Cardiac Effects of Mineralocorticoid Receptor Antagonism After Preeclampsia

NCT ID: NCT07238400

Last Updated: 2025-12-02

Basic Information

• Recruitment Status: NOT_YET_RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 90 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2025-12-01
• Study Completion Date: 2029-03-30

Brief Summary

The goal of this clinical trial is to determine if the medication eplerenone yields greater improvements in coronary microvascular function than chlorthalidone in women who experienced preeclampsia during pregnancy and subsequently developed chronic hypertension. The main Aims are:

• To test the hypothesis that, in women with prior preeclampsia, current chronic hypertension, and concentric LV remodeling, eplerenone improves coronary microvascular function vs. chlorthalidone.
• To test the hypothesis that, in women with prior preeclampsia, current chronic hypertension, and concentric LV remodeling, eplerenone improves cardiac structure and function vs. chlorthalidone.

Participants will:

• First receive pre-treatment with Amlodipine for 12 weeks prior to beginning the study medication.
• Start study treatment which involves daily self-administration of two oral capsules (eplerenone + potassium placebo or chlorthalidone + potassium), each taken once a day, for a total of 336 doses over 48 weeks.
• Attend study visits at weeks 2, 12, 24, 36, and 48. These visits will involve collecting information, measuring blood pressure, and gathering blood and urine samples. Echocardiography (cardiac ultrasound), eye exam, and cardiac PET/CT scan will be performed during the baseline and week 48 visits.

Detailed Description

Preeclampsia, a condition marked by hypertension and systemic endothelial/microvascular dysfunction in late pregnancy, affects 8% of childbearing U.S. women and is associated with two-fold risk of future material cardiovascular disease (CVD). The American College of Cardiology and American Heart Association now recognize preeclampsia as a sex-specific CVD risk factor to guide prescription of preventive statin therapy. Beyond this focused recommendation, however, specific strategies for CVD risk reduction in women with preeclampsia are not yet established. Recent preclinical evidence suggests that preeclampsia induces vascular smooth muscle cell mineralocorticoid receptor (MR) sensitivity that persists postpartum, promoting hypertension and CVD. Although MR signaling is known to underlie hypertension, MR activation also promotes cardiovascular, kidney, and metabolic disease via effects that are partially independent of blood pressure. Work by this team has implicated MR signaling in coronary microvascular dysfunction, a known predictor of heart failure with preserved ejection fraction (HFpEF) and CVD mortality. The central hypothesis is that, among women with prior preeclampsia who subsequently develop chronic hypertension, MR blockade will promote favorable cardiac remodeling and improve coronary microvascular function, independent of changes in blood pressure, and thereby reduce CVD risk in affected women. To test this hypothesis, the investigators propose a randomized, double-blind clinical study in humans. Women aged <55 years with a history of preeclampsia, current chronic hypertension, and concentric left ventricular remodeling will be randomized 1:1 to receive eplerenone (mineralocorticoid receptor antagonist) or chlorthalidone (thiazide-like diuretic) with potassium supplementation for 48 weeks, targeting equivalent blood pressure control in both groups using daily home blood pressure measurement and 24-hour ambulatory blood pressure monitoring. The investigators will measure coronary microvascular function (myocardial flow reserve, i.e., hyperemic stress/rest myocardial blood flow) quantified by cardiac positron emission tomography (PET/CT) and cardiac structure and function by cardiac ultrasound at baseline and 48 weeks. It is expected that, compared with chlorthalidone, eplerenone will yield greater improvements in coronary microvascular function and myocardial diastolic function after 48 weeks of treatment. If the hypotheses are affirmed, these findings would support the targeted use of MR antagonists much earlier than recommended by current guidelines for the management of hypertension to more effectively prevent HFpEF and other CVD among women with a history of preeclampsia.

Conditions

Hypertension

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Eplerenone

Participants will receive eplerenone 100 mg daily plus potassium placebo for 48 weeks

Group Type: ACTIVE_COMPARATOR

Eplerenone 100 mg daily

Intervention Type: DRUG

Participants with a history of preeclampsia and current chronic hypertension will receive 100mg capsules of eplerenone to self-administer daily over the 48-week duration of the study treatment.

Potassium Placebo

Intervention Type: DRUG

Participants taking eplerenone will also take a potassium placebo to self-administer daily over the 48-week duration of the study treatment.

Chlorthalidone

Participants will receive chlorthalidone 25 mg plus potassium 20 mEq daily for 48 weeks

Group Type: ACTIVE_COMPARATOR

Chlorthalidone 25 mg daily

Intervention Type: DRUG

Participants with a history of preeclampsia with current chronic hypertension will receive 25mg capsules of chlorthalidone to self-administer daily over the 48-week duration of the study treatment.

Potassium Chloride

Intervention Type: DRUG

Participants taking chlorthalidone will also take 20 mEq of potassium to self-administer daily over the 48-week duration of the study treatment.

Interventions

Eplerenone 100 mg daily

Participants with a history of preeclampsia and current chronic hypertension will receive 100mg capsules of eplerenone to self-administer daily over the 48-week duration of the study treatment.

Intervention Type: DRUG

Chlorthalidone 25 mg daily

Participants with a history of preeclampsia with current chronic hypertension will receive 25mg capsules of chlorthalidone to self-administer daily over the 48-week duration of the study treatment.

Intervention Type: DRUG

Potassium Placebo

Participants taking eplerenone will also take a potassium placebo to self-administer daily over the 48-week duration of the study treatment.

Intervention Type: DRUG

Potassium Chloride

Participants taking chlorthalidone will also take 20 mEq of potassium to self-administer daily over the 48-week duration of the study treatment.

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• Female with a history of preeclampsia (defined by ACOG criteria) in a singleton pregnancy without pre-gestational chronic hypertension.
• Current chronic hypertension (stage 1 or greater).
• Evidence of concentric left ventricular (LV) remodeling, defined as relative LV wall thickness >0.42, with or without LV hypertrophy.
• Age 18-55 years at time of randomization.

Exclusion Criteria

• Use of a mineralocorticoid receptor antagonist (MRA) or amiloride within the past 3 months or more than 30 days within the previous 12 months.
• Planned pregnancy, current pregnancy, or lactation.
• Systolic BP >150 mmHg and/or diastolic BP >95 mmHg while on antihypertensives, or systolic BP >160 mmHg and/or diastolic BP >100 mmHg if untreated.
• BMI >45 kg/m².
• Clinical atherosclerotic cardiovascular disease, including coronary, cerebrovascular, or peripheral artery disease.
• Diabetes mellitus.
• LV ejection fraction <40% or history of clinical heart failure (reduced or preserved ejection fraction).
• Hypertrophic or other genetic cardiomyopathy.
• Any moderate or greater valvular heart disease.
• eGFR <60 mL/min/1.73 m².
• Urine microalbumin/creatinine ratio >300 mg/g at screening.
• Abnormal electrolytes, hemoglobin, liver function tests, or TSH at screening or baseline.
• Plasma renin activity <1 mg/mL/hour and aldosterone >20 ng/dL (suggestive of primary aldosteronism).
• Use of oral contraceptives, progestin depot or implant (note: progestin-containing IUD is permitted), or menopausal hormone therapy.
• History of hypersensitivity or intolerance to calcium channel blockers, thiazides, or MRAs.
• Active substance abuse.
• Other serious medical illnesses or concerns about protocol adherence/mortality risk within 15 months.
• Participation in another interventional clinical study.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 55 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: No

Sponsors

Brigham and Women's Hospital

OTHER

Sponsor Role: collaborator

National Heart, Lung, and Blood Institute (NHLBI)

NIH

Sponsor Role: collaborator

Massachusetts General Hospital

OTHER

Sponsor Role: lead

Responsible Party

Michael C. Honigberg

Clinician Investigator, Assistant Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Michael Honigberg, MD

Role: PRINCIPAL_INVESTIGATOR

Massachusetts General Hospital

Locations

Brigham and Women's Hospital

Boston, Massachusetts, United States

Massachusetts General Hospital

Boston, Massachusetts, United States

Countries

United States

Central Contacts

Samantha Murillo, MSc

Role: CONTACT

smurillo2@mgh.harvard.edu

860-336-6097

Facility Contacts

Ellen Seely, MD

Role: primary

ESEELY@bwh.harvard.edu

617-732-5666

Samantha Murillo, MSc

Role: primary

smurillo2@mgh.harvard.edu

860-336-6097

Other Identifiers

2025P001799

Identifier Type: -

Identifier Source: org_study_id

R01HL181150

Identifier Type: NIH

Identifier Source: secondary_id

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