Pharmacotherapy

• In general, pharmacologic therapy in chronic HF is aimed at blocking the neurohormonal pathways that contribute to cardiac remodeling and the progression of HF resulting in reduced symptoms, hospitalizations, and mortality.
• The cornerstone of medical therapy for HF includes β-adrenergic blockade, neprilysin and RAAS inhibition, and diuretic therapy to improve symptoms of volume overload.
• Pharmacotherapy is determined by the presence of a preserved or reduced LVEF. Several pharmacotherapies for HFrEF have been demonstrated to reduce death and hospitalization and improve quality of life in HF. No pharmacotherapy has been unequivocally demonstrated to improve mortality in patients with HFpEF.

Chronic Medical Therapy with Reduced Ejection Fraction (Figure 5-2)

Figure 5-2 Chronic medical therapies for heart failure with reduced ejection fraction (HFrEF).

ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; ARNI, angiotensin receptor–neprilysin inhibitor; bpm, beats per minute; HR, heart rate; LVEF, left ventricular ejection fraction; NSR, normal sinus rhythm; SGLT2i, sodium–glucose cotransporter 2 inhibitor.

• First-line therapies—all patients with HFrEF should be placed on a β-blocker, angiotensin receptor–neprilysin inhibitor (ARNI) (or angiotensin-converting enzyme [ACE] inhibitor or angiotensin II receptor blocker [ARB]), mineralocorticoid receptor antagonist (MRA), and sodium-glucose cotransporter 2 (SGLT2) inhibitor.
• β-Adrenergic receptor antagonists (β-blockers) (Table 5-4). β-Blockers are a critical component of HF therapy and work by blocking the effects of chronic adrenergic stimulation on the heart.
  • Large randomized trials have documented the beneficial effects of β-blockers on functional status, disease progression, and survival in patients with NYHA class II–IV symptoms.¹
  • Typically, 2–3 months of therapy is required to observe significant effects on LV function, but reduction of cardiac arrhythmia and incidence of sudden cardiac death (SCD) may occur much earlier.²
  • β-Blockers should be instituted at a low dose and titrated with careful attention to blood pressure and heart rate. Some patients experience volume retention and worsening HF symptoms that typically respond to transient increases in diuretic therapy.
  • The survival benefit of β-blockers is proportional to the heart rate reduction and dosage achieved.
  • Individual β-blockers have unique properties, and the beneficial effects of β-blockers are not a class effect. Therefore, one of the three β-blockers with proven benefit on mortality in large clinical trials should be used:
    • Carvedilol^3,4
    • Metoprolol succinate⁵
    • Bisoprolol⁶
• Angiotensin receptor–neprilysin inhibitor. Sacubitril/valsartan is a combination of the neprilysin inhibitor (sacubitril) and ARB (valsartan).
  • Neprilysin is a neutral endopeptidase involved in the degradation of vasoactive peptides including the natriuretic peptides, bradykinin, and adrenomedullin. Inhibition of neprilysin increases the availability of these peptides, which exert favorable effects in HF.
  • Sacubitril/valsartan was shown to be superior to enalapril in reducing death and rehospitalization among NYHA class II–IV patients with HFrEF who were stably tolerant of ACE inhibitor or ARB therapy.⁷
  • Sacubitril/valsartan is approved for use in patients with HFrEF and NYHA class II–IV symptoms.
  • Rates of angioedema are increased with sacubitril/valsartan compared with ACE inhibitors (0.5% vs. 0.2%) and require a 36-hour ACE inhibitor washout prior to initiation. Angioedema rates were comparatively higher in African-Americans (2.4% vs. 0.5%).
• ACE inhibitors and ARBs target the compensatory RAAS activation and attenuate vasoconstriction, vital organ hypoperfusion, hyponatremia, hypokalemia, and fluid retention. These medications should be used as second-line therapy if patients cannot tolerate or afford ARNI.
  • ACE inhibitors
    • Multiple large clinical trials have clearly demonstrated that ACE inhibitors improve symptoms and survival in patients with LV systolic dysfunction.⁸
    • ACE inhibitors may also prevent the development of HF in patients with asymptomatic LV dysfunction and in those at high risk of developing structural heart disease or HF symptoms (e.g., patients with CAD, diabetes mellitus, hypertension).
    • No consensus exists on optimal dosing of ACE inhibitors in HF. Higher doses have been shown to reduce morbidity without improving overall survival.⁹
    • Most ACE inhibitors are excreted by the kidneys, necessitating careful dose titration in patients with renal insufficiency. ACE inhibitors should be used cautiously in the presence of renal dysfunction and use should be avoided in patients with bilateral renal artery stenosis. Renal function and potassium levels should be monitored with dose adjustment and periodically with chronic use.
    • A rise in serum creatinine up to 30% above baseline may be seen when initiating an ACE inhibitor and should not result in reflexive discontinuation of therapy.¹⁰
    • Additional adverse effects may include cough, rash, angioedema, dysgeusia, hyperkalemia, and leukopenia.
    • Oral potassium supplements, potassium salt substitutes, and potassium-sparing diuretics should be used with caution during treatment with an ACE inhibitor.
    • ACE inhibitors are contraindicated in pregnancy. Enalapril and captopril may be safely used by breastfeeding mothers.
  • ARBs
    • ARBs reduce morbidity and mortality associated with HF in patients who are not receiving an ACE inhibitor^11,12,13 and therefore should be instituted when ACE inhibitors are not tolerated.
    • In contrast to ACE inhibitors, ARBs do not increase bradykinin levels and therefore are not associated with cough.
    • Renal precautions and monitoring for ARB use are similar to ACE inhibitor use.
    • Use of ARBs is contraindicated in patients taking both ACE inhibitors and aldosterone antagonists due to a high risk for hyperkalemia.
    • ARBs are contraindicated in pregnancy and breastfeeding.
• MRAs attenuate aldosterone-mediated sodium retention, vascular reactivity, oxidant stress, inflammation, and fibrosis.
  • MRAs are recommended for use in patients with NYHA class II–IV HF and acceptable renal function (serum creatinine is <2.5 mg/dL in men or <2.0 mg/dL in women, and potassium is <5.0 mEq/L).
  • Spironolactone is a nonselective aldosterone receptor antagonist that has been shown to improve survival and decrease hospitalizations in NYHA class III–IV patients with low EF.¹⁴
  • Eplerenone is a selective aldosterone receptor antagonist without the estrogenic side effects of spironolactone. It has proven beneficial in patients with HF following MI¹⁵ and in less symptomatic HF patients (NYHA class II) with reduced EF.¹⁶
  • Life-threatening hyperkalemia may occur with the use of these agents. Serum potassium must be monitored closely after initiation; concomitant use of ACE inhibitors and NSAIDs and the presence of renal insufficiency increase the risk of hyperkalemia.
  • Gynecomastia may develop in 10%–20% of men treated with spironolactone; eplerenone should be used in this case.
• SGLT2 inhibitors promote osmotic diuresis and natriuresis and exert beneficial pleiotropic effects on the heart, vasculature, and metabolic profile.
  • Dapagliflozin and empagliflozin have been shown to decrease cardiovascular mortality and HF hospitalizations when added to standard therapy in patients with HFrEF with or without diabetes.^17,18
  • Canagliflozin has been shown to decrease the composite outcome of cardiovascular mortality, nonfatal MI, or nonfatal stroke in patients with type 2 diabetes and elevated cardiovascular risk. Post-hoc analysis showed canagliflozin reduced cardiovascular mortality and HF hospitalizations across a range of subgroups.¹⁹
  • Sotagliflozin is a dual SGLT1 and SGLT2 inhibitor that has been shown to reduce cardiovascular death and HF hospitalizations or urgent visits when initiated shortly before or after inpatient discharge in patients with HF and diabetes irrespective of EF.²⁰
  • Currently, the U.S. Food and Drug Administration (FDA) has approved dapagliflozin and empagliflozin for treatment of HFrEF independent of diabetes.
• Diuretic therapy in conjunction with restriction of dietary sodium and fluids often leads to clinical improvement in patients with symptomatic HF. Frequent assessment of the patient’s weight and careful observation of fluid intake and output are essential during initiation and maintenance of therapy.
  • Complications of therapy include hypokalemia, hyponatremia, hypomagnesemia, volume contraction alkalosis, intravascular volume depletion, and hypotension. Therefore, serum electrolytes, BUN, and creatinine levels should be monitored after institution of diuretic therapy.
  • Hypokalemia may be life threatening in patients who are receiving digoxin or are predisposed to ventricular arrhythmias.
  • Loop diuretics (furosemide, torsemide, bumetanide, ethacrynic acid) should be used in patients who require significant diuresis and in those with markedly decreased renal function.
    • Furosemide reduces preload acutely by causing direct venodilation when administered intravenously, making it useful for managing severe HF or acute pulmonary edema.
    • Use of loop diuretics may be complicated by hyperuricemia, hypocalcemia, ototoxicity, rash, and vasculitis. Furosemide, torsemide, and bumetanide are sulfa derivatives and may rarely cause drug reactions in sulfa-sensitive patients; ethacrynic acid can be used in such patients.
    • Dose equivalence of oral loop diuretics is approximately 50 mg ethacrynic acid = 40 mg furosemide = 20 mg torsemide = 1 mg bumetanide.
    • Torsemide and bumetanide have >80% oral bioavailability as compared to ∼50% bioavailability of furosemide. In patients requiring increased dosage of furosemide, transition to torsemide or bumetanide should be considered.
  • Thiazide diuretics (hydrochlorothiazide, chlorthalidone) can be used as initial agents in patients with normal renal function in whom only a mild diuresis is desired.
    • Metolazone, unlike other oral thiazides, exerts its action at the proximal and distal tubule and may be useful in combination with a loop diuretic in patients with a low glomerular filtration rate.
  • Potassium-sparing diuretics (amiloride, triamterene) do not exert a potent diuretic effect when used alone.
• Second-line therapies—In patients who have ongoing symptoms despite maximization of the four cornerstone medications mentioned above or have intolerance/contraindications preventing use of certain agents, additional therapies may provide benefit.
  • Vasodilator therapy alters preload and afterload to improve cardiac output.
    • Hydralazine acts directly on arterial smooth muscle cells to produce vasodilation and reduce afterload. Reflex tachycardia and increased myocardial oxygen consumption may occur in the setting of hydralazine use, requiring cautious use in patients with ischemic heart disease.
    • Nitrates are predominantly venodilators and help relieve symptoms of congestion. They also reduce myocardial ischemia by decreasing ventricular filling pressures and by directly dilating coronary arteries. Nitrate therapy may precipitate hypotension, especially in patients who have low preload or are taking phosphodiesterase inhibitors.
    • A combination of hydralazine and isosorbide dinitrate (starting dose: 37.5/20 mg three times daily), when added to β-blockers and ACEi/ARB, was shown to reduce mortality in African-American patients.²¹
    • In the absence of ACEi/ARBs, MRAs, and β-blockers, the combination of nitrates and hydralazine improves survival in patients with HFrEF²² and should therefore be considered for use in HFrEF patients unable to tolerate RAAS blockade.
  • Vericiguat is a soluble guanylate cyclase stimulator that increases cyclic guanosine monophosphate, leading to vasodilation and improved endothelial function.
    • Vericiguat was shown to reduce cardiovascular death and HF hospitalization in patients with HFrEF and worsening symptoms or recent decompensation.²³ It is indicated for use in this population as an addition to background therapy with ACE/ARB/ARNI, MRAs, and β-blockers.
  • Ivabradine is an inhibitor of the IKf channel involved in generating “pacemaker” currents in cardiac tissue.
    • Ivabradine was shown to reduce HF hospitalization and HF death in outpatients with HFrEF and is indicated for the reduction of HF hospitalization in patients with EF <35%, stable HF symptoms, and sinus rhythm with a resting heart rate ≥70 bpm who are already taking β-blockers at the highest tolerated dose.²⁴
  • Digitalis glycosides (digoxin) increase myocardial contractility and may attenuate the neurohormonal activation associated with HF.
    • Digoxin has been shown to decrease rates of HF hospitalizations without improving overall mortality.²⁵
    • Digoxin has a narrow therapeutic index, and serum levels should be followed closely, particularly in patients with unstable renal function.
    • The usual daily dose is 0.125–0.25 mg and should be decreased in patients with renal insufficiency.
    • Women and patients with higher serum digoxin levels (1.2–2.0 ng/mL) have an increased mortality risk.^26,27
    • Discontinuation of digoxin in patients who are stable on a regimen of digoxin, diuretics, and an ACE inhibitor may result in clinical deterioration.²⁸
    • Drug interactions with digoxin are common and may lead to toxicity. Agents that may increase levels include erythromycin, tetracycline, quinidine, verapamil, flecainide, and amiodarone. Electrolyte abnormalities (particularly hypokalemia), hypoxemia, hypothyroidism, renal insufficiency, and volume depletion may also exacerbate toxicity.
    • Digoxin is not dialyzable, and toxicity is only treatable by the administration of digoxin immune Fab.
• Therapies with unproven benefit
  • α-Adrenergic receptor antagonists have not been shown to improve survival in HF, and hypertensive patients treated with doxazosin as first-line therapy are at increased risk of developing HF.
  • Calcium channel blockers have no favorable effects on mortality in HFrEF.
    • Dihydropyridine calcium channel blockers such as amlodipine may be used in hypertensive HF patients already on maximal guideline-directed medical therapy (GDMT); however, these agents do not improve mortality.^29,30
    • Nondihydropyridine calcium channel blockers should be avoided in HFrEF because their negative inotropic effects may potentiate worsening HF.
• Sympathomimetic agents are reserved for the treatment of severe HF. Beneficial and adverse effects are mediated by stimulation of myocardial β-adrenergic receptors. The most important adverse effects are related to arrhythmias and exacerbation of myocardial ischemia. Patients with refractory chronic HF may benefit symptomatically from continuous ambulatory administration of parenteral inotropes as palliative therapy or as a bridge to mechanical ventricular support or cardiac transplantation. Risks include life-threatening arrhythmias or catheter-related infections.
  • Dobutamine (see Table 5-5) is a synthetic analog of dopamine with predominantly β₁-adrenoreceptor activity. It increases cardiac output, lowers cardiac filling pressures, and generally has a neutral effect on systemic blood pressure. Dobutamine tolerance has been described, and several studies have demonstrated increased mortality in patients treated with continuous dobutamine. Dobutamine has no significant role in the treatment of HF resulting from diastolic dysfunction or a high-output state.
  • Phosphodiesterase inhibitors increase myocardial contractility and produce vasodilation by increasing intracellular cyclic adenosine monophosphate. Milrinone is indicated for treatment of refractory HF. Hypotension may develop in patients who receive vasodilator therapy or have intravascular volume contraction, or both. Milrinone may improve hemodynamics in patients who are treated concurrently with dobutamine or dopamine. Data suggest that in-hospital short-term milrinone administration in addition to standard medical therapy does not reduce the length of hospitalization or the 60-day mortality or rehospitalization rate when compared with placebo.³¹
• Oral inotropes
  • Omecamtiv mecarbil binds cardiac myosin and directly augments cardiac sarcomere function. Use of omecamtiv mecarbil in addition to guideline medical therapy in patients with NYHA II-IV HF resulted in lower rates of the composite outcome of HF events or cardiovascular death.³² This agent is not yet FDA approved.

Table 5-4: Drugs Commonly Used for Treatment of Heart Failure

Drug	Initial Dose	Target
Angiotensin-Converting Enzyme Inhibitors
Captopril	6.25–12.5 mg tid	50 mg tid
Enalapril	2.5 mg bid	10 mg bid
Lisinopril	2.5–5.0 mg daily; can use bid	10–20 mg bid
Ramipril	1.25–2.5 mg bid	5 mg bid
Angiotensin Receptor Blockers
Valsartana	40 mg bid	160 mg bid
Losartan	25 mg daily; can use bid	25–100 mg daily
Candesartana	2–16 mg daily	2–32 mg daily
Angiotensin Receptor–Neprilysin Inhibitor
Entresto (sacubitril/valsartan)	24/26 mg bid	97/103 mg bid
IKf Channel Inhibitor
Ivabradine	5 mg bid	7.5 mg bid
Thiazide Diuretics
Hydrochlorothiazide	25–50 mg daily	25–50 mg daily
Metolazone	2.5–5.0 mg daily or bid	10–20 mg total daily
Loop Diuretics
Bumetanide	0.5–1.0 mg daily or bid	10 mg total daily (maximum)
Furosemide	20–40 mg daily or bid	400 mg total daily (maximum)
Torsemide	10–20 mg daily or bid	200 mg total daily (maximum)
Aldosterone Antagonists
Eplerenone	25 mg daily	50 mg daily
Spironolactone	12.5–25.0 mg daily	25 mg daily
β-Blockers
Bisoprolol	1.25 mg daily	10 mg daily
Carvedilol	3.125 mg bid	25–50 mg bid
Metoprolol succinate	12.5–25.0 mg daily	200 mg daily
Digoxin	0.125–0.25 mg daily	0.125–0.25 mg daily
Hydralazine/Isosorbide Dinitrate	37.5 mg/20 mg tid	75 mg/40 mg TID

^aValsartan and candesartan are the only U.S. Food and Drug Administration–approved angiotensin II receptor blockers in the treatment of heart failure.

Table 5-5: Inotropic/Sympathomimetic Agents^a

Drug	Dose	Mechanism	Effects/Side Effects
Dopamine	1–3 μg/kg/min	Dopaminergic receptors	Splanchnic vasodilation
	2–8 μg/kg/min	β1-Receptor agonist	+Inotropic
	7–10 μg/kg/min	α-Receptor agonist	↑ SVR
Dobutamine	2.5–15.0 μg/kg/min	β1- > β2- > α-receptor agonist	+Inotropic, ↓ SVR, tachycardia
Epinephrine	0.05–1 μg/kg/min; titrate to desired mean arterial pressure. May adjust dose every 10–15 min by 0.05–0.2 μg/kg/min to achieve desired blood pressure goal	β1 > α1 Low doses = β High doses = α	+Inotropic, ↑ SVR
Milrinoneb	50-μg/kg bolus IV over 10 min, 0.375–0.75 μg/ kg/min	↑ cAMP	+Inotropic, ↓ SVR

cAMP, cyclic adenosine monophosphate; SVR, systemic vascular resistance; ↑, increased; ↓, decreased.

^aIncreased risk of atrial and ventricular tachyarrhythmias.

^bNeeds dose adjustment for creatinine clearance.

Chronic Medical Therapy With Preserved Ejection Fraction (Figure 5-3)

Figure 5-3 Chronic medical therapies for heart failure with preserved ejection fraction (HFpEF).

ACEi, angiotensin-converting enzyme inhibitor; Afib, atrial fibrillation; ARB, angiotensin II receptor blocker; ARNI, angiotensin receptor–neprilysin inhibitor; CAD, coronary artery disease; LVEF, left ventricular ejection fraction; OSA, obstructive sleep apnea; SGLT2i, sodium–glucose cotransporter 2 inhibitor.

• No pharmacotherapy has been definitively shown to improve mortality in HFpEF.
  • The use of ACE inhibitors, ARBs, spironolactone, and β-blockers is reasonable and may be associated with a small reduction in HF hospitalization rates.
  • Sacubitril/valsartan did not reduce cardiovascular mortality or HF hospitalizations compared to valsartan in patients with HFpEF and EF >45%. However, sacubitril/valsartan did have a beneficial effect in patients who had less than normal LVEF. Therefore, FDA has approved sacubitril/valsartan for use in all patients with HFpEF, with benefit most likely in patients with less than normal LV systolic function.^33,34
  • Spironolactone reduced HF hospitalization in patients with HFpEF in a large randomized trial, but mortality was not reduced.³⁵
  • SGLT2 inhibitors have the most extensive data for improved outcomes in HFpEF. Empagliflozin reduced the composite outcome of HF hospitalizations and cardiac death in patients with HFpEF, independent of diabetes, driven by decrease in HF hospitalizations.³⁶ In a prespecified, pooled analysis from two placebo-controlled trials of type 2 diabetics with HF, sotagliflozin reduced cardiovascular death and HF hospitalizations or urgent visits, irrespective of EF.^20,37 SGLT2 inhibitors should be considered in all patients with HFpEF.
• Control of blood pressure, treatment of atrial fibrillation (AF), and treatment of coronary disease through pharmacotherapy and/or revascularization in accordance with practice guidelines is recommended.