Can spironolactone be initiated empirically for refractory hypertension?

From the Guidelines

Spironolactone can be started empirically for refractory hypertension, typically at a dose of 25-50 mg daily, as recommended by the 2024 ESC guidelines for the management of elevated blood pressure and hypertension 1. This approach is reasonable after confirming true treatment resistance (blood pressure remains above goal despite optimal doses of at least three antihypertensive medications including a diuretic) and addressing potential secondary causes and medication adherence issues. Before initiating spironolactone, baseline potassium and renal function should be checked, as hyperkalemia is a significant risk, especially in patients with chronic kidney disease or those taking other potassium-sparing medications or ACE inhibitors/ARBs. Regular monitoring of potassium, sodium, and renal function is necessary after starting therapy—typically at 2-4 weeks initially, then periodically thereafter. Spironolactone works as an aldosterone antagonist, blocking mineralocorticoid receptors that contribute to resistant hypertension through sodium retention and vascular remodeling. Some key points to consider when using spironolactone for refractory hypertension include:

• The addition of spironolactone to existing treatment should be considered in patients with resistant hypertension and uncontrolled BP despite use of first-line BP-lowering therapies 1.
• Spironolactone is associated with a greater risk of gynecomastia and impotence compared to eplerenone, and its use should be avoided with K+ supplements, other K-sparing diuretics, or significant renal dysfunction 1.
• If spironolactone is not tolerated, eplerenone (another mineralocorticoid receptor antagonist) can be considered as an alternative with fewer anti-androgenic side effects. Side effects may include gynecomastia, breast tenderness, menstrual irregularities, and sexual dysfunction, which should be discussed with patients. It is essential to follow the most recent guidelines, such as the 2024 ESC guidelines, for the management of refractory hypertension, as they provide the most up-to-date recommendations based on the latest evidence 1.

From the FDA Drug Label

Spironolactone tablets are indicated as add-on therapy for the treatment of hypertension, to lower blood pressure in patients who are not adequately controlled on other agents. The answer is no, spironolactone should not be started empirically for refractory hypertension, as it is indicated as add-on therapy for patients not adequately controlled on other agents 2.

From the Research

Refractory Hypertension Treatment

Refractory hypertension can be challenging to manage, and the use of spironolactone has been studied as a potential treatment option.

• The study published in the American Journal of Hypertension in 2002 3 found that spironolactone was effective in reducing blood pressure in patients with refractory hypertension.
• Another study published in the Journal of Hypertension in 2016 4 compared the efficacy of spironolactone versus sympathetic renal denervation in patients with resistant hypertension and found that spironolactone was more effective in reducing 24-hour systolic and diastolic blood pressure.

Efficacy of Spironolactone

The efficacy of spironolactone in treating refractory hypertension has been demonstrated in several studies.

• A review published in Current Hypertension Reports in 2016 5 surveyed recent studies on the use of mineralocorticoid receptor antagonists, including spironolactone, in the treatment of resistant hypertension and found that spironolactone was effective in reducing blood pressure.
• A study published in the Journal of the American Heart Association in 2020 6 found that spironolactone use was associated with improved outcomes in patients with heart failure with preserved ejection fraction and resistant hypertension.

Comparison with Other Treatments

Spironolactone has been compared to other treatments for refractory hypertension, including eplerenone.

• A review published in Current Hypertension Reports in 2019 7 compared the efficacy and tolerability of spironolactone and eplerenone in patients with resistant hypertension and found that spironolactone was more effective, but also had more anti-androgenic side effects.
• The study published in the Journal of Hypertension in 2016 4 found that spironolactone was more effective than sympathetic renal denervation in reducing blood pressure in patients with resistant hypertension.

Empirical Use of Spironolactone

Based on the available evidence, spironolactone can be considered as an empirical treatment option for refractory hypertension.

• The study published in the American Journal of Hypertension in 2002 3 found that spironolactone was safe and effective in reducing blood pressure in patients with refractory hypertension.
• The review published in Current Hypertension Reports in 2016 5 recommended that spironolactone be considered as a treatment option for patients with true resistant hypertension, if tolerated.