Mineralocorticoid Receptor Antagonists

1. Introduction

Heart failure (HF) is one of the leading causes of morbidity and mortality worldwide. Despite major advances in pharmacological and device therapies, HF continues to burden patients and healthcare systems. Among the therapeutic agents that have revolutionized the management of HF are mineralocorticoid receptor antagonists (MRAs).

MRAs, including spironolactone and eplerenone, are cornerstone therapies in heart failure with reduced ejection fraction (HFrEF) and are increasingly studied in other cardiovascular and renal disorders. They work by blocking aldosterone, a hormone that plays a crucial role in sodium retention, potassium excretion, vascular inflammation, and cardiac remodeling.

This article provides a detailed review of MRAs, focusing on:

Their pharmacology and differences (spironolactone vs. eplerenone).
Their role in reducing morbidity and mortality.
Risks, particularly hyperkalemia, and strategies for safe use.
Clinical trial evidence that shaped their use in guidelines.

2. Aldosterone and Mineralocorticoid Receptors: The Pathophysiological Basis

To understand why MRAs are so effective, it is essential to revisit the role of aldosterone in cardiovascular disease.

2.1 The Renin–Angiotensin–Aldosterone System (RAAS)

The RAAS regulates blood pressure, fluid balance, and electrolyte homeostasis.
Aldosterone is produced in the adrenal cortex (zona glomerulosa).
It binds to mineralocorticoid receptors (MRs) in the kidney, promoting sodium reabsorption and potassium excretion.

2.2 Aldosterone’s Role in Heart Failure

Beyond fluid and electrolyte regulation, aldosterone has maladaptive effects:

Myocardial fibrosis – stimulates collagen synthesis and cardiac remodeling.
Vascular inflammation and stiffness – contributes to hypertension and endothelial dysfunction.
Sympathetic activation – worsens neurohormonal imbalance in HF.
Arrhythmogenic effects – predisposes to ventricular arrhythmias.

Thus, aldosterone contributes not only to volume overload but also to structural progression of HF. Blocking its receptor with MRAs interrupts these harmful processes.

3. Mineralocorticoid Receptor Antagonists: Overview

MRAs competitively block the binding of aldosterone to its receptors. Two clinically approved MRAs are:

3.1 Spironolactone

The first MRA introduced in the 1960s.
Non-selective: binds to both mineralocorticoid and sex hormone receptors.
Side effects: gynecomastia, impotence, menstrual irregularities due to anti-androgenic and progestogenic activity.
Still widely used due to efficacy and low cost.

3.2 Eplerenone

A newer, more selective MRA developed to overcome spironolactone’s hormonal side effects.
Lower affinity for androgen and progesterone receptors.
Better tolerated but more expensive.
Similar efficacy in reducing morbidity and mortality.

3.3 Other MRAs (Emerging Agents)

Finerenone: a non-steroidal MRA with potent anti-fibrotic effects, studied in diabetic kidney disease and HF.
Not yet as widely used in HF as spironolactone and eplerenone.

4. Clinical Evidence: MRAs in Heart Failure

The use of MRAs in HF is supported by robust clinical trial data.

4.1 RALES Trial (1999) – Spironolactone in Severe HFrEF

Population: Patients with severe HF (NYHA class III–IV, LVEF < 35%).
Intervention: Spironolactone vs. placebo.
Results:
- 30% reduction in all-cause mortality.
- 35% reduction in hospitalization for worsening HF.
Conclusion: Spironolactone dramatically improved survival in advanced HFrEF.

4.2 EPHESUS Trial (2003) – Eplerenone Post-MI with LV Dysfunction

Population: Patients with acute MI, LVEF ≤ 40%, and HF symptoms or diabetes.
Intervention: Eplerenone vs. placebo.
Results:
- 15% reduction in all-cause mortality.
- 21% reduction in sudden cardiac death.
Conclusion: Eplerenone reduces mortality in post-MI patients with LV dysfunction.

4.3 EMPHASIS-HF Trial (2011) – Eplerenone in Mild HFrEF

Population: Patients with mild symptoms (NYHA class II, LVEF ≤ 35%).
Intervention: Eplerenone vs. placebo.
Results:
- 37% reduction in cardiovascular death or HF hospitalization.
- Benefits consistent across age groups, including elderly patients.
Conclusion: Eplerenone effective even in less symptomatic patients.

4.4 TOPCAT Trial (2014) – Spironolactone in HFpEF

Population: HF with preserved EF (LVEF ≥ 45%).
Results:
- No significant reduction in primary outcome (CV death, aborted cardiac arrest, hospitalization).
- Some benefit in reducing HF hospitalizations.
- Regional differences observed (stronger effect in Americas vs. Eastern Europe).
Conclusion: Spironolactone may have a role in selected HFpEF patients, but evidence less robust than in HFrEF.

5. Mechanisms of Benefit

The benefits of MRAs extend beyond diuresis.

5.1 Hemodynamic Effects

Reduce sodium and water retention → lower preload.
Decrease vascular stiffness → lower afterload.

5.2 Structural and Functional Effects

Prevent and reverse ventricular remodeling.
Reduce myocardial fibrosis.
Improve left ventricular systolic and diastolic function.

5.3 Neurohormonal Modulation

Suppress sympathetic activation.
Counteract harmful effects of angiotensin II.
Reduce arrhythmogenic potential by modulating myocardial excitability.

5.4 Clinical Outcomes

Decrease in sudden cardiac death.
Lower risk of hospitalization.
Improved functional capacity and quality of life.

6. Risks and Adverse Effects

Despite their proven benefits, MRAs carry important risks.

6.1 Hyperkalemia

Most feared complication.
Mechanism: By blocking aldosterone, MRAs reduce renal potassium excretion.
Risk factors:
- Chronic kidney disease (CKD).
- Diabetes mellitus.
- Concomitant use of ACE inhibitors/ARBs/ARNIs.
- Advanced age.
Monitoring is essential:
- Check serum potassium and creatinine at baseline.
- Recheck within 3–7 days of initiation or dose adjustment.
- Monitor regularly thereafter.
Management:
- Dose reduction or temporary discontinuation if K⁺ > 5.5 mmol/L.
- Use of potassium binders in resistant cases.

6.2 Renal Dysfunction

Risk of worsening renal function due to reduced sodium reabsorption and volume depletion.
More common in patients with pre-existing CKD.

6.3 Hormonal Side Effects (Spironolactone)

Gynecomastia in up to 10% of male patients.
Menstrual irregularities, breast tenderness in women.
Impotence in men.
Much less common with eplerenone due to receptor selectivity.

7. Practical Use of MRAs

7.1 Indications (per guidelines)

HFrEF (NYHA II–IV, LVEF ≤ 35%): Spironolactone or eplerenone recommended to reduce morbidity and mortality.
Post-MI with LVEF ≤ 40% and HF symptoms/diabetes: Eplerenone reduces mortality.
HFpEF: Consider spironolactone in selected patients, mainly to reduce hospitalizations.

7.2 Contraindications

Serum potassium > 5.0 mmol/L at baseline.
eGFR < 30 mL/min/1.73 m².
Known hypersensitivity.

7.3 Dosing

Spironolactone:
- Start 12.5–25 mg daily, titrate up to 50 mg.
Eplerenone:
- Start 25 mg daily, titrate to 50 mg daily.

7.4 Monitoring

Serum potassium and renal function at:
- Baseline.
- 3–7 days after initiation.
- 1 month.
- Every 3 months thereafter.

8. Comparative Overview: Spironolactone vs. Eplerenone

Feature	Spironolactone	Eplerenone
Selectivity	Non-selective (MR, androgen, progesterone receptors)	Highly selective for MR
Cost	Inexpensive	Expensive
Side effects	Gynecomastia, impotence, menstrual irregularities	Minimal hormonal effects
Evidence	RALES, TOPCAT	EPHESUS, EMPHASIS-HF
Use	Widely available, effective	Better tolerated, especially in men

9. Future Directions

9.1 Non-Steroidal MRAs

Finerenone and other agents show promise with less hyperkalemia risk.
Strong antifibrotic effects.
Positive data in diabetic kidney disease (FIDELIO-DKD, FIGARO-DKD).
Ongoing research in HF populations.

9.2 Combination Therapies

Integration of MRAs with ARNIs, SGLT2 inhibitors, and beta-blockers is reshaping the treatment paradigm in HFrEF.
Future strategies aim for quadruple therapy to maximize survival benefits.

9.3 Personalized Medicine

Biomarkers (e.g., galectin-3, ST2) and genetic profiling may help identify patients who benefit most from MRAs.