Clinical manifestations of heart failure may result from inappropriate intravascular and extravascular volume expansion caused by excessive sodium and fluid retention. As such, diuretics are fundamental in achieving and maintaining proper fluid balance to alleviate symptoms of heart failure. They are used both acutely and chronically to manage volume status. Although anecdotal studies have shown that diuretics can improve cardiac function, symptoms, and exercise tolerance,⁵ diuretics activate the sympathetic system and over time are thought to be detrimental in heart failure. Therefore, the use of diuretics alone, without neurohormonal blockade, is not recommended, as adrenergic activation has been associated with worse outcomes in heart failure.

Loop diuretics such as furosemide, bumetanide, and torsemide are the most commonly prescribed diuretics for heart failure. These compounds act to reversibly inhibit the Na⁺-K⁺-2Cl symporter in the ascending loop of Henle to enhance urinary sodium and water excretion. Loop diuretics also have venodilatory effects and have been shown to decrease right atrial and pulmonary venous wedge pressure within minutes of intravenous (IV) infusion.⁶ Oral bioavailability varies significantly and can be as low as 40% for furosemide and greater than 80% for bumetanide and torsemide. Thus, bumetanide and torsemide may be more effective in patients with significant volume overload or right-sided heart failure and subsequent intestinal edema.

Observational studies have suggested an association between higher dose diuretics and worse clinical outcomes,⁷ which may be mediated through increased renal injury, electrolyte abnormalities, and neurohormonal activation.⁸ The Diuretic Optimization Strategies Evaluation (DOSE) study, a randomized double-blind study, compared diuretic strategies in acute heart failure with IV furosemide using either twice daily bolus dosing or a continuous infusion at two doses (equivalent to outpatient dose vs. 2.5 times the outpatient dose). There was no difference in the co-primary endpoints of global assessment of symptoms or a change in creatinine at 72 hours in either the low- versus high-dose groups or the bolus versus continuous infusion groups.⁹ Of note, there was a trend toward greater relief of dyspnea and net fluid loss at 72 hours in the high-dose group.

Of note, loop diuretics initiate a renal homeostatic mechanism that increases distal solute and water resorption and in turn decreases diuretic effectiveness. This phenomenon can be overcome with a coadministration of a thiazide-like diuretic (eg, metolazone or chlorothiazide) that acts on the distal tubule
to block sodium reabsorption. Adding a thiazide-like diuretic can often precipitate a brisk diuresis and close monitoring is required to prevent excessive fluid and electrolyte loss (particularly hypokalemia and hyponatremia).

There is tremendous evidence supporting the use of angiotensin converting enzyme (ACE) inhibitors in patients with reduced (<40%) left ventricular ejection fraction (LVEF), and the use of these agents is indicated in all patients with LV systolic dysfunction. ACE inhibitors block ACE that is responsible for the conversion of angiotensin I to angiotensin II. In addition, they enhance kinin activity through the inhibition of kininase II. ACE inhibitors have been shown in several clinical trials to stabilize LV remodeling, improve symptoms, prevent hospitalizations, and prolong life in patients with reduced LVEF.¹⁰,¹¹,¹²,¹³ These large, randomized trials included varied patients, such as asymptomatic and symptomatic patients, elderly patients, women, and a wide range of etiologies of LV systolic dysfunction. The Studies on Left Ventricular Dysfunction (SOLVD) Prevention Study¹¹ and the Survival and Ventricular Enlargement (SAVE) Study¹³ have shown that enalapril and captopril, respectively, can reduce the development of symptoms, decrease hospitalizations, and prolong life, in asymptomatic patients with LV dysfunction. Furthermore, the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS I)¹⁰ demonstrated that the absolute benefit is greatest in patients with more severe disease (New York Heart Association [NYHA] Class IV heart failure), as the study showed a much larger effect size of enalapril than the SOLVD treatment and prevention trials. The impact of ACE inhibitors on heart failure outcomes appears to be a class effect. The beneficial effects of ACE inhibitors are dose dependent,¹⁴ and thus doses should be titrated as tolerated until they reach those used in clinical trials (Table 76.1).

Side effects of ACE inhibitors, such as azotemia and hypotension, are related to the suppression of renin-angiotensin system activity. These effects are generally well tolerated and do not require dose adjustment unless the patient is symptomatic, or the magnitude of hypotension or azotemia is significant. Hyperkalemia may also occur, especially with potassium supplementation or treatment with potassium-sparing diuretics such as spironolactone. The kinin effects of ACE inhibitors can lead to side effects including dry cough (up to 10% of patients) and angioedema. Replacement of the ACE inhibitor with an angiotensin receptor antagonist may alleviate the kinin-mediated side effects but not hyperkalemia or renal insufficiency. Patients with bilateral renal artery stenosis may experience acute renal failure upon the initiation of ACE inhibitors. In all patients, laboratories including electrolytes and renal function should be monitored on initiation and titration of ACE inhibitors.

Angiotensin receptor blockers (ARBs) antagonize the angiotensin type 1 receptor to inhibit the adverse biologic effects of angiotensin II on cardiac remodeling. This mechanism has no effect on bradykinin activity and thus avoids some of the adverse effects of ACE inhibitors. In systolic heart failure patients intolerant of ACE inhibitors, aggregate data suggest that ARBs are as effective as ACE inhibitors in reducing symptoms, hospitalizations, and mortality. In the Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM-Alternative)¹⁵ trial, candesartan reduced mortality and hospital admissions irrespective of background β-blocker therapy. Similar findings were seen in a study on valsartan (Valsartan Heart Failure Trial).¹⁶ There is also evidence to suggest that ARBs may be beneficial when added to ACE inhibitors. In the CHARM-Added trial, the addition of candesartan resulted in a 4% to 5% reduction in cardiovascular death and hospitalizations in patients taking a β-blocker and ACE inhibitor.¹² Of note, significantly higher rates of renal injury and hyperkalemia occurred in the candesartan group, and there was overall a low usage of spironolactone. As such, the general consensus has been that ACE inhibitors are first-line agents for reninangiotensin-aldosterone system (RAAS) blockade, and ARBs should be used in patients intolerant to ACE inhibitors, though this may be shifting with the advent of angiotensin receptor neprilysin inhibitor (ARNI) therapy. Per current practice guidelines, there is a Class IIb recommendation⁴ for combination therapy with ACE inhibitors and ARBs in patients intolerant to spironolactone, though the utility of this strategy in the context of modern therapies is uncertain.

The side effects of ARBs are similar to the non-kinin-mediated effects of ACE and include hypotension, azotemia, and hyperkalemia. An ARB can be used for patients who have an ACE cough and patients who have experienced angioedema with an ACE inhibitor can receive an ARB with enhanced monitoring. Initial and target doses of ARBs are listed in Table 76.2.

ARNIs are a newer class of RAAS antagonists for the treatment of heart failure, which combines an ARB and a neprilysin inhibitor. The first and currently only approved agent combines sacubitril with valsartan. Neprilysin is a zinc-dependent membrane endopeptidase and cleaves a variety of peptides including natriuretic peptides, bradykinin, and adrenomedullin. Inhibition of neprilysin increases levels of atrial natriuretic peptide, B-type natriuretic peptide, C-type natriuretic peptide and adrenomedullin which results in increased vasodilatation, natriuresis, and decreased left ventricular fibrosis and hypertrophy.¹⁷ Of note, neprilysin also breaks down angiotensin II, and its inhibition can lead to vasoconstriction and increased afterload. Thus, neprilysin inhibitors are combined with RAAS inhibitors to prevent deleterious potentiation of angiotensin II.

In the PARADIGM-HF (Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial, the use of sacubitril/valsartan resulted in a 20% relative risk reduction as compared to enalapril in the combined endpoint of cardiovascular mortality and heart failure hospitalizations¹⁸ in stable NYHA Class II to IV patients with LVEF less than 35%. A significant decrease in all-cause mortality was also noted. It is important to note
that there was no placebo arm in the PARADIGM-HF trial, and sacubitril/valsartan was being compared to the standard of care enalapril revealing an incremental benefit. PIONEER-HF (Comparison of Sacubitril-Valsartan versus Enalapril on Effect on NT-proBNP in Patients Stabilized from an Acute Heart Failure Episode), a study on in-hospital initiation of sacubitril/valsartan in acute heart failure patients, showed no difference in adverse events when compared to enalapril.¹⁹ Current guidelines recommend replacement with ARNI in Class II to III patients tolerating ACE inhibitor or ARB therapy.²⁰ The starting dose of sacubitril/valsartan is dependent on the dose of ACE inhibitor or ARB that the patient tolerates with a target dose of sacubitril/valsartan being 93 mg/107 mg. Recent guidelines suggest that ARNI can be initial therapy for systolic heart failure avoiding the need to transition from an ACE or ARB.

The most common side effect of ARNI is hypotension which can occur in up to 18% of patients. Hyperkalemia is also common; cough and angioedema are rarely observed. The combination of an ACE inhibitor and neprilysin inhibitor significantly increases the risk of angioedema thought to be secondary to high levels of bradykinin. Therefore, administration of an ARNI with an ACE inhibitor is contraindicated. When transitioning from an ACE inhibitor to ARNI, a 36-hour washout period following discontinuation of the ACE inhibitor is required prior to the first dose of ARNI.

β-Blockers alleviate the harmful effects of sustained cardiac adrenergic stimulation by blocking one or more α- and β-adrenergic receptors. Most of the harmful effects of β-adrenergic stimulation in the heart are thought to be mediated through the β1 receptor. Three β-blockers have been shown to improve outcomes in patients with heart failure: carvedilol (The Carvedilol Prospective Randomized Cumulative Survival [COPERNICUS] trial²¹), bisoprolol (Cardiac Insufficiency Bisoprolol Study II [CIBIS-II] trial²²), and sustained-release metoprolol succinate (Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure [MERIT-HF] trial²³). Carvedilol blocks α1, β1, and β2 receptors whereas bisoprolol and metoprolol are β1 selective. When given in combination with a RAAS blocker (ACE inhibitor or ARB) to patients with an LVEF less than 40%, these β-blockers decrease symptoms and hospitalizations, prolong survival, and promote reverse LV remodeling. Not all β-blockers improve clinical outcomes in heart failure²⁴,²⁵,²⁶; unlike with ACE inhibitors and ARBs, the benefits of β-blockers in heart failure do not represent a class effect.