Data Analyses for Ancillary WISE Femhrt Hormone Replacement Study

Study Overview
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Brief Summary
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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.

Detailed Description
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See Brief Summary above.

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

Conditions
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Myocardial Ischemia

Intervention / Treatment
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* Drug: 1/10 NA/EE
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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: Abnormal P-31 magnetic resonance spectroscopy (a fall in quantitative PCr/ATP ratio >15% from control) performed at a WISE or nonWISE site 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 Reversible stress radionuclide perfusion defect > equivocal and not attributable to breast/imaging artifact. performed as part of the WISE protocol 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.
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: Hormone replacement therapy<br>Hormone replacement therapy with 1 mg norethindrone/10 mcg thinyl estradiol (1/10 NA/EE) | Drug: 1/10 NA/EE<br>* Hormone replacement therapy with 1 mg norethindrone/10 mcg thinyl estradiol (1/10 NA/EE)<br>|
| Placebo Comparator: Placebo<br>1mg placebo | Drug: Placebo<br>* 1 mg placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Inducible Myocardial Ischemia | 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) | 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) | 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 | 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) | 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 | Quality of life assessed by menopausal symptoms and psychological questionnaires | Baseline | 
| Quality of Life - Menopause Symptoms | Quality of life assessed by menopausal symptoms and psychological questionnaires | 12 weeks | 
| Quality of Life - Health Survey | 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 | 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) | 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) | 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) | 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) | 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) | 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) |