Data Analyses for Ancillary WISE Femhrt Hormone Replacement Study

April 22, 2019 updated by: Noel Bairey Merz, Cedars-Sinai Medical Center

WISE Ancillary Study Data Analyses: Efficacy of Hormone Replacement on Myocardial Ischemia in Postmenopausal Women With Normal/Minimal Coronary Artery Disease: Data Analysis

The goal of the main trial was to evaluate the effect of low dose hormone replacement therapy with 1 mg norethindrone/10mcg ethinyl estradiol in postmenopausal women with a history of chest discomfort, myocardial ischemia and no obstructive CAD. For the purposes of this study as a core lab coordinating center, the investigators will be performing P31 MRS core lab analyses; hormone core lab analyses; lipid core lab analyses; glucose, insulin and HOMA core lab analyses; exercise stress test/Holter monitor core lab analyses; brachial artery reactivity test core lab analyses; full study data analyses for manuscript preparation and the writing and submission and publication of manuscript.

The main trial duration: December 1999 - May 2003.

The ancillary data analysis project duration: April 2006 - March 2010.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

See Brief Summary above.

Study Type

Interventional

Enrollment (Actual)

37

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • California
      • Los Angeles, California, United States, 90048
        • Cedars-Sinai Women's Heart Center, 8631 W. 3rd St, Suite 740

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Child
  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Genders Eligible for Study

Female

Description

Inclusion Criteria

  • Postmenopausal WISE and nonWISE study participants
  • Normal/minimally diseased coronary arteries (<50% luminal diameter stenosis in all epicardial coronary arteries) within 36 months of ancillary study entry and no intercurrent MI, PTCA, CABG

  • Any one (or multiple) of the following criteria suggestive of myocardial ischemia within 36 months of ancillary study entry:

    1. Abnormal P-31 magnetic resonance spectroscopy (a fall in quantitative PCr/ATP ratio >15% from control) performed at a WISE or nonWISE site
    2. Positive exercise stress test (> or = 1mm horizontal or downsloping, or > or =1.5mm upsloping ST segment depression measured 0.08 msec after the J point), performed and/or interpretated by a WISE or WISE ancillary ancillary trial investigator
    3. Reversible stress radionuclide perfusion defect > equivocal and not attributable to breast/imaging artifact. performed as part of the WISE protocol
    4. Coronary artery flow reserve <2.25 performed. as part of using the WISE protocol
  • No contraindications to 12 weeks of FemHRT or hormone replacement therapy
  • Normal mammogram and pelvic exam (including PAP smear for those with an intact uterus) within 12 months of study entry
  • Documented normal liver function testing (SGOT) within 3 months of study entry.

Exclusion Criteria

  • Documented myocardial infarction, coronary artery bypass surgery or mechanical revascularization
  • Systolic blood pressure >200 mmHg or diastolic blood pressure >105 mmHg
  • LDL-cholesterol >190 mg/dl, triglycerides > or = 300 mg/dl
  • Clinically significant hepatic or renal dysfunction (SGOT more than 1.2 times normal at baseline, serum creatinine >2)
  • Uncontrolled diabetes mellitus (FBS > or = 225 mg/dl) or new onset diabetes until stabilized
  • Clinically significant valvular heart disease, dilated cardiomyopathy, or congestive heart failure (NYHA Class IV or severe Class III)
  • Currently on hormone replacement therapy and unwilling/unable to withdraw treatment prior to study, (participants are eligible for study entry 4-8 weeks following hormone replacement therapy withdrawal, at the discretion of the WISE ancillary trial Principal Investigator)
  • Previous breast cancer, mammogram suggestive of cancer, or endometrial cancer without hysterectomy
  • Abnormal uterine bleeding or abnormal Pap smear (SIL I, II or III, carcinoma in situ, or cancer)
  • Previous deep venous thrombosis, pulmonary embolism, or other thromboembolic disorder.
  • Alcoholism or drug abuse
  • Participation in any other investigational drug or device study

Women with elevated diastolic (> or = 90 mm Hg) or systolic (> or = 140 mm Hg) blood pressure, LDL-cholesterol (> or = 160 mg/dl), fasting blood sugar (> or = 130 mg/dl) and women who smoke cigarettes will be told their risk factor levels and referred for evaluation and treatment by their private physician.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Double

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: Hormone replacement therapy
Hormone replacement therapy with 1 mg norethindrone/10 mcg thinyl estradiol (1/10 NA/EE)
Drug: 1/10 NA/EE
Hormone replacement therapy with 1 mg norethindrone/10 mcg thinyl estradiol (1/10 NA/EE)
Placebo Comparator: Placebo
1mg placebo
Drug: Placebo
1 mg placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Inducible Myocardial Ischemia
Time Frame: Baseline
Inducible myocardial ischemia measured by P-31 gated magnetic resonance cardiac spectroscopy (MRS) is reported as change (∆) in PCr/ATP ratio, with isometric submaximal handgrip stress. PCr/ATP ratio defined as (stress-[average of rest and recovery periods]) / average of rest and recover periods X 100, and expressed as % mean ± SD. For this trial, myocardial ischemia was pre-specified as a fall in quantitative PCR/ATP ratio >20% from rest, and a lower value is considered indicative of greater ischemia.
Baseline
Endothelial Dysfunction (FMD)
Time Frame: Baseline

Endothelial dysfunction refers to altered vasoactive, anticoagulant, and anti-inflammatory properties of endothelium, and dysregulated vascular growth remodeling that results from a loss of nitric oxide (NO) bioactivity in the endothelium. Brachial Artery Reactivity Testing (BART), high-frequency ultrasonographic imaging of the brachial artery, evaluates flow-mediated vasodilation (FMD), an endothelium-dependent function. The technique provokes the release of nitric oxide, resulting in vasodilation that can be quantitated as an index of endothelial dysfunction.

Flow-mediated vasodilation is typically expressed as the change in post-stimulus diameter as a percentage of the baseline diameter [diameter after cuff deflation - baseline diameter / baseline diameter) x 100].
Baseline
Endothelial Dysfunction (FMD)
Time Frame: 12 weeks

Endothelial dysfunction refers to altered vasoactive, anticoagulant, and anti-inflammatory properties of endothelium, and dysregulated vascular growth remodeling that results from a loss of nitric oxide (NO) bioactivity in the endothelium. Brachial Artery Reactivity Testing (BART), high-frequency ultrasonographic imaging of the brachial artery, evaluates flow-mediated vasodilation (FMD), an endothelium-dependent function. The technique provokes the release of nitric oxide, resulting in vasodilation that can be quantitated as an index of vasomotor function.

Flow-mediated vasodilation is typically expressed as the change in post-stimulus diameter as a percentage of the baseline diameter [diameter after cuff deflation - baseline diameter / baseline diameter) x 100].
12 weeks
Inducible Myocardial Ischemia
Time Frame: 12 weeks
Inducible myocardial ischemia measured by P-31 gated magnetic resonance cardiac spectroscopy (MRS) is reported as change (∆) in PCr/ATP ratio, with isometric submaximal handgrip stress. PCr/ATP ratio defined as (stress-[average of rest and recovery periods]) / average of rest and recover periods X 100, and expressed as % mean ± SD. For this trial, myocardial ischemia was pre-specified as a fall in quantitative PCR/ATP ratio >20% from rest, and a lower value is considered indicative of greater ischemia.
12 weeks

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Physical Functional Disability - Functional Capacity (METs)
Time Frame: Baseline
Physical functional disability measured by exercise stress testing. Functional capacity was measured as metabolism equivalents (METs), exercise duration, and exercise-induced chest pain. A MET is defined as the resting metabolic rate, that is, the amount or oxygen consumet at rest, sitting quietly in a chair, approximately 3.5 ml O2 / kg / min (1.2 kcallmin for a 70-kg person). As such, work at METs requires twice the resting metabolism or 7.0 ml O2/kg/min, and so on.
Baseline
Quality of Life - Menopause Symptoms
Time Frame: Baseline
Quality of life assessed by menopausal symptoms and psychological questionnaires
Baseline
Quality of Life - Menopause Symptoms
Time Frame: 12 weeks
Quality of life assessed by menopausal symptoms and psychological questionnaires
12 weeks
Quality of Life - Health Survey
Time Frame: Baseline

Quality of life assessed by cardiac symptoms and psychological questionnaires (SF 36 scale - Short Form Health Survey) The SF-36 includes one multi-item scale that assesses eight health concepts: 1) limitations in physical activities because of health problems; 2) limitations in social activities because of physical or emotional problems; 3) limitations in usual role activities because of physical health problems; 4) bodily pain; 5) general mental health (psychological distress and well-being); 6) limitations in usual role activities because of emotional problems; 7) vitality (energy and fatigue); and 8) general health perceptions.

Each scale is directly transformed into a 0-100 scale on the assumption that each question carries equal weight. The lower the score the more disability. The higher the score the less disability i.e., a score of zero is equivalent to maximum disability and a score of 100 is equivalent to no disability.
Baseline
Quality of Life - Health Survey
Time Frame: 12 weeks

Quality of life assessed by cardiac symptoms and psychological questionnaires (SF 36 scale - Short Form Health Survey) The SF-36 includes one multi-item scale that assesses eight health concepts: 1) limitations in physical activities because of health problems; 2) limitations in social activities because of physical or emotional problems; 3) limitations in usual role activities because of physical health problems; 4) bodily pain; 5) general mental health (psychological distress and well-being); 6) limitations in usual role activities because of emotional problems; 7) vitality (energy and fatigue); and 8) general health perceptions.

Each scale is directly transformed into a 0-100 scale on the assumption that each question carries equal weight. The lower the score the more disability. The higher the score the less disability i.e., a score of zero is equivalent to maximum disability and a score of 100 is equivalent to no disability.
12 weeks
Physical Functional Disability - Functional Capacity (METs)
Time Frame: Exit at 12 weeks
Physical functional disability measured by exercise stress testing. Functional capacity was measured as metabolism equivalents (METs), exercise duration, and exercise-induced chest pain. A MET is defined as the resting metabolic rate, that is, the amount or oxygen consumet at rest, sitting quietly in a chair, approximately 3.5 ml O2 / kg / min (1.2 kcallmin for a 70-kg person). As such, work at METs requires twice the resting metabolism or 7.0 ml O2/kg/min, and so on.
Exit at 12 weeks
Physical Functional Disability - Functional Capacity (Metabolism Equivalents)
Time Frame: Baseline
Physical functional disability measured by exercise stress testing. Functional capacity was measured as metabolism equivalents (METs), exercise duration, and exercise-induced chest pain.
Baseline
Physical Functional Disability - Functional Capacity (Metabolism Equivalents)
Time Frame: Exit (12 weeks)
Physical functional disability measured by exercise stress testing. Functional capacity was measured as metabolism equivalents (METs), exercise duration, and exercise-induced chest pain.
Exit (12 weeks)
Physical Functional Disability - Functional Capacity (Exercise Induced ST Segment Depression)
Time Frame: Baseline

Physical functional disability measured by exercise stress testing. Functional capacity was measured as metabolism equivalents (METs), exercise duration, and exercise-induced chest pain.

In electrocardiography, the ST segment connects the QRS complex and the T wave and has duration of 80 to 120 ms. It should be essentially level with the PR and TP segment. The normal ST segment has a slight upward concavity. Flat, downsloping, or depressed ST segment may indicate coronary ishcemia. Positive treadmill exercise stress test (>1.0 mm horizontal / downsloping or >1.5 upsloping ST segment depression measured 0.08 msec after the J point).
Baseline
Physical Functional Disability - Functional Capacity (Stress Induced ST Segment Depression)
Time Frame: Exit (12 weeks)

Physical functional disability measured by exercise stress testing. Functional capacity was measured as metabolism equivalents (METs), exercise duration, and exercise-induced chest pain.

In electrocardiography, the ST segment connects the QRS complex and the T wave and has duration of 80 to 120 ms. It should be essentially level with the PR and TP segment. The normal ST segment has a slight upward concavity. Flat, downsloping, or depressed ST segment may indicate coronary ishcemia. Positive treadmill exercise stress test (>1.0 mm horizontal / downsloping or >1.5 upsloping ST segment depression measured 0.08 msec after the J point).
Exit (12 weeks)

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Cedars-Sinai Medical Center

Collaborators

Johns Hopkins University
University of Alabama at Birmingham
University of Pittsburgh
University of Florida
Parke-Davis
Allegheny University

Investigators

  • Study Chair: C. Noel Bairey Merz, MD, Cedars-Sinai Medical Center
  • Principal Investigator: Carl Pepine, MD, University of Florida
  • Principal Investigator: Steve Reis, MD, University of Pittsburgh
  • Principal Investigator: Nathaniel Reichek, MD, Allegheny University of the Health Sciences
  • Principal Investigator: William Rogers, MD, University of Alabama at Birmingham
  • Principal Investigator: Vijay Misra, MD, University of Alabama at Birmingham
  • Principal Investigator: Robert B Weiss, MD, Johns Hopkins University
  • Principal Investigator: Sheryl Kelsey, PhD, University of Pittsburgh
  • Study Director: George Sopko, MD, National Institute of Health (WISE Project Officer)
  • Study Director: James Symons, PhD, Parke-Davis
  • Study Director: Connie McLaughlin, PharmD, Parke-Davis

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

December 1, 1999

Primary Completion (Actual)

May 1, 2003

Study Completion (Actual)

March 1, 2010

Study Registration Dates

First Submitted

January 11, 2008

First Submitted That Met QC Criteria

January 23, 2008

First Posted (Estimate)

January 24, 2008

Study Record Updates

Last Update Posted (Actual)

April 24, 2019

Last Update Submitted That Met QC Criteria

April 22, 2019

Last Verified

April 1, 2019

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 9260
  • IRB#0505140 (Other Identifier: University of Pittsburgh)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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