From the Guidelines
The four pillars of therapy for heart failure with reduced ejection fraction (HFrEF) should be initiated as soon as possible after diagnosis in all eligible patients, as recommended by the 2022 AHA/ACC/HFSA guideline 1. These pillars include:
- Angiotensin receptor-neprilysin inhibitors (ARNIs) like sacubitril/valsartan, or alternatively an ACE inhibitor (such as lisinopril, enalapril) or ARB (such as losartan, valsartan)
- Beta-blockers (metoprolol succinate, carvedilol, or bisoprolol)
- Mineralocorticoid receptor antagonists (spironolactone or eplerenone)
- SGLT2 inhibitors (dapagliflozin or empagliflozin) These medications should be started at low doses and gradually uptitrated to target doses as tolerated, with close monitoring of blood pressure, heart rate, renal function, and electrolytes, as outlined in the 2022 AHA/ACC/HFSA guideline 1. Beta-blockers should be initiated when patients are euvolemic and hemodynamically stable. ARNIs are preferred over ACE inhibitors when possible, but require a 36-hour washout period if switching from an ACE inhibitor to prevent angioedema. These medications work synergistically to reduce mortality, hospitalizations, and symptoms by addressing the neurohormonal activation, fluid retention, and maladaptive remodeling that characterize heart failure. Therapy should be individualized based on comorbidities, with caution in patients with hypotension, renal dysfunction, or hyperkalemia, but efforts should be made to include all four medication classes whenever possible, as supported by the evidence 1. Key considerations for initiation and titration include:
- Starting with low doses and uptitrating as tolerated
- Monitoring for changes in heart rate, blood pressure, electrolytes, renal function, and symptoms during uptitration
- Individualizing therapy based on patient symptoms, vital signs, functional status, tolerance, renal function, electrolytes, comorbidities, and ability to follow up
- Making repeated attempts at uptitration to optimize therapy, as recommended in the 2022 AHA/ACC/HFSA guideline 1.
From the FDA Drug Label
Spironolactone tablets are indicated for treatment of NYHA Class III-IV heart failure and reduced ejection fraction to increase survival, manage edema, and reduce the need for hospitalization for heart failure. The recommended initial dose is 2.5 mg. The recommended dosing range is 2.5 to 20 mg given twice a day. In patients with heart failure who have hyponatremia (serum sodium less than 130 mEq/L) or with serum creatinine greater than 1.6 mg/dL, therapy should be initiated at 2.5 mg daily under close medical supervision
The guidelines on initiating 4 pillars therapy for heart failure with reduced ejection fraction are not explicitly stated in the provided drug labels. However, based on the available information, the following can be inferred:
- Spironolactone is indicated for the treatment of NYHA Class III-IV heart failure and reduced ejection fraction.
- Enalapril is indicated for the treatment of symptomatic heart failure, usually in combination with diuretics and digitalis.
- The recommended initial dose of Enalapril is 2.5 mg, and the dosing range is 2.5 to 20 mg given twice a day.
- In patients with heart failure who have hyponatremia or with serum creatinine greater than 1.6 mg/dL, therapy should be initiated at 2.5 mg daily under close medical supervision. It is essential to note that the 4 pillars therapy typically includes ACE inhibitors or ARBs, beta-blockers, diuretics, and aldosterone antagonists. The provided drug labels only discuss Enalapril (an ACE inhibitor) and Spironolactone (an aldosterone antagonist). Therefore, the information provided is not sufficient to determine the guidelines for initiating 4 pillars therapy. 2, 2, 3
From the Research
Guidelines for Initiating 4 Pillars Therapy
The guidelines for initiating 4 pillars therapy for heart failure with reduced ejection fraction (HFrEF) emphasize the importance of starting these life-saving therapies as quickly as possible, with titration to target dose as a secondary consideration 4.
Key Components of 4 Pillars Therapy
The four key components of this therapy include:
- Angiotensin-converting enzyme inhibitors (ACEi) or angiotensin-receptor blockers (ARB)
- Beta blockers
- Mineralocorticoid receptor antagonists
- Sodium-glucose cotransporter 2 (SGLT2) inhibitors or other disease-modifying therapies
Timing of Initiation
These therapies should be initiated as soon as possible after diagnosis, unless there are specific contraindications 5.
Benefits of Early Initiation
Early initiation of these therapies has been shown to reduce mortality and hospitalization rates in patients with HFrEF 6, 7.
Dosing Considerations
The target dose of these therapies is often not reached in clinical trials, and the proven benefits of these therapies have been demonstrated with average doses that are less than the target dose 4.
Patient Selection
Patient selection for these therapies should be based on individual clinical characteristics, including the presence of symptoms, left ventricular ejection fraction, and other comorbidities 8, 5.
Monitoring and Titration
Patients should be closely monitored after initiation of these therapies, with titration of doses as needed to achieve optimal clinical response and minimize adverse effects 4, 5.