What is the primary treatment for heart failure with reduced ejection fraction (HFrEF)?

From the Guidelines

The primary treatment for heart failure with reduced ejection fraction (HFrEF) should include a combination of four medication classes: an angiotensin-converting enzyme inhibitor (ACEI) or an angiotensin receptor-neprilysin inhibitor (ARNI), a beta-blocker, a mineralocorticoid receptor antagonist (MRA), and an SGLT2 inhibitor, as this approach has been shown to improve morbidity, mortality, and quality of life in patients with HFrEF 1. The cornerstone therapy includes medications such as lisinopril (10-40 mg daily) or sacubitril/valsartan (24/26 mg to 97/103 mg twice daily); a beta-blocker such as carvedilol (3.125-25 mg twice daily), metoprolol succinate (12.5-200 mg daily), or bisoprolol (1.25-10 mg daily); a mineralocorticoid receptor antagonist (MRA) like spironolactone (12.5-50 mg daily) or eplerenone (25-50 mg daily); and an SGLT2 inhibitor such as dapagliflozin (10 mg daily) or empagliflozin (10 mg daily) 1. Key points to consider when initiating therapy include:

• Starting with low doses and gradually titrating to target doses as tolerated
• Regular monitoring of renal function, electrolytes, and blood pressure during initiation and dose adjustments
• Adding diuretics like furosemide (20-80 mg daily or twice daily) to manage fluid overload symptoms, although they do not improve mortality
• Considering device therapies like implantable cardioverter-defibrillators or cardiac resynchronization therapy for patients who remain symptomatic despite optimal medical therapy, based on specific criteria including ejection fraction and QRS duration 1. It is essential to prioritize the most recent and highest quality study, which in this case is the 2022 AHA/ACC/HFSA guideline for the management of heart failure, to ensure that treatment decisions are based on the best available evidence 1.

From the FDA Drug Label

In trials in patients treated with digitalis and diuretics, treatment with enalapril resulted in decreased systemic vascular resistance, blood pressure, pulmonary capillary wedge pressure and heart size, and increased cardiac output and exercise tolerance. Heart rate was unchanged or slightly reduced, and mean ejection fraction was unchanged or increased There was a beneficial effect on severity of heart failure as measured by the New York Heart Association (NYHA) classification and on symptoms of dyspnea and fatigue. In a multicenter, placebo-controlled clinical trial, 2,569 patients with all degrees of symptomatic heart failure and ejection fraction ≤35 percent were randomized to placebo or enalapril and followed for up to 55 months (SOLVD-Treatment) Use of enalapril was associated with an 11 percent reduction in all-cause mortality and a 30 percent reduction in hospitalization for heart failure.

The primary treatment for heart failure with reduced ejection fraction is enalapril.

• Key benefits of enalapril include:
  • Decreased systemic vascular resistance and blood pressure
  • Increased cardiac output and exercise tolerance
  • Improved symptoms of dyspnea and fatigue
  • Reduced hospitalization for heart failure
  • Reduced all-cause mortality
• Study evidence: The SOLVD-Treatment trial 2 demonstrated the efficacy of enalapril in patients with symptomatic heart failure and ejection fraction ≤35 percent.

From the Research

Primary Treatment for Heart Failure with Reduced Ejection Fraction

The primary treatment for heart failure with reduced ejection fraction (HFrEF) involves the use of multiple medications proven to improve clinical outcomes, as tolerated.

• The four key life-saving therapies for patients with HFrEF are:
  • Angiotensin-converting enzyme inhibitors (ACEi) or angiotensin II receptor blockers (ARB)
  • Beta-blockers
  • Mineralocorticoid receptor antagonists (MRA)
  • Angiotensin receptor neprilysin inhibitors (ARNI) 3
• New guidelines emphasize the importance of starting these therapies as quickly as possible, with titration to target dose as a secondary consideration 3
• The use of ACEi/ARB in patients hospitalized for HFrEF is associated with lower 1-year mortality risk and lower 1-6-year mortality risk in those with heart failure preserved ejection fraction (HFpEF) 4

Medication Use and Dosing

• Significant gaps in use and dose of guideline-directed medical therapy remain in contemporary outpatient HFrEF registry 5
• Few patients receive target doses of ACEi/ARB, ARNI, and beta-blocker, whereas most patients receive target doses of MRA therapy 5
• Older age, lower blood pressure, more severe functional class, renal insufficiency, and recent HF hospitalization are associated with lower medication utilization or dose 5

New Pharmacological Treatments

• New medications for treating chronic heart failure have been clinically applied, including ivabradine, levosimendan, omega-3, tolvaptan, recombinant human B-type natriuretic peptide (rhBNP), isosorbide dinitrate and hydralazine (ISDN/HYD), and angiotensin-neprilysin inhibition (LCZ696) 6
• A Bayesian network meta-analysis found that levosimendan, n3-PUFA, and omega-3 were effective in improving left ventricle ejection fraction, controlling heart rate, and decreasing B-type natriuretic peptide, respectively 6

Treatment Outcomes

• The treatment of HFrEF with drugs and implanted devices, as recommended in guidelines, can significantly improve clinical outcomes 7
• Maintaining or initiating patients with HFrEF hospitalized for acute decompensated heart failure on ACEi/ARB is associated with a reduced risk of mortality and 1-year admissions 4