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

SPironolactone Versus Amiloride for Treatment of REsistant Hypertension (SPARE Trial): A Comparison of Home Blood Pressure

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.

Study Overview

• Status: Recruiting
• Conditions: Resistant Hypertension
• Intervention / Treatment: Drug: Spironolactone; Drug: Amiloride

Detailed Description

The subjects with office SBP of 130-180 mmHg with 3 antihypertensive medications of different classes including thiazide or thiazide-like diuretics and daytime average daytime SBP of ≥ 130 mmHg are enrolled in the 4-week run-in period. During run-in period, subjects will receive sevikar HCT (5/20/12.5 mg, 5/40/12.5 mg or 10/40/12.5 mg). After a 4-week run-in period, subjects who have uncontrolled average home SBP, defined as average SBP of ≥ 130 mmHg, will be randomized to either spironolactone or amiloride. 118 subjects will be randomly assigned to one of the two treatment groups. Subjects randomly assigned to one of the two treatment groups will receive 12.5 mg of spironolactone and the other group will receive 5 mg of amiloride. Subjects who did not reach the target blood pressure after 4 weeks of treatment should be increased to 25 mg of spironolactone or 10 mg of amiloride. After 12 weeks of treatment, study will be end.

• Study Type: Interventional
• Enrollment (Anticipated): 118
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Sungha Park, M.D.; Phone Number: 02-2228-8460; Email: SHPARK0530@yuhs.ac

Study Locations

• Korea, Republic of
  • Seoul, Korea, Republic of
    • Recruiting
    • Severance Cardiovascular Hospital, Yonsei University Health System
    • Contact: Sungha Park, M.D.; Phone Number: 02-2228-8460; Email: SHPARK0530@yuhs.ac

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 19 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Age 19-75

• Patients with resistant hypertension

  1. 1st 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.
  2. 2nd 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)

Exclusion Criteria:

• 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
• If assigned to treatment for this trial in the past
• Uncorrected sodium or fluid depletion
• History of drug or alcohol dependence within 6 months
• The combination of medications known to affect blood pressure, except those permitted by the protocol.
• Other clinical conditions that, as determined by the investigator, cannot be safely completed according to the protocol or that the investigational product cannot be safely used a history of secondary hypertension that cannot be corrected
• Taking spironolactone or amiloride within 4 weeks from the time of screening
• If discontinued due to side effects of spironolactone or amiloride

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Spironolactone; 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; 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.
Experimental: Amiloride; 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; 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
average home systolic blood pressure at 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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
target blood pressure achievement rates	Comparison of home average night systolic blood pressures between spironolactone group and amiloride group	week 12

Collaborators and Investigators

• Sponsor: Yonsei University
• Investigators: Principal Investigator: Sungha Park, Severance Hospital

Study record dates

Study Major Dates

• Study Start (Actual): November 16, 2020
• Primary Completion (Anticipated): August 31, 2024
• Study Completion (Anticipated): December 31, 2024

Study Registration Dates

• First Submitted: March 31, 2020
• First Submitted That Met QC Criteria: March 31, 2020
• First Posted (Actual): April 2, 2020

Study Record Updates

• Last Update Posted (Actual): August 2, 2022
• Last Update Submitted That Met QC Criteria: July 28, 2022
• Last Verified: July 1, 2022

More Information

Terms related to this study

• Keywords: Resistant Hypertension; Spironolactone; Amiloride; Home Blood Pressure Monitoring
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Hypertension; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Hormones, Hormone Substitutes, and Hormone Antagonists; Natriuretic Agents; Membrane Transport Modulators; Diuretics; Sodium Channel Blockers; Hormone Antagonists; Mineralocorticoid Receptor Antagonists; Diuretics, Potassium Sparing; Acid Sensing Ion Channel Blockers; Epithelial Sodium Channel Blockers; Spironolactone; Amiloride
• Other Study ID Numbers: 4-2019-1334

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No