Until recently, angiotensin-converting enzyme (ACE) inhibitors were considered the definitive first line treatment for chronic symptomatic heart failure with reduced ejection fraction (NYHA class II/III) [1]. However, the development of novel drugs in heart failure, including the angiotensin receptor-neprilysin inhibitors (ARNIs), has recently changed this paradigm. Sacubitril/valsartan is a combination of sacubitril, a neprilysin inhibitor, and valsartan, an established angiotensin-receptor blocker. Sacubitril increases vasoactive peptide levels through inhibition of neprilysin, which is normally responsible for degradation of these peptides. In turn, blood volume is lowered, relieving the patient’s diseased heart. The PARADIGM-HF study, a randomized trial of sacubitril/valsartan compared to the established ACE-inhibitor enalapril in heart failure, was stopped early at 27 months due to overwhelming evidence of benefit in the sacubitril/valsartan study arm [3]. Specifically, patients in the sacubitril/valsartan arm demonstrated significantly less mortality and hospitalizations for heart failure. In 2015, sacubitril/valsartan was FDA approved for use in patients with chronic NYHA class II-IV heart failure, and in 2016 was officially designated by the ACC/AHA guidelines as the first-line therapy for patients with chronic symptomatic heart failure with reduced ejection fraction (NYHA class II/III), replacing ACE-inhibitors due to the increased survival benefit [4]. Notably, sacubitril/valsartan is contraindicated in patients taking ACE-inhibitors, and should be avoided in patients with a history of angioedema or other adverse reactions to ACE-inhibitors [3].

Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARB) remain a first-line option for patients displaying chronic reduced left ventricular systolic function (LVEF ⩽35–40%) who remain largely asymptomatic and are classified as NYHA class I. However, in cases of chronic symptomatic patients with reduced ejection fraction who meet the criteria for NYHA class II/III, patients on an ACE-inhibitor should be switched to sacubitril/valsartan, unless sacubitril/valsartan is contraindicated or unable to be tolerated [4]. Additionally, it is important that ARNIs should never be administered concurrently with ACE-inhibitors or ARBs [4].

There is strong evidence from several large multicenter trials worldwide that ACE inhibitors are able to improve symptoms and functional capacity, while simultaneously decreasing the rate of hospitalizations and mortality [5]. In patients who develop heart failure following an acute myocardial infarct, ACE inhibitors have been demonstrated to improve survival and reduce re-infarction rates [1]. Importantly, dosages should be up-titrated to the target dosages shown to be effective in clinical trials, with intermediate doses unlikely to have significant effect [1]. Monitoring should comprise of regular assessment of blood pressure (both supine and standing), renal function, and serum electrolytes (especially potassium) at regular intervals. For those who are unable to tolerate or are contraindicated against ACE inhibitors, angiotensin receptor blockers (ARBs) are a viable alternative that have been demonstrated to improve both morbidity and mortality [6, 7]. In persistently symptomatic patients already on ACE inhibitors and other optimal medical treatment including beta-blockers, ARBs on top of ACE inhibitors may also be considered [1].

Diuretics, including either loop or thiazide diuretics, are recommended in all heart failure patients with signs or a history of fluid retention. In general, they should be combined with an ARNI or ACE inhibitor/ARB and beta-blocker. Multiple intermediate-term studies have shown that diuretics can improve symptoms and exercise tolerance in heart failure patients [8–10]. Due to the principal potential adverse effects of electrolyte (in particular magnesium and potassium) and fluid depletion, serum electrolytes and renal function should be monitored at regular intervals. Loop diuretics may be effectively used in combination with thiazides in cases of treatment-refractory fluid overload [11].

In combination with ARNIs or ACE inhibitors, beta blockers should be prescribed to all patients with stable heart failure (NYHA II–IV) with reduced ejection fraction. Large, international multicenter clinical trials demonstrate that carvedilol, bisoprolol and metoprolol succinate are most effective in reducing the risk of death and combined risk of death or hospitalizations [1, 12]. Initiation of beta-blockers should be at a very low dose, incrementally increasing to the higher doses proven to be effective in clinical trials [1]. In patients with fluid retention, beta blockers must be prescribed with diuretics in order to avoid the exacerbation of fluid retention. Patients taking beta-blockers should be closely monitored for signs of hypotension, heart failure symptoms, fluid retention, and bradycardia.

Ivabradine is a new selective inhibitor of the cardiac pacemaker “funny”current I_f that lowers heart rate without reducing contractility; in a European 6558-patient multicenter study [13], it was found that among patients already on maximally tolerated beta-blocker dosages, ivabradine reduces the risk of HF hospitalization. Recently, the US Food and Drug Administration (FDA) granted approval for use of ivabradine, and a 2016 update to ACC/AHA recommends the use of ivabradine in chronic heart failure patients to reduce the risk of hospitalization in patients with EF ≤35%, who are in sinus rhythm with a resting heart rate of ≥70 bpm, and on maximally tolerated doses of beta-blockers or contraindicated to beta-blocker use [4].

Aldosterone-receptor antagonists, which include the agents spironolactone and eplerenone, are generally recommended in patients with advanced heart failure (NYHA II–IV) who demonstrate LVEF of 35% or lower, in addition to ARNIs or ACE inhibitors, β-adrenergic receptor blockers, and diuretics [1]. However, they must be avoided in patients with severe renal failure (creatinine 2.5 mg/dl or greater in men, 2.0 mg/dl in women) and hyperkalemia (>5.0 mEq/l), as they may cause life-threatening harm in this subgroup. In patients with a history of diabetes or recent MI, the threshold for LVEF for which aldosterone-receptor antagonists are acceptable is slightly higher at 40%. Nevertheless, the multicenter RALES (Randomized Aldactone Evaluation Study) trial demonstrated that these agents are able to reduce all-cause mortality as well as confer a reduced risk of sudden cardiac death and heart failure hospitalizations [14]; the subsequent follow-up multicenter studies, the EPHESUS (Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study) and EMPHASIS-HF (Eplerenone in Patients with Systolic Heart Failure and Mild Symptoms) trials, have confirmed their benefit [15, 16]. Patients on these agents should be monitored by regular assessment of serum potassium values, renal function, and fluid status, as well as examined for potential gynecomastia in the case of spironolactone.

The combination of hydralazine and isosorbide dinitrate, two vasodilators, is recommended for African-Americans with heart failure and reduced ejection fraction that is refractory to treatment with ARNIs or ACE inhibitors, beta-blockers, and aldosterone receptor antagonists, having demonstrated improved mortality [1, 17, 18]. Currently, benefit in non-African Americans is unclear [1]. Furthermore, there is some evidence to suggest that they may be useful in reducing morbidity and mortality in symptomatic heart failure patients who are unable to tolerate ACE inhibitors or ARBs [1, 19]. Patients should be monitored for adherence (found to be difficult due to the large number of tablets required) and checked for adverse reactions, which may include headache, GI distress and dizziness.

Digoxin, a cardiac glycoside that increases myocardial contractility via inhibition of the Na+/K+ATPase, has demonstrated that it can be beneficial in heart failure patients with reduced ejection fraction, with regard to decreasing frequency of related hospitalizations [1, 20, 21]. It is considered a viable option in those with persistent symptoms despite administration of ARNIs/ACE-inhibitors/ARBs, beta-blockers, diuretics and aldosterone antagonists. Importantly, patients should not be administered digoxin if they display significant sinus or atrioventricular block. While well tolerated by the majority of patients, adverse effects can include arrhythmias, GI distress and visual disturbances. Concomitant use of certain antibiotics or immunosuppressants may also increase the risk of digoxin toxicity [22]. Patients on digoxin should be monitored by assessing heart rate, atrioventricular conduction, serum potassium and digoxin levels, as well as renal function.

Due to the stasis of blood in dilated hypokinetic cardiac chambers and the peripheral vessels, patients with end-stage heart failure are especially at increased risk of thromboembolic events. However, anticoagulation is only recommended in patients with chronic heart failure combined with atrial fibrillation (AF) [1]. In heart failure patients without AF, a prior thromboembolic event, or a cardioembolic source (e.g. mobile LV thrombus), there has been demonstrated to be no benefit to anticoagulation. The choice of anticoagulant is generally one of warfarin, dabigatran, or apixaban, and is initiated on the basis of the nature of the patient’s AF (as well as cost, potential for drug interactions, and other individual clinical considerations).

In stage D heart failure, fluid restriction to 1.5–2 L per day is recommended, especially in patients with hyponatremia or congestive symptom [1].

While the drugs mentioned above will have been initiated while that patient was still in the relatively early stages of heart failure (stage A, B or C, NYHA class I-III), a deterioration to Stage D/ NYHA class III-IV almost always implies a severe heart failure refractory to guideline-directed medical therapy as detailed above. At this point, inotropes must be considered to support the failing heart [1]. Favored agents include adrenergic agonists, such as dopamine and dobutamine, and phosphodiesterase inhibitors, such as milrinone (see Table 1.2 for an overview, including dosing instructions).