Data Analyses for Ancillary WISE Femhrt Hormone Replacement Study

Overview

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.

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

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Treatment
    • Masking: Double (Participant, Investigator)
  • Study Primary Completion Date: May 2003

Detailed Description

See Brief Summary above.

Interventions

  • Drug: 1/10 NA/EE
    • Hormone replacement therapy with 1 mg norethindrone/10 mcg thinyl estradiol (1/10 NA/EE)
  • Drug: Placebo
    • 1 mg placebo

Arms, Groups and Cohorts

  • Active Comparator: Hormone replacement therapy
    • Hormone replacement therapy with 1 mg norethindrone/10 mcg thinyl estradiol (1/10 NA/EE)
  • Placebo Comparator: Placebo
    • 1mg placebo

Clinical Trial Outcome Measures

Primary Measures

  • 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.
  • 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].
  • 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].
  • 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.

Secondary Measures

  • 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.
  • Quality of Life – Menopause Symptoms
    • Time Frame: Baseline
    • Quality of life assessed by menopausal symptoms and psychological questionnaires
  • Quality of Life – Menopause Symptoms
    • Time Frame: 12 weeks
    • Quality of life assessed by menopausal symptoms and psychological questionnaires
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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).
  • 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).

Participating in This Clinical Trial

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.

Gender Eligibility: Female

Minimum Age: N/A

Maximum Age: N/A

Are Healthy Volunteers Accepted: No

Investigator Details

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

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Citations Reporting on Results

Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, Jackson RD, Beresford SA, Howard BV, Johnson KC, Kotchen JM, Ockene J; Writing Group for the Women's Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial. JAMA. 2002 Jul 17;288(3):321-33.

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