Resistant hypertension remains a persistent challenge in primary care and specialist settings alike. Despite guideline-directed therapy with ACE inhibitors or ARBs, calcium channel blockers, and thiazide-like diuretics, many patients continue to have suboptimal blood pressure control. Traditionally, spironolactone has been the fourth-line agent of choice, supported by evidence from PATHWAY-2 and subsequent studies.
However, its use is often limited by antiandrogenic side effects such as gynecomastia, menstrual irregularities, and a significant risk of hyperkalaemia, particularly in patients with chronic kidney disease or diabetes.
A new randomised controlled trial published in JAMA (May 2025) investigates whether amiloride, a potassium-sparing diuretic, could offer a viable alternative — without the hormonal side effects of spironolactone.
Study at a Glance
Title: Amiloride vs Spironolactone for Resistant Hypertension: A Randomized Clinical Trial
Journal: JAMA, May 2025
Design: Open-label, blinded-endpoint RCT
Participants: 118 adults with resistant hypertension
Setting: 14 centres across South Korea
Duration: 12 weeks
Intervention:
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Amiloride 5–10 mg daily
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Spironolactone 12.5–25 mg daily
(dose titrated based on BP and potassium)
Key Findings
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Blood Pressure Reduction:
Amiloride was non-inferior to spironolactone in reducing home systolic blood pressure.-
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Amiloride: -13.6 mmHg
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Spironolactone: -14.7 mmHg
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BP Control Rate:
66.1% of patients in the amiloride group achieved target BP (<130 mmHg), compared to 55.2% in the spironolactone group. -
Safety:
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Hyperkalaemia-related discontinuation was rare (one patient in amiloride group).
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No cases of gynecomastia or menstrual irregularities were reported.
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Hormonal Profile Independence:
Amiloride’s effect was consistent across patients regardless of plasma renin or aldosterone-to-renin ratio, whereas spironolactone’s efficacy varied based on these parameters.
Clinical Significance
This study reinforces the clinical utility of amiloride as a fourth-line agent for resistant hypertension — particularly in those:
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At risk of spironolactone-related hormonal side effects
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With pre-existing CKD or borderline potassium levels
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Seeking a once-daily oral alternative that is cost-effective and widely available
While spironolactone remains effective and widely recommended, it may not be suitable for every patient. Amiloride’s favourable safety profile — especially the absence of antiandrogenic effects — positions it as an attractive alternative.
Critical Appraisal: Strengths and Shortcomings
| Strengths | Limitations |
|---|---|
| Randomised controlled trial design | Small sample size (n=118) |
| Blinded endpoint assessment | Open-label — risk of performance bias |
| Practical dosing and escalation protocol | Short follow-up (12 weeks) |
| Clinically relevant endpoints (home BP) | Conducted in a single country (South Korea) |
| Evaluated hormonal influence | No ambulatory BP monitoring used |
| Focused safety monitoring (hyperkalaemia, hormonal side effects) | Lacked quality of life or adherence measures |
The trial is a robust starting point, but broader application requires caution. A longer-term, multicentre trial, incorporating cardiovascular endpoints, patient-reported outcomes, and ambulatory BP monitoring, would enhance confidence in switching practice.
Practical Takeaway for Primary Care and Specialist Teams
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Consider amiloride 5–10 mg daily for patients who:
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Experience spironolactone-related side effects
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Are at risk of hyperkalaemia
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Require additional BP control after triple therapy
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Continue to monitor electrolytes and renal function as per standard protocol for potassium-sparing diuretics.
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Use in patients with heart failure or severe CKD warrants careful individualised consideration and may still favour mineralocorticoid receptor antagonists (MRAs).
Final Thoughts
The JAMA 2025 study provides compelling evidence for amiloride as a non-inferior and potentially safer alternative to spironolactone for managing resistant hypertension. While more extensive research is needed, this trial offers clinicians greater flexibility in tailoring treatment plans — and improving adherence in patients unable to tolerate MRAs.
At CliniLink, we remain committed to bringing you evidence-based insights that are immediately applicable in practice. Stay tuned for more case studies and updates as the landscape of cardiovascular care evolves.