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TOPLINE:

Amiloride, a potassium-sparing diuretic, was noninferior to spironolactone in reducing home-measured systolic blood pressure (BP) after 12 weeks of treatment in patients with true resistant hypertension, with similar rates of achieving the systolic BP target (< 130 mm Hg) and a favorable safety profile.

METHODOLOGY:

• Spironolactone is the preferred drug for resistant hypertension, but its use is linked to hyperkalemia and antiandrogenic side effects; amiloride is a potential alternative, but the efficacy of these drugs has not been directly compared in trials.
• Researchers conducted a prospective randomized clinical trial between November 2020 and February 2024, at 14 sites in South Korea to assess whether amiloride was noninferior to spironolactone in reducing home-measured systolic BP in patients with resistant hypertension.
• They included 118 patients who were randomly assigned to receive either 12.5 mg/d spironolactone (n = 60; median age, 55 years; 70% men) or 5 mg/d amiloride (n = 58; median age, 53 years; 70.7% men), with the doses increased to 25 mg/d and 10 mg/d, respectively, if home systolic BP remained ≥ 130 mm Hg and the serum potassium level was < 5.0 mmol/L after 4 weeks.
• Resistant hypertension was defined as having a mean daytime home-measured systolic BP ≥ 130 mm Hg despite treatment with a triple combination of renin-angiotensin system inhibitors, calcium channel blockers, and thiazide-like diuretics.
• The primary endpoint was the between-group difference in the change in home-measured systolic BP from baseline to week 12, with the noninferiority margin set at −4.4 mm Hg for the lower bound of the CI.

TAKEAWAY:

• Mean home systolic BP decreased by 13.6 mm Hg with amiloride and by 14.7 mm Hg with spironolactone. The between-group difference was not significant, and the lower limit of the 95% CI exceeded −4.4 mm Hg, satisfying the criteria for noninferiority.
• No significant difference was observed between the groups with respect to the proportion of patients achieving the target home- or office-measured systolic BP < 130 mm Hg.
• The BP-lowering effect of spironolactone was reduced in cases of high baseline plasma renin activity or a low aldosterone to renin ratio, but amiloride showed efficacy regardless of these factors.
• Safety profiles of both drugs were favorable, with only one case of hyperkalemia-related discontinuation in the amiloride group and no cases of gynecomastia in either group.

IN PRACTICE:

“The main take-home message of this trial is that low-dose amiloride can now be considered a treatment option in patients with resistant hypertension, with BP lowering that is comparable with low-dose spironolactone. Both medications are inexpensive and have been available as generic agents for decades,” authors of an accompanying editorial wrote.

SOURCE:

This study was led by Chan Joo Lee, MD, of the Yonsei University College of Medicine in Seoul, Republic of Korea. It was published online on May 14, 2025, in JAMA.

LIMITATIONS:

The efficacy was not compared using higher doses of spironolactone, as seen in previous trials. Participants with an estimated glomerular filtration rate < 50 mL/min/1.73 m² were not included, thus limiting generalizability to patients with chronic kidney disease. Findings may not represent drug responses across various ethnicities since only South Korean patients were included.

DISCLOSURES:

This study received support from the Korea National Institute of Health research project and a research grant from Daiichi Sankyo Korea Co Ltd. Several authors reported receiving personal fees, grants, honoraria, or having steering committee membership from various sources including the funding agency.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.