Inotropic agents in heart failure with reduced ejection fraction

INTRODUCTION — Positive inotropic agents used to treat heart failure with reduced ejection fraction (HFrEF) include intravenous phosphodiesterase (PDE)-3 inhibitors (eg, milrinone), beta adrenergic receptor agonists (eg, dobutamine), intravenous calcium-sensitizing agents (eg, levosimendan, available in some countries outside the United States), and digoxin (available in oral and intravenous forms) (table 1). All of these drugs have beneficial hemodynamic effects in patients with HFrEF (also known as systolic HF) due in part to direct inotropic actions that cause an increase in cardiac output. In addition, several of these agents increase cardiac output due to direct arterial vasodilator effects (eg, milrinone, levosimendan, pimobendan) and/or the reflex withdrawal of neurohormonal vasoconstrictor mechanisms such as angiotensin II and norepinephrine (eg, dobutamine, digoxin).

Therapy with these agents is of potential value only in patients with decreased cardiac contractility. Those with HF with preserved ejection fraction (HFpEF; also known as diastolic HF) do not need inotropic support, and the myocardial effects of these agents may be detrimental in such patients. While the vasodilator action of some of these drugs may contribute to their overall hemodynamic effect in some patients, pure vasodilator drugs are more appropriate choices when an increase in contractility is not required.

The efficacy of acute intravenous inotropic support is well established in patients with severe myocardial systolic dysfunction. However, the efficacy of chronic administration of oral inotropic agents other than digoxin in ambulatory patients with HF remains unproven. On the contrary, available data suggest that the chronic use of many of these drugs may increase mortality. Digoxin is the only oral positive inotropic agent available for long-term ambulatory use in the United States.

Management of acute decompensated HF and an overview of therapy of HFrEF is presented separately. (See "Overview of the management of heart failure with reduced ejection fraction in adults".)

INDICATIONS

Intravenous therapy — Intravenous inotropic agents such as phosphodiesterase (PDE) inhibitors and beta adrenergic receptor agonists are used in selected patients with HFrEF requiring short-term or longer-term hemodynamic support. In some countries outside of the United Sates, the intravenous calcium-sensitizing agent levosimendan is also available for use in these settings.

Short-term hemodynamic support — In selected patients with decompensated HFrEF with low cardiac output and hypotension or evidence of end-organ hypoperfusion, we use short-term intravenous inotrope therapy. This approach is consistent with the 2013 American College of Cardiology/American Heart Association HF guidelines and the 2016 European Society of Cardiology (ESC) HF guidelines [1,2]. Given concerns about the risk of increased mortality and side effects with their use [3-5], intravenous inotropes should not be used in the routine inpatient management of acute decompensated HF in the absence of hypotension or organ hypoperfusion. (See 'Intravenous agents' below.)

Limited role of long-term hemodynamic support — Long-term intravenous infusion of an inotropic agent may be harmful and is generally not recommended in patients with current or prior symptoms of HF, except to serve as a bridge until definitive therapy is provided or as palliation in patients with end-stage HF refractory to standard medical therapy.

As bridge therapy — Intermediate- to long-term inotrope infusion may be useful in patients with refractory HF until definitive therapy is provided or resolution of the acute precipitating problem [1]. For refractory HF, potential treatment options include coronary revascularization (for ischemic cardiomyopathy), mechanical circulatory support (eg, left ventricular assist device), and cardiac transplantation. With appropriate protection against the risks of sudden death and catheter infection, selected patients may receive inotropic therapy on an outpatient basis. (See "Treatment of ischemic cardiomyopathy" and "Management of refractory heart failure with reduced ejection fraction", section on 'Intravenous inotropes' and "Treatment of advanced heart failure with a durable mechanical circulatory support device" and "Heart transplantation in adults: Indications and contraindications".)

The clinical improvements seen with inotropes (reduced hospitalization, less frequent worsening of HF) are beneficial because the patient is maintained in an optimal clinical condition prior to surgery. Such patients can be discharged from the hospital if clinically stable and managed on an outpatient basis with the assistance of a visiting nurse and a home infusion therapy program. The increased risk of sudden death associated with these agents can be mitigated with the use of an implantable cardioverter-defibrillator (ICD) and, if appropriate, pharmacotherapy (usually amiodarone) for the suppression of ventricular arrhythmias. (See "Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy", section on 'Evidence for use of ICD therapy'.)

Patients with severe HFrEF who are awaiting heart transplantation constitute a unique population with respect to the role of therapy for hemodynamic support. In this setting, the goal of HF management is to maintain the patient's clinical stability long enough to enable the patient to undergo transplantation when a donor heart becomes available. A variety of approaches have been used to "bridge" a patient to heart transplantation, including the use of mechanical ventricular assist devices. (See "Management of refractory heart failure with reduced ejection fraction" and "Treatment of advanced heart failure with a durable mechanical circulatory support device" and "Heart transplantation in adults: Indications and contraindications", section on 'Major society guidelines'.)

The benefit of outpatient intravenous inotropic therapy as a bridge to heart transplantation was illustrated in a report of 21 patients with severe HF who were treated with dobutamine (12 patients), milrinone (eight patients), or dopamine (one patient) for a mean duration of 146 days [6]. All but one of the patients received an ICD prior to hospital discharge. Intravenous inotropic therapy resulted in significant improvements in functional capacity, renal function, and hemodynamics as well as a decrease in the number of hospitalizations. Fifteen patients underwent heart transplantation, three died, and three were still awaiting transplantation at the end of follow-up. There were five episodes of catheter infection or thrombosis during home infusion therapy, one resulting in fatal septic shock. (See "Intravascular non-hemodialysis catheter-related infection: Clinical manifestations and diagnosis".)

Palliative care — Use of inotropes in the palliative care of patients with advanced HF is discussed separately. (See "Palliative care for patients with advanced heart failure: Decision support and management of symptoms", section on 'Use or withdrawal of intravenous inotropes'.)

Choice of intravenous inotropic agent — For patients with an indication for intravenous inotrope, the choice of agent is based upon the following baseline patient characteristics:

●Hypotension – In patients with baseline hypotension, dobutamine is generally preferred to a PDE-3 inhibitor (eg, milrinone) or the calcium-sensitizing agent levosimendan (available in some countries outside of the United States) since the latter types of agents also have prominent vasodilator effects.

●Renal insufficiency – Dobutamine is preferred to milrinone in patients with renal impairment. Dose adjustment is recommended when milrinone is used in patients with renal impairment. Accumulation of milrinone may lead to hypotension.

●Recent beta-blocker use – Oral beta blockers, such as metoprolol and carvedilol, are part of the evidence-based long-term management of HFrEF. Beta blockers are generally discontinued in patients who require inotropic support. For patients who have recently taken a beta blocker and thus may have residual beta-blocker effect that is contributing to hypoperfusion, a PDE-3 inhibitor is preferred to dobutamine. Since dobutamine acts primarily as a beta agonist, a beta blocker (particularly carvedilol [7]) may block its effectiveness. In countries where levosimendan is approved for clinical use, levosimendan or a PDE-3 inhibitor may be used to overcome the effects of beta blockade if beta blockade is thought to be contributing to hypotension causing hypoperfusion as suggested in the 2017 ESC HF guidelines [2]. It should be recognized that levosimendan and milrinone have direct vasodilator actions that may worsen hypotension. Since most beta blockaders are competitive antagonists, in some cases their effects can be overcome by using a higher dose of dobutamine. (See 'Compared with dobutamine therapy' below and 'Oral phosphodiesterase inhibitors' below.)

Long-term digoxin therapy — Digoxin is an inotrope that is a component of long-term therapy for HFrEF. Digoxin is used predominantly in oral form in the long-term treatment of HFrEF. Use of digoxin in patients with HFrEF is discussed separately. (See "Secondary pharmacologic therapy for heart failure with reduced ejection fraction".)

INOTROPIC AGENTS IN USE

Intravenous agents — Available intravenous inotropes include beta adrenergic receptor agonists and phosphodiesterase (PDE) inhibitors. An intravenous calcium-sensitizing agent is available in some countries in Europe and South America.

Intravenous beta adrenergic receptor agonists — While several beta adrenergic agonists in addition to dobutamine are available for clinical use, including isoproterenol, high-dose dopamine, norepinephrine, and epinephrine, most have substantial vascular effects such as vasoconstriction (eg, high-dose dopamine, norepinephrine) and vasodilation (eg, isoproterenol), which need to be considered in their selection.

Dobutamine — Dobutamine is the main beta adrenergic agent used for inotropic support in the United States. Dobutamine acts primarily as a beta-1 agonist. The dobutamine (-) isomer is an alpha-1 agonist and the (+) isomer is a beta-1 agonist and alpha-1 antagonist; the racemic mixture has mixed alpha-1 effect and minimal beta-2 effects and thus has minimal effect on peripheral vascular resistance [8].

As a result of studies suggesting potential risk of increased mortality with longer-term use, the administration of intravenous dobutamine has been largely limited to the inpatient management of patients with severe decompensated HF. In this setting, dobutamine appears to be as effective as the intravenous PDE-3 inhibitor milrinone [9].

Intravenous PDE inhibitors are an alternative to dobutamine. However, important differences exist. The PDE-3 inhibitors, unlike dobutamine, are potent arterial and venous dilators, and as such, the left heart filling pressure and systemic vascular resistance of the patient need to be considered in selecting the most appropriate inotropic agent. In addition, the response to beta adrenergic agonists is more likely to be attenuated due to desensitization of the beta adrenergic receptor pathway, a common occurrence in severe HF. The PDE inhibitors act distal to the beta receptor and are thus somewhat less susceptible to this problem.

Symptomatic improvement has been demonstrated in patients with advanced HF after treatment with a continuous infusion of dobutamine (at a rate of 5 to 7.5 mcg/kg per min) for three to five days [10-12]. It has been suggested that the benefit can last for 30 days or more in selected cases, a phenomenon that has been called a "dobutamine holiday" [12]. Possible mechanisms include a sustained improvement in myocardial contractility and left ventricular performance, a training-like effect on skeletal muscles, and an improvement in vascular endothelial function [13].

There are, however, no placebo-controlled data documenting improved survival from either intermittent or continuous dobutamine [14-17]. A small study randomly assigned 38 patients to ambulatory, intermittent, low-dose dobutamine (2.5 mcg/kg per min administered for 48 hours per week for six months) or to optimal standard therapy [15]. Dobutamine did not affect mortality or improve functional status; it did, however, reduce hospitalization for all causes and for worsening of HF. Another controlled trial, the results of which have never been published, evaluated intermittent ambulatory dobutamine infusion in 60 patients; the trial was stopped prematurely because of excess mortality in the dobutamine group [17].

As noted above, milrinone may also increase mortality compared with placebo in patients who do not require inotropic support at presentation [3]. In addition, a nonrandomized retrospective study from ADHERE suggested that, after attempted adjustment for differences in risk, milrinone and dobutamine were associated with increased mortality compared with patients treated with nitroglycerin or nesiritide [4]. Since sicker patients were treated with the inotropes, one cannot know if the adjustments were sufficient to address baseline differences.

Hypersensitivity myocarditis — An eosinophilic hypersensitivity myocarditis has been reported in 2.4 to 23 percent of patients treated with a dobutamine infusion, particularly if prolonged [18,19]. Management is discussed separately. (See "Myocarditis: Causes and pathogenesis", section on 'Hypersensitivity myocarditis' and "Treatment and prognosis of myocarditis in adults", section on 'Eosinophilic myocarditis'.)

Dopamine — When used at high-dose levels (ie, above the renal dose range of 1 to 3 mcg/kg per min), dopamine has beta-1 adrenergic effects leading to increased inotropy as well as alpha-1 adrenergic effects leading to arterial and venous constriction. Since vasoconstriction increases left ventricular afterload, high-dose dopamine is generally only used when an increase in systemic resistance is necessary to maintain an adequate arterial pressure. By contrast, at low doses, dopamine acts primarily on dopamine receptors leading to vasodilation, as discussed separately, but has little or no effect on inotropy. (See "Treatment of acute decompensated heart failure: Specific therapies", section on 'Specific agents'.)

Intravenous phosphodiesterase-3 inhibitors — PDE-3 inhibitors, such as milrinone and enoximone, decrease the rate of cyclic adenosine monophosphate (AMP) degradation. The ensuing increase in cyclic AMP concentration leads to enhanced calcium influx into the cell, a rise in cell calcium concentration, and increased contractility. These drugs also cause systemic arterial and venous dilation via inhibition of vascular PDE [20]. Administration of an intravenous PDE-3 inhibitor can provide acute hemodynamic and symptomatic benefit in patients with advanced HFrEF (New York Heart Association functional class III or IV) (table 2). Milrinone and enoximone exert similar potent hemodynamic effects in patients with HF due to decreased contractility, with increases in cardiac output and decreases in left heart filling pressures and systemic vascular resistance.

Intravenous milrinone is widely available for clinical use and intravenous enoximone is available for clinical use in Europe. (See 'Intravenous therapy' above.)

While the hemodynamic effects of PDE-3 inhibitors can be helpful for the short-term support of a patient with low cardiac output, the routine use of these agents has not been shown to be clinically useful and is not recommended. The routine use of milrinone was not supported by the OPTIME CHF, a controlled trial in 949 patients admitted to the hospital with an acute exacerbation of chronic HF and a mean left ventricular ejection fraction of 23 percent; patients requiring inotropic support were excluded [3]. The patients were randomly assigned to intravenous milrinone or placebo for 48 to 72 hours and then followed for 60 days. Milrinone therapy was associated with significant increases in hypotension requiring intervention and atrial arrhythmias and with nonsignificant increases in mortality in-hospital (3.8 versus 2.3 percent) and at 60 days (10.3 versus 8.9 percent). In a post hoc analysis, patients with ischemic cardiomyopathy did significantly worse with milrinone in terms of in-hospital mortality as well as the combined end point of rehospitalization or death [21]. By contrast, milrinone had a neutral to modestly beneficial effect in patients with a nonischemic cardiomyopathy.

An adverse mortality effect of milrinone was also suggested in a retrospective analysis from the Acute Decompensated Heart Failure (ADHERE) national registry [4]. After attempted adjustment for differences in risk, milrinone and dobutamine were associated with increased mortality compared with patients who were treated with nitroglycerin or nesiritide. However, since sicker patients were treated with the inotropes, one cannot know if the adjustments were sufficient.

Enoximone is an intravenous PDE-3 inhibitor with pharmacologic and hemodynamic effects that are similar to milrinone. This agent is available in some countries in Europe but not in the United States.

Intravenous calcium-sensitizing agents — Calcium-sensitizing agents (including intravenous levosimendan and oral pimobendan) enhance myocardial response to a given concentration of calcium [22-24]. These agents increase the sensitivity of the myocardial contractile apparatus to calcium, causing an increase in myofilament tension development and myocardial contractility. Studies suggest that these agents also have favorable effects on relaxation properties in failing hearts [24,25]. Most calcium-sensitizing agents have additional pharmacologic properties, such as PDE inhibition, which may increase inotropy and vasodilation and contribute significantly to their clinical profile. (See "Excitation-contraction coupling in myocardium".)

Levosimendan is an inotropic drug with PDE-3-inhibiting and calcium-sensitizing effects. Several studies have evaluated its efficacy and safety in patients with HF [23,26-29]. The short-term hemodynamic effects of intravenous administration of levosimendan include a dose-dependent reduction in cardiac filling pressures and an increase in cardiac index [26,27,30,31].

Despite improvement in indices of cardiac performance and HF, there is limited evidence of short- or long-term clinical benefit. Levosimendan is currently approved for intravenous use in some countries in Europe and South America but remains investigational in the United States [22,23].

Compared with placebo — The available evidence does not demonstrate a clear clinical benefit from intravenous levosimendan therapy compared with placebo:

●In the RUSSLAN trial, 504 patients were randomly assigned to a six-hour infusion of levosimendan or placebo [29]. With levosimendan therapy, the mortality rate was significantly lower at 14 days (11.7 versus 19.6), but the mortality difference was only borderline significant at 180 days (22.6 versus 31.4 percent, p = 0.053).

●In the REVIVE I and REVIVE II sequential trials, 700 patients with acute decompensated HF who remained dyspneic after intravenous diuretics were randomly assigned to intravenous levosimendan or placebo for 24 hours [32]. Although patients in the levosimendan group had lower B-type natriuretic peptide levels and reported greater improvement in symptoms for up to five days, levosimendan was associated with more frequent hypotension and cardiac arrhythmias and nominally but nonsignificantly higher risk of death in the two trials (49 of 350 versus 40 of 350; p = 0.29) at 90 days.

Compared with dobutamine therapy — The available evidence does not clearly support a clinical benefit from levosimendan compared with dobutamine therapy. The LIDO (n = 203) and SURVIVE (n = 1327) trials randomly assigned patients with severe HF to short-term infusion of either levosimendan or dobutamine; in the LIDO trial, both treatment arms received a 24-hour infusion, while in SURVIVE, the levosimendan infusion was for 24 hours, while the dobutamine infusion was for as long as deemed clinically appropriate beyond 24 hours (mean of 39.3 total hours) [28,33]. The earlier LIDO trial found greater hemodynamic improvement at 24 hours with levosimendan [28], but the SURVIVE trial found no difference in the percentage of patients who reported at least mild improvement in dyspnea (82 versus 83 percent, respectively) [33]. Although there was significantly lower mortality with levosimendan therapy compared with dobutamine therapy at both one month (8 versus 17 percent) and six months (26 versus 38 percent) in the LIDO trial [28], the much larger SURVIVE trial found no significant difference in mortality between the levosimendan and dobutamine treatment groups at one month (12 versus 14 percent) or six months (26 versus 28 percent) [33].

Subgroup analyses of the SURVIVE trial results suggested that clinical outcomes with levosimendan may be better than those with dobutamine in selected patients groups [34]. Among patients with prior history of HF, there was significantly lower mortality with levosimendan compared with dobutamine at day 14 (7.0 versus 10.3 percent) and borderline significantly lower mortality at day 5 (3.4 versus 5.8 percent; p = 0.05). Among the 669 patients treated with a beta blocker at baseline, mortality was significantly lower with levosimendan than dobutamine at day 5 (1.5 versus 5.1 percent). If true, it is unclear if this is because of added mortality with dobutamine or decreased mortality with levosimendan.

Digoxin — The safety and efficacy of digoxin therapy as a component of the long-term treatment of HFrEF are discussed separately. (See "Secondary pharmacologic therapy for heart failure with reduced ejection fraction".)

DRUG WITH UNPROVEN EFFICACY

Pimobendan — Pimobendan is an inotropic agent with phosphodiesterase-inhibiting and calcium-sensitizing effects. As discussed above, calcium-sensitizing agents enhance myocardial response to a given concentration of calcium [22-24].

Acute intravenous administration of pimobendan to patients with HFrEF results in increases in stroke volume and cardiac index and reductions in left ventricular end-diastolic pressure, systemic vascular resistance, and mean arterial pressure with an associated small elevation in heart rate [35]. In two randomized, placebo-controlled trials (PMRG and PICO) of patients with HFrEF, 12- to 24-week administration of oral pimobendan resulted in improvements in exercise duration [36,37], although in the larger study there was a nonsignificant trend toward greater mortality (hazard ratio 1.8, 95% CI 0.9-3.5) [37].

The long-term efficacy and safety of oral pimobendan for treatment of HFrEF has not been established. In the EPOCH study, 306 patients with New York Heart Association functional class II or III HF and left ventricular ejection fraction ≤45 percent despite conventional therapy were randomly assigned to 52 weeks of treatment with pimobendan or placebo [38]. The primary combined end point of sudden cardiac death, hospitalization for HF, or death from HF was less frequent in the pimobendan group (10.1 versus 15.3 percent), but this difference was not statistically significant. The combined adverse cardiac event rate in the pimobendan group was significantly lower than in the placebo group (15.9 versus 26.3 percent), but this end point included addition or increase in doses of background medications and decrease in specific activity scale.

Oral pimobendan is currently approved for use only in Japan [22].

DRUGS TO AVOID — Although intravenous inotropic agents may be helpful in providing hemodynamic support in selected patients with HFrEF, clinical trials of the chronic administration of oral inotropic agents (oral phosphodiesterase [PDE] inhibitors and beta blockers with intrinsic sympathomimetic activity [ISA]) have shown evidence of harm with increased mortality risk.

Other drugs to avoid in patients with HFrEF are discussed separately. (See "Drugs that should be avoided or used with caution in patients with heart failure".)

Oral phosphodiesterase inhibitors — Although there was previous interest in the use of oral PDE-3 inhibitors to treat HFrEF, clinical trials of chronic use of these agents showed evidence of harm. The efficacy and safety of more selective use of these agents have not been established. None of the oral PDE-3 inhibitors are currently approved for treatment of HF. The oral PDE inhibitor cilostazol is approved for treatment of intermittent claudication but is contraindicated in patients with HF, based upon evidence of harm with other PDE-3 inhibitors.

Chronic use of an oral PDE inhibitor, such as milrinone or enoximone, was associated with increased mortality compared with placebo [39,40]. A meta-analysis from the Cochrane Database included 21 randomized trials with a total of 8408 patients treated with a PDE inhibitor or placebo with greater than three months of follow-up [41]. The largest included trials were the VEST trial, which studied vesnarinone [42], and the PROMISE trial, which studied milrinone [39]. Compared with placebo, use of a PDE inhibitor was associated with a significant 17 percent increase in mortality (relative risk 1.17, 95% CI 1.06-1.30). PDE inhibitors increased cardiac death, sudden death, arrhythmias, and vertigo. These adverse effects were seen with or without concurrent vasodilator therapy.

Why the oral use of PDE inhibitors worsens long-term outcome is not clear but likely is due at least in part to increased ventricular and atrial arrhythmias. It is possible that the chronic use of PDE inhibitors in lower doses may be safer [43], but the long-term efficacy and safety of this approach remain to be demonstrated in controlled trials.

It has been postulated that the use of a PDE inhibitor might permit the successful initiation and upward titration of beta blockade. Such an approach might be effective in medically refractory patients. It has also been proposed that a PDE inhibitor and beta blocker might be used together long term. In a randomized short-term study, the hemodynamic responses to enoximone were maintained or enhanced by metoprolol or carvedilol [7], and in a series of 30 patients with refractory New York Heart Association class IV HF who were treated with the combination of enoximone and metoprolol, this regimen was well tolerated by 80 percent of patients [44]. While the short- or long-term use of a PDE inhibitor with beta blockade may be useful in selected circumstances (eg, to stabilize hemodynamics in a patient with decompensation in the setting of new beta blockade), the safety and efficacy of the routine use of this combination have not been established.

Beta blockers with ISA — Beta blockers with ISA are not recommended in patients with HF. It was previously suggested that beta blockers that also have significant ISA may offer a safer way of providing chronic inotropic support to the failing heart. However, a prospective, multicenter study of 512 patients demonstrated a significant excess mortality in patients treated with one such agent, xamoterol, as compared with placebo (9.1 versus 3.7 percent at 100 days) [45].

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".)

SUMMARY AND RECOMMENDATIONS

●Short-term inotropic support – Short-term intravenous inotrope therapy is used as a temporizing measure in patients with decompensated heart failure with reduced ejection fraction (HFrEF) with hypotension or evidence of end-organ hypoperfusion with low cardiac output caused by systolic dysfunction. Given concerns about the risk of increased mortality and side effects with their use, intravenous inotropes should not be used in the routine inpatient management of acute decompensated HF in the absence of hypotension or organ hypoperfusion. (See 'Short-term hemodynamic support' above.)

●Limited role of long-term inotropic support – Intermediate- to long-term inotrope infusion may be useful in patients with refractory HF as a bridge to definitive therapy (eg, cardiac transplantation) or resolution of the acute precipitating problem, or as a component of palliative care in patients with end-stage HFrEF. (See 'Limited role of long-term hemodynamic support' above.)

●Inotropic agents – Intravenous inotropic agents include phosphodiesterase (PDE)-3 inhibitors (eg, milrinone), beta agonists (eg, dobutamine), and calcium-sensitizing agents (eg, levosimendan, which is available in some countries outside of the United States). (See 'Intravenous phosphodiesterase-3 inhibitors' above and 'Intravenous calcium-sensitizing agents' above and 'Intravenous beta adrenergic receptor agonists' above.)

•Intravenous inotropes – For patients with an indication for intravenous inotrope who have recently taken a beta blocker and thus may have residual beta-blocker effect that is contributing to hypoperfusion, we suggest a PDE-3 inhibitor (eg, milrinone) or levosimendan (where clinically available) rather than dobutamine (Grade 2C). (See 'Choice of intravenous inotropic agent' above.)

•Oral inotropes – The inotrope digoxin is a component of long-term therapy for HFrEF. Use and efficacy of digoxin are discussed in a separate topic review. (See 'Long-term digoxin therapy' above and "Secondary pharmacologic therapy for heart failure with reduced ejection fraction".)

We recommend against use of other oral inotropic agents, such as oral PDE inhibitors and beta blockers with intrinsic sympathomimetic activity (eg, xamoterol) (Grade 1A). When added to conventional therapy for HFrEF, each of these oral inotropic agents has been associated with an increase in mortality. (See 'Drugs to avoid' above.)