Is spironolactone effective for treating resistant hypertension?

Is Spironolactone Effective for Resistant Hypertension?

Yes, spironolactone is highly effective for resistant hypertension and is the preferred fourth-line agent, demonstrating superior blood pressure reduction compared to other add-on therapies and placebo. 1, 2

Evidence-Based Recommendation

Primary Treatment Approach

Add low-dose spironolactone (25-50 mg once daily) as the fourth-line agent for resistant hypertension after optimizing a three-drug regimen that includes a diuretic. 1

• The 2017 ACC/AHA guidelines explicitly state that spironolactone is "common add-on therapy in resistant hypertension" and aldosterone antagonists are "preferred agents in primary aldosteronism and resistant hypertension." 1
• The 2024 ESC guidelines recommend "addition of low-dose spironolactone to existing treatment" as first-line therapy for resistant hypertension. 1
• The 2020 ISH guidelines recommend adding spironolactone as the fourth-line agent in patients with serum potassium <4.5 mmol/L and eGFR >45 mL/min/1.73m². 1

Magnitude of Blood Pressure Reduction

Spironolactone produces clinically significant blood pressure reductions averaging 20-26/8-11 mm Hg when added to existing multi-drug regimens. 1, 3, 2, 4

• The landmark PATHWAY-2 trial (2015) demonstrated spironolactone reduced home systolic blood pressure by 8.70 mm Hg more than placebo (p<0.0001) and was superior to both bisoprolol and doxazosin as add-on therapy. 2
• A 2008 AHA Scientific Statement reported spironolactone (12.5-50 mg daily) lowered blood pressure by an average of 25/12 mm Hg in patients on 4 medications including a diuretic and ACE inhibitor or ARB. 1
• A retrospective study of 344 patients showed blood pressure reductions of 26.0/10.7 mm Hg at 6 months. 3
• Meta-analysis of 869 patients demonstrated weighted mean differences of -16.67 mm Hg systolic and -6.11 mm Hg diastolic compared to placebo. 4

Superiority Over Alternative Agents

Spironolactone is more effective than other fourth-line options including beta-blockers, alpha-blockers, and even renal denervation. 1, 2, 5

• PATHWAY-2 showed spironolactone was superior to bisoprolol by 4.48 mm Hg and to doxazosin by 4.03 mm Hg for home systolic blood pressure. 2
• The DENERVHTA trial demonstrated spironolactone reduced 24-hour systolic blood pressure 17.9 mm Hg more than renal denervation (p=0.010). 5
• The 2024 ESC guidelines list eplerenone, beta-blockers, or alpha-blockers only as alternatives if spironolactone is not tolerated. 1

Dosing Strategy

Start with spironolactone 25 mg once daily and increase to 50 mg daily if tolerated and needed for blood pressure control. 1, 6, 3

• FDA labeling recommends 25-100 mg daily for hypertension, with doses greater than 100 mg/day generally not providing additional blood pressure reduction. 6
• The 2017 ACC/AHA guidelines specify a usual dose range of 25-100 mg once daily. 1
• Most clinical trials used 25-50 mg daily with excellent efficacy. 3, 2

Safety Monitoring Requirements

Monitor serum potassium and renal function closely, particularly in patients with baseline eGFR 30-50 mL/min/1.73m² or those on ACE inhibitors/ARBs. 1, 6

• Hyperkalemia (K+ >6.0 mmol/L) occurred in approximately 4% of patients and led to discontinuation in 4.1% of cases. 3
• The 2020 ISH guidelines recommend spironolactone only when serum potassium is <4.5 mmol/L and eGFR >45 mL/min/1.73m². 1
• Risk of hyperkalemia is increased in older patients, those with diabetes, CKD, or concurrent use of ACE inhibitors, ARBs, or NSAIDs. 1
• Gynecomastia occurs in approximately 5.2% of males and is more common with spironolactone than eplerenone. 1, 3

Mechanism of Action

Spironolactone's effectiveness in resistant hypertension is primarily due to aldosterone blockade and enhanced sodium excretion, addressing the volume retention that underlies most cases of resistant hypertension. 1, 2

• The superiority of spironolactone in PATHWAY-2 supports a primary role of sodium retention in resistant hypertension. 2
• Spironolactone was effective throughout the distribution of baseline plasma renin, though its margin of superiority was greater at lower renin levels. 2
• The blood pressure response was not predicted by baseline aldosterone levels, suggesting benefit beyond primary aldosteronism. 1

Common Pitfalls to Avoid

• Do not withhold spironolactone due to concurrent ACE inhibitor or ARB use - this combination is standard in resistant hypertension trials, though potassium monitoring is essential. 1, 3, 2
• Do not use spironolactone with other potassium-sparing diuretics or potassium supplements - this significantly increases hyperkalemia risk. 1
• Do not skip verification of true resistant hypertension - exclude pseudoresistance (poor measurement technique, white coat effect, nonadherence) and secondary causes before adding spironolactone. 1
• Do not use in patients with significant renal dysfunction (eGFR <30-45 mL/min/1.73m²) without very close monitoring or consider alternative agents. 1

Alternative Agents When Spironolactone is Contraindicated

If spironolactone is not tolerated or contraindicated, consider eplerenone, amiloride, doxazosin, or bisoprolol as alternatives. 1

• Eplerenone has lower risk of gynecomastia but often requires twice-daily dosing and is less potent. 1
• Amiloride showed blood pressure reductions of 12.2/4.8 mm Hg in African-American patients, slightly superior to spironolactone 25 mg in one trial. 1
• The 2024 ESC guidelines recommend bisoprolol or doxazosin as second-line alternatives after spironolactone. 1