Spironolactone vs Amiloride for Resistant Hypertension: A Randomized Clinical Trial

Abstract

Importance: Amiloride has been proposed as an alternative to spironolactone for treating resistant hypertension. However, no randomized clinical trials have compared the efficacy of spironolactone and amiloride in patients with resistant hypertension.

Objective: To determine whether amiloride is noninferior to spironolactone in reducing home-measured systolic blood pressure (SBP) in patients with resistant hypertension.

Design, setting, and participants: Prospective, open-label, blinded end-point randomized clinical trial conducted at 14 sites in South Korea. From November 16, 2020, to February 29, 2024, 118 patients with home SBP of 130 mm Hg or greater after a 4-week run-in period with a fixed-dose triple medication combination (angiotensin receptor blocker, calcium channel blocker, and thiazide) were enrolled.

Intervention: Patients were randomized in a 1:1 ratio to receive 12.5 mg/d of spironolactone (n = 60) or 5 mg/d of amiloride (n = 58). If home SBP remained 130 mm Hg or greater and serum potassium was less than 5.0 mmol/L after 4 weeks, dosages were increased to 25 mg/d and 10 mg/d, respectively.

Main outcomes and measures: The primary end point was the between-group difference in home SBP change at week 12, with a noninferiority margin of -4.4 mm Hg for the lower bound of the confidence interval. Secondary end points included achievement rates of home- and office-measured SBP of less than 130 mm Hg.

Results: The median age of the study population was 55 years, with 70% male. There were no differences between groups in demographic characteristics other than use of α-blockers (8.6% in the amiloride group and 0% in the spironolactone group). The mean baseline home SBPs were 141.5 (SD, 7.9) mm Hg and 142.3 (SD, 8.5) mm Hg in the amiloride and spironolactone groups, respectively. At week 12, mean home SBP measurements were changed from baseline by -13.6 (SD, 8.6) mm Hg and -14.7 (SD, 11.0) mm Hg in the amiloride and spironolactone groups, respectively (between-group difference in change, -0.68 mm Hg; 90% CI, -3.50 to 2.14 mm Hg), with amiloride demonstrating noninferiority to spironolactone. Home-measured achievement rates of SBP less than 130 mm Hg in the amiloride and spironolactone groups were 66.1% and 55.2%, respectively, and office-measured achievement rates of SBP less than 130 mm Hg were 57.1% and 60.3%, respectively, with no difference between the 2 groups. One case of hyperkalemia-related discontinuation occurred in the amiloride group, with no cases of gynecomastia in either group.

Conclusions and relevance: Amiloride was noninferior to spironolactone in lowering home SBP, suggesting that it could be an effective alternative for treatment of resistant hypertension.

Trial registration: ClinicalTrials.gov Identifier: NCT04331691.

Figure 1.. Flow of Participants Through a Trial of Amiloride vs Spironolactone for Resistant Hypertension

^aResistant hypertension was defined as daytime mean systolic blood pressure (SBP)≥130 mm Hg on a 24-hour ambulatory blood pressure measurement within 12 months and office SBP of 130 to 180 mm Hg despite taking 3 or more antihypertensive medications of different classes, including diuretics, for at least 4 weeks without dose changes. ^bParticipants who did not meet the daytime SBP criteria of 24-hour ambulatory blood pressure measurement within 12 months, had a change in dose of 3 or more antihypertensive drugs including a diuretic for at least 4 weeks, or did not meet the office SBP criteria. ^cThe 1:1 randomization was stratified by sex and age (<60 years vs ≥60 years). ^dParticipants included in the primary analysis received the study drug at least once and had at least 1 measurement of home SBP after baseline. Four participants in the amiloride group and 2 in the spironolactone group who did not complete the study but completed at least 4 weeks of the study and had home SBP measurements were included in the primary analysis.

Figure 2.. Change in Home SBP in Patients Treated With Amiloride vs Spironolactone

The parallel dot plot contains 1 vertical line for each patient, extending from the home systolic blood pressure (SBP) measurement at baseline to the home SBP at 12 weeks. Descending lines indicate a reduction in home SBP over time; ascending lines indicate an increase. Baseline home SBP measurements are shown in ascending order for the amiloride group and descending order for the spironolactone group. The tops and bottoms of the boxes in the box plots indicate the IQR, with the line indicating the median. Whiskers extend to the upper and lower adjacent values, the location of the furthest point within a distance of 1.5 IQRs from the first and third quartiles. Dots indicate more extreme values.

Figure 3.. Difference in Home SBP Change Between Amiloride and Spironolactone Treatment in Prespecified Subgroups

The difference in change in home systolic blood pressure (SBP) between the 2 groups from baseline to week 12 and the confidence interval were calculated using the analysis-of-covariance model adjusted for baseline home SBP.