Comparison of Spironolactone and Amiloride on Home Blood Pressure in Resistant Hypertension

NCT04331691 | Completed Phase 4

• 1 other identifier: 4-2019-1334
• Study Type: interventional
• Target: 118
• Locations: 1 country
• Sites: 1

Brief Summary

Resistant hypertension is defined as blood pressure that remains above goal despite concurrent use of three antihypertensive agents of different classes including diuretics. Patients with resistant hypertension has at least 1.5-fold higher cardiovascular risk than those with non-resistant hypertension. Therefore, controlling blood pressure is crucial in patients with resistant hypertension. It has been unclear which antihypertensive agent should be added in patients who cannot reach target blood pressure despite use of three antihypertensive agents. There have been three randomized clinical trials that proved the efficacy of spironolactone in resistant hypertension, but they were small sized, comparison study to placebo. Recently published PATHWAY-2 study which compared the efficacy of spironolactone with placebo, doxazosin, and bisoprolol showed superiority of spironolactone in blood pressure lowering in patients with resistant hypertension. Thus, revised ACC/AHA and ESC/ESH guideline for arterial hypertension recommended spironolactone as the fourth agent for resistant hypertension. However, in real world, adherence to spironolactone may not be adequate because of adverse effect such as gynecomastia, hyperkalemia, and so on. Recently, sub-study of PATHWAY-2 revealed that amiloride changes systolic blood pressure by -22.2 mmHg (95% CI, -24.7 to -19.7) which is comparable with the effect of spironolactone (-21.8 mmHg; 95% CI, -24.2 to -19.3). However, it was not randomized clinical trial to compare the effect between spironolactone and amiloride in patients with resistant hypertension. This study aims to compare the effect of spironolactone and amiloride on home blood pressure in resistant hypertensive patients and to compare the rate of target blood pressure achievement between spironolactone and amiloride in resistant hypertensive patients.

Conditions

Resistant Hypertension

Keywords

Resistant Hypertension; Spironolactone; Amiloride; Home Blood Pressure Monitoring

Outcome Measures

Primary Outcomes (1)

• The difference between spironolactone versus amiloride for changes in home SBP from baseline to week 12.

  Comparison of the change of average home systolic blood pressure at week 12 from the introduction phase between spironolactone group and amiloride group

  week 12

Secondary Outcomes (1)

• target blood pressure achievement rates

  week 12

Study Arms (2)

Spironolactone

ACTIVE COMPARATOR

After randomization, this group will receive 12.5 mg of spironolactone daily. Subjects who did not reach the target blood pressure after 4 weeks of treatment should be increased to 25 mg of spironolactone. After 12 weeks of treatment, study will be end.

Drug: Spironolactone

Amiloride

EXPERIMENTAL

After randomization, this group will receive 5 mg of amiloride daily. Subjects who did not reach the target blood pressure after 4 weeks of treatment should be increased to 10 mg of amiloride. After 12 weeks of treatment, study will be end.

Drug: Amiloride

Interventions

Spironolactone DRUG

After randomization, this group will receive 12.5 mg of spironolactone daily. Subjects who did not reach the target blood pressure after 4 weeks of treatment should be increased to 25 mg of spironolactone. After 12 weeks of treatment, study will be end.

Spironolactone

Amiloride DRUG

After randomization, this group will receive 5 mg of amiloride daily. Subjects who did not reach the target blood pressure after 4 weeks of treatment should be increased to 10 mg of amiloride. After 12 weeks of treatment, study will be end.

Amiloride

Eligibility Criteria

• Age: 19 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age 19-75
• Patients with resistant hypertension
• st screening: ven while taking three or more types of antihypertensive medications including diuretics without changing the dose for 1 month, the average office systolic blood pressure measured in three times is 130-180 mmHg and daytime systolic blood pressure is ≥130 mmHg.
• nd screening: An average systolic blood pressure of home blood pressure monitoring is ≥130 mmHg during the run-in period of antihypertensive drugs including diuretics (Sevikar HCT 5/20/12.5 mg, 5/40/12.5 mg or 10/40/12.5 mg).
• Patients with resistant hypertension who have agreed to participate in the study: when they have the ability to write a written consent in accordance with the Korean Good Clinical Practice (KGCP) and local laws.
• Patients who can change the currently used antihypertensive treatment to Sevikar HCT 5/20/12.5 mg, 5/40/12.5 mg or 10/40/12.5 mg without giving unacceptable risk (investigator's judgment)

You may not qualify if:

• White-coat uncontrolled hypertension
• Severe hypertension (WHO classification criteria grade 3 average diastolic blood pressure ≥ 110 mmHg or average systolic blood pressure ≥ 180 mmHg)
• Known cardiovascular disease (including stroke and TIA), including a history of angina, heart failure, myocardial infarction or revascularization, or cerebrovascular disease prior to 6 months
• Congestive heart failure of III-IV according to NYHA functional classification
• Clinically meaningful ventricular tachycardia, atrial fibrillation, atrial flutter, or other arrhythmia that the investigator has deemed clinically meaningful.
• Hypertrophic obstructive cardiomyopathy, severe obstructive coronary artery disease, aortic stenosis, hemodynamically significant aortic valve or stenosis on the mitral valve
• Renal insufficiency (basal estimated glomerular filtration rate (eGFR) \<50 ml / min / 1.73m2)
• Hyperkalemia (\> 5.0 mmol / L, which can be reconfirmed if errors are suspected in the results)
• Gastrointestinal diseases that can cause potential malabsorption the gastro-intestinal tract is severely narrowed; Kock pouch (a continent pouch formed by the terminal ileum after colectomy)
• Bile stasis or biliary obstruction
• liver disease or aspartate aminotransferase (AST) / alanine aminotransferase (ALT) levels \> 2-fold the normal upper limit (ULN)
• Pregnant or fertile women who are not contraceptive or woman who are lactating
• Intolerant to test drug/drug group or its components
• Subjects who are currently participating in other clinical trials and who have taken other investigational product within the past month.
• Subjects who have condition or a disease that may impede the completion of the test, according to the investigator's opinion

Sponsors & Collaborators

• Yonsei University: lead

Study Sites (1)

Severance Cardiovascular Hospital, Yonsei University Health System

Seoul, South Korea

Location

Related Publications (1)

• Lee CJ, Ihm SH, Shin DH, Jeong JO, Kim JH, Chun KH, Ryu J, Lee HY, Choi S, Lee EM, Choi JH, Kim KI, Shin J, Pyun WB, Kim DH, Park S, Williams B. Spironolactone vs Amiloride for Resistant Hypertension: A Randomized Clinical Trial. JAMA. 2025 Jun 17;333(23):2073-2082. doi: 10.1001/jama.2025.5129.

  PMID: 40366680 DERIVED

MeSH Terms

Interventions

Spironolactone; Amiloride

Intervention Hierarchy (Ancestors)

Lactones; Organic Chemicals; Pregnenes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Pyrazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Study Officials

• Sungha Park

  Severance Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 31, 2020
• First Posted: April 2, 2020
• Study Start: November 16, 2020
• Primary Completion: May 23, 2024
• Study Completion: May 23, 2024
• Last Updated: September 24, 2024

Record last verified: 2024-09

Locations

KR (1)