A Study of Stress Echocardiography in Post-Menopausal Women at Risk for Coronary Disease

Study Overview
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Brief Summary
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The study is designed to see if stress echocardiography can be used as a screening exam in peri-, or post-menopausal women with a risk of developing of coronary artery disease and experiencing future cardiac events.

Detailed Description
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The clinical trial is designed to determine the prognostic value of stress echocardiography as a screening examination in peri-, or post-menopausal female patients with an intermediate likelihood of coronary artery disease (CAD) based on risk factors to identify patients at higher risk of experiencing future cardiac events.Female patients who are able to adequately exercise will undergo a symptom-limited exercise echocardiogram. Patients who are unable to adequately exercise or are predicted to be unable to exercise adequately (because of orthopedic/neurologic limitations, lung disease or debility), will perform dobutamine stress echocardiography. All patients will receive DEFINITY at rest and stress to enhance wall motion assessment.

Official Title
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SMART: Stress Echocardiography in Menopausal Women at Risk for Coronary Artery Disease Trial

Conditions
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Coronary Artery Disease, Heart Disease

Intervention / Treatment
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* Drug: Perflutren Lipid Microsphere Injectable Suspension


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Peri or Post menopausal women either: without symptoms but with risk factors for heart disease OR experiencing atypical chest pain, OR experiencing exertional dyspnea AND 2 or more risk factors for CAD Must be able to perform an exercise stress test Peri-or post-menopausal (including surgical menopause) based on history. Post-menopausal is defined as females age 40-65 who self-report the absence of menstrual periods for at least 12 months. Peri-menopausal is defined as females age 40-65 who self-report the absence or irregularity of menstrual periods for 6-12 months. Surgical menopause is defined as females who have had a bilateral salpingo-oophorectomy with or without hysterectomy. Exclusion Criteria: Previous confirmed heart disease

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 65 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: Diagnostic
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Definity<br>All patients will undergo a gray scale baseline unenhanced imaging session (apical 2- or 4 chamber view), as well as a DEFINITY (Perflutren Lipid Microsphere Injectable Suspension)-enhanced rest and a DEFINITY enhanced exercise or dobutamine stress echocardiography imaging session. The unenhanced and DEFINITY-enhanced rest and stress echocardiography imaging sessions will be performed on the same day. For the DEFINITY-enhanced imaging sessions all patients will receive diluted DEFINITY intravenously (IV). Diluted DEFINITY will be prepared by mixing 1 mL of activated DEFINITY® with 9 mL of normal saline in a 10 mL syringe. | Drug: Perflutren Lipid Microsphere Injectable Suspension<br>* Activated DEFINITY 10ug/kg by bolus injection<br>* Other names: DEFINITY;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Abnormal Contrast Stress Echocardiography and With Future Major Adverse Cardiac Events (MACE) at 2 and 5 Years Follow-Up | Peri- or post-menopausal female participants with an intermediate pre-test likelihood of coronary artery disease (CAD) received a Definity contrast-enhanced stress echocardiography study at baseline using either treadmill exercise or dobutamine stresss. Images were evaluated for wall motion abnormalities. The results were compared to patient history on 2-year and 5-year follow up to identify the potential of stress echocardiography for predicting those at higher risk of experiencing future cardiac events. Major adverse cardiac events (MACE) are defined as Cardiac death Myocardial infarction Cardiac revascularization (PCI or CABG) Hospitalization for chest pain or to rule out myocardial infarction Development of typical angina Development of heart failure | 2 year and 5 year follow up | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Abnormal ECG and With Major Adverse Cardiac Events (MACE) at 2 Year Follow-Up | Prognostic value of stress ECG testing for identifying female patients at increased risk of major adverse cardiac events (MACE) at 2-year follow-up Peri- or post-meopausal female subjects with an intermediate pre-test likelihood of coronary artery disease (CAD) received resting ECG at baseline. ECG was evaluated as normal or abnormal. The results were compared to patient history on 2-year follow up to identify the potential for ECG to predict those at higher risk of experiencing future cardiac events. Major adverse cardiac events (MACE) are defined as Cardiac death Myocardial infarction Cardiac revascularization (PCI or CABG) Hospitalization for chest pain or to rule out myocardial infarction Development of typical angina Development of heart failure | 2-year follow-up | 
| Change in Brain Natriuretic Peptide (BNP) in Subjects With and Without Major Adverse Cardiac Events at 2-year Follow-up. | The value of exercise-induced changes in blood concentration of cardiac peptide, brain natriuretic peptide (BNP in pg/mL in blood), was assessed in identifying patients with cardiac events at 2-year follow-up. The change in mean BNP blood concentration from rest to stress at baseline is summarized using number of subjects with and without MACE at 2-year follow-up Major adverse cardiac events (MACE) are defined as Cardiac death Myocardial infarction Cardiac revascularization (PCI or CABG) Hospitalization for chest pain or to rule out myocardial infarction Development of typical angina Development of heart failure | 2 year follow up | 
| Change in Atrial Natriuretic Peptide (ANP) in Subjects With and Without Major Adverse Cardiac Events at 2-year Follow-up. | The value of exercise-induced changes in blood concentration of cardiac peptide, atrial natriuretic peptide (ANP in pg/mL in blood), was assessed in identifying patients with cardiac events at 2-year follow-up. The change in mean ANP blood concentration from rest to stress at baseline is summarized using number of subjects with and without major adverse cardiac events (MACE) at 2-year follow-up. Major adverse cardiac events (MACE) are defined as Cardiac death Myocardial infarction Cardiac revascularization (PCI or CABG) Hospitalization for chest pain or to rule out myocardial infarction Development of typical angina Development of heart failure | 2 year follow up | 
| Change in Brachial Artery Reactivity Was Assessed in in a Subset of Participants With and Without Major Adverse Cardiac Events at 2-year and 5-year Follow-up. | A subset of the study population of peri- or post-meopausal female participants with an intermediate pre-test likelihood of coronary artery disease (CAD) was assessed for brachial artery reactivity at baseline. Brachial diameter was assessed using ultrasound and a pressure cuff both before and after administration of sublingual nitroglycerin. The results were compared to patient history on 2-year and 5-year follow up to identify the potential for brachial artery reactivity to predict those at higher risk of experiencing future cardiac events.The brachial artery reactivity was summarized using number of subjects with and without MACE on follow-up. Major adverse cardiac events (MACE) are defined as Cardiac death Myocardial infarction Cardiac revascularization (PCI or CABG) Hospitalization for chest pain or to rule out myocardial infarction Development of typical angina Development of heart failure | 2 year and 5 year follow up | 
| Mean Baseline Calcium Score of Participants With and Without Major Cardiac Events at 2-year Follow up. | Coronary artery calcium scoring assesses calcification of the coronary arteries using electron-beam computed tomography (EBCT). It is a sum of lesion scores of area and density above a threshold density. There is no intrinsic upper limit to the calcium score but values above 1000 may not be measurable. A subset of peri- or post-meopausal females with an intermediate pre-test likelihood of coronary artery disease (CAD) received resting EBCT at baseline. Images were evaluated for calcium score and results compared to patient history on 2-year follow up, Mean calcium score with confidence interval was summarized for subjects with and without major cardiac events (MACE) at 2-year follow up. Calcium score for general population: Score Description Relative Risk 0 No evidence of CAD 0 1-112 Average Risk of CAD 1.9 100-400 Moderate risk of CAD 4.3 400-999 High risk of CAD 7.2 1000 Very high risk of CAD 10.8 | 2 year follow up | 
| The Presence of Wall Motion Abnormalities on Definity Stress Echocardiography Assessed for Participants With Both Normal and Abnormal Angiography | In the sub-set of efficacy-evaluable participants who underwent clinically indicated coronary angiography, the accuracy of exercise echocardiography vs. angiography was determined for the detection of CAD. Positive angiography was defined as any stenosis greater than or equal to 50% in any vessel. Wall motion index change indicating abnormal motion was defined as greater than or equal to 13% in 2 or more segments. Angiography was required to have taken place within 60 days following stress echocardiography. | 60 days | 
| Participants With Positive and Negative Angiography Compared With Their ECG Results | In the sub-set of efficacy-evaluable participants who underwent clinically indicated coronary angiography, the accuracy of exercise ECG vs. angiography was determined for the detection of CAD. Positive angiography was defined as any stenosis greater than or equal to 50% in any vessel. | 60 days | 
| Number of Participants With Abnormal ECG and With Future Major Adverse Cardiac Events (MACE) at 5 Years Follow-Up | Prognostic value of stress ECG testing for identifying female patients at increased risk of major adverse cardiac events (MACE) at 5-year follow-up Peri- or post-meopausal female participants with an intermediate pre-test likelihood of coronary artery disease (CAD) received resting ECG at baseline. ECG was evaluated as normal or abnormal. The results were compared to patient history on 5-year follow up to identify the potential for ECG to predict those at higher risk of experiencing future major adverse cardiac events (MACE) at 5-year follow up. Major adverse cardiac events (MACE) are defined as Cardiac death Myocardial infarction Cardiac revascularization (PCI or CABG) Hospitalization for chest pain or to rule out myocardial infarction Development of typical angina Development of heart failure | 5 year follow up | 
| Change in Brain Natriuretic Peptide (BNP) in Participants With and Without Major Adverse Cardiac Events at 5-year Follow-up. | The value of exercise-induced changes in blood concentration of the cardiac peptide, brain natriuretic peptide (BNP in pg/mL in blood), was assessed in identifying patients with cardiac events at 5-year follow-up. The change in mean BNP blood concentration at baseline from rest to stress is summarized using number of participants with and without MACE at 5-year follow up. Major adverse cardiac events (MACE) are defined as Cardiac death Myocardial infarction Cardiac revascularization (PCI or CABG) Hospitalization for chest pain or to rule out myocardial infarction Development of typical angina Development of heart failure | 5 year follow up | 
| Change in Atrial Natriuretic Peptide (ANP) in Participants With and Without Major Adverse Cardiac Events at 5-year Follow-up. | The baseline value of exercise-induced changes in blood concentration of the cardiac peptide, atrial natriuretic peptide (ANP in pg/mL in blood), was assessed in identifying patients with cardiac events at 5-year follow-up. The change in mean ANP blood concentration from rest to stress at baseline was summarized using number of subjects with and without major adverse cardiac events (MACE) at 5-year follow up. Major adverse cardiac events (MACE) are defined as Cardiac death Myocardial infarction Cardiac revascularization (PCI or CABG) Hospitalization for chest pain or to rule out myocardial infarction Development of typical angina Development of heart failure | 5 year follow up | 
| Mean Calcium Score of Participants With and Without Major Cardiac Events at 5-year Follow up. | Coronary artery calcium scoring assesses calcification of the coronary arteries using electron-beam computed tomography (EBCT). It is a sum of lesion scores of area and density above a threshold density. There is no intrinsic upper limit to the calcium score but values above 1000 may not be measurable. A subset of peri- or post-meopausal females with an intermediate pre-test likelihood of coronary artery disease (CAD) received resting EBCT at baseline. Images were evaluated for calcium score and results compared to patient history on 5-year follow up, Mean calcium score with confidence interval was summarized for subjects with and without major cardiac events (MACE) at 5-year follow up Calcium score for general population: Score Description Relative Risk 0 No evidence of CAD 0 1-112 Average Risk of CAD 1.9 100-400 Moderate risk of CAD 4.3 400-999 High risk of CAD 7.2 1000 Very high risk of CAD 10.8 | 5 year follow up |