EWISE: Study of Eplerenone in Women With Chest Pain, Coronary Vascular Dysfunction and Evidence of Myocardial Ischemia

Study Overview
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Brief Summary
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Some women have chest pain even without having a blockage in one of the major blood vessels that supplies blood to the heart. In many of these women the microscopic (small) blood vessels in the heart do not function normally. This study seeks to determine if treatment with eplerenone, a commercially available diuretic, can improve the function of these microscopic blood vessels and, possibly, improve the chest pain.

Detailed Description
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INDICATION: Coronary Vascular Dysfunction (Endothelial Dysfunction and/or Microvascular angina). OBJECTIVES: To investigate effects of aldosterone blockade (eplerenone) on coronary vascular function. PATIENT POPULATION: Women who meet the National Heart, Lung and Blood Institute-sponsored WISE (Women Ischemia Syndrome Evaluation) study criteria of chest discomfort, coronary vascular dysfunction and undergoing evaluation for myocardial ischemia in the absence of significant coronary artery stenosis. STUDY DESIGN: A prospective, randomized, double blind placebo-controlled, comparative trial of eplerenone, given in the presence of a renin-angiotensin blocker (ACE-I or ARB in the case of ACE-I intolerance). TREATMENT: Eplerenone 25mg titrated to 50mg as tolerated per day versus placebo for four months PRIMARY EFFICACY PARAMETER(S): Epicardial coronary artery endothelial function at Week 16 (adjusted for baseline treatment group and site by treatment interaction variables) comparing the eplerenone group to the placebo group. SECONDARY EFFICACY PARAMETERS: Microvascular coronary endothelial function at Week 16 (adjusted for baseline treatment group and site by treatment interaction variables) comparing the eplerenone group to the placebo group. OTHER EFFICACY PARAMETERS: Coronary flow reserve Chest discomfort as measured by the Seattle Angina Questionnaire DASI SAFETY PARAMETERS: Blood pressure, pulse rate and frequency and occurrence of adverse events. The latter will include serum K and Creatinine. STATISTICAL RATIONALE AND ANALYSIS: A statistical rationale for the number of patients in the study has been provided. Interim analyses are planned after 10 patients have completed treatment in each group. ANTICIPATED TOTAL NUMBER OF PATIENTS: 50 (25 per treatment group). ANTICIPATED NUMBER OF PATIENTS AT EACH SITE: Approximately 13. PARTICIPATING SITES: University of Florida (Carl Pepine, MD), Emory University (Arshed Quyyumi, MD), Rhode Island Hospital (Barry Sharaf, MD), and Mayo Clinic (Amir Lerman, MD). There is an existing relationship between the first 3 sites and the Mayo Clinic site is familiar with all necessary protocol procedures and is anxious to participate. The University of Florida will serve as the main contracting site.

Official Title
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A Double-Blind, Multicenter, Placebo Controlled Study of Aldosterone Blockade (Eplerenone) in Women With Chest Pain, Coronary Vascular Dysfunction and Evidence of Myocardial Ischemia in the Absence of Significant Epicardial Coronary Artery Disease

Conditions
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Ischemic Heart Disease

Intervention / Treatment
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* Drug: Eplerenone
* Drug: Placebo or sugar pill


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Non-pregnant women with chest discomfort who are 21 to 75 years of age and from diverse racial/ethnic groups. Suspected ischemic heart disease (IHD) but no severe coronary stenosis (> 50% diameter reduction) on coronary angiography used to qualify for WISE. Endothelial dysfunction, defined as failure to dilate to intracoronary acetylcholine (< 5% increase in mean lumen diameter). If possible, patients should be taking stable, maximally tolerated dose of either an angiotensin-converting enzyme inhibitor [ACEI] (or an angiotensin II receptor blocker [ARB] if ACEI intolerant) Exclusion Criteria: Women who are breast-feeding or who are pregnant. Women of childbearing potential may be enrolled but must agree not to become pregnant during the course of the study and must practice a method of birth control considered reliable by the investigator. If established on hormonal contraceptives for more than 3 months, patients will be allowed to participate provided that this therapy remains constant throughout the study. If a patient becomes pregnant or begins breast-feeding during the study, she must be withdrawn immediately. Acute ischemic syndrome defined as acute myocardial infarction [MI] (by enzyme or electrocardiogram [ECG] criteria) or unstable angina within 1 month of entry. Uncontrolled moderate hypertension: sitting blood pressure > 160/95mmHg with measurements recorded on at least 2 occasions (for blood pressure control patients must first be stabilized, preferably with a diuretic, and remain on that dosing regimen throughout participation in the study). Severe heart failure defined as New York Heart Association (NYHA) Class III or IV on treatment. Coronary revascularization by either coronary artery bypass grafting (CABG) or percutaneous transluminal coronary angioplasty (PTCA) or stent placement. Conditions likely to influence outcomes independent of IHD: severe lung, renal (creatinine >1.8 or creatinine clearance [CrCl] ≤ 50ml/min) or hepatic disease; surgically uncorrected significant congenital or valvular heart disease; and other diseases likely to be fatal or require frequent hospitalizations within the next six months. Adherence or retention reasons: recent alcoholism or drug abuse; psychiatric illness including severe depression; dementia; active participation in any other research trial other than WISE; or unwilling to complete follow-up evaluations including repeat testing. Hypersensitivity to any medications to be used in the study Documented obstructive hypertrophic cardiomyopathy. Aortic stenosis (valve area < 1.5cm). Left ventricular (LV) dysfunction (ejection fraction <= 35%). History of significant cocaine or amphetamine abuse. Serum potassium > 5.0meq/l at baseline Taking potent CYP3A4 inhibitors (ketoconazole, itraconazole, nefazodone, troleandomycin, clarithromycin, ritonavir, nelfinavir) Intolerance to ACEI and ARB medications Use of potassium supplements or potassium sparing diuretics

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Eplerenone<br>Eplerenone 25 mg (1 pill)daily for 1 week then uptitrated to 50 mg (2 pills)daily for 15 weeks. | Drug: Eplerenone<br>* Eplerenone 25 mg (1 pill) daily for 1 week then uptitrated to 50 mg (2 pills) daily for 15 weeks.<br>|
| Placebo Comparator: Placebo or sugar pill<br>Placebo blinded as 25 mg tablet once daily for 1 week then uptitrated to 2 pills daily for 15 weeks. | Drug: Placebo or sugar pill<br>* Placebo blinded as 25 mg tablet(1 pill) once daily for 1 week then uptitrated to 50 mg (2 pills) daily for 15 weeks.<br>* Other names: Placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Epicardial Coronary Artery Endothelial Function (Adjusted) at Week 16 Comparing the Eplerenone Group to the Placebo Group | The primary measure was the relative change in coronary diameter to acetylcholinem (ACH) at 16 weeks adjusted for baseline reactivity to acetylcholine. Change in coronary artery diameter after ACH was measured in mm at baseline and 16 weeks. Percent change at 16 weeks - percent change at baseline was the outcome. | 16 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Microvascular Coronary Flow Reserve(Adjusted) at Week 16 Adjusted for Baseline Coronary Flow Reserve Comparing the Eplerenone Group to the Placebo Group | Coronary flow reserve is a ratio of coronary blood flow velocity before and after adenosine. The outcome measure is the difference between the coronary flow reserve at 16 weeks adjusted for coronary flow reserve at baseline. | 16 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Microvascular Disease, Women, Ischemic Heart Disease, WISE