What is the next step for a patient with resistant hypertension on eplerenone (Generic: Eplerenone) 25 mg once a day, carvedilol (Generic: Carvedilol) 25 mg twice daily, lisinopril (Angiotensin-Converting Enzyme (ACE) inhibitor) 40 mg once a day, with hypokalemia and Chronic Kidney Disease (CKD) stage 3A?

Management of Resistant Hypertension with Hypokalemia and CKD 3A

Discontinue eplerenone immediately and switch to spironolactone 25 mg once daily as your fourth-line agent, while simultaneously replacing the current diuretic with chlorthalidone 25 mg daily (or a loop diuretic if volume overload is present). 1, 2

Critical Problem: Eplerenone is Contraindicated

The patient's current regimen contains a fundamental error that must be corrected first:

• Eplerenone is absolutely contraindicated in patients with CKD 3A (eGFR 45-59 mL/min/1.73m²) when creatinine clearance is ≤50 mL/min, which is highly likely in this patient 2
• The FDA label explicitly states eplerenone should not be used when creatinine clearance is ≤30 mL/min for heart failure patients, but for hypertension specifically, it is contraindicated when creatinine clearance is <50 mL/min 2
• The paradoxical hypokalemia in a patient on eplerenone suggests either non-adherence, inadequate dosing, or that the mineralocorticoid receptor antagonist effect is being overwhelmed by other factors 1

Immediate Action Steps

Step 1: Stop Eplerenone and Optimize Diuretic Therapy

• Discontinue eplerenone immediately due to the CKD 3A contraindication 2
• Switch to chlorthalidone 25 mg once daily as the preferred thiazide-like diuretic, which provides superior 24-hour blood pressure control and addresses the hypokalemia concern 1, 3
• If the patient has clinical volume overload or if eGFR is approaching <30 mL/min, use a loop diuretic (furosemide 20-80 mg twice daily or torsemide 5-10 mg once daily) instead, as thiazides become ineffective at lower GFR 1, 3
• Volume overload from inadequate diuretic therapy is the most common unrecognized cause of treatment resistance 3, 4

Step 2: Add Spironolactone as Fourth-Line Agent

• Once potassium levels normalize with chlorthalidone, add spironolactone 25 mg once daily as the most effective fourth-line agent for resistant hypertension 1, 3, 5, 4
• Spironolactone is superior to eplerenone for resistant hypertension because it requires lower doses (25-100 mg daily vs. 50-200 mg daily for eplerenone) and has proven efficacy in this population 1, 5
• Monitor serum potassium before starting, within the first week, at one month, and periodically thereafter 2
• Check serum potassium and creatinine within 3-7 days after adding spironolactone, given the patient is already on lisinopril (an ACE inhibitor) 2

Step 3: Verify Current Medications are Optimally Dosed

• Lisinopril 40 mg once daily is at maximum recommended dose - this is appropriate 1, 6
• Carvedilol 25 mg twice daily (50 mg total daily) is at maximum recommended dose - this is appropriate 1
• Ensure the patient is actually taking these medications as prescribed, as non-adherence accounts for approximately 50% of apparent treatment resistance 4, 7

Critical Monitoring Strategy

• Measure serum potassium and creatinine before starting spironolactone, within the first week, at one month, and periodically thereafter 2
• Withhold spironolactone if serum potassium rises to ≥5.5 mEq/L and restart at lower dose when potassium falls below 5.5 mEq/L 1, 2
• Continue the ACE inhibitor (lisinopril) even if eGFR falls below 30 mL/min/1.73m², unless there is symptomatic hypotension, uncontrolled hyperkalemia despite medical treatment, or serum creatinine rises by more than 30% within 4 weeks 1
• Reassess blood pressure response within 2-4 weeks of medication adjustments 5, 4

Address Contributing Factors

• Confirm true resistant hypertension with 24-hour ambulatory blood pressure monitoring to exclude white-coat effect, which accounts for approximately 50% of apparent resistant hypertension 5, 4
• Restrict dietary sodium to <2400 mg/day, as high sodium intake significantly contributes to treatment resistance 3, 5, 4
• Screen for and discontinue interfering substances: NSAIDs, decongestants, stimulants, certain antidepressants, and oral contraceptives 3, 5, 7
• Screen for secondary causes: primary aldosteronism (even with normal potassium), obstructive sleep apnea, renovascular disease, and thyroid dysfunction 5, 7, 8

Common Pitfalls to Avoid

• Never combine ACE inhibitors with ARBs - this increases adverse events (hyperkalemia, acute kidney injury) without cardiovascular or renal benefits 1
• Avoid potassium supplements or other potassium-sparing diuretics (amiloride, triamterene) when using spironolactone with an ACE inhibitor in CKD 1
• Do not use eplerenone in patients with creatinine clearance <50 mL/min when treating hypertension 2
• Hyperkalemia associated with ACE inhibitors or mineralocorticoid receptor antagonists can often be managed with measures to reduce serum potassium (dietary restriction, diuretic optimization, potassium binders) rather than discontinuing these beneficial agents 1

If Blood Pressure Remains Uncontrolled

If blood pressure remains >130/80 mmHg after optimizing the four-drug regimen (ACE inhibitor + beta-blocker + chlorthalidone + spironolactone) at maximal tolerated doses for 3 months:

• Consider adding a vasodilating agent: alpha-blocker (doxazosin), centrally-acting agent (clonidine), or direct vasodilator (hydralazine, with minoxidil reserved as last resort) 5, 4, 8
• Refer to a hypertension specialist for further evaluation and management, particularly to investigate secondary causes and consider device-based therapies 5, 4