Abstract Body: Background:
While spironolactone is a cornerstone therapy for resistant hypertension, amiloride offers a potential alternative with fewer antiandrogenic effects. This sub-study explores whether baseline characteristics—smoking status, body mass index (BMI), and aldosterone-to-renin ratio (ARR)—influence the efficacy of amiloride versus spironolactone.

Methods:
A post-hoc analysis of a prospective, open-label, randomized trial (Trial Registration: ClinicalTrials.gov Identifier: NCT04331691) (N=118) comparing amiloride (5-10 mg/d) and spironolactone (12.5-25 mg/d) in patients with resistant hypertension. Subgroup efficacy was assessed by changes in home systolic blood pressure (SBP) at 12 weeks. Interaction analyses evaluated treatment effects in smokers vs nonsmokers, BMI above and below the median (29.7 kg/m2), and ARR above and below the median (5.3 ng/dL per ng/mL/h).

Results:
Amiloride demonstrated greater SBP reduction in current smokers (between-group difference: +7.15 mm Hg [90% CI: -2.75 to 17.06], P_interaction=0.049) and participants with higher BMI (-15.5 vs -12.2 mm Hg with spironolactone; P_interaction=0.03). Spironolactone showed enhanced efficacy in patients with elevated ARR (-18.8 vs -10.5 mm Hg; P_interaction=0.04), whereas amiloride’s effect was consistent across ARR strata. No significant interactions were observed by age, sex, or diabetes. Safety profiles were comparable, with hyperkalemia occurring once in the amiloride group and no gynecomastia events.

Conclusion:
Amiloride may be preferentially effective in smokers and individuals with higher BMI, potentially due to its mechanism independent of aldosterone activity. Conversely, spironolactone’s efficacy correlates with ARR, suggesting utility in volume-overload phenotypes. These findings highlight the importance of personalized treatment selection in resistant hypertension based on smoking status, adiposity, and aldosterone-renin profiles.