What is causing this patient's diastolic hypertension to remain elevated despite treatment with lisinopril (angiotensin-converting enzyme inhibitor) and spironolactone (aldosterone antagonist), given their history of hypertension and possible heart failure?

Persistent Diastolic Hypertension Despite ACE Inhibitor and Aldosterone Antagonist Therapy

The most likely cause of persistent diastolic hypertension in this patient is inadequate diuretic therapy, which is the most common reason for treatment failure in resistant hypertension, followed by medication nonadherence, white-coat effect, or an undiagnosed secondary cause. 1, 2

Immediate Diagnostic Steps to Identify the Cause

Confirm True Resistant Hypertension

• Perform 24-hour ambulatory blood pressure monitoring to exclude white-coat hypertension, which accounts for approximately 50% of apparent resistant hypertension cases 2
• Verify medication adherence through direct questioning, pill counts, or pharmacy records, as nonadherence is responsible for roughly half of treatment resistance 2
• Ensure proper BP measurement technique using appropriate cuff size for large arms, as improper technique leads to falsely elevated readings 1

Assess for Inadequate Diuretic Therapy (Most Common Cause)

• Insufficient diuretic therapy is the most frequent cause of resistant hypertension 1
• Determine which diuretic the patient is taking—if hydrochlorothiazide, switch to chlorthalidone (12.5-25 mg daily) or indapamide (1.5-2.5 mg daily), as thiazide-like diuretics are significantly more effective 1, 2
• If eGFR <30 mL/min/1.73m² or clinical volume overload is present, switch to loop diuretics (furosemide 20-250 mg daily), as thiazides become ineffective at lower GFR 1, 2
• Volume overload is a common unrecognized cause of treatment failure 2

Screen for Secondary Causes of Hypertension

Primary Aldosteronism (Even with Normal Potassium)

• Obtain morning plasma aldosterone and plasma renin activity, with an aldosterone/renin ratio >20-30 being suggestive 2
• This is crucial because whether the good response to antialdosterone agents is due to undiscovered primary aldosteronism or secondary aldosteronism induced by multiple therapy is unknown 1

Other Secondary Causes to Evaluate

• Screen for obstructive sleep apnea 1, 2
• Assess renal function including baseline eGFR and consider renal artery stenosis, particularly in younger patients 2
• Check TSH for thyroid dysfunction 2
• Review medication list for interfering substances: NSAIDs, stimulants, oral contraceptives, certain antidepressants 2

Lifestyle Factors Contributing to Resistance

• Assess for binge drinking of alcohol, which may explain difficult-to-control blood pressure 1
• Evaluate sodium intake—restrict to <2400 mg/day, as high sodium significantly contributes to treatment resistance 2
• Address obesity if present, as weight loss produces significant BP reductions 2

Optimize Current Antihypertensive Regimen

Maximize Lisinopril Dosing

• Increase lisinopril to maximal tolerated dose, typically 40 mg daily 2
• Lisinopril produces greater systolic and diastolic BP reductions than hydrochlorothiazide and is similar to beta-blockers in reducing diastolic BP 3
• Peak effect occurs around 6 hours with duration lasting at least 24 hours 3

Verify Spironolactone Dosing and Response

• Confirm the patient is taking spironolactone 25-50 mg daily, as this dose provides significant additional blood pressure reduction (mean reduction of 21.7/8.5 mmHg) when added to multidrug regimens 1, 4
• Spironolactone at low doses (25-50 mg/day) produces good additional antihypertensive response with fewer adverse effects 1
• Monitor serum potassium and creatinine concentrations, as many patients may have poor renal function and are likely taking concomitant renin-angiotensin system blockers 1

Add or Optimize Third Drug Class

• Ensure the regimen includes a long-acting calcium channel blocker at maximal tolerated dose if not already prescribed 2, 5
• The standard three-drug regimen should include: a long-acting calcium channel blocker, a renin-angiotensin system blocker (ACE inhibitor or ARB), and an appropriate diuretic 5, 6

Consider Additional Fourth or Fifth-Line Agents

If blood pressure remains uncontrolled after optimizing the above regimen:

Alternative Mineralocorticoid Receptor Antagonists

• Amiloride showed greater additional antihypertensive effect than spironolactone in one placebo-controlled randomized trial 1
• Eplerenone (50-200 mg daily) as an alternative if spironolactone causes gynecomastia 2, 7

Other Fourth-Line Options

• Beta-blockers (vasodilating types: labetalol, carvedilol, or nebivolol) represent the safest option for patients who cannot undergo regular laboratory monitoring 2
• Doxazosin, clonidine, or other antihypertensive drugs not already in use 5

Monitoring Strategy

• Reassess BP response within 2-4 weeks of any medication adjustment 2
• Check serum potassium and renal function regularly, particularly after adding or adjusting spironolactone 2
• Target BP <130/80 mmHg, though individualize for elderly patients based on frailty 1, 2

When to Refer to Specialist

Refer to a hypertension specialist if BP remains uncontrolled (>130/80 mmHg) after optimizing the four-drug regimen with lifestyle modifications, or if complications arise such as severe hyperkalemia, progressive renal dysfunction, or difficulty managing the regimen 2

Common Pitfalls to Avoid

• Do not continue hydrochlorothiazide—switch to chlorthalidone or indapamide for superior efficacy 2
• Do not assume spironolactone is contraindicated with ACE inhibitors—this combination is standard in resistant hypertension trials, though potassium monitoring is essential 7
• Do not overlook pseudohypertension in elderly patients, where extreme arterial stiffness makes compression difficult, yielding falsely elevated readings 1
• Avoid extremely rapid falls in blood pressure, which may cause underperfusion of the brain, cerebral infarction, or damage to myocardium and kidneys 1