What are the 4 medications used in heart failure? A Guide to the Four Pillars

October 8, 2025 •

5 min read

According to the 2022 guidelines from the American Heart Association and other major cardiology societies, patients with heart failure with reduced ejection fraction (HFrEF) should receive a combination of four core therapies. These four medication classes are now considered the foundational pillars of treatment for many heart failure patients, significantly reducing hospitalizations and improving survival.

Quick Summary

An overview of the four primary medication classes used to treat heart failure with reduced ejection fraction. The guide details how angiotensin receptor-neprilysin inhibitors, beta-blockers, mineralocorticoid receptor antagonists, and SGLT2 inhibitors work together to improve patient outcomes and quality of life.

Key Points

Quadruple Therapy: For heart failure with reduced ejection fraction (HFrEF), the standard of care is a four-drug regimen consisting of an ARNI, a beta-blocker, an MRA, and an SGLT2 inhibitor.
Neurohormonal Blockade: The four pillars work synergistically to block the hormonal systems that worsen heart failure over time, leading to significant improvements in outcomes.
ARNI over ACEi/ARB: Angiotensin Receptor-Neprilysin Inhibitors (ARNIs) like sacubitril/valsartan (Entresto) are often preferred over older ACE inhibitors or ARBs due to their superior ability to reduce mortality and hospitalizations in HFrEF patients.
Broader Ejection Fraction Benefits: SGLT2 inhibitors (e.g., dapagliflozin, empagliflozin) have shown benefits across the full spectrum of heart failure, including preserved ejection fraction (HFpEF) and mildly reduced ejection fraction (HFmrEF), regardless of diabetes status.
Careful Management Required: While highly effective, this combination therapy requires close medical supervision to monitor for side effects like low blood pressure, high potassium levels, and kidney function changes.
Rapid Initiation is Key: Evidence now supports initiating all four medication classes early in treatment, rather than waiting to titrate each drug individually, to provide the most substantial and timely patient benefits.

Heart failure is a chronic, progressive condition in which the heart muscle is unable to pump enough blood to meet the body's needs for blood and oxygen. For decades, the standard of care has been to use medications to slow disease progression and manage symptoms. However, major cardiology guidelines now recommend a powerful combination of four drug classes, known as "quadruple therapy," for most patients with heart failure with reduced ejection fraction (HFrEF). Getting patients on these four medications as soon as possible has been shown to provide the most substantial benefits, including improved life expectancy and a lower risk of hospitalization.

The Four Pillars of Heart Failure Treatment

The four core classes of medications are designed to work together by blocking the harmful neurohormonal activation that contributes to the progression of heart failure. Each class targets a different aspect of the disease process, providing a synergistic effect that offers better protection for the heart and better outcomes for the patient.

Angiotensin Receptor-Neprilysin Inhibitors (ARNIs)

This class of medication works by targeting two distinct pathways involved in heart failure. The 'angiotensin receptor' component (e.g., valsartan) blocks the effects of the hormone angiotensin II, which constricts blood vessels and worsens heart failure. The 'neprilysin inhibitor' component (e.g., sacubitril) increases the levels of beneficial natriuretic peptides, which improve artery function, reduce sodium retention, and decrease the strain on the heart.

Example Drug: Sacubitril/valsartan (Entresto)
Key Benefits: Superior to ACE inhibitors and ARBs at reducing cardiovascular mortality and hospitalization.
Common Side Effects: Dizziness, low blood pressure, increased potassium levels, and potential kidney function changes. A dry cough or swelling of the lips or throat can occur, though less frequently than with ACE inhibitors.

Beta-Blockers

Often called beta-adrenergic receptor-blocking agents, beta-blockers work by blocking the effects of stress hormones like adrenaline and noradrenaline. They prevent the heart from beating too quickly and forcefully, which over time helps protect and strengthen the heart muscle.

Example Drugs: Bisoprolol (Zebeta), carvedilol (Coreg), and metoprolol succinate (Toprol XL) are the specific beta-blockers recommended for heart failure.
Key Benefits: Reduce hospitalizations, lower mortality risk, and can improve heart function over time.
Common Side Effects: Dizziness, fatigue, and a slow heart rate. Abruptly stopping a beta-blocker can be dangerous and worsen heart failure symptoms.

Mineralocorticoid Receptor Antagonists (MRAs)

MRAs are diuretics that block the effects of the hormone aldosterone, which in heart failure can cause fluid and salt retention and promote harmful cardiac remodeling. By blocking aldosterone, these medications help the kidneys excrete excess fluid and sodium while retaining potassium.

Example Drugs: Spironolactone (Aldactone), eplerenone (Inspra), and the newer, non-steroidal MRA finerenone (Kerendia).
Key Benefits: Reduce mortality and hospitalizations, and improve cardiac function. Finerenone was recently approved for patients with preserved or mildly reduced ejection fraction (HFpEF/HFmrEF).
Common Side Effects: Increased potassium levels (hyperkalemia), and spironolactone can cause breast tenderness or enlargement in men (gynecomastia) due to its non-selective nature.

Sodium-Glucose Cotransporter-2 (SGLT2) Inhibitors

Originally developed for type 2 diabetes, SGLT2 inhibitors have shown remarkable benefits for heart failure patients, regardless of diabetes status. They work by inhibiting the SGLT2 enzymes in the kidneys, which causes the excretion of glucose and sodium in the urine. This action has a mild diuretic effect and is linked to multiple protective mechanisms for the heart and kidneys.

Example Drugs: Dapagliflozin (Farxiga) and empagliflozin (Jardiance).
Key Benefits: Reduce the risk of cardiovascular death and hospitalization, improve symptoms, and have protective effects on the kidneys. These benefits apply to heart failure with reduced, preserved, and mildly reduced ejection fraction.
Common Side Effects: Increased urination, urinary tract infections, and yeast infections.

Comparison of the Four Heart Failure Drug Classes


Feature	ARNI	Beta-Blocker	MRA	SGLT2 Inhibitor
Mechanism	Blocks angiotensin and boosts natriuretic peptides.	Blocks adrenaline and stress hormones; slows heart rate.	Blocks aldosterone; reduces fluid retention and fibrosis.	Blocks glucose/sodium reabsorption in kidneys; cardioprotective.
Example Drugs	Sacubitril/valsartan (Entresto)	Carvedilol, metoprolol succinate, bisoprolol	Spironolactone, eplerenone, finerenone	Dapagliflozin (Farxiga), empagliflozin (Jardiance)
Role in Therapy	Primary component for HFrEF; often replaces ACEi/ARB.	Primary component for HFrEF.	Primary component for HFrEF; also used for HFpEF.	Primary component for HFrEF, HFmrEF, and HFpEF.
Typical Side Effects	Dizziness, low blood pressure, high potassium, potential cough.	Fatigue, dizziness, slow heart rate.	High potassium, gynecomastia (spironolactone).	Increased urination, UTIs, yeast infections.
Key Outcome Benefit	Reduced mortality, lower hospitalization risk vs ACEi.	Reduced mortality and hospitalization.	Reduced mortality and hospitalization, better symptoms.	Reduced cardiovascular death and hospitalization across EF spectrum.

The Importance of Combination Therapy

Contemporary heart failure management emphasizes the use of these four medication classes together, in a timely manner, to maximize clinical benefits. Historically, doctors would optimize one drug class before starting another, but newer evidence shows that starting all four as quickly as the patient can tolerate offers the best outcomes. The combination provides comprehensive neurohormonal blockade, addressing multiple pathways that contribute to the disease's progression simultaneously. This leads to profound reductions in mortality and hospitalizations that are not achievable with single-agent therapy.

It is essential for patients to work closely with their healthcare provider to titrate doses and manage potential side effects, especially as the therapy is initiated. Regular monitoring of kidney function and potassium levels is common, particularly with MRAs and ARNIs. Diuretics, often called 'water pills,' may also be used in addition to the four core medications to manage fluid retention and swelling.

Conclusion

The landscape of heart failure treatment has been revolutionized by the adoption of quadruple therapy. The combination of ARNIs, beta-blockers, MRAs, and SGLT2 inhibitors represents the most effective pharmacological strategy to improve the lives and longevity of patients with heart failure. These four medication classes target the disease through multiple pathways, offering a synergistic approach that is far superior to older, less comprehensive regimens. While managing this combination therapy requires careful monitoring and patient adherence, the benefits—including significant reductions in hospital stays and mortality—are profound. Patients and their families should partner with their medical team to understand the role of each medication and commit to the treatment plan for the best possible long-term outcome. For those seeking further information, the American Heart Association provides extensive resources on managing heart failure (www.heart.org/en/health-topics/heart-failure).

Frequently Asked Questions

Quadruple therapy is the modern, guideline-recommended treatment strategy for heart failure with reduced ejection fraction (HFrEF). It involves using a combination of four core medication classes: an ARNI, a beta-blocker, a mineralocorticoid receptor antagonist (MRA), and an SGLT2 inhibitor.

An Angiotensin Receptor-Neprilysin Inhibitor (ARNI) is a combination medication that blocks the effects of harmful angiotensin while boosting beneficial natriuretic peptides. This dual action helps relax blood vessels, reduce sodium and fluid retention, and decrease the overall strain on the heart, leading to better outcomes than older ACE inhibitors.

While many beta-blockers exist, specific ones have been proven to be most effective for heart failure treatment. These include bisoprolol, carvedilol, and sustained-release metoprolol succinate. They help by slowing the heart rate and reducing the heart's workload.

No. Although originally developed for diabetes, SGLT2 inhibitors like dapagliflozin (Farxiga) and empagliflozin (Jardiance) have been shown to benefit heart failure patients whether or not they have type 2 diabetes. Their cardioprotective and renal benefits extend beyond glucose control.

The most significant side effect of MRAs is an increase in potassium levels in the blood (hyperkalemia), which requires regular monitoring. Spironolactone, a type of MRA, can also cause breast tenderness or enlargement in men.

While the core four medications are primarily recommended for heart failure with reduced ejection fraction (HFrEF), recent evidence shows benefits for SGLT2 inhibitors and some MRAs in patients with preserved or mildly reduced ejection fraction (HFpEF/HFmrEF) as well.

No, you should never stop taking your heart failure medication abruptly without consulting your doctor. Many of these drugs, particularly beta-blockers, can cause a worsening of symptoms or even a heart attack if stopped suddenly. They are long-term therapies that require medical guidance to adjust or discontinue.