What are the management steps for hyperkalemia in a patient taking an angiotensin‑converting enzyme inhibitor or an angiotensin receptor blocker together with a mineralocorticoid receptor antagonist?

Management of Hyperkalemia in Patients on ACE Inhibitor/ARB Plus Mineralocorticoid Receptor Antagonist

When hyperkalemia develops in patients taking ACE inhibitors or ARBs combined with MRAs, potassium levels >5.5 mEq/L should generally trigger discontinuation or dose reduction of the MRA unless other reversible causes are identified. 1

Prevention: Monitoring Protocol Before Hyperkalemia Occurs

Initial Assessment and Contraindications

• Do not initiate MRA therapy if baseline potassium is >5.0 mEq/L or serum creatinine is >2.5 mg/dL in men or >2.0 mg/dL in women (or eGFR <30 mL/min/1.73 m²). 1
• Verify eGFR is >30 mL/min/1.73 m² before starting, particularly in elderly patients where creatinine may not accurately reflect kidney function. 1

Medication Adjustments at MRA Initiation

• Discontinue or reduce potassium supplements when starting an MRA (unless there is documented history of hypokalemia requiring careful monitoring). 1
• Counsel patients to avoid high-potassium foods and NSAIDs. 1
• Consider every-other-day dosing for patients with marginal renal function (eGFR 30-49 mL/min/1.73 m²). 1

Monitoring Schedule

• Check potassium and renal function at 2-3 days, again at 7 days, then monthly for 3 months, then every 3 months thereafter. 1
• Any addition or dose increase of ACE inhibitor/ARB should trigger a new monitoring cycle. 1
• For finerenone specifically, monitor within the first month after starting, after dose adjustments, and periodically during continued therapy. 2

Management Algorithm When Hyperkalemia Develops

Mild Hyperkalemia (K+ 5.0-5.5 mEq/L)

• Identify and address reversible causes first: 1
  • Dehydration or diarrhea episodes
  • Recent addition of NSAIDs or other potassium-sparing medications
  • Dietary indiscretion with high-potassium foods
  • Worsening renal function from other causes
• Consider reducing MRA dose rather than discontinuing. 1
• Intensify monitoring frequency.

Moderate Hyperkalemia (K+ 5.5-6.0 mEq/L)

• Generally discontinue or significantly reduce MRA dose. 1
• This threshold affected 15.6% of patients on eplerenone in EPHESUS trial (vs 11.2% on placebo). 3
• Institute potassium-lowering measures:
  • Loop diuretics (IV or oral) to increase renal potassium excretion 1
  • Dietary potassium restriction
  • Consider potassium binders (patiromer or sodium zirconium cyclosilicate) for chronic management 1

Severe Hyperkalemia (K+ ≥6.0 mEq/L)

This is life-threatening and requires immediate treatment: 1

1. Cardiac membrane stabilization (first priority):

   • Calcium chloride or gluconate IV 1
   • Hypertonic saline (3-5%) if hyponatremia present 1

2. Shift potassium intracellularly (temporary, 1-4 hours):

   • Insulin IV ± glucose 1
   • Beta-2 agonists (IV or nebulized) 1
   • Sodium bicarbonate if metabolic acidosis present 1

3. Remove potassium from body (definitive):

   • Loop diuretics 1
   • Potassium binders (sodium polystyrene sulfonate, patiromer, or sodium zirconium cyclosilicate) 1
   • Hemodialysis for refractory cases 1

4. Discontinue MRA immediately. 1

Special Considerations and Risk Factors

High-Risk Populations Requiring Extra Vigilance

• CKD patients: Risk increases progressively when creatinine >1.6 mg/dL; 11% of stage 4-5 CKD patients have K+ >5.5 mEq/L at baseline. 1, 4
• Diabetes: 18% hyperkalemia rate with MRA+ACEi/ARB (vs 13% placebo). 3
• Proteinuria: 16% hyperkalemia rate with MRA (vs 11% placebo). 3
• Combined diabetes and proteinuria: 26% hyperkalemia rate (vs 16% placebo). 3
• Age >65 years: Increased risk, particularly with reduced muscle mass affecting creatinine accuracy. 1, 5

Medication-Specific Risks

• Spironolactone has the strongest hyperkalemia effect when combined with ACEi/ARB, even higher than dual ACEi+ARB combination. 6
• Higher ACE inhibitor doses increase risk (captopril ≥75 mg daily; enalapril or lisinopril ≥10 mg daily). 1
• Triple therapy (ACEi + ARB + MRA) should be routinely avoided as it dramatically increases hyperkalemia risk without additional benefit. 1, 7

Reintroduction Strategy After Hyperkalemia

When to Consider Restarting MRA

• After hyperkalemia resolves and reversible causes are addressed
• If cardiovascular or renal benefits clearly outweigh risks
• Note: In real-world practice, 47% discontinue MRA after hyperkalemia and 76% are never reintroduced within the subsequent year. 8

Safer Reintroduction Approach

• Start with lowest dose (spironolactone 12.5 mg or eplerenone 25 mg every other day). 1
• For finerenone, start at 10 mg daily if eGFR 25-60 mL/min/1.73 m²; increase to 20 mg after one month only if K+ ≤4.8 mmol/L. 2
• Implement intensive monitoring (check K+ at 2-3 days, 7 days, then weekly for first month).
• Consider adding SGLT2 inhibitor if patient has diabetes and CKD, as SGLT2 inhibitors significantly reduce hyperkalemia risk and can reverse potassium elevation caused by MRA+ACEi/ARB combinations. 6

Critical Pitfall to Avoid

Never combine ACE inhibitor with ARB in an attempt to maximize RAAS blockade - this is explicitly contraindicated as it increases hyperkalemia and acute kidney injury risk without providing cardiovascular or renal benefits. 1, 7, 9 If maximal RAAS blockade is desired, optimize the dose of a single agent (ACEi OR ARB) rather than combining both. 7, 9