How should spironolactone be started, dosed, monitored, and what are the contraindications and alternatives in patients with heart failure with reduced ejection fraction (NYHA class II‑IV) or recent myocardial infarction with left‑ventricular dysfunction?

Use of Spironolactone in Cardiac Patients

Add spironolactone 25 mg once daily to ACE inhibitor and diuretic therapy in patients with NYHA class III–IV heart failure and reduced ejection fraction (≤35%), provided serum potassium is ≤5.0 mEq/L and serum creatinine is ≤2.5 mg/dL. 1, 2

Patient Selection and Indications

Spironolactone is indicated for advanced heart failure (NYHA class III–IV) with reduced ejection fraction to improve survival and reduce hospitalizations. 1, 2

Specific Inclusion Criteria:

• Left ventricular ejection fraction ≤35% 2
• NYHA class III or IV symptoms, or history of NYHA class IV symptoms within the past 6 months 2
• Already receiving optimized therapy with ACE inhibitor (or ARB) and loop diuretic 1, 3
• Serum potassium ≤5.0 mEq/L at baseline 1, 2
• Serum creatinine ≤2.5 mg/dL at baseline 2

Absolute Contraindications:

• Baseline serum potassium >5.0 mEq/L 2
• Baseline serum creatinine >2.5 mg/dL 2
• Concomitant use of potassium supplements or potassium-sparing diuretics 1, 3, 2

Dosing Protocol

Start spironolactone at 25 mg once daily. 1, 2

• If the patient is intolerant of 25 mg daily, reduce to 25 mg every other day at 1–4 weeks. 2
• If the patient tolerates 25 mg daily at 8 weeks, the dose may be increased to 50 mg daily at the investigator's discretion. 2
• The mean effective dose in the landmark RALES trial was 26 mg daily. 2

Monitoring Requirements

Check serum potassium and creatinine within 1 week of initiation or dose titration, then regularly thereafter. 2

Specific Monitoring Schedule:

• Measure serum potassium and creatinine 4–6 days after starting spironolactone 3
• Repeat every 4 weeks for the first 12 weeks 2
• Then every 3 months for the first year 2
• Then every 6 months thereafter 2

Management of Hyperkalemia:

• If serum potassium rises to ≥5.5 mEq/L, reduce the dose by 50% or discontinue if it continues to increase. 3, 2
• If hyperkalemia occurs, decrease the dose or discontinue spironolactone and treat hyperkalemia. 2

Management of Renal Dysfunction:

• If serum creatinine increases by 30–50% from baseline, discontinue spironolactone. 4
• Monitor volume status and renal function periodically to detect excessive diuresis, symptomatic dehydration, hypotension, and worsening renal function. 2

Common Adverse Effects and Management

Gynecomastia occurs in approximately 9% of male patients treated with spironolactone at a mean dose of 26 mg daily. 1, 2

• The risk of gynecomastia increases in a dose-dependent manner with onset varying from 1–2 months to over a year. 2
• Gynecomastia is usually reversible upon discontinuation. 2
• If painful gynecomastia develops, spironolactone may need to be stopped. 1

Hyperkalemia occurred in 18.7% of patients in the TOPCAT trial, compared to 9.1% in the placebo group. 5

Other electrolyte abnormalities include hyponatremia, hypomagnesemia, hypocalcemia, hypochloremic alkalosis, and hyperglycemia. 2

Mechanism of Benefit

Aldosterone promotes vascular and myocardial fibrosis, potassium and magnesium depletion, sympathetic activation, endothelial dysfunction, parasympathetic inhibition, and baroreceptor dysfunction. 1

ACE inhibitors insufficiently suppress circulating aldosterone levels, providing the rationale for adding spironolactone. 1

At the low dose of 12.5–50 mg daily, spironolactone is believed not to have an appreciable diuretic effect but rather acts through aldosterone receptor antagonism. 1

Mortality and Morbidity Benefits

In the RALES trial, spironolactone reduced the risk of death by 30% (95% CI 18–40%, p<0.001) in patients with NYHA class III–IV heart failure. 2

Spironolactone reduced the risk of hospitalization for cardiac causes by 30% (95% CI 18–41%, p<0.001). 2

Both death from progressive heart failure and sudden cardiac death were reduced in RALES. 1

The mortality reduction was significant even in the 11% of patients receiving a beta-blocker. 1

Role in Heart Failure with Preserved Ejection Fraction

In the TOPCAT trial, spironolactone did not significantly reduce the primary composite outcome of cardiovascular death, aborted cardiac arrest, or heart failure hospitalization in patients with HFpEF (LVEF ≥45%). 5

However, spironolactone did reduce hospitalization for heart failure specifically (12.0% vs. 14.2%, HR 0.83,95% CI 0.69–0.99, p=0.04). 5

The potential efficacy of spironolactone was greatest at the lower end of the LVEF spectrum (LVEF <50%: HR 0.72 for primary outcome; LVEF ≥60%: HR 0.97). 6

In elderly women with HFpEF, spironolactone stabilized clinical symptoms, improved diastolic function (increased lateral e', reduced lateral E/e'), and reduced myocardial fibrosis markers. 7

Drug Interactions and Medications to Avoid

Avoid concomitant use of potassium supplements, potassium-containing salt substitutes, or potassium-sparing diuretics. 1, 3, 2

The risk of hyperkalemia is increased by concomitant use of ACE inhibitors, angiotensin receptor blockers, and other drugs that increase potassium. 2

NSAIDs should be avoided because they worsen renal function, promote fluid retention, and blunt the effect of ACE inhibitors and diuretics. 3, 2

Nephrotoxic drugs (e.g., aminoglycosides, cisplatin) can worsen renal function when used concomitantly. 2

Integration into Heart Failure Regimen

Spironolactone should be added only after the patient is already on optimized therapy with an ACE inhibitor (or ARB) and a beta-blocker, both titrated to target doses. 1, 3

The typical sequence is: (1) ACE inhibitor first, (2) beta-blocker once euvolemic and stable, (3) spironolactone if symptoms persist at NYHA class III–IV. 1, 3

Loop diuretics should always be co-administered with an ACE inhibitor and adjusted to maintain euvolemia. 1, 3

Spironolactone is not a substitute for ACE inhibitors, beta-blockers, or diuretics but rather an adjunctive agent. 8

Real-World Safety Considerations

In clinical practice, side effects related to spironolactone use are more common than reported in clinical trials. 4

The rate of spironolactone withdrawal in ambulatory heart failure patients is approximately 25%, with reasons including hyperkalemia (17.1%), renal function deterioration (14.5%), and gynecomastia (5.3% of males). 4

Close monitoring of serum potassium and creatinine is essential, as side effects are more common in routine practice than in controlled trials. 4

Alternative Formulations

For patients who have difficulty swallowing tablets, a liquid suspension formulation (CaroSpir®) is available as a banana-flavored oral suspension containing 25 mg/5 mL of spironolactone. 9