Spironolactone: A longtime ally in the fight against heart failure, hypertension, edema, and primary aldosteronism
26 Dec 2025
Spironolactone as a diuretic has a wide array of both diagnostic and therapeutic uses — from treatment of non-cardiac edema to its established use in cardiovascular disease. In high doses, spironolactone is indicated to treat edema secondary to hepatic cirrhosis, nephrotic syndrome and heart failure with reduced ejection fraction (HFrEF). In low doses, it can be given as adjuvant treatment in essential hypertension or resistant hypertension. Additionally, spironolactone is a recognized diagnostic and therapeutic agent for primary aldosteronism.
Spironolactone reduces risk of death in patients with severe heart failure
The adjuvant use of spironolactone in NYHA classes III and IV heart failure has been supported since the landmark RALES trial, published in 1999.1 This double-blind study enrolled 1,663 patients with severe HFrEF who were already on ACE inhibitors, loop diuretics, and digoxin. The trial was stopped early after an interim analysis showed efficacy, with a 30% reduction in mortality—attributed to decreased risk of death from heart failure progression and sudden cardiac events. The study was stopped after a mean follow-up of 24 months because it was determined that spironolactone significantly reduced the risk of death from all causes and was therefore effective for the treatment of heart failure.
Figure. Kaplan–Meier analysis of the probability of survival among patients in the placebo group and patients in the spironolactone group. The risk of death was 30 percent lower
among patients in the spironolactone group than among patients in the placebo
group (P<0.001)1
Additional significant findings included fewer hospitalizations for heart failure and improved NYHA class symptoms. Importantly, the study showed no significant difference in serum sodium, blood pressure, or heart rate between groups, and serious hyperkalemia was not increased. The RALES trial’s results led to increased adoption of spironolactone in heart failure management.2
While population-based studies suggest hyperkalemia incidence increased with spironolactone use, such cases often involved inappropriate prescribing—patients who did not meet eligibility criteria, had serum potassium ≥5.0 mmol/L, or had contraindications.3,4
ACA, AHA, and HFSA guidelines endorse spironolactone in heart failure
The 2022 guidelines from the American College of Cardiology (ACA), American Heart Association (AHA), and Heart Failure Society of America (HFSA) recommend spironolactone for HFrEF patients with NYHA class II–IV symptoms.5 It is indicated when estimated glomerular filtration rate (eGFR) exceeds 30 mL/min/1.73 m² and serum potassium is below 5.0 mEq/L. Evidence shows consistent improvements in all-cause mortality, HF hospitalizations, and sudden cardiac death across diverse etiologies and severities. Patient selection and close monitoring of serum potassium, renal function, and diuretic doses are crucial to minimize hyperkalemia and renal impairment risks. In patients taking MRA whose serum potassium cannot be maintained below 5.5 mEq/L, treatment should be discontinued. The guidelines also suggest benefits of spironolactone in HF with preserved ejection fraction (HFpEF) and mildly reduced ejection fraction (HFmrEF).5
Resistant hypertension—defined as blood pressure above goal despite three antihypertensive drug classes—often includes a thiazide diuretic, calcium channel blocker, and RAS blocker. The AHA recommends adding an MRA like spironolactone after optimizing doses of other drugs.6
Spironolactone reduces risk
of death in patients with severe HF5
The ASPIRANT trial showed spironolactone effectively lowers systolic BP in resistant hypertension.7 Spironolactone was found to be the most effective drug to add to a triple antihypertensive regimen when compared to other antihypertensives. In a crossover trial comparing it to placebo, doxazosin, and bisoprolol, spironolactone reduced systolic BP by an average of 8.7 mmHg (p<0.0001), outperforming other agents.8
Treatment of primary aldosteronism
Spironolactone is effective preoperatively and as long-term therapy for primary aldosteronism, particularly in patients unsuitable for surgery.9 It is used for 4–8 weeks preoperatively alongside antihypertensives. Long-term, it improves blood pressure and corrects hypokalemia, with benefits including lower microalbuminuria—a marker of endothelial health.10 Dosing must be individualized as patients taking spironolactone perioperatively receive a higher dose. Patients who are not candidates for surgery take daily spironolactone as medical management added at a low dose to their current antihypertensives, monitoring serum potassium and renal function for the duration of their treatment. Patients on long-term therapy for 3 months to 14 years did not experience suppressed adrenal function.11
Flexible dosing for various indications
Dosing varies based on indication:
● For HFrEF and NYHA class II–IV, start at 25 mg daily, titrate to 50 mg after one month if tolerated.5
● For essential hypertension uncontrolled by other meds, 25 mg daily may suffice, with titration based on response.
● In resistant hypertension, starting doses are as low as daily, with once-dailyadministration.6
● For edema or hyperaldosteronism, doses range from 100 mg daily (for edema) to 100–400 mg daily for perioperativemanagement.12
● For long-term hyperaldosteronism maintenance, therapy must be started at a low dose of 12.5–25 mg daily, with dosing determined individually.9,12
Spironolactone remains a cost-effective, versatile agent with a well-established safety profile when used appropriately.13 Its role in managing heart failure, hypertension, and primary aldosteronism continues to be supported by robust clinical evidence. With adherence to guidelines for good prescribing, patient education on adverse effects, and careful monitoring, spironolactone can be a reliable partner in long-term health management.
Spironolactone reduces risk of death in patients with severe heart failure
The adjuvant use of spironolactone in NYHA classes III and IV heart failure has been supported since the landmark RALES trial, published in 1999.1 This double-blind study enrolled 1,663 patients with severe HFrEF who were already on ACE inhibitors, loop diuretics, and digoxin. The trial was stopped early after an interim analysis showed efficacy, with a 30% reduction in mortality—attributed to decreased risk of death from heart failure progression and sudden cardiac events. The study was stopped after a mean follow-up of 24 months because it was determined that spironolactone significantly reduced the risk of death from all causes and was therefore effective for the treatment of heart failure.
Additional significant findings included fewer hospitalizations for heart failure and improved NYHA class symptoms. Importantly, the study showed no significant difference in serum sodium, blood pressure, or heart rate between groups, and serious hyperkalemia was not increased. The RALES trial’s results led to increased adoption of spironolactone in heart failure management.2
While population-based studies suggest hyperkalemia incidence increased with spironolactone use, such cases often involved inappropriate prescribing—patients who did not meet eligibility criteria, had serum potassium ≥5.0 mmol/L, or had contraindications.3,4
ACA, AHA, and HFSA guidelines endorse spironolactone in heart failure
The 2022 guidelines from the American College of Cardiology (ACA), American Heart Association (AHA), and Heart Failure Society of America (HFSA) recommend spironolactone for HFrEF patients with NYHA class II–IV symptoms.5 It is indicated when estimated glomerular filtration rate (eGFR) exceeds 30 mL/min/1.73 m² and serum potassium is below 5.0 mEq/L. Evidence shows consistent improvements in all-cause mortality, HF hospitalizations, and sudden cardiac death across diverse etiologies and severities. Patient selection and close monitoring of serum potassium, renal function, and diuretic doses are crucial to minimize hyperkalemia and renal impairment risks. In patients taking MRA whose serum potassium cannot be maintained below 5.5 mEq/L, treatment should be discontinued. The guidelines also suggest benefits of spironolactone in HF with preserved ejection fraction (HFpEF) and mildly reduced ejection fraction (HFmrEF).5
Resistant hypertension—defined as blood pressure above goal despite three antihypertensive drug classes—often includes a thiazide diuretic, calcium channel blocker, and RAS blocker. The AHA recommends adding an MRA like spironolactone after optimizing doses of other drugs.6
The ASPIRANT trial showed spironolactone effectively lowers systolic BP in resistant hypertension.7 Spironolactone was found to be the most effective drug to add to a triple antihypertensive regimen when compared to other antihypertensives. In a crossover trial comparing it to placebo, doxazosin, and bisoprolol, spironolactone reduced systolic BP by an average of 8.7 mmHg (p<0.0001), outperforming other agents.8
Treatment of primary aldosteronism
Spironolactone is effective preoperatively and as long-term therapy for primary aldosteronism, particularly in patients unsuitable for surgery.9 It is used for 4–8 weeks preoperatively alongside antihypertensives. Long-term, it improves blood pressure and corrects hypokalemia, with benefits including lower microalbuminuria—a marker of endothelial health.10 Dosing must be individualized as patients taking spironolactone perioperatively receive a higher dose. Patients who are not candidates for surgery take daily spironolactone as medical management added at a low dose to their current antihypertensives, monitoring serum potassium and renal function for the duration of their treatment. Patients on long-term therapy for 3 months to 14 years did not experience suppressed adrenal function.11
Flexible dosing for various indications
Dosing varies based on indication:
● For HFrEF and NYHA class II–IV, start at 25 mg daily, titrate to 50 mg after one month if tolerated.5
● For essential hypertension uncontrolled by other meds, 25 mg daily may suffice, with titration based on response.
● In resistant hypertension, starting doses are as low as daily, with once-dailyadministration.6
● For edema or hyperaldosteronism, doses range from 100 mg daily (for edema) to 100–400 mg daily for perioperativemanagement.12
● For long-term hyperaldosteronism maintenance, therapy must be started at a low dose of 12.5–25 mg daily, with dosing determined individually.9,12
Spironolactone remains a cost-effective, versatile agent with a well-established safety profile when used appropriately.13 Its role in managing heart failure, hypertension, and primary aldosteronism continues to be supported by robust clinical evidence. With adherence to guidelines for good prescribing, patient education on adverse effects, and careful monitoring, spironolactone can be a reliable partner in long-term health management.