Written by Peter Liu
Spoon Feed
For resistant hypertension, amiloride was noninferior to spironolactone in lowering blood pressure at 3-month follow-up.
Amiloride strikes back! The return of a forgotten diuretic in resistant hypertension
For patients with resistant hypertension – i.e. uncontrolled hypertension despite three agents, including a diuretic – mineralocorticoid receptor antagonists (MRA), such as spironolactone, are usually considered next-line agents by the AHA. However, risks of hyperkalemia and antiandrogenic side effects frequently limit use. Another potassium-sparing diuretic, amiloride, has been known to cause less hyperkalemia than spironolactone. However, it has generally been thought to have more modest blood-pressure lowering effects than MRAs.
In a recent prospective, open-label, blinded end-point RCT in South Korea, amiloride was found to be a possible alternative to spironolactone in this setting. Among 118 patients, 12-week home SBP reductions were −13.6 mm Hg with amiloride vs. −14.7 mm Hg with spironolactone. The difference was −0.68 mm Hg (90%CI −3.50 to 2.14), which met the noninferiority margin of −4.4 mm Hg. Considering secondary outcomes, the proportion of patients with SBP <130 mm Hg were also similar between groups. Patients with elevated aldosterone-to-renin ratios probably had better blood pressure response with spironolactone, but those with tobacco use or elevated BMI probably favored amiloride.
This suggests amiloride may be a more tolerable, equivalent treatment option to spironolactone for many patients with resistant hypertension, except in patients with elevated aldosterone-to-renin ratios, who may respond better to MRAs that target this pathology directly.
How does this change my practice?
I rarely use amiloride, since ENaC blockers have less blood pressure lowering effect than other antihypertensives. My past prescribing of amiloride has been to add a potassium-sparing diuretic to a potassium-wasting diuretic, to balance the effects on potassium. Based on this study, I will likely begin writing amiloride for patients with resistant hypertension who do not have elevated aldosterone levels and are at high risk of MRA toxicity.
Source
Spironolactone vs Amiloride for Resistant Hypertension: A Randomized Clinical Trial. JAMA. 2025 May 14:e255129. doi: 10.1001/jama.2025.5129. Epub ahead of print. PMID: 40366680
