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Mineralocorticoid Receptor, Coronary Microvascular Function, and Cardiac Efficiency in Hypertension

Primary Purpose

Hypertension, Left Ventricular Hypertrophy

Status
Recruiting
Phase
Phase 4
Locations
United States
Study Type
Interventional
Intervention
Eplerenone
Chlorthalidone
Potassium
Sponsored by
Brigham and Women's Hospital
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional basic science trial for Hypertension

Eligibility Criteria

18 Years - 69 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  1. History of hypertension

    1. Seated systolic BP < 160 mmHg and diastolic < 100 mmHg if on antihypertensives
    2. Seated systolic BP 141-200 mmHg and/or diastolic BP 90-114 mmHg if not on antihypertensives

  2. LVH by echocardiogram

    1. For men: LV mass index > 134 g/m2
    2. For women: LV mass index > 110 g/m2
  3. We will also allow inclusion of people with pre-diabetes and treated hypothyroidism

Exclusion Criteria:

  • Use of MR antagonist (eplerenone, spironolactone, or finerenone) or amiloride (amiloride inhibits ENaC, which is a key mediator of MR's actions) within the past year
  • Orthostatic hypotension
  • Major medical illness, including diabetes mellitus
  • Documented coronary disease (prior revascularization and/or myocardial infarction
  • LV ejection fraction < 40%
  • Cerebrovascular disease
  • Peripheral vascular disease
  • Known genetic cardiomyopathy
  • Renal disease (eGFR < 60 mL/min/1.73m2)
  • Hepatic disease
  • Bronchospastic lung disease
  • Alcohol or substance abuse
  • Hormone replacement therapy
  • Abnormal values for electrolytes, liver enzymes or TSH
  • Hemoglobin A1c ≥ 6.5%
  • Pregnancy or lactation
  • All individuals <18 and >70 years will be excluded due to safety concerns of administering an angiotensin-II infusion in these patient groups.

Sites / Locations

  • Brigham and Women's HospitalRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Active Comparator

Arm Label

Eplerenone

Chlorthalidone + potassium

Arm Description

Participants be placed on enalapril 10 mg and weaned off their other anti-hypertensives prior to the Pre-Treatment Assessment. Amlodipine (5 to 10 mg) will be added if needed to control blood pressure. After the Pre-Treatment Assessment, participants randomized to this arm will receive 50 mg eplerenone . At 2 weeks, eplerenone will be increased to 100 mg. Amlodipine (5 to 10 mg) will be added at 6 weeks or later if needed to achieve the BP target of <135/85 mmHg.

Participants be placed on enalapril 10 mg and weaned off their other anti-hypertensives prior to the Pre-Treatment Assessment. Amlodipine (5 to 10 mg) will be added if needed to control blood pressure. After the Pre-Treatment Assessment, participants randomized to this arm will receive 12.5 mg chlorthalidone + 10 mEq potassium. At 2 weeks, chlorthalidone will be increased to 25 mg + 20 mEq potassium. Amlodipine (5 to 10 mg) will be added at 6 weeks or later if needed to achieve the BP target of <135/85 mmHg.

Outcomes

Primary Outcome Measures

Change in myocardial flow reserve
Change in myocardial flow reserve (ratio of hyperemic stress myocardial blood flow to rest myocardial blood flow)

Secondary Outcome Measures

Change in myocardial external efficiency
Change in myocardial external efficiency (ratio of myocardial work to oxygen consumption)

Full Information

First Posted
October 20, 2022
Last Updated
July 25, 2023
Sponsor
Brigham and Women's Hospital
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1. Study Identification

Unique Protocol Identification Number
NCT05593055
Brief Title
Mineralocorticoid Receptor, Coronary Microvascular Function, and Cardiac Efficiency in Hypertension
Official Title
Mineralocorticoid Receptor, Coronary Microvascular Function, and Cardiac Efficiency in Hypertension
Study Type
Interventional

2. Study Status

Record Verification Date
July 2023
Overall Recruitment Status
Recruiting
Study Start Date
October 20, 2022 (Actual)
Primary Completion Date
April 2027 (Anticipated)
Study Completion Date
April 2028 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Brigham and Women's Hospital

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
The investigators' goal is to show that in hypertensive men and women with left ventricular hypertrophy (LVH) treatment with a mineralocorticoid receptor (MR) antagonist, versus a thiazide-like diuretic, will improve coronary microvascular function and cardiac efficiency, which will associate with improvements in LV structure and function. The investigators will achieve this through a randomized, controlled, basic experimental study involving humans (BESH).
Detailed Description
The investigators are recruiting individuals with hypertension and LVH, as defined by echocardiography, who are on chronic angiotensin converting enzyme inhibitor (ACEi) or angiotensin receptor blockade (ARB). Participants will be transitioned to enalapril, ACEi, with washout of all other anti-hypertensives and then randomized to add-on treatment for 9 months with eplerenone (MR antagonist) or chlorthalidone (thiazide-like diuretic) + potassium. The investigators will use cardiac PET to quantify changes in coronary microvascular function and cardiac efficiency; echocardiography to assess changes in cardiac function and structure. The investigators will define the impact of eplerenone as compared with chlorthalidone on coronary microvascular function (Aim 1) and cardiac efficiency (Aim 2) and determine the relationship between coronary microvascular function and cardiac efficiency. Additionally, the investigators will determine whether improvements in coronary microvascular function and/or cardiac efficiency correlate with improvements in myocardial structure and function (chamber dimensions, diastolic function, and global longitudinal strain) in individuals with hypertension and LVH. Participants be placed on enalapril 10 mg and weaned off their other anti-hypertensives prior to the Pre-Treatment Assessment. After the Pre-Treatment Assessment, participants will be randomized to the following daily medications: 50 mg eplerenone or 12.5 mg chlorthalidone + 10 mEq potassium. At 2 weeks, eplerenone will be increased to 100 mg and chlorthalidone to 25 mg + 20 mEq potassium. Amlodipine (5 to 10 mg) will be added at 6 weeks or later if needed to achieve the BP target of <135/85 mmHg. Study outcomes will be assessed at baseline and 9 months after randomization. The primary outcome measures will be: 1) myocardial flow reserve (MFR, ratio of stress over rest myocardial blood flow); and 2) myocardial external efficiency (MEE, ratio of myocardial work over myocardial oxygen consumption and LV mass). The investigators will also measure: 1) myocardial oxygen consumption (MVO2); 2) myocardial function (peak global longitudinal strain, tissue Doppler mitral annular early diastolic relaxation velocity [e'], and the ratio of mitral E velocity to e' [E/e']) as measured by 2D echocardiography; 3) markers of cardiovascular injury and remodeling, including high sensitivity troponin and procollagen III amino terminal propeptide (PIIINP); and 4) measures of renin-angiotensin-aldosterone system under resting conditions, with upright posture, and with angiotensin-II stimulation.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Hypertension, Left Ventricular Hypertrophy

7. Study Design

Primary Purpose
Basic Science
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
Model Description
Participants are randomized to chlorthalidone or eplerenone.
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
75 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Eplerenone
Arm Type
Active Comparator
Arm Description
Participants be placed on enalapril 10 mg and weaned off their other anti-hypertensives prior to the Pre-Treatment Assessment. Amlodipine (5 to 10 mg) will be added if needed to control blood pressure. After the Pre-Treatment Assessment, participants randomized to this arm will receive 50 mg eplerenone . At 2 weeks, eplerenone will be increased to 100 mg. Amlodipine (5 to 10 mg) will be added at 6 weeks or later if needed to achieve the BP target of <135/85 mmHg.
Arm Title
Chlorthalidone + potassium
Arm Type
Active Comparator
Arm Description
Participants be placed on enalapril 10 mg and weaned off their other anti-hypertensives prior to the Pre-Treatment Assessment. Amlodipine (5 to 10 mg) will be added if needed to control blood pressure. After the Pre-Treatment Assessment, participants randomized to this arm will receive 12.5 mg chlorthalidone + 10 mEq potassium. At 2 weeks, chlorthalidone will be increased to 25 mg + 20 mEq potassium. Amlodipine (5 to 10 mg) will be added at 6 weeks or later if needed to achieve the BP target of <135/85 mmHg.
Intervention Type
Drug
Intervention Name(s)
Eplerenone
Intervention Description
After the Pre-Treatment Assessment, participants in the eplerenone arm will be given 50 mg eplerenone. At 2 weeks, eplerenone will be increased to 100 mg.
Intervention Type
Drug
Intervention Name(s)
Chlorthalidone
Intervention Description
After the Pre-Treatment Assessment, participants in the chlorthalidone arm will be given 12.5 mg chlorthalidone + 10 mEq potassium. At 2 weeks, chlorthalidone will be increased to 25 mg + 20 mEq potassium.
Intervention Type
Drug
Intervention Name(s)
Potassium
Intervention Description
After the Pre-Treatment Assessment, participants in the chlorthalidone arm will be given 12.5 mg chlorthalidone + 10 mEq potassium. At 2 weeks, chlorthalidone will be increased to 25 mg + 20 mEq potassium.
Primary Outcome Measure Information:
Title
Change in myocardial flow reserve
Description
Change in myocardial flow reserve (ratio of hyperemic stress myocardial blood flow to rest myocardial blood flow)
Time Frame
9 months
Secondary Outcome Measure Information:
Title
Change in myocardial external efficiency
Description
Change in myocardial external efficiency (ratio of myocardial work to oxygen consumption)
Time Frame
9 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
69 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: History of hypertension Seated systolic BP < 180 mmHg and diastolic < 110 mmHg if on antihypertensives Seated systolic BP 141-200 mmHg and/or diastolic BP 90-114 mmHg if not on antihypertensives LVH by echocardiogram For men: LV mass index > 134 g/m2 For women: LV mass index > 110 g/m2 We will also allow inclusion of people with treated hypothyroidism, pre-diabetes and diabetes controlled by diet, exercise, and/or metformin. Exclusion Criteria: Use of MR antagonist (eplerenone, spironolactone, or finerenone) or amiloride (amiloride inhibits ENaC, which is a key mediator of MR's actions) within the past year Orthostatic hypotension Major medical illness, including uncontrolled diabetes mellitus (Hemoglobin A1c >7.5) LV ejection fraction < 40% New York Heart Association class III to IV congestive heart failure or unstable angina A history in the prior 6 months of Q-wave myocardial infarction, stroke, transient ischemic attack, percutaneous transluminal coronary angioplasty, or coronary artery bypass graft History of secondary hypertension Known genetic cardiomyopathy Renal disease (seum creatinine >1.5 mg/dL for men and >1.3 mg/dL for women) Hepatic disease Bronchospastic lung disease Alcohol or substance abuse Hormone replacement therapy Abnormal values for electrolytes, liver enzymes or TSH Pregnancy or lactation All individuals <18 and >70 years will be excluded due to safety concerns of administering an angiotensin-II infusion in these patient groups.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Gail K Adler, MD, PhD
Phone
781-223-2686
Email
gadler@bwh.harvard.edu
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Gail K Adler, MD, PhD
Organizational Affiliation
Brigham and Women's Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
Brigham and Women's Hospital
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02115
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Gail K Adler, MD, PhD
Phone
617-732-6660
Ext
15899
Email
gadler@partners.org
First Name & Middle Initial & Last Name & Degree
Gail K Adler, MD, PhD

12. IPD Sharing Statement

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Mineralocorticoid Receptor, Coronary Microvascular Function, and Cardiac Efficiency in Hypertension

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