Following diuretics, vasodilators are the most commonly used intravenous (IV) therapy for acute decompensated heart failure (ADHF), but strong evidence is lacking for the use of nitrates, nitroprusside, and nesiritide on clinical outcomes and therefore these drugs are most commonly used for symptomatic improvement [1]. The long-term use of angiotensin converting enzyme (ACE) inhibitors is associated with improved symptoms and lower mortality in patients with systolic heart failure. However, the benefits of early IV ACE inhibitors in ADHF have not been established and may actually be harmful. In the CONSENSUS 2 trial, early IV enalapril was studied in patients with acute myocardial infarction (AMI). In patients with AMI and ADHF, IV enalapril was associated with decreased survival 180 days after AMI [2]. The American College of Emergency Physicians supports the early use of IV ACE inhibitors [3], while the European Society of Cardiology does not [4]. Until studied further, IV ACE inhibitors should be avoided in the setting of ADHF.

The Heart Failure Society of America recommends the use of IV vasodilators as part of treatment for ADHF. Research has shown that only 18 % patients receive these medications and less than 1 % receive sodium nitroprusside [5]. Nitroprusside is considered an older agent which acts as an arterial and venous vasodilator, reduces systemic vascular resistance and left ventricular filling pressures, and increases cardiac output. Despite increasing studies evaluating beneficial effects of vasodilators in ADHF, there has been limited data on nitroprusside and long-term effects in ADHF. This agent has been associated with worse outcomes in patients with AMI and ADHF [6]. In a study of 812 men with presumed AMI, there was no difference in mortality rates between nitroprusside and placebo group. However, the efficacy of nitroprusside was related to the time of treatment such that the drug led to increased mortality with early administration from the onset of pain related to AMI (mortality at 13 weeks, 24.2 % vs. 12.7 %; p = 0.025) and decreased mortality with later treatment. Administration requires close hemodynamic monitoring due to the risk of hypotension, especially with a depressed cardiac output and unstable blood pressure [5]. Therefore, this drug should likely be avoided unless the clinical picture is one of hypertensive crisis, and prompt blood pressure control is clinically indicated.

Nesiritide was approved by the FDA in 2001, but retrospective data raised the issue of worsening renal function and increased mortality which led to a dramatic decrease in the use of this medication [7, 8]. The ASCEND-HF (Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure) trial was a randomized trial that studied 7,141 patients with ADHF. ASCEND-HF demonstrated that nesiritide improved heart failure symptoms but showed that older patients (>55 years) experienced a higher mortality rate [9]. Natriuretic peptides (NPs) cause vasodilation and decrease in renal perfusion pressures which can result in systemic hypotension and worsening of renal function [10]. This is important to keep in mind as studies have shown that glomerular filtration rate is the strongest predictor of mortality in ADHF. The Acute Decompensated Heart Failure National (ADHERE) registry showed that 63 % of patients with heart failure with renal dysfunction (GFR <60 mL/min) was strongly correlated with in-hospital mortality [11].

In 2015, the US Food and Drug Administration approved the use of sacubitril/valsartan (Entresto) for treatment of chronic and stable but symptomatic heart failure. Mechanism of blocking renin-angiotensin-aldosterone system along with inhibition of neprilysin, an enzyme that degrades natriuretic peptides, is one of the current leading strategies for symptomatic heart failure and for left ventricular ejection fraction less than 40 %. However, it is contraindicated in patients with a history of ACE inhibitor- or ARB-induced angioedema [10]. Entresto has not been specifically studied in ADHF in the emergency department and at this point should be avoided in this setting until further research.

Calcium channel blockers have negative inotropic properties and therefore should be avoided in ADHF as they have been associated with worse outcomes. In one study, post AMI patients with an ejection fraction <40 % who received diltiazem were more likely to develop clinical heart failure as compared to placebo [12]. Verapamil use has been associated with hemodynamic deterioration due to its negative inotropic effects and concern for worsening heart failure [13]. In addition, the dihydropyridines, such as nifedipine, have also been associated with clinical deterioration in patients with systolic heart failure [14].

Conversely, patients with diastolic heart failure in the setting of hypertension may benefit from diltiazem or verapamil by controlling blood pressure and slowing heart rate, which can improve diastolic filling in this group of patients. Diltiazem can also be considered in patients with ADHF and atrial fibrillation with rapid ventricular response when there is not an adequate clinical response to digoxin or amiodarone.

New potential therapies include IV clevidipine, a short-acting dihydropyridine L-type calcium channel blocker that is arterial selective and has no effect on myocardial contractility or central venous pressure, making it a favorable therapy for patients with ADHF with elevated blood pressure [1]. However, safety profile needs to be elucidated because of reports of reflex tachycardia and resulting atrial fibrillation and further study is warranted [1].

Beta-blockers have generally been avoided in patients with ADHF. Concern due to the negative inotropic effects and hemodynamic compromise leads physicians to stop beta-blockers even though evidence is lacking [15]. Furthermore, in clinical trials of beta-blockers for AMI, patients with significant heart failure have been excluded.

Many patients presenting with ADHF are on a regimen including beta-blockers and in most cases the drug can be continued. In a systematic review and meta-analysis evaluating effects of beta-blocker withdrawal in ADHF, discontinuation of beta-blockers was associated with increased mortality and rehospitalization [15]. Looking at the effects of beta-blocker withdrawal in patients being treated with inotropes, the improved outcomes are hypothesized to be secondary to the antiarrhythmic effects of beta-blockers as inotropes are pro-arrhythmic. Moreover, the IMPACT-HF study reported the rate of beta-blocker use at 60 days after discharge when initiated before discharge was 91 % compared to 73 % when initiated post-discharge. Therefore, this data suggests that discontinuation of beta-blockers during hospitalization results in decrease use after discharge, leading to poor long-term outcomes.

It is important to keep in mind that in patients presenting with hypotension or end-organ hypoperfusion where inotropic therapy is being considered, beta-blocker therapy may need to be discontinued. However, there is overwhelming data to support the long-term benefits of beta-blockers in patients with systolic heart failure. After patients have been compensated, an attempt should be made to reinstitute the beta-blocker. Short-acting beta-blocker therapy, such as esmolol, can be considered but should be used with caution in ADHF when uncontrolled cardiac ischemia is present or for control of tachyarrhythmia as necessary.

Class I antiarrhythmic drugs in the Vaughn-Williams classification system produce a greater negative inotropic and more frequent pro-arrhythmic effects in patients with systolic heart failure and thus should not be used in such patients [16]. The most common side effects seen in heart failure patients with this class are ventricular arrhythmias and sudden death [17]. The Cardiac Arrhythmia Suppression Trial (CAST) demonstrated that the Class Ic agents (flecainide and moricizine) were associated with pro-arrhythmia and increased mortality in patients that suffered an AMI and had decreased systolic function [18, 19]. Another Class Ic agent, propafenone, should also be avoided because of a significant increase in mortality during heart failure episodes [17]. Class Ia drugs (procainamide, quinidine, disopyramide) have also been associated with increased mortality in patients with decreased left ventricular systolic function [17]. Class III antiarrhythmics include sotalol which is known to be a racemic mixture of D- and L-isomers, acquiring different effects on potassium channels and β-receptors. The Survival with Oral D-Sotalol (SWORD) trial revealed that the d-isomer of sotalol (pure potassium channel blocker) was associated with a higher relative risk of mortality in patients with an ejection fraction of 40 % or less. Even though there no studies directly evaluating ibutilide in ADHF, pro-arrhythmic effects are a concern in patients with ADHF [17]. Nonetheless, amiodarone has proven to be safe in patients with systolic heart failure and is recommended in heart failure accompanied by atrial fibrillation when clinically indicated [20].

Despite being one of the oldest cardiovascular agents, digoxin’s mechanism of action and utility in medicine has been controversial due to concerns regarding clinical efficacy and safety profile [21]. Digitalis can be used as a rate control drug in atrial fibrillation and leads to improved symptoms in chronic systolic heart failure. Favorable hemodynamic effects include increase in ejection fraction and cardiac index along with reduction in the pulmonary capillary wedge pressure. The Digitalis Investigation Group study was a randomized, double-blind placebo controlled trial that included 6,800 chronic heart failure patients with NYHA classes II–III, EF ≤45 % which showed decreased mortality due to worsening heart failure with digoxin but concurrent increase in mortality due to other cardiac causes such as arrhythmias [21].

Caution is warranted in the setting of ADHF as it has been associated with adverse effects in AMI accompanied by heart failure [22]. In another study in patients with AMI and ADHF, the use of digoxin was a predictor of life-threatening pro-arrhythmic events [23]. However, utility of this agent may be considered in ADHF associated with atrial fibrillation with rapid ventricular response [24]. Patients who derive less benefit from digoxin therapy include female gender, those with hypertension, or a relatively preserved ejection fraction [21]. Cardiac glycosides still play an important role in patients with severe heart failure who cannot tolerate other disease-modifying agents.

Inotropes should be avoided in ADHF and only considered when there is significant systemic hypotension or end-organ hypoperfusion. In clinical trials such as OPTIME-CHF (Outcomes of a Prospective Trial of Intravenous Milrinone, a phosphodiesterase inhibitor, for Exacerbation of Chronic Heart Failure) which randomized patients with ADHF to 48 h of milrinone infusion, use of inotropes was associated with more adverse events including high incidence of atrial fibrillation or flutter and hypotension [25]. Inotropes increase oxygen demand and may worsen arrhythmias or myocardial ischemia [26, 27]. Another randomized trial studying the short-term use of milrinone across 78 community and tertiary care hospitals in the United States did not improve signs or symptoms of ADHF, and thus there is no support for the routine use of IV milrinone as an adjunct to standard therapy in the treatment of ADHF [28]. Other trials have also demonstrated that the beta-agonist dobutamine is associated with adverse cardiac events when used in ADHF [29, 30]. Milrinone and dobutamine have similar hemodynamic effects including increase in cardiac output and decrease in cardiac filling pressures. Milrinone lowers filling pressures to a greater degree and leads to a greater decrease in systemic vascular resistance compared with dobutamine that greatly increases myocardial oxygen demand comparatively [25].