Coronary Artery Disease
Conditions
Keywords
Regadenoson (Lexiscan), PET N-13 ammonia imaging, Myocardial Blood Flow (MBF), Regadenoson Stress
Brief summary
Blockage of the heart arteries (coronary artery disease) can lead to angina (chest pain), heart attacks, heart failure, and/or death. Positron emission tomography (PET) stress myocardial perfusion imaging (MPI) is a powerful tool to help identify blockages in the coronary arteries. During the PET MPI test, a drug is given to mimic the effects of exercise on the heart. The study was done to measure blood flow to the heart using two similar drugs approved to mimic the effects of exercise on the heart in people during a heart stress test. The first drug, called adenosine, has been approved for this use for several decades. The second drug, called regadenoson, was approved in 2008. The investigators were looking at whether the increase in blood flow to the heart with the newer drug (regadenoson) was similar to the increase in blood flow with the older drug (adenosine). This information is important for the use of these drugs in patients and for interpreting the blood flow values.
Detailed description
The hypothesis for this study was that Regadenoson will produce a very similar degree of maximal hyperemia (increased blood flow) as adenosine, the other vasodilator agent. There were only 2 days on study for each subject. On Day 1 of the study, subjects were interviewed and had a physical exam, including a resting 12-lead electrocardiogram (ECG) to exclude evidence of silent ischemia or myocardial infarction, and other cardiovascular disorders. Subjects were instructed to have a light meal at least 4 hours prior to the PET MPI. Subjects were instructed to abstain from caffeine-containing products for 24 hours prior to the PET scan. Day 1 of the study occurred less than or equal to 4 weeks of Day 2. On Day 2 of the study, each subject underwent three PET N-13 ammonia (10-20 mCi) dynamic emission acquisitions: resting, regadenoson (0.4 mg/5 mL IV), and adenosine (140 microgram/kg/min; order of regadenoson vs adenosine was randomized according to subject's birth year), and three transmission acquisitions for attenuation correction. Each emission acquisition was separated by 50 min to allow for radioactive decay. At the end of the drug infusions, subjects were monitored for 5-30 min. Based on the known short biological half-lives of these stress agents, the pharmacologic effects of each drug should have dissipated by the time the next drug was administered.
Interventions
DRUGRegadenoson
Regadenoson (0.4 mg/5 ml IV) was administered intravenously over 10 seconds, followed immediately by saline flush.
DRUGAdenosine
Adenosine (140 μg/kg/min) was administered intravenously over 6 minutes.
DRUGN-13 ammonia
Ammonia N-13 Injection is a radioactive diagnostic agent for Positron Emission Tomography (PET) indicated for diagnostic PET imaging of the myocardium under rest or pharmacologic stress conditions to evaluate myocardial perfusion in patients with suspected or existing coronary artery disease. The N-13 ammonia used in the study was synthesized by the Mayo Cyclotron Facility as per routine institutional clinical protocol.
Sponsors
Astellas Pharma Inc
Mayo Clinic
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
DIAGNOSTIC
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
30 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
* Healthy male and female volunteers over the age of 30. * Written informed consent will be obtained from each subject. * Each subject will undergo a history and physical examination
Exclusion criteria
* Any cardiovascular or pulmonary symptoms or exam findings * History of low blood pressure (\< 90/50 mmHg) * Prior cardiac history * History of hypertension * History of hyperlipidemia * History of diabetes mellitus * History of asthma or chronic obstructive pulmonary disease * Weight of \> 450 pounds * Chronic kidney disease * Other serious illness such as cancer * Current smoking * Medication use (with the exception of acetaminophen, aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), and thyroid hormone replacement) * Illicit drug use * Prior allergic reaction to adenosine, regadenoson, or aminophylline * Pregnancy
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Global Hyperemic Myocardial Blood Flow (MBF) | Day 2, approximately 4 hours after arrival in positron emission tomography (PET) unit | MBF is the rate of blood supplied to the myocardium, or heart muscle. Hyperemic MBF is the rate of myocardial blood flow in the heart muscle during either regadenoson or adenosine stress. Myocardial blood flow was calculated using commercial software (PMOD Technologies, version 2.4). The Hyperemic MBF was measured approximately 4 hours after arrival in the PET unit. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Global Cardiac Flow Rate | Day 2, approximately 4 hours after arrival in positron emission tomography (PET) unit | Cardiac Flow Rate was calculated using the equation: hyperemic MBF/resting MBF. |
| Hyperemic Segmental MBF | Day 2, approximately 4 hours after arrival in positron emission tomography (PET) unit | Regional MBFs were calculated using commercial software (PMOD Technologies, version 2.4). After the apical and basal slices of the left ventricular myocardium were chosen, the software automatically defined 4 myocardial regions of interest (segments) in the apical planes. The hyperemic MBF was measured approximately 4 hours after arrival in the PET unit, depending on the randomization. |
| Resting Global MBF and Resting Segmental MBF | Day 2, approximately 35 minutes after arrival in positron emission tomography (PET) unit | MBF is the rate of blood supplied to the myocardium, or heart muscle. Global Myocardial blood flow was calculated using commercial software (PMOD Technologies, version 2.4). Regional MBFs were calculated using commercial software (PMOD Technologies, version 2.4). After the apical and basal slices of the left ventricular myocardium were chosen, the software automatically defined 4 myocardial regions of interest (segments) in the apical planes. |
| Heart Rate (Beats Per Minute (BPM)) | Day 2, approximately 35 minutes and approximately 4 hours after arrival in the PET unit | The resting heart rate was measured approximately 35 minutes after arrival in the PET unit. The hyperemic heart rate was measured approximately 4 hours after arrival in the PET unit, depending on the randomization. |
| Hyperemic Blood Pressure (mmHg) | Day 2, approximately 4 hours after arrival in the PET unit | Blood pressure was measured approximately 4 hours after arrival in the PET unit, depending on the randomization. |
| Segmental CFR | Day 2, approximately 4 hours after arrival in positron emission tomography (PET) unit | CFR was calculated using the equation: hyperemic MBF/resting MBF. |
Countries
United States
Participant flow
Recruitment details
From June 30 to December 27, 2011 subjects were recruited at Mayo Clinic in Rochester, Minnesota.
Participants by arm
| Arm | Count |
|---|---|
| Entire Study Population Includes groups randomized to receive Regadenoson first and Adenosine first. | 12 |
| Total | 12 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| First Intervention | Adverse Event | 1 | 1 |
Baseline characteristics
| Characteristic | Entire Study Population |
|---|---|
| Age Continuous | 44 years STANDARD_DEVIATION 8 |
| Body Mass Index | 26.1 kg/m^2 STANDARD_DEVIATION 4.3 |
| Region of Enrollment United States | 12 participants |
| Sex: Female, Male Female | 6 Participants |
| Sex: Female, Male Male | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 1 / 12 | 1 / 12 |
| serious Total, serious adverse events | 0 / 12 | 0 / 12 |
Outcome results
Primary
Global Hyperemic Myocardial Blood Flow (MBF)
MBF is the rate of blood supplied to the myocardium, or heart muscle. Hyperemic MBF is the rate of myocardial blood flow in the heart muscle during either regadenoson or adenosine stress. Myocardial blood flow was calculated using commercial software (PMOD Technologies, version 2.4). The Hyperemic MBF was measured approximately 4 hours after arrival in the PET unit.
Time frame: Day 2, approximately 4 hours after arrival in positron emission tomography (PET) unit
Population: Analysis per protocol; one participant in each group experienced an ischemic ECG with the first stress drug, and they were withdrawn from the study. This is a per intervention presentation.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Regadenoson | Global Hyperemic Myocardial Blood Flow (MBF) | 3.1 mL/min/gm | Standard Deviation 1.4 |
| Adenosine | Global Hyperemic Myocardial Blood Flow (MBF) | 3.1 mL/min/gm | Standard Deviation 1.2 |
Comparison: Statistical analysis for hyperemic global MBF between Regadenoson and Adenosine groups (per intervention), alpha level of 0.05.p-value: 0.14t-test, 2 sided
Secondary
Global Cardiac Flow Rate
Cardiac Flow Rate was calculated using the equation: hyperemic MBF/resting MBF.
Time frame: Day 2, approximately 4 hours after arrival in positron emission tomography (PET) unit
Population: Analysis per protocol, one participant in each group experienced an ischemic ECG with the first stress drug, and they were withdrawn from the study. This is a per intervention presentation.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Regadenoson | Global Cardiac Flow Rate | 3.8 ratio | Standard Deviation 1.5 |
| Adenosine | Global Cardiac Flow Rate | 4.0 ratio | Standard Deviation 1.4 |
Comparison: Statistical analysis for Cardiac Flow Rate (CFR) between Regadenoson and Adenosine groups (per intervention), alpha level of 0.05p-value: 0.21t-test, 2 sided
Secondary
Heart Rate (Beats Per Minute (BPM))
The resting heart rate was measured approximately 35 minutes after arrival in the PET unit. The hyperemic heart rate was measured approximately 4 hours after arrival in the PET unit, depending on the randomization.
Time frame: Day 2, approximately 35 minutes and approximately 4 hours after arrival in the PET unit
Population: Analysis per protocol; one participant in each group experienced an ischemic ECG with the first stress drug, and they were withdrawn from the study. This is a per intervention presentation.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Regadenoson | Heart Rate (Beats Per Minute (BPM)) | Resting heart rate | 62 bpm | Standard Deviation 10 |
| Regadenoson | Heart Rate (Beats Per Minute (BPM)) | Hyperemic heart rate | 98 bpm | Standard Deviation 16 |
| Adenosine | Heart Rate (Beats Per Minute (BPM)) | Resting heart rate | 60 bpm | Standard Deviation 9 |
| Adenosine | Heart Rate (Beats Per Minute (BPM)) | Hyperemic heart rate | 93 bpm | Standard Deviation 15 |
Comparison: Statistical analysis comparing Regadenoson and Adenosine groups (per intervention) for resting heart rate, alpha level of 0.05.p-value: 0.28t-test, 2 sided
Comparison: Statistical analysis comparing Regadenoson and Adenosine groups (per intervention) for hyperemic heart rate, alpha level of 0.05.p-value: 0.51t-test, 2 sided
Secondary
Hyperemic Blood Pressure (mmHg)
Blood pressure was measured approximately 4 hours after arrival in the PET unit, depending on the randomization.
Time frame: Day 2, approximately 4 hours after arrival in the PET unit
Population: Analysis per protocol; one participant in each group experienced an ischemic ECG with the first stress drug, and they were withdrawn from the study. This is a per intervention presentation.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Regadenoson | Hyperemic Blood Pressure (mmHg) | Systolic | 130 mmHg | Standard Deviation 17 |
| Regadenoson | Hyperemic Blood Pressure (mmHg) | Diastolic | 72 mmHg | Standard Deviation 11 |
| Adenosine | Hyperemic Blood Pressure (mmHg) | Systolic | 132 mmHg | Standard Deviation 23 |
| Adenosine | Hyperemic Blood Pressure (mmHg) | Diastolic | 75 mmHg | Standard Deviation 17 |
Comparison: Statistical analysis comparing Regadenoson and Adenosine groups (per intervention) for systolic blood pressure, alpha level of 0.05.p-value: 0.31t-test, 2 sided
Comparison: Statistical analysis comparing Regadenoson and Adenosine groups (per intervention) for diastolic blood pressure, alpha level of 0.05.p-value: 0.08t-test, 2 sided
Secondary
Hyperemic Segmental MBF
Regional MBFs were calculated using commercial software (PMOD Technologies, version 2.4). After the apical and basal slices of the left ventricular myocardium were chosen, the software automatically defined 4 myocardial regions of interest (segments) in the apical planes. The hyperemic MBF was measured approximately 4 hours after arrival in the PET unit, depending on the randomization.
Time frame: Day 2, approximately 4 hours after arrival in positron emission tomography (PET) unit
Population: Analysis per protocol; one participant in each group experienced an ischemic ECG with the first stress drug, and they were withdrawn from the study. This is a per intervention presentation.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Regadenoson | Hyperemic Segmental MBF | Hyperemic MBF Anterior | 2.5 mL/min/gm | Standard Deviation 0.5 |
| Regadenoson | Hyperemic Segmental MBF | Hyperemic MBF Septum | 3.1 mL/min/gm | Standard Deviation 0.8 |
| Regadenoson | Hyperemic Segmental MBF | Hyperemic MBF Inferior | 3.5 mL/min/gm | Standard Deviation 1.6 |
| Regadenoson | Hyperemic Segmental MBF | Hyperemic MBF Lateral | 2.9 mL/min/gm | Standard Deviation 0.6 |
| Adenosine | Hyperemic Segmental MBF | Hyperemic MBF Lateral | 2.9 mL/min/gm | Standard Deviation 1.1 |
| Adenosine | Hyperemic Segmental MBF | Hyperemic MBF Anterior | 2.6 mL/min/gm | Standard Deviation 0.8 |
| Adenosine | Hyperemic Segmental MBF | Hyperemic MBF Inferior | 3.6 mL/min/gm | Standard Deviation 1.3 |
| Adenosine | Hyperemic Segmental MBF | Hyperemic MBF Septum | 3.2 mL/min/gm | Standard Deviation 1.4 |
Comparison: Statistical analysis comparing Regadenoson and Adenosine groups (per intervention), for Hyperemic MBF Anterior, alpha level of 0.05.p-value: 0.57t-test, 2 sided
Comparison: Statistical analysis comparing Regadenoson and Adenosine groups (per intervention) for Hyperemic MBF Septum, alpha level of 0.05.p-value: 0.13t-test, 2 sided
Comparison: Statistical analysis comparing Regadenoson and Adenosine groups (per intervention)for Hyperemic MBF Inferior, alpha level of 0.05.p-value: 0.44t-test, 2 sided
Comparison: Statistical analysis comparing Regadenoson and Adenosine groups (per intervention) for Hyperemic MBF Lateral, alpha level of 0.05.p-value: 0.74t-test, 2 sided
Secondary
Resting Global MBF and Resting Segmental MBF
MBF is the rate of blood supplied to the myocardium, or heart muscle. Global Myocardial blood flow was calculated using commercial software (PMOD Technologies, version 2.4). Regional MBFs were calculated using commercial software (PMOD Technologies, version 2.4). After the apical and basal slices of the left ventricular myocardium were chosen, the software automatically defined 4 myocardial regions of interest (segments) in the apical planes.
Time frame: Day 2, approximately 35 minutes after arrival in positron emission tomography (PET) unit
Population: Resting MBF was measured on all subjects prior to the interventions.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Regadenoson | Resting Global MBF and Resting Segmental MBF | Resting Global MBF | 0.8 ml/min/gm | Standard Deviation 0.2 |
| Regadenoson | Resting Global MBF and Resting Segmental MBF | Resting Anterior MBF | 0.7 ml/min/gm | Standard Deviation 0.2 |
| Regadenoson | Resting Global MBF and Resting Segmental MBF | Resting Septum MBF | 0.9 ml/min/gm | Standard Deviation 0.2 |
| Regadenoson | Resting Global MBF and Resting Segmental MBF | Resting Inferior MBF | 0.8 ml/min/gm | Standard Deviation 0.2 |
| Regadenoson | Resting Global MBF and Resting Segmental MBF | Resting Lateral MBF | 0.8 ml/min/gm | Standard Deviation 0.2 |
Secondary
Segmental CFR
CFR was calculated using the equation: hyperemic MBF/resting MBF.
Time frame: Day 2, approximately 4 hours after arrival in positron emission tomography (PET) unit
Population: Analysis per protocol, one participant in each group experienced an ischemic ECG with the first stress drug, and they were withdrawn from the study. This is a per intervention presentation.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Regadenoson | Segmental CFR | CFR Anterior | 3.4 ratio | Standard Deviation 1.1 |
| Regadenoson | Segmental CFR | CFR Septum | 3.5 ratio | Standard Deviation 0.7 |
| Regadenoson | Segmental CFR | CFR Inferior | 4.4 ratio | Standard Deviation 1.4 |
| Regadenoson | Segmental CFR | CFR Lateral | 3.9 ratio | Standard Deviation 1 |
| Adenosine | Segmental CFR | CFR Lateral | 4.0 ratio | Standard Deviation 1.1 |
| Adenosine | Segmental CFR | CFR Anterior | 3.7 ratio | Standard Deviation 1 |
| Adenosine | Segmental CFR | CFR Inferior | 4.6 ratio | Standard Deviation 1.3 |
| Adenosine | Segmental CFR | CFR Septum | 3.6 ratio | Standard Deviation 1.6 |
Comparison: Statistical analysis comparing Regadenoson and Adenosine groups (per intervention for CFR Anterior, alpha level of 0.05.p-value: 0.78t-test, 2 sided
Comparison: Statistical analysis comparing Regadenoson and Adenosine groups (per intervention) for CFR Septum, alpha level of 0.05p-value: 0.42t-test, 2 sided
Comparison: Statistical analysis comparing Regadenoson and Adenosine groups (per intervention for CFR Inferior, alpha level of 0.05p-value: 0.96t-test, 2 sided
Comparison: Statistical analysis comparing Regadenoson and Adenosine groups (per intervention) for CFR Lateral, alpha level of 0.05.p-value: 0.13t-test, 2 sided