What is the best treatment approach for a patient with chronic hypertension that has not responded to initial therapy?

Management of Chronic Hypertension Not Responsive to Initial Therapy

For patients with chronic hypertension unresponsive to initial therapy, add low-dose spironolactone (25 mg daily) to existing treatment as the preferred next step for resistant hypertension, after confirming medication adherence and optimizing to guideline-recommended triple therapy (RAS blocker + calcium channel blocker + thiazide diuretic). 1, 2

Define the Clinical Scenario

Resistant hypertension is defined as blood pressure remaining above goal (≥130/80 mmHg) despite adherence to optimal doses of three antihypertensive medications from different classes, including a diuretic, OR controlled blood pressure requiring four or more medications. 1, 3

Refractory hypertension is even more severe: uncontrolled BP while taking ≥5 drugs, including a diuretic. 1

Step 1: Verify True Treatment Resistance

Before escalating therapy, confirm the following:

• Medication adherence: Non-adherence affects 10-80% of hypertensive patients and is the most common cause of apparent treatment resistance. 2, 4, 5
• White coat hypertension: Confirm elevated readings with home BP monitoring (target <135/85 mmHg) or 24-hour ambulatory monitoring (target <130/80 mmHg). 2, 5
• Proper BP measurement technique: Use validated devices with appropriate cuff size. 6
• Interfering substances: Screen for NSAIDs, decongestants, oral contraceptives, excessive alcohol, high sodium intake, and other substances that elevate BP or interfere with medications. 2, 5

Step 2: Optimize Current Regimen to Guideline-Recommended Triple Therapy

The foundation of resistant hypertension management is ensuring patients receive optimal triple therapy BEFORE adding a fourth agent. 1, 2

Preferred Triple Therapy Combination:

• RAS blocker (ACE inhibitor or ARB) at maximum tolerated dose
• Dihydropyridine calcium channel blocker (amlodipine 5-10 mg daily)
• Thiazide or thiazide-like diuretic (chlorthalidone 12.5-25 mg daily preferred over hydrochlorothiazide due to longer half-life and proven CVD reduction) 1, 2, 7

Common Pitfalls in Current Therapy:

• Inadequate diuretic dosing: Nearly half of patients with resistant hypertension have suboptimal diuretic therapy. Switch to long-acting thiazide-like diuretics (chlorthalidone or indapamide) rather than hydrochlorothiazide. 4, 5
• Beta-blockers as primary agents: Beta-blockers are NOT first-line for uncomplicated hypertension unless there are compelling indications (coronary artery disease, heart failure with reduced ejection fraction, post-MI, atrial fibrillation requiring rate control). 1, 2
• Suboptimal drug combinations: Avoid combining two RAS blockers (ACE inhibitor + ARB), which increases adverse events without benefit. 1, 2

Step 3: Reinforce Lifestyle Modifications

Lifestyle changes provide additive BP reductions of 10-20 mmHg and are ESSENTIAL in resistant hypertension: 1, 2

• Sodium restriction: <2.3 g (100 mEq) daily, ideally <1.5 g daily 1, 2
• Potassium supplementation: 3500-5000 mg/day 1
• Weight loss: Target BMI 20-25 kg/m² if overweight 1, 2
• Physical activity: ≥150 minutes moderate-intensity or 75 minutes vigorous-intensity aerobic exercise weekly, plus resistance training 2-3 times/week 1, 2
• Alcohol limitation: <14 units/week for men, <8 units/week for women, preferably complete avoidance 2
• DASH diet: Rich in whole grains, fruits, vegetables, low-fat dairy, reduced saturated fat 1

Step 4: Add Spironolactone as Fourth-Line Agent

Once triple therapy is optimized and BP remains uncontrolled, add spironolactone 25 mg daily as the preferred fourth-line agent. 1, 2, 7

Rationale:

• Spironolactone addresses occult volume expansion and primary aldosteronism (present in ~20% of resistant hypertension patients), providing additional BP reductions of 20-25/10-12 mmHg when added to triple therapy. 1, 2, 3
• The 2024 ESC guidelines specifically recommend spironolactone for resistant hypertension with strong supporting evidence. 1, 2

Monitoring Requirements:

• Check serum potassium and creatinine within 1-2 weeks of initiating spironolactone, especially in patients with reduced kidney function or those already on RAS blockers. 2, 7
• Hyperkalemia risk is significant when combining spironolactone with ACE inhibitors/ARBs; hold or reduce dose if potassium rises significantly. 2, 7

Alternative Fourth-Line Agents (if spironolactone contraindicated or not tolerated):

• Eplerenone (alternative mineralocorticoid receptor antagonist) 1, 2
• Beta-blocker (bisoprolol) if not already indicated 1
• Alpha-blocker (doxazosin) 1, 2
• Amiloride (potassium-sparing diuretic) 1, 2
• Centrally acting agents (clonidine) 1, 7

Step 5: Screen for Secondary Causes of Hypertension

Secondary hypertension is common in resistant cases and often multiple causes coexist: 1, 3, 4

Key Secondary Causes to Evaluate:

Obstructive sleep apnea: Look for non-restorative sleep, snoring, daytime sleepiness. CPAP therapy modestly lowers BP if utilized. 1, 5

Primary aldosteronism: Prevalence ~20% in resistant hypertension. Screen with unprovoked or excessive hypokalemia, onset of diastolic hypertension in older patients (≥65 years). Adrenalectomy is treatment for unilateral disease; medical therapy with spironolactone for bilateral disease. 1, 3

Renal artery stenosis: Consider renal artery revascularization ONLY in specific situations (expert opinion): 1) refractory hypertension (≥5 drugs including diuretic), 2) worsening renal function (ischemic nephropathy), 3) intractable heart failure. For fibromuscular dysplasia (90% women, diagnosed in early 50s), angioplasty without stenting is effective. 1

Chronic kidney disease: Use RAS blockers as part of treatment strategy, especially with albuminuria. 2

Step 6: Consider Interventional Therapies for Refractory Cases

Catheter-based renal denervation may be considered for resistant hypertension patients with BP uncontrolled despite three-drug combination who express preference after shared risk-benefit discussion, if performed at medium-to-high volume center. 1

Baroreflex activation therapy is another novel interventional option showing promise for safely lowering BP in refractory cases. 3

Blood Pressure Targets and Monitoring

• General target: 120-129/70-79 mmHg for most adults if well tolerated 2
• Minimum target: <140/90 mmHg for all patients 1, 2, 8
• Elderly patients: Target systolic BP 130-139 mmHg; avoid diastolic BP <60 mmHg 2
• Reassessment timing: Within 2-4 weeks after any medication adjustment, with goal of achieving target BP within 3 months 2, 7

When to Refer to Hypertension Specialist

Refer patients with: 2, 7

• BP remaining uncontrolled (≥160/100 mmHg) despite four-drug therapy at optimal doses
• Multiple drug intolerances
• Suspected secondary hypertension requiring specialized evaluation
• Refractory hypertension (≥5 drugs)

Critical Pitfalls to Avoid

• Adding fourth agent before optimizing triple therapy: This violates guideline-recommended stepwise approaches and exposes patients to unnecessary polypharmacy. 7
• Inadequate diuretic therapy: Most common correctable cause—ensure long-acting thiazide-like diuretic at adequate dose. 4, 5
• Not checking adherence first: Non-adherence is the most common cause of apparent resistance. 2, 4
• Delaying treatment intensification: Prompt action reduces cardiovascular risk; aim for target BP within 3 months. 7
• Using beta-blockers without compelling indication: Not first-line for uncomplicated hypertension. 2
• Combining ACE inhibitor + ARB: Increases adverse events without additional benefit. 1, 2