Beyond Three: What are the Core First Line Drugs for CHF (Congestive Heart Failure)?

October 13, 2025 •

3 min read

According to the American Heart Association, more than 6 million adults in the United States have heart failure. While many may ask, “What are the three first line drugs for CHF?”, contemporary treatment guidelines now specify four foundational drug classes for managing chronic heart failure with reduced ejection fraction (HFrEF). These synergistic medications are key to improving patient survival and quality of life.

Quick Summary

Modern guideline-directed medical therapy for heart failure with reduced ejection fraction includes four foundational drug classes. These include renin-angiotensin system inhibitors (ARNI, ACEi, or ARB), beta-blockers, mineralocorticoid receptor antagonists (MRAs), and sodium-glucose cotransporter-2 (SGLT2) inhibitors, which work synergistically to improve outcomes.

Key Points

Four Foundational Classes: Modern guidelines for HFrEF include four core medication classes, not just three, which are prescribed together for optimal outcomes.
ARNI as First-line RASi: Angiotensin Receptor-Neprilysin Inhibitors (ARNI) are now recommended as the preferred renin-angiotensin system inhibitor for many HFrEF patients due to superior morbidity and mortality benefits over ACE inhibitors.
Essential Beta-Blockade: Specific beta-blockers (bisoprolol, carvedilol, metoprolol succinate) are critical for reducing mortality and hospitalizations in HFrEF by slowing heart rate and reducing workload.
SGLT2 Inhibitors for All: The newest cornerstone of HFrEF therapy is the SGLT2 inhibitor class, which reduces hospitalizations and cardiovascular death regardless of the patient's diabetes status.
MRAs to Complete the Picture: Mineralocorticoid Receptor Antagonists (MRAs), like spironolactone or eplerenone, block the harmful effects of aldosterone and are a vital part of the complete GDMT regimen.
Titration and Monitoring: The initiation and up-titration of these medications require close medical supervision to achieve target doses while managing potential side effects like hypotension or electrolyte imbalance.

The Evolving Landscape of Heart Failure Treatment

Historically, congestive heart failure (CHF) treatment focused on symptom management with diuretics and digoxin. The current approach is based on understanding the neurohormonal pathways involved in heart failure progression and using multiple drugs to interrupt these harmful mechanisms that cause cardiac damage. Guideline-Directed Medical Therapy (GDMT) for heart failure with reduced ejection fraction (HFrEF) now involves the simultaneous use of multiple drug classes to improve heart function and patient outcomes. Current guidelines recommend four foundational pillars of therapy for managing HFrEF.

The Four Foundational Pillars of Modern CHF Treatment

1. Renin-Angiotensin System (RAS) Inhibitors

This class blocks the renin-angiotensin-aldosterone system (RAAS), which affects blood pressure and heart function. Types used in heart failure include:

Angiotensin-Converting Enzyme (ACE) Inhibitors: Traditional therapy cornerstone, relaxing blood vessels and reducing heart workload. Examples: lisinopril, enalapril. Side effect: dry cough.
Angiotensin II Receptor Blockers (ARBs): Used if ACE inhibitors cause cough (e.g., valsartan, losartan). They block angiotensin II receptors for similar benefits.
Angiotensin Receptor-Neprilysin Inhibitors (ARNIs): The most recent approach, combining an ARB (valsartan) with a neprilysin inhibitor (sacubitril). Entresto (sacubitril/valsartan) shows better results than ACE inhibitors alone. Guidelines favor ARNI as the initial RAS inhibitor for most HFrEF patients who tolerate it.

2. Beta-Blockers

These medications slow heart rate and reduce heart muscle contractions, easing the heart's workload. They counteract stress hormones that worsen heart failure. Effective beta-blockers for HFrEF include carvedilol, bisoprolol, and extended-release metoprolol succinate. Dosing starts low and increases gradually.

3. Mineralocorticoid Receptor Antagonists (MRAs)

MRAs, such as spironolactone and eplerenone, block aldosterone. This helps excrete excess salt and water while retaining potassium. By blocking aldosterone's harmful effects on heart muscle, MRAs reduce mortality and hospitalizations in HFrEF. Kidney function and potassium levels require monitoring.

4. Sodium-Glucose Cotransporter-2 (SGLT2) Inhibitors

Initially for type 2 diabetes, SGLT2 inhibitors like dapagliflozin (Farxiga) and empagliflozin (Jardiance) are now crucial in HFrEF. They cause kidneys to excrete more glucose and sodium. Studies show these drugs reduce hospitalizations and cardiovascular death in HFrEF, including in patients without diabetes. They are a fundamental part of the four-drug regimen.

Modern First-Line Medication Regimen for HFrEF

Contemporary practice involves building a regimen with all four foundational classes in a timely manner. ACC/AHA guidelines recommend starting with an ARNI, beta-blocker, MRA, and SGLT2 inhibitor as suitable. If an ARNI is not tolerated, an ACE inhibitor or ARB is used. This approach is primarily for HFrEF (ejection fraction ≤40%). For heart failure with preserved ejection fraction (HFpEF), SGLT2 inhibitors and MRAs are also recommended, but the evidence for other classes differs.

Comparison of Key First-Line Medication Classes for HFrEF


Drug Class	Mechanism of Action	Primary Benefit(s)	Key Side Effect(s)
RAS Inhibitors (ARNI/ACEi/ARB)	Blocks the RAAS system to relax blood vessels, lower blood pressure, and reduce cardiac remodeling.	Reduces cardiovascular mortality and hospitalization. ARNI is superior to ACEi alone.	Cough (ACEi), hypotension, hyperkalemia, renal dysfunction.
Beta-Blockers	Blocks the effects of adrenergic hormones (adrenaline), slowing heart rate and reducing contractility.	Reduces mortality, hospitalizations, and heart rate. Improves long-term prognosis.	Fatigue, bradycardia, dizziness, low blood pressure.
MRAs	Blocks aldosterone, increasing sodium and water excretion while retaining potassium.	Reduces mortality, improves heart failure symptoms, reduces cardiac fibrosis.	Hyperkalemia, renal dysfunction, gynecomastia (spironolactone).
SGLT2 Inhibitors	Increases urinary excretion of glucose and sodium by blocking renal transporters.	Reduces hospitalizations and cardiovascular mortality regardless of diabetes status.	Dehydration, genitourinary infections.

Conclusion: The New Standard for CHF Therapy

The question "what are the three first line drugs for CHF" reflects outdated paradigms. The current GDMT for HFrEF is based on four essential medication classes: RAS inhibitors (ideally ARNI), beta-blockers, MRAs, and SGLT2 inhibitors. This four-pillared approach offers significant benefits over single therapies. Starting and adjusting these medications requires careful medical supervision to monitor for side effects like low blood pressure, electrolyte changes, or kidney issues. This comprehensive strategy dramatically improves outcomes and quality of life for patients with this condition. {Link: American Heart Association https://www.ahajournals.org/doi/10.1161/CIR.0000000000001063}

Frequently Asked Questions

Both ACE inhibitors and ARBs block the renin-angiotensin-aldosterone system to relax blood vessels and reduce the heart's workload. ARBs are generally prescribed for patients who experience a persistent dry cough, a common side effect of ACE inhibitors.

While it seems counterintuitive, select beta-blockers, when used long-term in stable patients, counteract the damaging effects of chronic sympathetic nervous system over-activation that worsens heart failure. They improve left ventricular function and significantly reduce morbidity and mortality over time.

An ARNI (Angiotensin Receptor-Neprilysin Inhibitor) is a combination drug (sacubitril/valsartan) that is superior to ACE inhibitors alone for many HFrEF patients. It combines the benefits of an ARB (valsartan) with a neprilysin inhibitor (sacubitril) that increases beneficial natriuretic peptides. When switching from an ACE inhibitor to an ARNI, a 36-hour washout period is required to prevent angioedema.

Yes. Clinical trials have demonstrated that SGLT2 inhibitors like dapagliflozin and empagliflozin provide significant cardiovascular benefits for HFrEF patients, regardless of their diabetes status, by reducing heart failure hospitalizations and cardiovascular mortality.

The most significant side effects of MRAs are hyperkalemia (high potassium levels) and potential kidney function issues, necessitating close monitoring. Spironolactone can also cause endocrine side effects like gynecomastia in men, which is less common with the more selective MRA, eplerenone.

Diuretics, or 'water pills' (e.g., furosemide), are used to manage symptoms like fluid retention and congestion, which can cause shortness of breath and swelling. While they improve symptoms, they are not typically considered one of the core four prognostic-altering drug classes that directly improve survival.

These medications are started at low doses and gradually increased to the highest dose tolerated by the patient, a process known as titration. This is done under careful medical supervision to minimize side effects while maximizing therapeutic benefits.