ACE inhibitors (ACEi) reduce mortality and the risk of hospitalization for heart failure at all degrees of heart failure [3]. ACEi are therefore a key element of drug therapy for chronic heart failure and should be initiated in all patients. ACE inhibitors block the conversion of angiotensin I to angiotensin II by ACE, whereas the angiotensin II-AT₁ receptor blockers (ARBs) exert their effect by blocking the angiotensin II type 1 receptor. ACEi and ARBs thus share the same mechanism of action, which is to reduce the effect of angiotensin II. Both ACEi and ARBs are thought to have a class effect with no difference in clinical benefit for different drugs within each group. The evidence for clinical benefit in heart failure is stronger for ACEi than for ARBs, and ACEi are the preferred drugs, while ARBs are referred to those patients who are allergic to ACEi or suffer from unwanted side effects, especially cough (Chap.​ 36).

ACEi reduce blood pressure by lowering both arterial and venous smooth muscle tone. The benefit of ACEi in heart failure is independent of their blood pressure-lowering effect. In addition to its direct effect on vascular tone, ACEi reduce aldosterone secretion from the adrenal cortex and reduce the release of antidiuretic hormone from the pituitary gland, both of which are favorable effects in patients with chronic heart failure. ACEi also affects renal blood flow by decreasing vascular tone in the renal arterioles which leads to increased renal blood flow, although glomerular filtration is reduced because of a relatively larger effect on the postglomerular efferent arterioles than the preglomerular afferent arterioles.

Treatment with ACEi is initiated at low doses and titrated to target doses established through clinical trials (captopril 50 mg three times/day, enalapril 10 mg twice/day, lisinopril 20–40 mg/day, ramipril 5 mg twice/day, or trandolapril 4 mg/day). Because there is no negative inotropic effect, ACEi may be initiated even while the patient still has signs and symptoms of congestion. During titration, regular control of renal function and potassium levels are required because of the renal effects of ACEi. In the inpatient setting, titration is done over days, whereas stable outpatients may be titrated over weeks.

The most common side effects of ACEi are related to symptoms of low blood pressure. In addition, some patients may experience hyperkalemia due to reduced levels of aldosterone, and in patients with hypovolemia, where renal perfusion is more dependent on angiotensin II activation, ACEi may cause functional renal insufficiency. Between 5 and 20 % of patients on ACE inhibitors develop a dry cough, because of blockage of bradykinin degradation, and these patients are then switched to an ARB [4].

Together with ACEi, blockade of the adrenergic beta-receptors is the key element of medical therapy at all stages of chronic heart failure with reduced ejection fraction. Initially thought to be detrimental due to its negative inotropic and chronotropic effects, beta-blockade has consistently been shown to markedly reduce mortality and morbidity in patients with heart failure [5]. There is no substantial evidence proving that one beta-blocker is superior to another, but target doses and effect on mortality have been most clearly demonstrated for carvedilol, bisoprolol, and sustained release metoprolol, which are therefore most commonly used in clinical practice.

Beta-blockers exert their effect by inhibiting the beta-type adrenergic receptors. This attenuates the effect of catecholamines on heart rate, cardiac contractility, and oxygen consumption, as well as vascular muscle tone. In addition to their effect on the heart, beta-blockers inhibit renin release by the kidneys. How these multiple mechanisms translate into long-term improved cardiac function and reduced morbidity and mortality is not fully understood, and beyond the scope of this chapter, but is most likely an effect of protecting the failing heart from the detrimental effect of a chronic increase in catecholamine levels. Some studies suggest that beta-blockade suppresses cardiac myocyte apoptosis. The main clinical effect stems from blockade of the β1-receptor, while the clinical benefit of blocking the β2- and β3-receptors is less clear. Available beta-blockers differ in their selectivity for the β1-receptor, but this does not translate into differences in clinical effect.

Beta-blockers, like ACE inhibitors, are initiated at a low dose and titrated to target doses derived from clinical trials. In contrast to ACE inhibitors, beta-blockers have a negative inotropic effect and should therefore not be started while the patient has signs and symptoms of congestion. Often, the patient will be slightly more symptomatic during the first couple of days after initiation; uptitration of beta-blocker dose is therefore done more slowly than ACE inhibition in order to avoid causing a decompensation episode.

Usually, an ACEi is titrated first, and the beta-blocker is added sequentially in the outpatient setting. Sustained metoprolol can be initiated at 25 mg/day (12.5 mg/day in NYHA class IV) and titrated slowly (monthly) to a maximum dosage of 200 mg/day. Carvedilol is begun at 3.125 mg twice/day and titrated every 2 weeks to a maximum dose of 25–50 mg twice/day. Bisoprolol is begun at a dose of 1.25 mg/day and titrated to 10 mg/day. Side effects of beta-blockers are plentiful but mostly benign and usually taper off within a week of treatment onset or dose titration. Most common side effects are symptoms of hypotension and low heart rate such as dizziness, tiredness, and headache.

The mineralocorticoid aldosterone is an important contributor to the pathophysiology of heart failure. Aldosterone exerts a variety of detrimental effects in patients with chronic heart failure. Initially thought to be secreted almost exclusively by the adrenal gland, causing renal retention of sodium in exchange of potassium, aldosterone-producing cells and aldosterone receptors are also found in several other organs, including the heart, where aldosterone acts locally to promote extracellular fibrosis. The main trigger for aldosterone release is angiotensin II, but even though ACE inhibition initially lowers aldosterone levels, they rise again to high levels during chronic ACE inhibition.

MRAs improve survival and reduce rehospitalization by one third for patients with symptomatic chronic heart failure with reduced ejection fraction (NYHA class II–IV) [6, 7]. The administration of MRAs inhibits the detrimental effects of increased levels of aldosterone in heart failure patients. Thus, MRAs cause natriuresis, a decrease in intravascular water volume and decreased blood pressure. In the heart, evidence suggests that MRAs reduce interstitial fibrosis. Furthermore, MRAs reduce the risk of sudden death in heart failure likely by reducing the incidence of ventricular arrhythmias related to hypokalemia owing to the potassium-sparing effect of MRA.

The two currently available MRAs are spironolactone and eplerenone, with no documented differences in clinical effect. However, because eplerenone has much lower affinity for progesterone and androgen receptors, it does not cause gynecomastia and breast tenderness. The main side effect of both MRAs is intrinsic to the blockade of aldosterone in that they cause hyperkalemia. Therefore, MRAs should not be initiated in patients with K⁺ above 5.0 or estimated glomerular filtration rate below 30 ml/min/1.73 m [2], and renal function and potassium levels should be monitored regularly during treatment.

In patients with sinus rhythm, heart rate is determined by the rate of depolarization of the sinus node. A major determinant of the rate of depolarization is the “funny” (I _f) current, which is caused by sodium and potassium ions crossing the so-called f-channels in the sinus node cells. Ivabradine is a pure inhibitor of the funny current and causes a decrease in heart rate without the negative inotropic and blood pressure-lowering effects of beta-blockers. For patients in sinus rhythm who have an elevated resting heart rate (>75 BPM) despite having been titrated to their maximally tolerated beta-blocker dose, ivabradine reduces the risk of being hospitalized for worsening heart failure and the risk of death [8]. The rationale for using ivabradine in heart failure patients is that the lowering of heart rate provides more time for diastole, facilitating better filling of the ventricles and increased coronary perfusion, which occurs during diastole (Chaps.​ 1 and 52). Despite the fact that ivabradine has been tested on top of treatment with beta-blockers, its most common use is in patients who are intolerant of beta-blockers because of their negative inotropic and blood pressure-lowering effect.

Digoxin is a glycoside, which may be used for lowering heart rate in patients who are in atrial fibrillation, where ivabradine does not work. Digoxin slows conduction in the atrioventricular (av) node, by augmenting parasympathetic tone, which leads to a lower heart rate, longer diastole, and hence improved left ventricular filling. In addition, digoxin exerts some positive inotropic effect by inhibiting the Na/K pump, which in turn promotes Na/Ca exchange and causes an increase in intracellular calcium levels that improves contractile force. Digoxin has a narrow therapeutic window; side effects of elevated serum levels of digoxin are gastrointestinal and neurological disturbances, while digoxin intoxication may cause ventricular arrhythmias and death. While digoxin for patients in sinus rhythm has been shown to reduce the risk of hospitalization for worsening heart failure, this was before the introduction of beta-blockade as standard therapy, and digoxin is now rarely used in patients in sinus rhythm [9].

For patients with chronic heart failure, a main cause of symptoms is fluid retention and volume overload. In patients with signs and symptom of fluid retention, diuretic therapy with loop diuretics has a quick and marked effect on symptoms. Hence, diuretic therapy is essential in these patients, and loop diuretics are among the most fundamental drugs for providing symptomatic relief, although they do not affect long-term mortality and morbidity. In particular, loop diuretics are paramount in the symptomatic treatment of patients with acute decompensated heart. In these patients, loop diuretics are often administered intravenously to improve bioavailability (because intestinal absorption of oral agents may be limited by bowel wall edema) and maximize effect. In the acute phase, large doses of loop diuretics may be necessary. Conversely, once an episode of decompensation is well treated, the need for loop diuretics is reduced, and most stable patients require only a small oral dose daily (e.g., furosemide 40–80 mg/day). The diuretic effect of furosemide lasts 6 h, after which the kidneys are highly sodium avid, and diuretic efficacy will be lost if the patient is not maintained on a low-sodium diet as well.