Coronary Artery Disease
Conditions
Keywords
Lumason, Dobutamine stress echo, stress echo, coronary artery disease
Brief summary
The purpose of this study was to assess the safety and efficacy of Lumason-enhanced dobutamine stress echo (CE-DSE) in subjects having a suboptimal left ventricular endocardial border delineation (LV EBD) at rest and who were scheduled for coronary angiography.
Detailed description
The study was designed to assess the safety and efficacy of Lumason at improving the visualization of the LV EBD during pharmacologic stress echocardiography examinations and for detection or exclusion of the coronary artery disease (CAD). The study population consisted of adult subjects referred for pharmacological stress echocardiography and with suboptimal image quality during unenhanced ultrasound imaging at rest who had known or suspected CAD. Subjects enrolled in the study represented subjects who could benefit most from contrast-enhanced ultrasound (CEUS) stress echocardiography.
Interventions
DRUGLumason
Lumason (sulfur hexafluoride-type A microspheres) an ultrasound contrast agent was administered as 2 single 2-mL IV injections during rest and stress echocardiography
Sponsors
Bracco Diagnostics, Inc
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
DIAGNOSTIC
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Provided written Informed Consent and was willing to comply with protocol requirements; * Was at least 18 years of age; * Had suspected or known CAD and was scheduled to undergo coronary angiography within 6 months after the LUMASON DSE. * Had undergone a previous echocardiography prior to enrollment; resulting in suboptimal unenhanced images at rest, defined as ≥ 2 suboptimal adjacent segments in any apical view.
Exclusion criteria
* Was a pregnant or lactating female. Excluded the possibility of pregnancy by testing on site at the institution (serum or urine βHCG) within 24 hours prior to the start of LUMASON administration(s), by surgical history (e.g., tubal ligation or hysterectomy), post menopausal with a minimum 1 year without menses; * Had any known hypersensitivity to 1 or more ingredients of LUMASON (sulfur hexafluoride or to any components of LUMASON); * Had any known hypersensitivity to dobutamine; * Had an ongoing or recent (within the last 30 days) acute myocardial infarction; * Had known right-to-left, bidirectional or transient cardiac shunt (ruled out with agitated saline study performed before administration of LUMASON); * Had electrolyte (especially potassium and magnesium) abnormalities; * Had unstable pulmonary and/or systemic hemodynamic conditions e.g.: * decompensated or inadequately controlled congestive heart failure (NYHA Class IV); * hypovolemia; * uncontrolled hypertension, i.e. resting systolic blood pressure \>200 mmHg or diastolic blood pressure \>110 mmHg; * unstable angina; * acute coronary syndrome; * aortic dissection; * acute pericarditis, * myocarditis, or endocarditis; * stenosis of the main left coronary artery; * hemodynamically significant outflow obstruction of the left ventricle, including hypertrophic obstructive cardiomyopathy; * hemodynamically significant cardiac valvular defect; * acute pulmonary embolism; * Had uncontrolled cardiac arrhythmias; * Had significant disturbance in conduction; * Had hypertrophic subaortic stenosis; * Had an acute illness (e.g., infections, hyperthyroidism, or severe anemia); * Was previously entered into this study or received an investigational compound within 30 days before admission into this study; * Had been treated with any other contrast agent either intravascularly or orally within 48 hours of the first LUMASON administration; * Had any medical condition or other circumstances which would significantly decrease the chances of obtaining reliable data, achieving study objectives, or completing the study and/or postdose follow-up examinations; In addition, due to the use of Atropine in subjects who had not reached targeted heart rate with peak dobutamine infusion, subjects with the following were excluded: * Glaucoma; * Pyloric stenosis; * Prostatic hypertrophy.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Sensitivity and Specificity for Detection or Exclusion of Coronary Artery Disease (CAD) | Participants were followed until they had coronary angiography or up to 6 months post dose to collect clinical information on cardiac events if no coronary angiography were performed | The diagnostic performance of the echocardiographic images was compared to the truth standard to determine sensitivity and specificity. A diagnosis of coronary artery disease (CAD) was determined for both the echo images and truth standard (positive diagnosis for CAD is defined as \>/= 50% stenosis of any vessel on coronary angiography or if no coronary angiography is performed the occurence of a cardiac event based on clinical information for up to 6 months post dose; otherwise the diagnosis is negative). Results for sensitivity and specificity are reflected based on difference between contrast enhanced stress echo and unenhanced stress echo. Results for analysis of data based on majority assessment from the three off-site blinded readers are presented. Sensitivity and specificity are the percentages of correctly diagnosed subjects by stress echo over the total positive and negative subjects according to the truth standard respectively. |
| Reader-Specific Percentages of Participants Identified as Having a Critical Shift From Suboptimal to Optimal Echocardiographic Images | Participants were followed until they had coronary angiography or up to 6 months post dose to collect clinical information on cardiac events if no coronary angiography was performed | The percentage of subjects with suboptimal images (defined as \>= 2 adjacent segments with inadequate left ventricular endocardial border delineation (LV EBD) in any of the 3 apical views) at unenhanced stress echo converted to adequate (reduction of suboptimal segments in any of the 3 apical views) at contrast-enhanced stress echo |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Total LV EBD | Participants were followed until they had coronary angiography or up to 6 months post dose to collect clinical information on cardiac events if no coronary angiography was performed | Measured as the change in the total LV EBD score based on the 17 segments, from peak stress unenhanced vs. peak stress contrast-enhanced. Total LV EBD score ranges from 0 to 34 and higher score is better outcome. |
| Number of Participants With Adverse Events | up to 72 hours post dose | To obtain safety data in subjects administered Lumason during echocardiography |
Countries
Canada, Germany, Italy, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Lumason Lumason (sulfur hexafluoride lipid-type A microspheres) 2 mL IV injection
Lumason: Lumason (sulfur hexafluoride-type A microspheres) an ultrasound contrast agent was administered as 2 single 2-mL IV injections during rest and stress echocardiography | 173 |
| Total | 173 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | discontinued | 1 |
| Overall Study | Not dosed | 2 |
Baseline characteristics
| Characteristic | Lumason |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 97 Participants |
| Age, Categorical Between 18 and 65 years | 76 Participants |
| Age, Continuous | 65.0 years STANDARD_DEVIATION 10.47 |
| BMI | 30.33 kg/m^2 STANDARD_DEVIATION 7.252 |
| Height | 169.3 cm STANDARD_DEVIATION 10.49 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 5 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants |
| Race (NIH/OMB) More than one race | 4 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 160 Participants |
| Sex: Female, Male Female | 52 Participants |
| Sex: Female, Male Male | 121 Participants |
| Weight | 86.99 kg STANDARD_DEVIATION 21.781 |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 173 |
| other Total, other adverse events | 21 / 173 |
| serious Total, serious adverse events | 3 / 173 |
Outcome results
Primary
Reader-Specific Percentages of Participants Identified as Having a Critical Shift From Suboptimal to Optimal Echocardiographic Images
The percentage of subjects with suboptimal images (defined as \>= 2 adjacent segments with inadequate left ventricular endocardial border delineation (LV EBD) in any of the 3 apical views) at unenhanced stress echo converted to adequate (reduction of suboptimal segments in any of the 3 apical views) at contrast-enhanced stress echo
Time frame: Participants were followed until they had coronary angiography or up to 6 months post dose to collect clinical information on cardiac events if no coronary angiography was performed
Population: The analysis population for EBD included all subjects who received Lumason and had EBD data available at peak stress for both UE-DSE and CE-DSE.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| CE-DSE - UE-DSE | Reader-Specific Percentages of Participants Identified as Having a Critical Shift From Suboptimal to Optimal Echocardiographic Images | 84.4 percentage of participants |
| Reader 2 | Reader-Specific Percentages of Participants Identified as Having a Critical Shift From Suboptimal to Optimal Echocardiographic Images | 93.7 percentage of participants |
| Reader 3 | Reader-Specific Percentages of Participants Identified as Having a Critical Shift From Suboptimal to Optimal Echocardiographic Images | 78.8 percentage of participants |
Primary
Sensitivity and Specificity for Detection or Exclusion of Coronary Artery Disease (CAD)
The diagnostic performance of the echocardiographic images was compared to the truth standard to determine sensitivity and specificity. A diagnosis of coronary artery disease (CAD) was determined for both the echo images and truth standard (positive diagnosis for CAD is defined as \>/= 50% stenosis of any vessel on coronary angiography or if no coronary angiography is performed the occurence of a cardiac event based on clinical information for up to 6 months post dose; otherwise the diagnosis is negative). Results for sensitivity and specificity are reflected based on difference between contrast enhanced stress echo and unenhanced stress echo. Results for analysis of data based on majority assessment from the three off-site blinded readers are presented. Sensitivity and specificity are the percentages of correctly diagnosed subjects by stress echo over the total positive and negative subjects according to the truth standard respectively.
Time frame: Participants were followed until they had coronary angiography or up to 6 months post dose to collect clinical information on cardiac events if no coronary angiography were performed
Population: Analysis population for coronary artery disease (CAD) included all subjects who received Lumason, had overall diagnostic conclusion of CAD available at peak stress for both UE-DSE and CE-DSE and had a definite truth standard diagnosis (Positive, Negative) for CAD (coronary angiography or 6 months collection of cardiac events follow-up data).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| CE-DSE - UE-DSE | Sensitivity and Specificity for Detection or Exclusion of Coronary Artery Disease (CAD) | Sensitivity | 8.0 percentage of participants |
| CE-DSE - UE-DSE | Sensitivity and Specificity for Detection or Exclusion of Coronary Artery Disease (CAD) | Specificity | 33.7 percentage of participants |
Comparison: Sensitivity: superiority test comparing CE-DSE and UE-DSE based on the differencep-value: 0.0896McNemar
Comparison: Specificity: superiority test comparing CE-DSE and UE-DSE based on the differencep-value: <0.0001McNemar
Secondary
Change in Total LV EBD
Measured as the change in the total LV EBD score based on the 17 segments, from peak stress unenhanced vs. peak stress contrast-enhanced. Total LV EBD score ranges from 0 to 34 and higher score is better outcome.
Time frame: Participants were followed until they had coronary angiography or up to 6 months post dose to collect clinical information on cardiac events if no coronary angiography was performed
Population: The analysis population for EBD included all subjects who received Lumason and had EBD data available at peak stress for both UE-DSE and CE-DSE.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| CE-DSE - UE-DSE | Change in Total LV EBD | Reader 3 | 17.8 score on a scale | Standard Deviation 7.04 |
| CE-DSE - UE-DSE | Change in Total LV EBD | Reader 1 | 17.5 score on a scale | Standard Deviation 10.83 |
| CE-DSE - UE-DSE | Change in Total LV EBD | Reader 2 | 13.4 score on a scale | Standard Deviation 8.57 |
| Reader 2 | Change in Total LV EBD | Reader 3 | 23.6 score on a scale | Standard Deviation 7.47 |
| Reader 2 | Change in Total LV EBD | Reader 1 | 28.1 score on a scale | Standard Deviation 8.32 |
| Reader 2 | Change in Total LV EBD | Reader 2 | 30.5 score on a scale | Standard Deviation 4.81 |
| Reader 3 | Change in Total LV EBD | Reader 3 | 5.8 score on a scale | Standard Deviation 9.17 |
| Reader 3 | Change in Total LV EBD | Reader 2 | 17.1 score on a scale | Standard Deviation 7.87 |
| Reader 3 | Change in Total LV EBD | Reader 1 | 10.6 score on a scale | Standard Deviation 11.98 |
Secondary
Number of Participants With Adverse Events
To obtain safety data in subjects administered Lumason during echocardiography
Time frame: up to 72 hours post dose
Population: Safety analysis population includes all subjects who received Lumason
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| CE-DSE - UE-DSE | Number of Participants With Adverse Events | Number of subjects with adverse events (AE) | 21 participants |
| CE-DSE - UE-DSE | Number of Participants With Adverse Events | Number of subjects with AEs by intensity - Mild | 15 participants |
| CE-DSE - UE-DSE | Number of Participants With Adverse Events | Number of subjects with AEs by intensity -Moderate | 5 participants |
| CE-DSE - UE-DSE | Number of Participants With Adverse Events | Number of subjects with AEs by intensity - Severe | 1 participants |
| CE-DSE - UE-DSE | Number of Participants With Adverse Events | Number of subjects with serious AEs | 3 participants |