5 to 6.0 meq/L, the dose should be decreased (eg, spironolactone dose from 50 to 25 mg/day, or from 12.5 every other day to stop) [4,5]. If the serum potassium level is >6.0 meq/L or renal function is worsening, MRA should be discontinued. After resolution of hyperkalemia (potassium level <5.0 meq/L) and stabilization of renal function for least 72 hours, restarting at reduced dose may be considered, depending upon the assessed risk of recurrent hyperkalemia and/or renal insufficiency.
We suggest early initiation of MRA therapy (eg, before hospital discharge) when feasible. Observational data suggest that inclusion of spironolactone therapy at discharge from hospitalization for HF exacerbation may reduce mortality. In a study of 946 patients hospitalized with HFrEF, discharge use of spironolactone was associated with reduced all-cause death at 2.2 years (adjusted hazard ratio [HR] 0.62, 95% CI 0.41-0.93) [6]. However, this study did not compare initiation by discharge with later initiation. The mortality benefit in the EPHESUS trial was significant by 30 days (3.2 versus 4.6 percent), suggesting that an MRA should be started before discharge in patients with MI who fulfill the EPHESUS criteria [7].
However, if an angiotensin system blocker (angiotensin receptor-neprilysin inhibitor [ARNI], angiotensin-converting enzyme [ACE] inhibitor, or single agent angiotensin II receptor blockers [ARB]) is started or uptitrated shortly before hospital discharge, we suggest that spironolactone initiation be delayed until the first outpatient visit and evaluation of serum potassium and creatinine.
●Cautions – Risk factors for hyperkalemia among patients treated with MRA include renal dysfunction, older age, more severe HF, diabetes mellitus (DM), higher baseline serum potassium concentration, volume depletion, renal dysfunction, and certain concomitant medications [5,8-14]. In patients taking an MRA, potassium supplement or potassium-containing salt substitutes, potassium-sparing diuretic (eg, amiloride), nonsteroidal anti-inflammatory agents, and certain herbal remedies that increase the risk of hyperkalemia (table 4) should be avoided. Patients with HFrEF taking an MRA should take only one concomitant renin angiotensin system inhibitor (ARNI, ACE inhibitor, or single agent ARB).
Estimates of renal function (even estimated glomerular filtration rate [eGFR]) are imperfect criteria for identifying patients at risk for hyperkalemia with MRA therapy. The risk of hyperkalemia is higher in patients with renal dysfunction, but some with renal dysfunction will not develop hyperkalemia and might benefit from MRA therapy. Conversely, some without significant renal dysfunction may develop hyperkalemia. Also, estimates of GFR are valid only with a stable serum creatinine. These parameters cannot be accurately assessed in patients with a rising or falling serum creatinine (see "Assessment of kidney function"). Since clinical trials have excluded patients with serum creatinine ≥2.5 mg/dL (221 micromol/L) or eGFR <30 mL/min per 1.73 m2, the available data are insufficient to determine the benefits and risks of MRA therapy in such patients, and therapy may be unsafe.
Endocrine side effects of spironolactone (gynecomastia, breast pain, menstrual irregularities, impotence, and decreased libido) result from nonselective binding to androgen and progesterone receptors. Eplerenone has greater specificity for the mineralocorticoid receptor, resulting in a lower incidence of endocrine side effects (1 versus 10 percent) [15]. (See "Epidemiology, pathophysiology, and causes of gynecomastia", section on 'Drugs'.)
Monitoring — Given the frequency and risk of hyperkalemia, patients treated with an MRA require careful monitoring. In the RALES, EPHESUS, and EMPHASIS-HF trials, serious hyperkalemia (serum potassium >6 meq/L) occurred in 2 to 5.5 percent of patients receiving an MRA [4,8-10]. Serum potassium and creatinine should be checked at baseline and rechecked soon (eg, in one to two weeks, sooner in patients at high risk for hyperkalemia) after starting or uptitrating spironolactone or eplerenone and periodically thereafter (eg, in one to three months) depending on the baseline value and changes with drug initiation [1]. Serum potassium concentration and creatinine should also be checked when a change in renal function or volume or electrolyte status is suspected (eg, with vomiting or diarrhea). A specific approach to minimizing the risk of hyperkalemia has been proposed (table 5) [13].
Evidence on MRAs — Spironolactone and eplerenone, which compete with aldosterone for the mineralocorticoid receptor, prolong survival in selected patients with HFrEF as demonstrated in randomized controlled trials [4,7,9] (table 1).
●Class III or IV HF – The efficacy and safety of spironolactone (25 to 50 mg daily) was compared with placebo in the randomized controlled RALES trial which enrolled 1663 patients with New York Heart Association (NYHA) class III or IV HF and LVEF ≤35 percent [8,9]. All patients were receiving loop diuretics, nearly all patients were receiving an ACE inhibitor, and the majority were taking digitalis; approximately 10 percent were taking a beta-blocker. The study was stopped because of significant benefits at an average follow-up of 24 months: a 30 percent reduction in overall mortality with spironolactone (35 versus 46 percent for placebo; relative risk [RR] 0.70, 95% CI 0.60-0.82), reductions in death from HF and sudden death, and a 35 percent reduction in hospitalization for HF [9]. The benefit of spironolactone was evident at three months and persisted for the two-year duration of the study. Other effects of spironolactone included improved NYHA functional class, reductions in systolic and diastolic blood pressure, reduced incidence of hypokalemia (0.5 versus 10 percent for placebo) and a dose-related increase in the risk of hyperkalemia.
●Class II HF – The efficacy of eplerenone compared with placebo in patients with less symptomatic HF was demonstrated in the randomized controlled EMPHASIS-HF trial [4]. The study enrolled 2737 patients with NYHA class II HF and either an LVEF ≤30 percent or LVEF >30 and ≤35 percent and QRS duration >130 msec. The patients had been hospitalized for a cardiovascular reason (approximately half had been hospitalized for HF) within six months or had a plasma level of B-type natriuretic peptide (BNP) of at least 250 pg/mL or N-terminal pro-BNP (NT-proBNP) of at least 500 pg/mL in men and 750 pg/mL in women. Nearly all were receiving an ACE inhibitor or ARB as well as a beta blocker. The study was stopped prematurely at 21 months due to evidence of benefit with eplerenone, including a significantly reduced mortality rate (12.5 versus 15.5; HR 0.76, 95% CI 0.62-0.93) and lower rate of death from cardiovascular causes (HR 0.76, 95% CI 0.61-0.94). Patients receiving eplerenone also had a significantly lower rate of the primary outcome of death from cardiovascular causes or hospitalization for HF (18.3 versus 25.9 percent in the placebo group; HR 0.63, 95% CI 0.54-0.74). Hospitalizations for HF and for any cause were also reduced in the eplerenone group.
●Post-MI with HF and/or diabetes – The efficacy of eplerenone versus placebo in 6632 patients post-MI was evaluated in the EPHESUS trial [10]. Study subjects had an MI 3 to 14 days previously and an LVEF ≤40 percent (mean 33 percent) with evidence of HF (present in 90 percent) and/or DM. Most of the subjects in EPHESUS were also receiving treatment with an ACE inhibitor or ARB (87 percent) and a beta blocker (75 percent). At 16 months, patients treated with eplerenone had a significantly reduced rate of all-cause mortality (14.4 versus 16.7 percent, RR 0.85, 95% CI 0.75-0.96), which was entirely due to a reduction in cardiovascular mortality (12.3 versus 14.6 percent). Eplerenone was also associated with significant reductions in sudden cardiac death, which accounted for approximately one-half of the mortality benefit, and hospitalizations for HF. The mortality benefit with eplerenone was significant by 30 days after randomization (3.2 versus 4.6 percent) [7]. Gynecomastia, impotence, or breast pain occurred with equal frequency in both groups (1.0 versus 1.1 percent).
SGLT2 inhibitor — The indication for sodium-glucose cotransporter 2 (SGLT2) inhibitors for HFrEF is discussed above. (See 'Approach to secondary therapy' above and 'Evidence on SGLT2 inhibitors' below.)
SGLT2 inhibitors reduce blood glucose by increasing urinary glucose excretion and they reduce the risk of progression of diabetic kidney disease; other myocardial and vascular effects have been proposed. (See "Sodium-glucose co-transporter 2 inhibitors for the treatment of hyperglycemia in type 2 diabetes mellitus" and "Treatment of diabetic kidney disease", section on 'Type 2 diabetes: Treat with additional kidney-protective therapy'.)
Dosing — SGLT2 inhibitors are taken once daily with or without food. The most direct dosing information for SGLT2 inhibitor to treat HFrEF is available for the two drugs studied in randomized trials patients with HFrEF with and without DM. The dose for dapagliflozin is 10 mg once daily [16]. The dose for empagliflozin is 10 mg once daily [17].
The dose for canagliflozin is based upon randomized trials in patients with type 2 DM (most without prior HF) in which canagliflozin reduced hospitalization for HF [18,19]. The dose of canagliflozin is 100 mg once daily.
Contraindications and precautions — SGLT2 inhibitors should be avoided in the following clinical settings (see "Sodium-glucose co-transporter 2 inhibitors for the treatment of hyperglycemia in type 2 diabetes mellitus", section on 'Contraindications and precautions'):
●Presence of type 1 DM.
●Presence of type 2 DM with prior diabetic ketoacidosis (DKA) or a condition predisposing to DKA (including pancreatic insufficiency, drug or alcohol addiction).
Patients with type 2 DM treated with SGLT2 inhibitor should receive education on the symptoms and risks of DKA and appropriate steps to take if symptoms or signs occur, including discontinuing SGLT2 inhibitor and seeking immediate medical attention [20]. Temporary discontinuation of SGLT2 inhibitor and monitoring for ketoacidosis are recommended in situations known to predispose to ketoacidosis (such as prolonged fasting due to illness or perioperative state). For patients who are scheduled to undergo surgery, it may be appropriate to temporarily discontinue dapagliflozin at least three days prior to surgery [20]. (See "Sodium-glucose co-transporter 2 inhibitors for the treatment of hyperglycemia in type 2 diabetes mellitus", section on 'Diabetic ketoacidosis'.)
●Volume depletion or symptomatic hypotension.
●eGFR <30 ml per minute per 1.73 m2 (except for empagliflozin, for which the threshold is <20 ml per minute per 1.73 m2), end-stage kidney disease, or rapidly declining renal function.
Of note, SGLT2 inhibitors have less glycemic benefit in patients with more severe kidney disease at initiation. Therefore, eGFR thresholds for starting these drugs to treat hyperglycemia are generally higher (≥45 ml per minute per 1.73 m2 for dapagliflozin and empagliflozin, ≥30 ml per minute per 1.73 m2 for canagliflozin, ≥60 ml per minute per 1.73 m2 for ertugliflozin). (See "Sodium-glucose co-transporter 2 inhibitors for the treatment of hyperglycemia in type 2 diabetes mellitus", section on 'Contraindications and precautions'.)
●Presence of the following conditions (see "Sodium-glucose co-transporter 2 inhibitors for the treatment of hyperglycemia in type 2 diabetes mellitus", section on 'Contraindications and precautions'):
•Frequent bacterial urinary tract infections or genitourinary yeast infections. In the EMPEROR-Reduced trial, uncomplicated genital tract infections were more frequent with empagliflozin compared with placebo (1.7 versus 0.6 percent) [17]. Complicated genital infections were uncommon in both treatment groups (0.3 percent in both). (See "Sodium-glucose co-transporter 2 inhibitors for the treatment of hyperglycemia in type 2 diabetes mellitus", section on 'Genitourinary tract'.)
•Presence of risk factors for foot amputation (including those with neuropathy, foot deformity, vascular disease, and/or history of previous foot ulceration). Patients taking SGLT2 inhibitors should be monitored for signs and symptoms of foot ulceration. (See "Sodium-glucose co-transporter 2 inhibitors for the treatment of hyperglycemia in type 2 diabetes mellitus", section on 'Amputations'.)
Evidence on SGLT2 inhibitors — Use of SGLT2 inhibitors to improve outcomes in patients with HFrEF is based on the results of randomized trials:
●In patients with HFrEF with or without type 2 DM, clinical outcomes were improved in randomized trials by the addition of SGLT2 inhibitor dapagliflozin (DAPA-HF trial [16]) or empagliflozin (EMPEROR-Reduced trial [17]) to optimized treatment for HFrEF compared to placebo [16,17,21].
●In contrast, only patients with type 2 DM were enrolled in randomized trials showing that canagliflozin reduced hospitalization for HF [18,19].
Dapagliflozin — The DAPA-HF trial found that the SGLT2 inhibitor dapagliflozin added to optimized pharmacologic therapy (including MRA, if indicated) and device therapy (including cardiac resynchronization therapy [CRT], if indicated) reduced all-cause mortality and worsening HF in adults with NYHA functional class II, III, or IV HFrEF with or without DM [16]. 4744 patients were randomly assigned to dapagliflozin 10 mg once daily or placebo, with median follow-up of 18.2 months.
●The primary outcome (composite of worsening HF or cardiovascular death) was reduced with dapagliflozin compared with placebo (16.3 versus 21.2 percent; HR 0.74, 95% CI 0.65-0.85). A worsening HF event (hospitalization or an urgent visit for HF) occurred in 237 patients (10.0 percent) in the dapagliflozin group and in 326 patients (13.7 percent) in the placebo group (HR 0.70, 95% CI 0.59-0.83). Hospitalization for HF was also significantly reduced with dapagliflozin (9.7 versus 13.4 percent; HR 0.70, 95% CI 0.59-0.83).
●All-cause mortality was significantly reduced with dapagliflozin compared with placebo (11.6 versus 13.9 percent; HR 0.83, 95% CI 0.71-0.97). Death from cardiovascular causes was also significantly reduced with dapagliflozin (9.6 versus 11.5 percent; HR 0.82, 95% CI 0.69-0.98).
●Findings in patients without DM were similar to those in patients with DM. The frequency of adverse events including volume depletion, renal dysfunction, and major hypoglycemia were similar in the two treatment groups. However, a patient-level meta-analysis combining this trial with the EMPEROR-Reduced trial found no significant differences in the effect on renal composite outcome between the two trials (pooled HR 0.62, 95% CI 0.43-0.90) [21]. The renal composite outcome was defined as first occurrence of 50 percent or greater sustained decline in eGFR, end-stage renal disease (sustained eGFR <10 or 15 mL/min/1.73 m2 [lower cut-off if baseline eGFR <30 mlL/min/ 1.73 m2], chronic dialysis treatment, or receiving a renal transplant), or renal death.
The DEFINE-HF trial provided additional limited evidence of benefit from dapagliflozin compared with placebo in 263 patients with HFrEF and elevated natriuretic peptide level [22]. Use of dapagliflozin over 12 weeks did not affect mean NT-proBNP but increased the frequency of clinical meaningful improvement in HF-related health status or natriuretic peptide level. There were similar effects in patients with and without DM.
Empagliflozin — The EMPEROR-Reduced trial found that the SGLT2 inhibitor empagliflozin added to optimized pharmacologic therapy (including MRA, if indicated) and device therapy (including CRT, if indicated) reduced hospitalization for HF as well as a composite outcome of cardiovascular death or hospitalization for HF in adults with NYHA functional class II, III, or IV HFrEF with or without DM [17]. 3730 patients were randomly assigned to empagliflozin 10 mg daily or placebo, with median follow-up of 16 months.
●The primary outcome (composite of hospitalization for HF and cardiovascular death) was reduced with empagliflozin compared with placebo (19.4 versus 24.7 percent; HR 0.75, 95% CI 0.65-0.86), and this effect was seen in patients with and without DM. The rate of hospitalization for HF was also reduced with empagliflozin (13.2 versus 18.3 percent; HR 0.69, 95% CI 0.59-0.81).
●Death from cardiovascular causes was not significantly different in the two groups (7.6 versus 8.1 percent; HR 0.92, 95% CI 0.75-1.12). All-cause mortality was also not significantly different (13.4 versus 14.2 percent; HR 0.92, 95% CI 0.77-1.10). However, a meta-analysis (combining this trial with the DAPA-HF trial) found no significant differences in these outcomes between the two trials and the pooled analysis showed significant reductions in mortality (HR 0.87, 95% CI 0.77-0.98) and cardiovascular death (HR 0.86, 95% CI 0.76-0.98) [21].
●The annual rate of decline in the estimated glomerular filtration rate was lower in the empagliflozin group than in the placebo group (–0.55 versus –2.28 mL per minute per 1.73 m2 of body surface area per year), and the risk of serious adverse renal outcomes (composite of chronic dialysis, renal transplantation, or profound sustained reduction in the eGFR) was lower in empagliflozin-treated patients (1.6 versus 3.1 percent; HR 0.50, 95% CI 0.32-0.77).
Other SGLT2 inhibitors — Direct evidence on the effects of canagliflozin, ertugliflozin, and sotagliflozin on HF outcomes is available only in patients with type 2 DM. It remains to be determined whether these SGLT2 inhibitors have similar effects in patients without type 2 DM.
●Canagliflozin - Clinical trials in patients with type 2 DM (most without prior HF) found that canagliflozin reduced the risk of hospitalization for HF compared with placebo [18,19]. As discussed separately, meta-analyses of clinical trials of dapagliflozin, empagliflozin, and canagliflozin have shown that these SGLT2 inhibitors reduced hospitalization for HF in patients with type 2 DM, regardless of presence of established atherosclerotic cardiovascular disease or HF at baseline. These trials of SGLT2 inhibitors in patients with type 2 DM are discussed further separately. (See "Sodium-glucose co-transporter 2 inhibitors for the treatment of hyperglycemia in type 2 diabetes mellitus", section on 'Cardiovascular effects'.)
●Ertugliflozin - A randomized trial in patients with type 2 DM and atherosclerotic cardiovascular disease found lower rates of hospitalization for HF with ertugliflozin compared with placebo, although the risk of major adverse cardiovascular events was not reduced [23]. This trial is discussed further separately. (See "Sodium-glucose co-transporter 2 inhibitors for the treatment of hyperglycemia in type 2 diabetes mellitus", section on 'Cardiovascular effects'.)
●Sotagliflozin - The SOLOIST-WHF trial found that the SGLT2 inhibitor sotagliflozin, when added to standard therapy, reduced hospitalizations and urgent visits for HF in patients with type 2 DM recently hospitalized for worsening HF [24]. A total of 1222 patients were randomly assigned to receive sotagliflozin or placebo and were followed for a median of nine months. The trial ended early and events were investigator-defined because of loss of funding. Sotagliflozin inhibits SGLT2 as well as SGLT1; it is an investigational drug in the United States.
•The rate of the primary outcome (a composite of the total number of cardiovascular deaths and hospitalizations and urgent visits for HF) was reduced with sotagliflozin (51.0 versus 76.3 percent; hazard ratio [HR] 0.67, 95% CI 0.52-0.85), largely driven by reduced hospitalizations and urgent visits for HF (40.4 versus 63.9 percent; HR 0.64, 95% CI 0.49-0.83). The benefits of sotagliflozin were consistent in prespecified subgroups, including in patients with LVEF <50 percent or ≥50 percent, but less than one-quarter of patients had an LVEF ≥50 percent.
•The rate of cardiovascular deaths was similar in the two groups (10.6 versus 12.5 percent; HR 0.84; 95% CI 0.58-1.22). The rate of death from any cause was 13.5 in the sotagliflozin group and 16.3 in the placebo group (HR 0.82; 95% CI 0.59-1.14).
•Diarrhea was more common with sotagliflozin than with placebo (6.1 versus 3.4 percent). Severe hypoglycemia was also more common with sotagliflozin (1.5 versus 0.3 percent).
Vericiguat — Vericiguat is an oral soluble guanylate cyclase stimulator with associated vasodilatory effects. The indications for vericiguat are described above. (See 'Approach to secondary therapy' above.)
Dosing and cautions — 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 on vericiguat — In the Vericiguat Global Study in Subjects with Heart Failure with Reduced Ejection Fraction (VICTORIA) trial, 5050 patients with chronic HF (NYHA functional class II, III, or IV), LVEF <45 percent (86 percent with LVEF <40 percent), and recently elevated natriuretic peptide level were randomly assigned to vericiguat (target dose 10 mg once daily) or placebo [25]. During a median of 10.8 months, the rate of the combined endpoint of death from cardiovascular causes or first HF hospitalization (the primary outcome) was significantly lower with vericiguat compared with placebo (35.5 versus 38.5 percent; HR 0.90, 95% CI 0.82-0.98). However, 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 nominally but not significantly higher rates of symptomatic hypotension (9.1 versus 7.9 percent) and syncope (4.0 versus 3.5 percent) with vericiguat compared with placebo.
Hydralazine plus nitrate — Indications for hydralazine plus nitrate therapy for HFrEF in addition to initial pharmacologic therapy and MRA therapy (if indicated) are described above. (See 'Approach to secondary therapy' above.)
Evaluation of a patient with HFrEF who may be a candidate for the addition of hydralazine plus nitrate therapy should include a review of the medical regimen to ensure that other therapy, including beta blocker, angiotensin system blocker (ARNI, ACE inhibitor, or ARB), MRA (if appropriate), and diuretics (as indicated) has been optimized (at a maximally tolerated dose up to target). Volume depletion may increase susceptibility to hypotension with hydralazine plus nitrate therapy.
Use of hydralazine plus nitrate in a patient who are unable to take an angiotensin system blocker (ARNI, ACE inhibitor, or single agent ARB) is discussed separately. (See "Initial pharmacologic therapy of heart failure with reduced ejection fraction in adults", section on 'Approach'.)
Dosing and cautions — Clinicians prescribing hydralazine plus nitrate therapy should be aware of and discuss potential barriers to adherence with patients prior to initiation of therapy. Adherence to this therapy has been poor (estimated as at least 7 percent of eligible patients [26]), likely due to inconvenient dosing (large number of tablets and frequency of administration) and the high rates of adverse reactions.
Initial and target doses of hydralazine and isosorbide dinitrate (as a fixed-dose combination tablet or as separate tablets) are included in the table (table 3). However, we consider a combination of generic hydralazine hydrochloride tablet plus isosorbide dinitrate tablet a reasonable substitute for the fixed-dose combination tablet. The fixed-dose combination tablet, isosorbide dinitrate-hydralazine, is more expensive but more convenient than dosing the two drugs individually.
Although direct evidence of efficacy is lacking, isosorbide mononitrate extended release (30 to 120 mg daily) may be used in place of isosorbide dinitrate to improve compliance. The use of isosorbide mononitrate in this setting is not included in the 2017 ACC/AHA/HFSA HF guideline update [2].
Slow titration of hydralazine and nitrate dose is recommended 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, reduction in hydralazine plus nitrate therapy is recommended, but concurrent HF therapy (such as beta blocker, ACE inhibitor or ARB, and MRA therapy) should be continued, if possible.
Other adverse effects of hydralazine plus nitrate therapy are nausea and vomiting, sinus congestion, and tachycardia [27]. Arthralgia leading to discontinuation or dose reduction occurred in 5 to 10 percent of patients in V-HeFT I and II; 2 to 3 percent of patients in these trials had sustained elevations in antinuclear antibody titers [28]. Less commonly (eg, 0.2 to 2 percent in A-HeFT, V-HeFT I and II [28]), hydralazine can cause a drug-induced lupus syndrome (including symptoms such as arthralgias, myalgias, joint swelling, pericarditis/pleuritis, rash, and fever). An additional rare but serious complication is antineutrophil cytoplasmic antibody-associated vasculitis, which is associated with a pauci-immune glomerulonephritis with manifestations including hematuria, rise in serum creatinine, and edema. Clinical manifestations of drug-induced lupus or vasculitis should trigger an immediate evaluation; appropriate treatment of either syndrome includes prompt discontinuation of hydralazine/nitrate. (See "Drug-induced lupus" and "Clinical spectrum of antineutrophil cytoplasmic autoantibodies", section on 'Hydralazine'.)
The combination of hydralazine plus oral nitrate is contraindicated in patients with hypersensitivity to either component. 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'.)
Monitoring — For patients treated with hydralazine, we suggest obtaining a baseline antinuclear antibody level prior to initiation of hydralazine and periodically during prolonged therapy even if the patient is asymptomatic, given the risk of drug-induced lupus [29]. These studies are also indicated if the patient develops symptoms such as arthralgia, fever, chest pain, or persistent malaise. The United States Food and Drug Administration labeling also recommends following the complete blood count, but blood dyscrasias from hydralazine therapy are rare and patients with HFrEF often have additional 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".)
Evidence on hydralazine plus nitrate — The addition of hydralazine plus nitrate to standard HFrEF therapy reduces morbidity and mortality.
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) [30,31]. 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 2) [30]. 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 by echocardiography. Nearly all patients were receiving an angiotensin system blocker and the majority were receiving a beta blocker; spironolactone was used in 39 percent. While enrollment was restricted to self-identified Black people, 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 hydralazine plus nitrate arm (6.2 versus 10.2 percent with placebo at a mean of 10 months) (table 1). Active therapy was also associated with a significantly lower rate of first and recurrent hospitalizations for HF, and in total all-cause hospitalizations, and a significantly greater improvement in quality of life [30-32]. At six months, the blood pressure had fallen by a mean of 1.9/2.4 mmHg in the hydralazine plus nitrate arm compared with a small increase of 1.2/0.8 mmHg.
An observational study evaluated the impact of hydralazine plus isosorbide dinitrate following hospital admission for acute decompensated HF with cardiac index ≤2.2 L/min/m2 [33]. All 239 patients were prescribed an ACE inhibitor and/or ARB therapy at discharge, and approximately two-thirds were on a beta blocker. Hydralazine plus isosorbide dinitrate was prescribed to 142 patients at discharge at the discretion of the treating clinician. Patients in the hydralazine plus nitrate group had lower cardiac index (1.7 versus 1.9 L/min/m2) on admission and showed greater improvement in cardiac index and lowering of systemic vascular resistance compared with controls. During follow-up (median of 26.3 months), patients receiving hydralazine plus nitrate had a lower rate of all-cause mortality (34 versus 41 percent) and all-cause mortality/HF hospitalization (70 versus 80 percent), irrespective of race, although there was a trend toward greater significance in Black patients.
Ivabradine — Indications for ivabradine use for HFrEF are described above. (See 'Approach to secondary therapy' above.)
Dosing and cautions — Baseline assessment prior to ivabradine therapy includes evaluation of heart rate on physical examination and 12-lead electrocardiogram (ECG). The patients should have no or minimal evidence of volume overload at the time of initiation of ivabradine. In patients taking a beta blocker, the drug should be continued at the same maximally tolerated dose.
Initial and target doses of ivabradine are included in the table (table 3).
Symptomatic bradycardia and visual side effects (phosphenes, which is transient enhanced brightness in a restricted area of the visual field) 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. Meta-analyses have identified a small increased risk of atrial fibrillation with ivabradine therapy (eg, 5.3 versus 4.6 percent in controls) [34,35].
Monitoring — Monitoring for ivabradine therapy includes baseline and follow-up assessment of heart rate (including baseline ECG), symptoms and signs of HF (particularly evidence of volume overload), and bradycardia.
Evidence on ivabradine — The randomized controlled SHIFT trial found that the selective sinus node inhibitor ivabradine reduced the primary composite outcome of cardiovascular death or hospital admission for worsening HF compared with placebo in 6558 patients with HFrEF with an LVEF ≤35 percent, and a sinus heart rate of ≥70 beats per minute (bpm) who were treated with a beta blocker if tolerated [36]. After a median follow up of 24 months, patients receiving ivabradine experienced the primary end point less frequently than those in the placebo group (24 versus 29 percent) largely due to reduced hospitalizations for HF (HR 0.74, 95% CI 0.66-0.83) and reduced deaths due to HF (HR 0.74, 95% CI 0.58-0.94).
A later analysis found that all-cause mortality (HR 0.83, 95% CI 0.72-0.96) and HF hospitalization (HR 0.70, 95% CI 0.61-0.80) were significantly reduced among patients with heart rate ≥75 bpm but not among patients with heart rate <75 bpm [37].
SHIFT demonstrated that controlling heart rate is important in patients with HF. However, although nearly 90 percent of patients were taking a beta blocker, only 23 percent of patients were receiving target doses of beta blocker and only 56 percent of patients were receiving ≥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 evidence-based therapies [38].
The available evidence does not support use of ivabradine as a substitute for beta blocker therapy for HFrEF, since the evidence for beta blocker therapy in this setting is substantially stronger. While certain beta blockers (carvedilol, metoprolol succinate, and bisoprolol) have proven efficacy in reducing all-cause mortality in patients with HFrEF, ivabradine had no significant effect on all-cause or cardiovascular mortality in the SHIFT trial [36,38]. (See "Initial pharmacologic therapy of heart failure with reduced ejection fraction in adults", section on 'Beta blocker'.)
Digoxin
Role — Use of digoxin for patients with HFrEF with persistent NYHA functional class III and IV symptoms despite optimal initial therapy plus all other indicated secondary pharmacologic therapies and CRT (if indicated) is described above. (See 'Approach to secondary therapy' above.)
The 2016 European Society of Cardiology (ESC) HF guidelines included a similar weak recommendation for use of digoxin in symptomatic patients despite evidence-based therapy [3]. The 2013 American College of Cardiology/American Heart Association (ACC/AHA) HF guidelines included a more general statement that digoxin can be beneficial in patients with HFrEF to decrease hospitalizations for HF [39]. The comments in the guidelines note that digoxin may be added during initial therapy for HF with severe symptoms or may be used only in patients with persistent symptoms despite guideline-directed therapy for HFrEF.
Some patients in sinus rhythm with HFrEF present for care while taking digoxin but are not yet optimally treated with other evidence-based therapies such as an ACE inhibitor, ARB, or ARNI; a beta blocker; and an MRA. In such patients, we may continue digoxin while initiating and/or titrating these other agents. The decision to continue digoxin therapy while initiating and/or titrating other therapy is based upon weighing the potential risks and benefits for each patient, including consideration of the patient's renal function and risk of digoxin toxicity. If the patient is asymptomatic, in sinus rhythm, and has improved systolic function after these medications (including at least an ACE inhibitor, ARB, or ARNI; and a beta blocker) have been initiated and titrated, we attempt a trial of discontinuation of digoxin [40].
The role of digoxin and other agents for rate control in patients with atrial fibrillation and HF is discussed separately. (See "The management of atrial fibrillation in patients with heart failure".)
While a body of data has indicated that digoxin can provide clinical benefits in patients with HFrEF, its use remains controversial, resulting in a steady decline in its use over the last decade [41]. This reflects two factors. First, because much of the controlled data on digoxin preceded the widespread use of contemporary guideline-directed therapies, it is unclear whether and to what extent the observed benefits of digoxin apply to patients receiving optimal guideline-directed therapy. Second, although clinical benefits were evident in controlled trials of digoxin in HFrEF, there was also evidence to suggest an increase in adverse events, particularly when serum digoxin concentrations exceeded 1.0 ng/mL Given the limited available evidence for the use of digoxin in HFrEF, careful patient selection and drug dosing are particularly important.
Digoxin is not indicated for primary stabilization of patients with an acute exacerbation of HF. (See "Treatment of acute decompensated heart failure: Specific therapies".)
Dosing and cautions — Digoxin dose is individualized based upon renal function, ideal body weight, and concomitant medications that may affect digoxin levels [42,43]. The target serum digoxin level for treatment of HFrEF is between 0.5 and 0.8 ng/mL (0.64 to 1.0 nmol/L). The typical daily dose to achieve this target level usually ranges from 0.0625 mg (given as 0.125 mg every other day) to 0.25 mg per day [44]. A common strategy is to use standard initial dosing (particularly for individuals with ideal body weight, 61 to 80 kg) of 0.125 mg per day for individuals with a creatinine clearance ≥30 mL/min and 0.0625 mg per day (which can be given as 0.125 mg every other day) for individuals with a creatinine clearance <30 mL/min (table 3). A nomogram may be helpful in determining an initial dose based upon ideal body weight and renal function, particularly for patients with small or large body size and/or renal dysfunction (table 6) [42,43]. Of note, loading doses of digoxin (as may be used for rate control in patients with atrial fibrillation) are not indicated in patients with HF. Indications for monitoring digoxin level are discussed below. (See 'Monitoring' below.)
Digoxin is contraindicated in patients with significant sinus or atrioventricular (AV) block (unless the block has been addressed with a permanent pacemaker). We suggest avoiding digoxin use in the setting of acute or subacute kidney injury. As noted below, the digoxin dose should be adjusted in patients with impaired renal function.
Digoxin has a narrow toxic to therapeutic window. Toxic effects include arrhythmias, conduction disturbances, and constitutional symptoms such as nausea, vomiting, and visual disturbances. Digoxin-related cardiac arrhythmias and extracardiac symptoms can occur when the serum digoxin concentration is in the therapeutic or even subtherapeutic range; as a result, digoxin toxicity is a clinical concern irrespective of circulating levels (unless the value is zero). Identification and management of digoxin toxicity are discussed 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".)
Digoxin should be used with caution when taken in combination with drugs that depress sinus or AV nodal function (eg, beta blockers) or affect digoxin levels. Inhibitors of P-glycoprotein efflux transporters (eg, amiodarone, dronedarone, propafenone, and quinidine) can increase serum digoxin levels (table 7). Inducers of P-glycoprotein (eg, phenytoin, rifampin, etc) can decrease serum digoxin levels (table 7). Diuretics may increase digoxin toxicity as a result of decrease in the glomerular filtration rate and the development of electrolyte abnormalities, especially hypokalemia. Specific interactions of digoxin with other medications may be determined using the Lexicomp drug interactions program included within UpToDate. (See "Treatment with digoxin: Initial dosing, monitoring, and dose modification", section on 'Dose adjustment with concomitant medications'.)
For patients with cardiac amyloidosis, digoxin should generally be avoided, as the inotropic effects are not generally beneficial in this population. Further, because digoxin binds avidly to amyloid fibrils, patients with amyloidosis may be at an increased risk of digoxin toxicity [45]. Additionally, as a result of the binding of digoxin to myocardial amyloid fibrils, cardiac digoxin concentration may exceed the serum digoxin concentration, potentially causing toxicity despite "therapeutic" serum digoxin levels. However, careful use of digoxin (in combination with a beta blocker or as an alternative to a beta blocker when beta blocker use is contraindicated) may be helpful for rate control for patients with cardiac amyloidosis in atrial fibrillation with a rapid ventricular response [46]. (See "Amyloid cardiomyopathy: Treatment and prognosis", section on 'Treatment'.)
Monitoring — Prior to initiation of digoxin and periodically during use, serum electrolytes (particularly potassium and magnesium levels) and renal function (including blood urea nitrogen and serum creatinine levels) should be assessed. Since hypokalemia, hypomagnesemia, or hypercalcemia may increase the risk of digoxin-induced arrhythmias, these abnormalities should be corrected prior to and during treatment with digoxin. Hypothyroidism is a risk factor for digoxin toxicity, so thyroid function tests should be checked before initiating digoxin in patients being treated for hypo- or hyperthyroidism.
Consensus is lacking on the role of monitoring serum digoxin levels in patients treated with digoxin for HFrEF. Some experts do not routinely measure digoxin levels if low doses are used and there is no clinical evidence of toxicity. Alternatively, some experts routinely check a digoxin level after steady state is reached (which is 7 to 10 days for most patients and up to three weeks in patients with severe renal impairment). For patients with HFrEF, the target serum digoxin level for maximal efficacy and minimal risk of toxicity is between 0.5 and 0.8 ng/mL (figure 1) [47,48]. When the digoxin level is checked, the information is generally used to avoid levels above the therapeutic range. Higher serum levels should be avoided since they are associated with an increased risk of toxicity without evidence of enhanced efficacy.
A digoxin level may be helpful in the following clinical settings:
●Suspicion of digoxin toxicity in the setting of new onset anorexia, nausea, or vomiting, or development of arrhythmias characteristic of digoxin toxicity (eg, AV junctional rhythms or ventricular bigeminy). (See "Digitalis (cardiac glycoside) poisoning" and "Cardiac arrhythmias due to digoxin toxicity".)
●Fluctuating or worsening renal function (including development of acute kidney injury). (See "Treatment with digoxin: Initial dosing, monitoring, and dose modification", section on 'Dose adjustments'.)
●Initiation of an interacting medication such as amiodarone.
●Worsening of HF symptoms with suspicion of low medication adherence/compliance.
When digoxin levels are monitored, the serum digoxin level should be measured when steady state is achieved, which is 7 to 10 days for most patients (and up to three weeks in patients with severe renal impairment) after starting digoxin or changing the dose of digoxin. 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) [47,48]. Digoxin levels should be checked when there is evidence of a decrement in renal function, a change in clinical status (eg, worsening HF), or evidence of possible toxicity.
The digoxin level is best determined as a trough concentration obtained immediately before administering the daily (or every other day) dose. Otherwise, blood samples should be obtained at least six hours, but optimally at least 12 hours, after administration of digoxin to ensure completion of distribution from the blood to the tissues. In patients with advanced kidney disease or who are on hemodialysis, the digoxin level should be checked at least 12 to 24 hours after the prior dose. Serum digoxin concentrations measured prior to these times may be falsely elevated.
Assuming that a patient is receiving the prescribed dose, the digoxin level was drawn at the correct time, at steady state, and under conditions of stable renal function, there is a linear relationship between digoxin dose and serum concentration. As an example, a steady state concentration is measured and is found to be 1.6 ng/mL (2.05 nmol/L) in a patient taking a daily maintenance dose (for this example, 0.25 mg daily). Assuming the desired serum concentration is 0.8 ng/mL (1.0 nmol/L), the dose should be reduced by 50 percent (to 0.125 mg daily in this example).
When a low digoxin level is detected, inadequate compliance should be excluded before the digoxin dose is raised.
Evidence on digoxin — Clinical trials have found that digoxin reduces HF hospitalization but not all cause mortality in patients with HFrEF.
●Randomized trials – Randomized controlled trials in patients with HFrEF have shown that digoxin improved clinical symptoms, quality of life, and exercise tolerance while lowering rates of hospitalization for HF, but did not improve survival [44,49-56]. One limitation of randomized trials studying the efficacy of digoxin in HFrEF is that they did not include as background therapy some key components of current therapy such as beta blockers, MRAs, and device therapies (eg, implantable cardioverter-defibrillators and CRT). Thus, these trials provide only indirect evidence of the efficacy of digoxin in contemporary management of HFrEF.
The effect of digoxin on patient survival and hospitalization was addressed in the Digitalis Investigation Group (DIG) main trial [44]. The trial enrolled nearly 6800 patients with symptomatic HF, an LVEF ≤45 percent, and normal sinus rhythm who were randomly assigned to digoxin or placebo. Most patients had NYHA class II or III HF (84 percent) and ischemic heart disease (70 percent); 94 percent were treated with an ACE inhibitor. After three years, there was no difference in survival between the digoxin and placebo groups; the overall mortality rate was approximately 11 percent per year. Thus, digoxin is different from some other inotropic agents that decrease survival in patients with HFrEF (eg, milrinone [57]). It is also different from agents that improve survival in patients with HFrEF: ACE inhibitors, ARNIs, beta blockers, and MRAs. (See "Inotropic agents in heart failure with reduced ejection fraction" and 'Goals of therapy' above.)
Patients assigned to digoxin therapy had a significant decrease in hospitalization, primarily due to a decrease in hospitalization for HF (26.8 versus 34.7 percent) at 3 year follow-up [44]. Hospitalization for suspected digoxin toxicity was higher in the digoxin group (2 versus 0.9 percent in the placebo group). There was also a significant reduction in the combined end point of death from HF and hospitalization for worsening HF (figure 2). The benefit of digoxin on these clinical outcomes was independent of age [58]. Patients assigned to digoxin therapy had a nominally lower mortality rate from worsening HF that did not reach statistical significance (11.6 versus 13.2 percent for placebo, p = 0.06); this nominal benefit was counterbalanced by a significant increase in non-HF cardiac deaths, which included death from arrhythmia (15 versus 13 percent).
●Benefit in high-risk groups – In a prespecified analysis of three high-risk subgroups of patients with HF with LVEF <45 percent in the DIG trial (NYHA class III or IV, LVEF <25 percent, and cardiothoracic ratio >55 percent), digoxin improved several two-year outcomes compared with placebo in each of these subgroups, including a composite outcome of HF-specific mortality or HF hospitalization, and a composite of all-cause mortality or all-cause hospitalization [59]. In contrast, in a low-risk group (NYHA class I or II symptoms, LVEF ≥25 percent, and cardiothoracic ratio ≤55 percent), digoxin improved a composite of HF-specific morality or HF hospitalization but did not significantly improve the composite of all-cause mortality or all-cause hospitalization.
●Therapeutic serum digoxin concentration – Clinical trials in patients with normal sinus rhythm that demonstrated benefit from digoxin therapy have targeted mean serum digoxin concentrations ranging from 0.5 to 1.75 ng/mL (0.64 to 2.25 nmol/L) [44,50,51]. Post hoc analyses from the DIG trial demonstrated that when the patients were stratified according to the serum digoxin concentration, there was a correlation between the digoxin level and patient survival, such that death and hospitalizations were reduced in patients with a serum digoxin level between 0.5 and 0.9 ng/mL (0.64 to 1.2 nmol/L), regardless of the ejection fraction or sex; this reduction remains significant even after multivariable adjustment (which included estimated glomerular filtration rate) [47,60]. By contrast, higher serum levels were associated with a nominal but not statistically significant trend toward increased mortality after multivariable adjustment. Data suggest that the therapeutic window for serum digoxin level (0.5 and 0.8 ng/mL [0.64 to 1.0 nmol/L]) is similar in men and women [47,61,62]. In an analysis from the DIG trial restricted to men with an LVEF ≤45 percent, the 3782 subjects were divided into four groups: those receiving placebo, and those with a serum digoxin concentration at one month of 0.5 to 0.8 ng/mL, 0.9 to 1.1 ng/mL, and ≥1.2 ng/mL [47]. All-cause mortality at 37 months was significantly lower for those with a serum digoxin concentration of 0.5 to 0.8 ng/mL than for the placebo group (29.9 versus 36.2 percent), while mortality was increased for those with a serum digoxin concentration above 1.2 ng/mL. These associations remained significant after multivariable adjustment. There was a similar inverse relationship between serum digoxin concentrations and survival in the 318 women with sufficient data [61].
●Impact on functional status – Most studies of the effect of digoxin on exercise capacity have shown that exercise tolerance and peak VO2 improved with digoxin [50,53,55,63-66], although an improvement in peak VO2 was not seen in some studies that included patients with mild, NYHA class I disease [54,67].
●Adverse outcomes with digoxin withdrawal – Two randomized controlled trials (PROVED and RADIANCE) examined the effects of digoxin withdrawal in patients with stable HF treated with diuretics and digoxin (PROVED) or diuretics, ACE inhibitors, and digoxin (RADIANCE) [55,56]. 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, at three months, patients withdrawn from digoxin showed worsened maximal exercise capacity, increased incidence of treatment failures, lower ejection fractions, increased body weight, and higher heart rate [55]. Deterioration occurred even in patients with mild disease [68].
•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) [56]. A deterioration in quality of life was also observed.
In a follow-up study combining data from both RADIANCE and PROVED, several features were associated with an increased risk of clinical deterioration after digoxin withdrawal, including cardiac enlargement by chest radiograph, a lower LVEF, increased age, and lack of ACE inhibitor therapy [69].
A later observational study of patients with HF with an LVEF ≤45 percent receiving contemporary therapy (majority receiving beta blocker and ACE inhibitor or ARB; some treated with an MRA) found an association between digoxin withdrawal and worse clinical outcomes [70]. The propensity matched cohort (adjusted for multiple factors and balanced for acute kidney injury) of hospitalized patients receiving digoxin included 698 patients in whom digoxin was discontinued before discharge and 698 patients in whom digoxin was continued. At 30 days, digoxin discontinuation was associated with a significantly higher risk of all-cause mortality (HR 1.80, 95% CI 1.26-2.57) and the combined endpoint of HF readmission or all-cause mortality (HR 1.36, 95% CI 1.09-1.71); these risks were also significantly increased at six months and one year. At four years postdischarge, digoxin discontinuation was associated with significantly increased risks of the combined endpoint of HF readmission or all-cause mortality (HR 1.20, 95% CI 1.07-1.34), HF readmission (HR 1.21, 95% CI 1.05-1.39), and all-cause readmission (HR 1.16, 95% CI 1.04-1.31), but not all-cause mortality (HR 1.09, 95% CI 0.97-1.24). Study limitations include the risk of bias despite propensity matching and lack of information on use of digoxin and other HF therapies during follow-up. However, the results of this study suggest that the previously observed clinical benefits of digoxin remain relevant in the current era.
DURATION OF THERAPY — Pharmacologic therapy for treatment of HFrEF is generally continued indefinitely, as tolerated, although limited data on the risk of withdrawal of therapy and the optimum duration of therapy are available.
There is a risk of recurrent adverse remodeling and HF with withdrawal of treatment for HFrEF even in patients with recovery of LV systolic function. In a small open-label trial in patients with dilated cardiomyopathy with LVEF recovered to ≥50 percent, there was a high risk of relapse (subclinical or symptomatic) after withdrawal of pharmacologic therapy that included an angiotensin system blocker in all, a beta blocker in most, and a mineralocorticoid receptor antagonist (MRA) in nearly half the patients [71]. These findings are discussed further separately. (See "Initial pharmacologic therapy of heart failure with reduced ejection fraction in adults", section on 'Duration of therapy'.)
Evidence on the risk of withdrawal of digoxin is discussed above. (See 'Evidence on digoxin' above.)
Predictors of durable recovery of ventricular systolic function have not been established.
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 (including risk of hospitalization) and reduction in mortality rate. The following secondary pharmacologic agents for HFrEF include clinical outcomes (table 1 and table 3) [1-3] (see 'Goals of therapy' above):
•Improvement in symptoms including reduction in hospitalization for HF has been demonstrated with the following secondary therapies: mineralocorticoid receptor antagonist (MRA), sodium-glucose cotransporter 2 (SGLT2 inhibitor), vericiguat, hydralazine plus nitrate, ivabradine, and digoxin.
•Prolongation of patient survival has been documented with the following secondary therapies: MRA, SGLT2 inhibitor, and hydralazine plus nitrate.
●Approach to secondary pharmacologic therapy – Secondary pharmacologic therapy is prescribed for specific subgroups of patients with HFrEF in addition to optimal (maximum tolerated up to target doses) initial pharmacologic therapy (generally a diuretic, renin angiotensin system antagonist or alternative, and beta blocker). Each patient with HFrEF may take none, one or more of the secondary agents (in addition to continued initial pharmacologic therapy), depending upon the patient's characteristics (see 'Approach to secondary therapy' above) (Related Pathway(s): Heart failure: Secondary pharmacologic therapy in adults with compensated chronic heart failure with reduced ejection fraction (HFrEF).):
•Add MRA if indicated – The following are two partially overlapping indications for MRA therapy. MRA use is limited to patients whose serum potassium and renal function can be carefully monitored and who have baseline serum potassium <5 mEq/L (table 5); an estimated glomerular filtration rate ≥30 mL/min per 1.73 m2 is also generally required. (See 'Mineralocorticoid receptor antagonist' above.)
-For patients with persistent symptoms on initial therapy – For patients with HFrEF who have symptomatic HF (New York Heart Association [NYHA] class II, III, or IV) (table 2) and a left ventricular ejection fraction (LVEF) ≤35 percent on optimal (maximum tolerated up to target doses) initial pharmacologic therapy, we recommend the addition of an MRA (Grade 1A).
-For patients post-myocardial infarction (MI) with an LVEF ≤40 percent – For patients post-MI with an LVEF ≤40 percent who are already receiving therapeutic doses of renin angiotensin system inhibitor and have either symptomatic HF or diabetes mellitus, we recommend the addition of an MRA (Grade 1B).
Given the relative costs we suggest spironolactone rather than eplerenone for initial MRA therapy (Grade 2B). Spironolactone is switched to eplerenone if endocrine side effects occur.
•If symptoms persist on initial therapy plus MRA (if indicated), and one or more additional agents, as indicated – For patients with persistent symptoms on optimal initial therapy plus MRA (if indicated), the options for additional pharmacologic therapy are the SGLT2 inhibitor, vericiguat, hydralazine plus nitrate, ivabradine, and digoxin. The choice among these agents is made based upon evidence of efficacy, criteria for use, contraindications, risks of adverse drug effects and patient compliance. For most patients in this setting, we suggest next adding dapagliflozin (Grade 2C).
-SGLT2 inhibitor – An SGLT2 inhibitor is a treatment option for patients with HFrEF with type 2 DM (dapagliflozin, empagliflozin, canagliflozin, or ertugliflozin) or without type 2 DM (dapagliflozin or empagliflozin). For patients with HFrEF and concurrent type 2 DM, an SGLT2 inhibitor may also be used as a component of therapy to treat hyperglycemia and to reduce progression of diabetic kidney disease. SGLT2 inhibitors are contraindicated in patients with type 1 DM and others at risk for developing diabetic ketoacidosis, as well as in patients with symptomatic hypotension, or severely decreased or rapidly declining kidney function. (See 'SGLT2 inhibitor' above and "Sodium-glucose co-transporter 2 inhibitors for the treatment of hyperglycemia in type 2 diabetes mellitus" and "Treatment of diabetic kidney disease", section on 'Type 2 diabetes: Treat with additional kidney-protective therapy'.)
-Vericiguat – Vericiguat is an additional therapy for patients who have NYHA Class II to IV HF, LVEF <45 percent, and have either been hospitalized in the last six months or received outpatient intravenous diuretic therapy. (See 'Vericiguat' above.)
-Hydralazine plus nitrate – The combination of hydralazine plus nitrate is an alternative or additional add-on therapy for patients with persistent symptoms on initial therapy plus MRA (if indicated). This drug combination may be particularly helpful for patients with persistent hypertension despite compliance with other drug therapies for HFrEF. Use of this combination is limited by generally poor adherence, likely caused by inconvenient dosing (large number of tablets and frequency of administration) and the high rate of adverse reactions. (See 'Hydralazine plus nitrate' above.)
-Ivabradine – Ivabradine is indicated for patients with an LVEF ≤35 percent in sinus rhythm with a resting heart rate ≥70 beats per minute and who are either on a maximum tolerated dose of beta blocker or have a contraindication to beta blocker use. (See 'Ivabradine' above.)
-Digoxin – Digoxin is an additional option for add-on therapy for patients with HFrEF who continue to have NYHA functional class III and IV symptoms despite optimal initial therapy plus all other indicated secondary pharmacologic therapies and cardiac resynchronization therapy (if indicated); some experts also require an LVEF <25 percent (figure 2). (See 'Digoxin' above.)
●Duration of therapy – Pharmacologic therapy for treatment of HFrEF is generally continued indefinitely, as tolerated, although limited data on the risk of withdrawal of therapy and the optimum duration of therapy are available. (See 'Duration of therapy' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Marc A Pfeffer, MD, PhD, who contributed to an earlier version of this topic review.
