Is it safe to prescribe non-steroidal Mineralocorticoid Receptor Antagonists (MRAs) to patients with heart failure or hypertension?

Prescribing Non-Steroidal MRAs for Heart Failure and Hypertension

Yes, prescribe non-steroidal MRAs (specifically finerenone) for patients with heart failure with mildly reduced or preserved ejection fraction (HFmrEF/HFpEF), and consider them for resistant hypertension, though evidence for cardiovascular outcomes in primary hypertension without heart failure remains limited. 1

Heart Failure Indications

Heart Failure with Reduced Ejection Fraction (HFrEF)

• Steroidal MRAs (spironolactone, eplerenone) remain the standard for HFrEF patients with LVEF ≤35% and NYHA class II-IV symptoms 1, 2
• These patients must already be on beta-blockers and ACE inhibitors/ARBs/ARNI before adding an MRA 1, 2
• Steroidal MRAs reduce cardiovascular death by 28% and heart failure hospitalizations by 37% in HFrEF 3

Heart Failure with Mildly Reduced or Preserved Ejection Fraction (HFmrEF/HFpEF)

• Non-steroidal MRAs (finerenone) are now recommended for HFmrEF/HFpEF patients to reduce heart failure hospitalizations 1, 3
• The 2024 ESC guidelines specifically state that ARBs and/or MRAs may be considered in symptomatic HFpEF patients with blood pressure above target to reduce heart failure hospitalizations 1
• Recent meta-analysis shows non-steroidal MRAs reduce the composite of cardiovascular death or heart failure hospitalization by 13% in HFmrEF/HFpEF (HR 0.87), primarily driven by an 18% reduction in heart failure hospitalizations 3
• Unlike in HFrEF, MRAs do not significantly reduce cardiovascular death in HFmrEF/HFpEF populations 3

Hypertension Indications

Resistant Hypertension

• Spironolactone is the most effective add-on therapy for resistant hypertension when blood pressure remains uncontrolled despite three-drug combinations 1
• The 2024 ESC guidelines recommend adding low-dose spironolactone to existing treatment in resistant hypertension 1
• If spironolactone is not tolerated, consider eplerenone, amiloride, higher-dose thiazide/thiazide-like diuretics, or loop diuretics 1

Primary Hypertension Without Heart Failure

• The 2024 ESC guidelines downgraded MRAs from Class I to Class IIa recommendation for primary hypertension due to lack of dedicated cardiovascular outcome trials in this population 1
• While spironolactone effectively lowers blood pressure, evidence for reducing cardiovascular events in general hypertensive populations without heart failure is lacking 1
• MRAs should be considered (not routinely prescribed) for primary hypertension only after optimizing other guideline-directed therapies 1

Patient Selection Criteria

Eligibility Requirements

• Serum creatinine ≤2.5 mg/dL for men and ≤2.0 mg/dL for women (or eGFR >30 mL/min/1.73 m²) 1, 2
• Serum potassium <5.0 mEq/L at baseline 1, 2
• For heart failure patients: LVEF ≤35% (HFrEF) or >40% (HFmrEF/HFpEF) with symptomatic disease 1, 2
• Already receiving beta-blockers and ACE inhibitors/ARBs/ARNI (for heart failure patients) 2

Contraindications

• Serum potassium ≥5.0 mEq/L 1, 2
• Severe renal dysfunction (eGFR <30 mL/min/1.73 m²) 1, 2
• Concurrent use of ACE inhibitor + ARB + MRA (triple combination increases hyperkalemia risk) 4

Monitoring Protocol

Initial Monitoring

• Check potassium and renal function at 3 days and 1 week after initiating therapy 2
• Continue monitoring at least monthly for the first 3 months 2
• Recheck at 1,2,3, and 6 months after achieving maintenance dose, then every 6 months thereafter 4

Management of Hyperkalemia

• If potassium rises to 5.5-6.0 mmol/L: halve the MRA dose and monitor closely 5, 4
• If potassium exceeds 6.0 mmol/L: stop MRA immediately 4
• Before adjusting MRA dose, systematically evaluate volume status, blood pressure, nephrotoxic medications (especially NSAIDs), and concurrent illness 5

Acceptable Renal Function Changes

• Creatinine increases up to 50% above baseline or up to 3.0 mg/dL are acceptable 5
• eGFR decreases to ≥25 mL/min/1.73 m² are tolerable 5
• These changes represent functional hemodynamic effects rather than true nephrotoxicity and are typically reversible 5

Steroidal vs. Non-Steroidal MRAs

Steroidal MRAs (Spironolactone, Eplerenone)

• Switch from spironolactone to eplerenone if male patients develop gynecomastia or breast discomfort (occurs in ~10% of men) 4
• Conversion: spironolactone 25 mg = eplerenone 25 mg starting dose; target dose is 50 mg daily for both 4
• Eplerenone has lower rates of sexual side effects but may be slightly less effective (15% vs 30% relative risk reduction in mortality) 4

Non-Steroidal MRAs (Finerenone)

• Finerenone is more selective for the mineralocorticoid receptor, resulting in fewer sexual side effects 6
• Approved for diabetic nephropathy and chronic kidney disease with demonstrated reduction in heart failure hospitalizations 6
• The 2023 ESC diabetes guidelines recommend finerenone for patients with type 2 diabetes and chronic kidney disease 6
• Ongoing trials are evaluating finerenone specifically in heart failure populations 6

Common Pitfalls to Avoid

Underutilization

• Despite Class I recommendations, only 22-33% of eligible heart failure patients receive MRA therapy 2
• Fear of hyperkalemia leads to inappropriate withholding of life-saving therapy 7

Premature Discontinuation

• Do not stop MRAs prematurely for modest creatinine elevations 5
• Stopping RAAS blockers (including MRAs) is associated with 2-4 fold higher risk of adverse cardiovascular events 5
• Continue MRAs if potassium ≤5.5 mmol/L and eGFR >25 mL/min/1.73 m² 5

Medication Interactions

• Identify and stop NSAIDs, which are the most common cause of hyperkalemia and renal dysfunction in MRA-treated patients 5, 4
• Advise patients to avoid salt substitutes high in potassium 4
• Never combine ACE inhibitor + ARB + MRA (triple combination) 4

Inadequate Monitoring

• Real-world hyperkalemia rates (24-36%) are much higher than clinical trial rates (2-5%) 2, 7
• This discrepancy reflects inadequate monitoring and patient selection in clinical practice 7
• Serious hyperkalemia (>6.0 mmol/L) remains rare (2.9% vs 1.4% placebo) with proper monitoring 3

Safety Profile

Hyperkalemia Risk

• MRAs double the risk of hyperkalemia compared to placebo (OR 2.27) 3
• However, MRAs also halve the risk of hypokalaemia (OR 0.51; 7% vs 14% placebo) 3
• Patient education regarding potassium content in foods minimizes hyperkalemia risk 7

Renal Function

• Some rise in creatinine is expected and acceptable after initiating MRAs 5
• Refer to heart failure specialist if creatinine increases >100% or to >3.5 mg/dL, or if eGFR falls to <20 mL/min/1.73 m² 5