Resistant Hypertension: Amiloride Found Noninferior to Spironolactone, JAMA Study Finds

The study evaluated whether amiloride could be a suitable alternative to spironolactone as a fourth-line antihypertensive agent. Patients included in the trial had resistant hypertension, defined as persistently elevated blood pressure despite being on combination therapy of an angiotensin receptor blocker, calcium channel blocker, and thiazide diuretic.

The study by Chan Joo Lee, Division of Cardiology, Severance Cardiovascular Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea, and colleagues was conducted across 14 centers in South Korea. The open-label trial enrolled 118 adults who continued to have a home systolic blood pressure (SBP) of 130 mm Hg or higher after a 4-week run-in period with the triple fixed-dose regimen. Participants were then randomized to receive either 12.5 mg of spironolactone or 5 mg of amiloride daily, with dose escalation at week 4 if blood pressure remained uncontrolled and serum potassium was within acceptable limits.

The study led to the following findings:

• At 12 weeks, both amiloride and spironolactone led to significant reductions in home-measured systolic blood pressure.
• The average reduction in systolic blood pressure was 13.6 mm Hg with amiloride and 14.7 mm Hg with spironolactone.
• The difference in blood pressure reduction between the two groups was minimal and met the predefined criteria for noninferiority.
• A slightly higher proportion of patients in the amiloride group (66.1%) achieved home systolic blood pressure below 130 mm Hg compared to the spironolactone group (55.2%), though the difference was not statistically significant.
• Office blood pressure control rates were similar between the two treatment groups.
• The median age of the study population was 55 years, with about 70% of participants being male.
• The two groups' baseline characteristics were balanced, except for the amiloride group's higher use of α-blockers.
• One case of hyperkalemia-related treatment discontinuation occurred in the amiloride group.
• There were no cases of gynecomastia in either treatment group.

The researchers note that while spironolactone has long been regarded as the most effective fourth-line drug in resistant hypertension, its side effects—including hormonal disturbances like gynecomastia—often limit its long-term use. The findings from the trial suggest that amiloride could serve as a viable alternative, especially for patients who are intolerant to spironolactone.

"The study provides strong evidence supporting the use of amiloride as an effective and safe alternative to spironolactone in managing resistant hypertension. These findings could influence future guidelines and clinical decision-making regarding treatment strategies in such patients," the researchers concluded.

Reference:

Lee CJ, Ihm S, Shin D, et al. Spironolactone vs Amiloride for Resistant Hypertension: A Randomized Clinical Trial. JAMA. Published online May 14, 2025. doi:10.1001/jama.2025.5129