Treatment of Heart Failure

Treatment of Heart Failure is a topic covered in the Washington Manual of Medical Therapeutics.

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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, while reducing symptoms, hospitalizations, and mortality.
  • The cornerstone of medical therapy for HF includes RAAS blockade, β-adrenergic blockade, vasodilators, and diuretic therapy for 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 (HFrEF)

  • β-Adrenergic receptor antagonists (β-blockers) (Table 5-3). β-Blockers are a critical component of HF therapy and work by blocking the toxic 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.
      Table 5-3: Drugs Commonly Used for Treatment of Heart Failure
      DrugInitial DoseTarget
      Angiotensin-Converting Enzyme Inhibitors
      Captopril6.25–12.5 mg tid50 mg tid
      Enalapril2.5 mg bid10 mg bid
      Fosinopril5–10 mg daily; can use bid20 mg daily
      Lisinopril2.5–5.0 mg daily; can use bid10–20 mg bid
      Quinapril2.5–5.0 mg bid10 mg bid
      Ramipril1.25–2.5 mg bid5 mg bid
      Trandolapril0.5–1.0 mg daily4 mg daily
      Angiotensin Receptor Blockers
      Valsartana40 mg bid160 mg bid
      Losartan25 mg daily; can use bid25–100 mg daily
      Irbesartan75–150 mg daily75–300 mg daily
      Candesartan a2–16 mg daily2–32 mg daily
      Olmesartan20 mg daily20–40 mg daily
      Angiotensin Receptor-Neprilysin Inhibitor
      Entresto (Sacubitril/Valsartan)24/26 mg bid97/103 mg bid
      IKf Channel Inhibitor
      Ivabradine5 mg bid7.5 mg bid
      Thiazide Diuretics
      HCTZ25–50 mg daily25–50 mg daily
      Metolazone2.5–5.0 mg daily or bid10–20 mg total daily
      Loop Diuretics
      Bumetanide0.5–1.0 mg daily or bid10 mg total daily (maximum)
      Furosemide20–40 mg daily or bid400 mg total daily (maximum)
      Torsemide10–20 mg daily or bid200 mg total daily (maximum)
      Aldosterone Antagonists
      Eplerenone25 mg daily50 mg daily
      Spironolactone12.5–25.0 mg daily25 mg daily
      β-Blockers
      Bisoprolol1.25 mg daily10 mg daily
      Carvedilol3.125 mg bid25–50 mg bid
      Metoprolol succinate12.5–25.0 mg daily200 mg daily
      Digoxin0.125–0.25 mg daily0.125–0.25 mg daily

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

      HCTZ, hydrochlorothiazide.

    • Improvement in LVEF, exercise tolerance, and functional class are common after the institution of a β-blocker.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 achieved.3
    • Individual β-blockers have unique properties, and the beneficial effect of β-blockers may not be a class effect. Therefore, one of the three β-blockers with proven benefit on mortality in large clinical trials should be used4:
      • Carvedilol5,6
      • Metoprolol succinate7
      • Bisoprolol8
  • Angiotensin-converting enzyme (ACE) inhibitors (see Table 5-3) attenuate vasoconstriction, vital organ hypoperfusion, hyponatremia, hypokalemia, and fluid retention attributable to compensatory activation of the renin–angiotensin system. They are the first choice for antagonism of the RAAS.
    • Multiple large clinical trials have clearly demonstrated that ACE inhibitors improve symptoms and survival in patients with LV systolic dysfunction.4
    • 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).
    • Currently, no consensus has been reached regarding the optimal dosing of ACE inhibitors in HF, although higher doses have been shown to reduce morbidity without improving overall survival.9
    • Absence of an initial beneficial response to treatment with an ACE inhibitor does not preclude long-term benefit.
    • 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, increase in serum creatinine, proteinuria, hyperkalemia, and leukopenia.
    • Oral potassium supplements, potassium salt substitutes, and potassium-sparing diuretics should be used with caution during treatment with an ACE inhibitor.
    • Agranulocytosis and angioedema are more common with captopril than with other ACE inhibitors, particularly in patients with associated collagen vascular disease or serum creatinine >1.5 mg/dL.
    • ACE inhibitors are contraindicated in pregnancy. Enalapril and captopril may be safely used by breastfeeding mothers.
  • Angiotensin II receptor blockers (ARBs) (see Table 5-3) inhibit the renin–angiotensin system via specific blockade of the angiotensin II receptor.
    • ARBs reduce morbidity and mortality associated with HF in patients who are not receiving an ACE inhibitor11,12,13 and therefore should be instituted when ACE inhibitors are not tolerated.4
    • 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 ACE inhibitors and aldosterone antagonists due to a high risk for hyperkalemia.
    • ARBs are contraindicated in pregnancy and breastfeeding.
  • Sacubitril/valsartan (Entresto™) is a combination of the ARB valsartan and the neprilysin inhibitor sacubitril.
    • 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.14,15
    • Sacubitril/valsartan is approved for use in patients with HFrEF and NYHA class II–IV symptoms who are already tolerant to ACE inhibitors or ARBs.
    • Forthcoming clinical trials will determine its role as initial therapy for HFrEF and in treatment of NYHA class IV HF.
    • Rates of angioedema are increased with sacubitril/valsartan compared with ACE inhibitors.
  • Mineralocorticoid receptor antagonists (MRAs) attenuate aldosterone-mediated sodium retention, vascular reactivity, oxidant stress, inflammation, and fibrosis.
    • 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.16
    • Eplerenone is a selective aldosterone receptor antagonist without the estrogenic 
side effects of spironolactone. It has proven beneficial in patients with HF 
following MI17 and in less symptomatic HF patients (NYHA class II) with 
reduced EF.18
    • 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) (see Table 5-3).
    • 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.
  • Vasodilator therapy alters preload and afterload conditions to improve cardiac output.
    • Hydralazine acts directly on arterial smooth muscle to produce vasodilation and to reduce afterload.
    • Nitrates are predominantly venodilators and help relieve symptoms of venous and pulmonary congestion. They also reduce myocardial ischemia by decreasing ventricular filling pressures and by directly dilating coronary arteries.
    • A combination of hydralazine and isosorbide dinitrate (starting dose: 37.5/20 mg three times daily), when added to standard therapy with β-blockers and ACE inhibitors, has been shown to reduce mortality in African American patients.19
    • In the absence of ACE inhibitors, ARBs, aldosterone receptor antagonists, and β-blockers, the combination of nitrates and hydralazine improves survival in patients with HFrEF20 and should therefore be considered for use in all HFrEF patients unable to tolerate RAAS blockade.
    • Reflex tachycardia and increased myocardial oxygen consumption may occur in the setting of hydralazine use, requiring cautious use in patients with ischemic heart disease.
    • Nitrate therapy may precipitate hypotension in patients with reduced preload.
  • Ivabradine is an inhibitor of the IKf channel involved in generating “pacemaker” currents in cardiac tissue.
    • Use of ivabradine in outpatients with HFrEF was shown to reduce HF hospitalization and HF death,21 and it 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.15
  • Digitalis glycosides increase myocardial contractility and may attenuate the neurohormonal activation associated with HF.
    • Digoxin has been show to decrease rates of HF hospitalizations without improving overall mortality.22
    • 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.
    • Clinical benefits may not be related to serum levels. Although serum digoxin levels of 0.8–2.0 ng/mL are considered therapeutic, toxicity can occur in this range.
    • Women and patients with higher serum digoxin levels (1.2–2.0 ng/mL) have an increased mortality risk.23,24
    • Discontinuation of digoxin in patients who are stable on a regimen of digoxin, diuretics, and an ACE inhibitor may result in clinical deterioration.25
    • 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.
  • 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.26
  • 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; however, these agents do not improve mortality.27,28
    • Nondihydropyridine calcium channel blockers should be avoided in HFrEF because their negative inotropic effects may potentiate worsening HF.
  • Diuretic therapy (see Table 5-3), 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. Frequent complications of therapy include hypokalemia, hyponatremia, hypomagnesemia, volume contraction alkalosis, intravascular volume depletion, and hypotension. Serum electrolytes, BUN, and creatinine levels should be followed after institution of diuretic therapy. Hypokalemia may be life threatening in patients who are 
receiving digoxin or in those who have severe LV dysfunction that predisposes them to ventricular arrhythmias. Potassium supplementation or a potassium-sparing diuretic should be considered in addition to careful monitoring of serum potassium levels.
    • Potassium-sparing diuretics (amiloride) do not exert a potent diuretic effect when used alone.
    • 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.
    • 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.29
      • 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.

Chronic Medical Therapy With Preserved Ejection Fraction (HFpEF)

  • No pharmacotherapy has been definitively shown to improve mortality in HFpEF.
  • Control of blood pressure is recommended.
    • The use of ACE inhibitors, ARBs, spironolactone, and β-blockers is reasonable. Use of these particular agents may be associated with a small reduction in HF hospitalization rates.13
    • Spironolactone reduced HF hospitalization in patients with HFpEF in a large randomized trial, but mortality was not reduced.30
  • Treatment of atrial fibrillation through rate or rhythm control in accordance with practice guidelines is recommended.
  • Treatment of coronary disease and angina through pharmacotherapy and/or revascularization in accordance with practice guidelines is recommended.

Parenteral Agents

  • Parenteral vasodilators should be reserved for patients with severe HF not responding to oral medications. Intravenous (IV) vasodilator therapy may be guided by central hemodynamic monitoring (pulmonary artery catheterization) to assess efficacy and avoid hemodynamic instability. Parenteral agents should be started at low doses, titrated to the desired hemodynamic effect, and discontinued slowly to avoid rebound vasoconstriction.
  • Nitroglycerin is a potent vasodilator with effects on venous and, to a lesser extent, arterial vascular beds. It relieves pulmonary and systemic venous congestion and is an effective coronary vasodilator. Nitroglycerin is the preferred vasodilator for treatment of HF in the setting of acute MI or unstable angina.
  • Sodium nitroprusside is a direct arterial vasodilator with less potent venodilatory properties. Its predominant effect is to reduce afterload, and it is particularly effective in patients with HF who are hypertensive or who have severe aortic or mitral valvular regurgitation. Nitroprusside should be used cautiously in patients with myocardial ischemia because of a potential reduction in regional myocardial blood flow (coronary steal).
    • The initial dose of 0.25 μg/kg/min can be titrated (maximum dose of 10 μg/kg/min) to the desired hemodynamic effect or until hypotension develops.
    • The half-life of nitroprusside is 1–3 minutes, and its metabolism results in the release of cyanide, which is metabolized by the liver to thiocyanate and is then excreted via the kidney.
    • Toxic levels of thiocyanate (>10 mg/dL) may develop in patients with renal insufficiency. Thiocyanate toxicity may manifest as nausea, paresthesias, mental status changes, abdominal pain, and seizures.
    • Methemoglobinemia is a rare complication of treatment with nitroprusside.
  • Recombinant BNP (nesiritide) is an arterial and venous vasodilator.
    • IV infusion of nesiritide reduces right atrial and LV end-diastolic pressures and systemic vascular resistance and results in an increase in cardiac output.
    • It is administered as a 2-μg/kg IV bolus, followed by a continuous IV infusion starting at 0.01 μg/kg/min.
    • Nesiritide is approved for use in acute HF exacerbations and relieves HF symptoms early after its administration.31 It does not have an effect on survival or rehospitalization in patients with HF.32
    • Hypotension is the most common side effect of nesiritide, and its use should be avoided in patients with systemic hypotension (systolic blood pressure <90 mm Hg) or evidence of cardiogenic shock. Episodes of hypotension should be managed with discontinuation of nesiritide and cautious volume expansion or vasopressor support if necessary.
  • Inotropic agents
    • Sympathomimetic agents are potent drugs 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 the arrhythmogenic nature of these agents and the potential for exacerbation of myocardial ischemia. Treatment should be guided by careful hemodynamic and ECG monitoring. Patients with refractory chronic HF may benefit symptomatically from continuous ambulatory administration of IV inotropes as palliative therapy or as a bridge to mechanical ventricular support or cardiac transplantation. However, this strategy may increase the risk of life-threatening arrhythmias or indwelling catheter–related infections.4
    • Norepinephrine, rather than dopamine (Table 5-4), should be used for stabilization of the hypotensive HF patient. Although a large randomized trial found no mortality difference between dopamine and norepinephrine in a cohort of undifferentiated shock patients, there were more adverse events (primarily arrhythmic) in the dopamine group, and subgroup analysis of those with cardiogenic shock (n = 280) showed an increased rate of death at 28 days in the dopamine group.33
      Table 5-4: Inotropic Agents
      DrugDoseMechanismEffects/Side Effects
      Dopamine1–3 μg/kg/minDopaminergic receptorsSplanchnic vasodilation

      2–8 μg/kg/minβ1-Receptor agonist+Inotropic

      7–10 μg/kg/minα-Receptor agonist↑ SVR
      Dobutamine2.5–15.0 μg/kg/minβ1- > β2- > α-Receptor agonist+Inotropic, ↓ SVR, tachycardia
      Epinephrine0.05–1 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 goalβ1 > α1Low doses = β
      High doses = α
      +Inotropic, ↑ SVR
      Milrinoneb50-μg/kg bolus IV over 10 min, 0.375–0.75 μg/
kg/min↑ cAMP+Inotropic, ↓ SVR

      aIncreased risk of atrial and ventricular tachyarrhythmias.

      bNeeds dose adjustment for creatinine clearance.

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

    • Dobutamine (see Table 5-4) 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.
    • Epinephrine (see Table 5-4) may be considered in patients with refractory cardiogenic shock; however, its use has been associated with increased mortality. Escalation of therapy to include epinephrine should prompt consideration of mechanical circulatory support.
    • Phosphodiesterase inhibitors increase myocardial contractility and produce vasodilation by increasing intracellular cyclic adenosine monophosphate (cAMP). 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.34

Antiarrhythmic Therapy

  • Suppression of asymptomatic ventricular premature beats or nonsustained ventricular tachycardia (NSVT) using antiarrhythmic drugs in patients with HF does not improve survival and may increase mortality as a result of the proarrhythmic effects of the drugs.35,36,37
  • For patients with atrial fibrillation (AF) as a suspected cause of new-onset HF, a rhythm control strategy should be pursued. For patients with preexisting HF who develop AF, despite evidence suggesting improved symptom status in patients treated with rhythm control, the use of antiarrhythmic drug therapy for the maintenance of sinus rhythm has not been shown to improve mortality.38
  • Agents recommended for the maintenance of sinus rhythm in HF with reduced LVEF include dofetilide and amiodarone. Sotalol may also be considered in patients with mildly depressed LVEF. These agents require close monitoring of the QT interval.
  • In patients with severe LV systolic dysfunction and HF, dronedarone should not be used.39
  • Catheter ablation for atrial fibrillation in patients with HF as compared with medical therapy was associated with a lower rate of mortality in one randomized trial, but guideline consensus for use has not been formalized.40

Anticoagulant and Antiplatelet Therapy

  • Although patients with HF are at relatively greater risk for thromboembolic events, the absolute risk is modest, and routine anticoagulation is not recommended in HF patients in the absence of AF, prior thromboembolism, or a prior cardioembolic source.
  • In patients with AF, use of the CHADS2 or CHADS2-VASc risk score is recommended for determining when to use anticoagulant therapies.
  • The novel anticoagulants dabigatran, rivaroxaban, and apixaban have been shown to be effective in HF patients with nonvalvular AF.
  • There are insufficient data to support the routine use of aspirin in patients with HF who do not have coronary disease or atherosclerosis. Furthermore, certain data suggest that aspirin use may reduce the beneficial effects of ACE inhibitors.41

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