Congestive heart failure Pharmacological treatments for patients with heart failure with reduced ejection fraction

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Acute Pharmacotherapy
Chronic Pharmacotherapy in HFpEF
Chronic Pharmacotherapy in HFrEF Diuretics ACE Inhibitors Angiotensin receptor blockers Aldosterone Antagonists Beta Blockers Ca Channel Blockers Nitrates Hydralazine Positive Inotropics Anticoagulants Angiotensin Receptor-Neprilysin Inhibitor Antiarrhythmic Drugs Nutritional Supplements Hormonal Therapies Drugs to Avoid Drug Interactions Treatment of underlying causes Associated conditions
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ACC/AHA Guideline Recommendations Initial and Serial Evaluation of the HF Patient Hospitalized Patient Patients With a Prior MI Sudden Cardiac Death Prevention Surgical/Percutaneous/Transcather Interventional Treatments of HF Patients at high risk for developing heart failure (Stage A) Patients with cardiac structural abnormalities or remodeling who have not developed heart failure symptoms (Stage B) Patients with current or prior symptoms of heart failure (Stage C) Patients with refractory end-stage heart failure (Stage D) Coordinating Care for Patients With Chronic HF Quality Metrics/Performance Measures
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Congestive heart failure end-of-life considerations
Specific Groups: Special Populations Patients who have concomitant disorders Obstructive Sleep Apnea in the Patient with CHF NSTEMI with Heart Failure and Cardiogenic Shock
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mitra Chitsazan, M.D.[2]

Overview

The major goals of pharmacologic treatment for patients with HFrEF are reducing mortality, reducing the risk of repeated hospitalizations due to worsening HF, and improving clinical status, functional capacity, and quality of life. The mainstay of treatment for HFrEF is the modulation of the [[renin-angiotensin-aldosterone] system] (RAAS) and sympathetic nervous system.

Therapuetic approach

• The major goals of pharmacologic treatment for patients with HFrEF are:
  • 1) Reducing mortality (either all-cause or cardiovascular)
  • 2) Reducing the risk of repeated hospitalizations due to worsening HF
  • 3) Improving clinical status, functional capacity, and quality of life
• The cornerstone of pharmacologic management of HFrEF is the modulation of the [[renin-angiotensin-aldosterone] system] (RAAS) and sympathetic nervous system (i.e., neurohormonal blockade).

For all patients: To reduce mortality

• Angiotensin-converting enzyme inhibitors (ACE-I) or an angiotensin receptor-neprilysin inhibitor (ARNI), beta-blockers, and mineralocorticoid receptor antagonists (MRA) reduce mortality, reduce the risk of repeated HF hospitalizations, and improve symptoms in patients with HFrEF.
• Thus, a combination of an ACE-I/ARNI, a beta-blocker, and an MRA is recommended as class I therapies for all HFrEF patients unless they are contraindicated or not tolerated. These drugs should be uptitrated to the doses used in the clinical trials or to maximally tolerated doses.
• Unless contraindicated or not tolerated, the sodium-glucose co-transporter 2 (SGLT2) inhibitors (dapagliflozin and empagliflozin) are also recommended for all HFrEF patients and should be added to pharmacotherapy of HFrEF patients that are already taking an ACE-I/ARNI, a beta-blocker, and an MRA, regardless of diabetes status.

For all patients with HFrEF (LVEF<40%)

ACE-I/ARNI

BB

MRA

SGLT2i

Captopril Enalapril Lisinopril Ramipril

Sacubitrl/valsartan

Bisoprolol Carvedilol Metoprolol succinate Nebivolol

Eplerenone Spironolactone

Dapagliflozin Empagliflozin

For selected patients: To reduce mortality/HF hospitalization

Diuretics

• Diuretics reduce HF symptoms and HF hospitalization and improve exercise capacity. However, their effects on mortality are remained to be elucidated.
• Loop diuretics can reduce volume overload and reduce shortness of breath and edema, and thus are recommended in patients with signs or symptoms of volume overload.
• A rise in BUN and Cr may reflect a reduction in renal perfusion, and further diuresis should only be undertaken with careful monitoring of renal function.

Angiotensin II receptor blockers

• An angiotensin II receptor blocker (ARB) can be used in selected patients who are intolerable of ACE-I or ARNI due to serious side effects.
• Angiotensin II receptor antagonists block the activation of angiotensin II AT1 receptors. Blockade of AT1 receptors directly causes vasodilation, reduces secretion of vasopressin, and reduces production / secretion of aldosterone. Because angiotensin II receptor antagonists do not inhibit the breakdown of bradykinin or other kinins, they are rarely associated with the persistent dry cough and/or angioedema, side effects which limit ACE inhibitor therapy. Commonly administered agents in the management of heart failure include Candesartan, Valsartan, Telmisartan, Losartan, Irbesartan, and Olmesartan. The effectiveness of switching to an ARB from and ACE inhibitor was demonstrated for candesartan in the CHARM Alternative trial .
• In general, ARBs are as effective or slightly less effective than ACE inhibitors in the treatment of congestive heart failure. It is a class 2a recommendation to substitute an ARB as an alternative to ACE inhibitors if the patient is already taking an ARB for another indication.
• The efficacy of adding an ARB to an ACE inhibitor was assessed in the CHARM Added trial. While there was a reduction in the composite primary endpoint in the study, there was no reduction in mortality. Furthermore, the VALIANT trial demonstrated that an ARB should not be added to an ACE inhibitor in the post MI setting.
• These negative results for adding ARBs on top of an ACE inhibitor in the post MI setting are in contrast to the results of the EMPHASIS HF trial which demonstrated that the addition of eplerenone (an aldosterone antagonist) to ACE inhibition improved clinical outcomes including mortality among patients with class II or III heart failure with a reduced LVEF. Thus, based upon the mortality benefit observed in the EMPHASIS HF trial, an aldosterone antagonist rather than and ARB should be added to an ACE inhibitor in patients with
• NYHA class III or IV heart failure who has an LVEF < 35%
• NYHA class II heart failure and an LVEF < 30%
• Post-MI patient who has an LVEF < 40% who has heart failure symptoms or diabetes
• "Triple therapy", the combined use of an ACE inhibitor, an ARB and an aldosterone antagonist is a relative contraindication.

I_f-Channel inhibitor

Ivabradine can be beneficial to reduce HF hospitalization for patients with symptomatic (NYHA class II-III) stable chronic HFrEF (LVEF ≤ 35%) who are in sinus rhythm with a heart rate of 70 bpm or greater at rest and are receiving guideline-directed medical therapy (including a beta-blocker at the maximum tolerated dose, an ACE-I or ARNI, and an MRA).

Combination of hydralazine and isosorbide dinitrate

• The combination of hydralazine and a nitrate (particularly among black patients) can be added if the patient continues to have symptoms despite receiving an ACE inhibitor (or ARNI in the intolerant patient), a beta blocker and an MRA.
• The initial dose is isosorbide dinitrate 20 mg three times a day along with hydralazine 25 mg three times a day.
• The dose(s) can be increased every 2 to 4 weeks to a target dose of isosorbide dinitrate 40 mg three times a day and hydralazine 75 mg three times a day.

Digoxin

• Digitalis can strengthen the contractility of the heart and can also be useful to achieve rate control in patients with heart failure who also have atrial fibrillation.
• In the DIG trial, digoxin reduced the rate of re-hospitalization but did not improve mortality among all patients enrolled in the trial.
• However, in a retrospective analysis, mortality was reduced in male patients who had digoxin levels between 0.5 and 0.8 ng/mL and was increased in male patients with digoxin levels > 1.2 ng/ml. A similar trend was observed among women patients: there was a trend towards lower mortality at digoxin concentrations between 0.5 to 0.9 ng/ml, but significantly higher mortality at digoxin concentrations > 1.2 ng/ml.
• Digoxin should not be used as primary therapy for congestive heart failure.
• The administration of digoxin is reasonable in patients with NYHA class II-IV heart failure symptoms who have an LVEF of < 40% despite treatment with angiotensin-converting enzyme inhibitors or ARNI, beta blockers, and an aldosterone antagonist.
• Small doses of 0.125 mg per day of digoxin are often effective in maintaining a serum digoxin level between 0.5 and 0.8 ng/ml.