Clinical trial NCT02130453
Conditions: Ischemia
Keywords: Ischemia Coronary artery disease Nuclear stress test Stress Echocardiogram Echocardiography strain measurement Ultrasound cardiac imaging ReSTE SPECT Regadenoson
Sponsor: M.D. Anderson Cancer Center
Start date: 2014-09-30; Completion date: 2024-06-28
Enrollment: 161 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
The goal of this clinical research study is to compare regadenoson nuclear stress testing with echocardiography strain measurements (an ultrasound imaging method that measures hearts function) in detecting coronary artery disease.

Detailed description:
If you agree to take part in this study, you will have the echocardiography strain measurement performed. This will be done while you lie on an exam table. An ultrasound technician will apply a vaseline-like gel to your chest and will take the measurements by holding a transducer (a device that resembles a microphone) against your chest, sliding it back and forth. This will take about 10 minutes.

After the resting strain measurement is done, you will have the first set of nuclear images. This will be done just like the echocardiography strain measurement. Once these images are completed, you will be given regadenoson by vein over about 10 seconds. Within 2 to 4 minutes of receiving the regadenoson, measurements will be repeated. These measurements will take about 2 minutes to complete. At about 30 minutes after regadenoson was given, you will have the final images for the nuclear portion of the testing (this is the usual timing for nuclear images after regadenoson).

You will receive the same treatment during your stress test, including the same amount of regadenoson, as you would if you did not take part in this study. Some participants may be asked to allow a repeat of the strain measurements that will include an additional dose of regadenoson if the first set of images are not good enough and additional images may be taken.

Length of Study:

Your participation on this study will be over 30 days after the tests OR after surgery, whichever occurs later. Researchers will collect information from your medical record for up to 30 days after your tests.

If you have surgery or are hospitalized in the 30 days after the tests, you will be called and asked about any problems you have been having. This call should take about 10 minutes.

This is an investigational study. Regadenoson is FDA approved and is routinely used for nuclear perfusion stress testing. The use of strain measurement during an echocardiogram to detect coronary disease is investigational.

Up to 300 participants will be enrolled in this study. All will take part at MD Anderson.

Arms: arm 1: Echocardiography strain measurement performed taking about 10 minutes. After resting strain measurement done, first set of nuclear images performed. Once these images are completed, participant given Regadenoson 0.4 mg by vein over about 10 seconds. Within 2 to 4 minutes of receiving the Regadenoson, measurements repeated. These measurements will take about 2 minutes to complete. arm 2: After resting strain measurement done, first set of nuclear images taken. Once these images are completed, participant given Regadenoson 0.4 mg by vein over about 10 seconds. Within 2 to 4 minutes of receiving Regadenoson, measurements repeated. These measurements take about 2 minutes to complete. At about 30 minutes after Regadenoson given, participant will have final images for the nuclear portion of the testing.
Interventions: intervention 1: Regadenoson
Intervention descriptions: intervention 1: 0.4 mg by vein given during nuclear stress testing with echocardiography strain measurements.

Protocol documents:
Prot_SAP_000.pdf: 
Use of Regadenoson for a Stress Echocardiogram Protocol Using Speckle 
Tracking Imaging. 
2013-0881 
1.0 Background 
Current protocols used in clinical practice for stress echocardiography 
evaluation include exercise efforts (bicycle and treadmill) and pharmacologic 
stimulation. The pharmacologic stress echocardiography in the US is almost 
exclusively performed with Dobutamine.  
In clinical practice vasodilator agents for stress testing have been limited for the 
use of perfusion imaging with nuclear isotopes. Nuclear stress testing is more 
expensive, equipment heavy, less available and much less portable than 
echocardiography imaging systems. It also exposes patients to a significant 
radiation dose (1). 
Stress echocardiography is known for its comparable accuracy in detection of 
obstructive coronary artery disease when compared with nuclear methods. In a 
highly quoted pooled analysis of 18 studies in 1304 patients who underwent 
exercise or pharmacologic stress echocardiography in conjunction with thallium 
or technetium- labeled radioisotope imaging, sensitivity and specificity were 
80% and 86% for echocardiography. Corresponding values were 84% and 77% 
for myocardial perfusion imaging, respectively (2). 
The main limitation of stress echocardiography has been imaging quality and 
the fact that segmental dysfunction recognition depends on the human eye 
assessment of wall thickening (3). New, validated, ultrasound imaging 
technology now exists to aid in the recognition of segmental systolic 
dysfunction in more objective ways, namely the use of speckle tracking 
imaging(4). This technology uses the systolic tracking of speckles to define 
tissue deformation of the different cardiac segments in all the dimensions of 
cardiac, systolic, mechanical motion. The quality of this technology for precise 
segmental function analysis relies on the use of higher frame rates (5); which 
can be defeated in the case of tachycardia. Since a certain level of tachycardia is 
needed for accuracy in Dobutamine stress echocardiography testing (DSE), 
therefore combining DSE with speckle tracking imaging would be sub optimal. 
Speckle tracking imaging values in its longitudinal dimension has also proven 
more reliable for all-cause mortality prediction than more traditionally accepted 
measures such as Left Ventricular ejection fraction (LVEF) and wall motion 
score index (WMSI) (6). 
The use of vasodilatation for stress echocardiography examination has been 
performed successfully in the past, also with the use of regadenoson, but for the 
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main purpose of perfusion imaging with echocardiography, using ultrasound 
contrast agents.  
Regadenoson is a pharmacologic stress agent indicated for radionuclide 
myocardial perfusion imaging in patients unable to undergo adequate exercise 
stress. It is a low affinity agonist for the A1 adenosine receptor with weak to no 
affinity for the A2B and A3 adenosine receptors. Activation of the A2A 
adenosine receptor by regadenoson produces coronary vasodilation and 
increases coronary blood flow. 
 
We propose a study in our cancer patients already scheduled for regadenoson 
nuclear stress testing obtaining rest and peak hyperemia longitudinal strain 
images to compare accuracy in detection of coronary artery disease between 
modalities as well as obtaining possible additional prognostic information in 
this population. 
If the regadenoson-strain data accuracy is comparable to perfusion imaging this 
would constitute a new stress modality that is free of radiation exposure to our 
cancer patients. The main comparison group will be those cases interpreted as 
abnormal with nuclear imaging that proceed to coronary angiography (Grp 1). 
Patients undergoing stress testing in anticipation of a cancer related surgery of 
intermediate to significant risk (Grp 2) will provide 30d post-operative major 
cardiac event (MACE) rates for comparision. MACE is defined as: 
1. Acute coronary syndrome (ACS): 
unstable angina 
abnormal troponin consistent with current guidelines for the diagnosis 
of acute myocardial infarction (AMI) 
AMI 
revascularization 
2. 
LV dysfunction defined as either a drop in LVEF to <50% or >10% 
decrease from baseline. 
3. 
Ventricular arrhythmias: 
ventricular tachycardia (VT) 
ventricular fibrillation (VF) 
4. 
Stroke 
5. 
Sudden cardiac death 
 
2.0 Objectives 
 
Primary objective: We aim at demonstrating that the angiogram (by either 
coronary angiography or coronary CT angiogram) and the regadenoson stress 
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echocardiography (ReSTE) are equivalent in classifying ischemia among 
SPECT positive patients; this corresponds to test if ReSTE is as accurate as 
SPECT in the diagnosis of ischemia at least among SPECT positive patients 
(Grp 1). 
Secondary aims: assess whether or not ReSTE adds predictive information 
above and beyond SPECT in predicting 30d post-operative cardiac events (Grp 
2). 
 
3.0 Patient Eligibility 
 
Inclusion Criteria: 
1. 
Cancer patients who are scheduled for (perfusion) nuclear stress testing 
using regadenoson as stress agent.  
2. Indications for stress testing is either:  
as part of a pre-operative evaluation prior to a planned cancer related 
surgery that is considered to be at least of intermediate risk (Intra-
peritoneal, intra-thoracic, head and neck surgery, orthopedic or 
prostate surgery) OR 
as part a cardiology evaluation for symptoms described in a 
cardiology consult as typical angina, or of significant suspicion for 
coronary disease or symptoms described as likely of a 
cardiac/coronary etiology. 
3. 
Patients with a history of LV dysfunction will be still candidates for 
enrollment in the study if they have documented LVEF recovery (most 
recent documented LVEF of 50% or higher) for at least 6 months prior to 
SPECT regardless of current cardiac medication regimen. 
4. Age 18 - 80 years. 
Exclusion Criteria:  
1. Patients consented for the trial that on the baseline 2D study have poor  
 
acoustic echo windows (i.e. a reader is unable to see in definition 2 or more  
 
segments from the apical views) will not be eligible to continue in the trial  
 
and peak hyperemia images will not be obtained. 
2. Any patient with tachycardia defined as HR of 100 or higher at the day of  
 
SPECT will not be eligible for this study. 
3. Second or third degree AV block. 
4. Sinus node dysfunction. 
5. Patients with allergy to regadenoson. 
6. Patients with left bundle branch block (LBBB) and/or artificial pacemaker. 
 
4.0 Research Plan and Methods  
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Study Outline: 
Upon signed informed consent and enrollment, patients will be imaged during 
regadenoson infusion using the stated imaging protocol. If two contiguous 
segments in any of the apical views are not visible patients will not be 
registered in the study and will be entered in CoRE as screen failures due to 
eligibility criteria.   
For ECHO, images will be stored for strain analysis in the ECHO PAC system 
and will be analyzed by a single blinded investigator (Jose Banchs). All strain 
will be obtained using the 2D strain analysis pathway. Global longitudinal 
strain (GLS), 2D  LVEF with bi-plane Simpsons method of calculation, end 
diastolic volume (EDV bi-plane), end systolic volume (ESV bi-plane) and 
stroke volume (SV) values will be obtained and saved.  
SPECT images will be interpreted by a blinded pool of faculty that includes 
radiologists and cardiologists from the institution. On those patients (Grp 2) 
who are studied pre-operatively the proposed surgery description and total 
surgical time will be recorded. Immediate post-op cardiac events (MACE) and 
30 day post-operative cardiac events (MACE) will be recorded from inpatient 
records by chart review or if needed by telephone contact to patients. The post-
operative events will be used to report prognostic accuracy of both testing 
methods and for comparison. 
Patients who have coronary angiography or coronary CT angiograms will have 
the imaging data and test report data saved and stored for the final analysis (Grp 
1). 
The accuracy of both tests will be compared in those patients with angiogram 
data (Grp 1). 
Study Design:  Prospective comparison for demonstration of equivalence. Will 
attempt to show same specificity and sensitivity with ReSTE compared to 
SPECT at detecting (segmental/coronary) distribution defects. 
Study “treatment”:  
The only agent will be standard dose regadenoson for nuclear stress test; 
unchanged from our current protocol: “Regadenoson (5 mL, containing 0.4 mg 
of regadenoson) should be given as a rapid (approximately 10 seconds) 
injection into a peripheral vein using a 22 gauge or larger catheter or needle. 
Administer a 5 mL saline flush immediately after the injection of regadenoson.” 
Study Population: The study population consists of cancer patients being 
evaluated with regadenoson nuclear stress tests for evaluation of chest pain or 
pre-operatively (cancer related surgery). We will concentrate on recruiting 
patients who are being evaluated pre-operatively for surgery that is considered 
to be at least of intermediate risk based on the American College of Cardiology  
Guidelines on Perioperative Cardiovascular Evaluation and Care for Non-
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cardiac Surgery (7); since a large number of patients that come for the test in 
our center are ordered to have perfusion stress test directly from the surgical or 
the pre-operative assessment clinics.  
Planned Study Duration:  Approximately 48 months. Given that 
approximately 900 patients come thru our department per year to get evaluation 
with SPECT but only approximately 300 will undergo catheterization, final 
timing depends on recruitment rate and volumes given our inclusion criteria 
items 2-3. 
Imaging Protocol:  
All ReSTE studies will be performed on GE systems (VIVID E9). Special 
attention will be given to avoid foreshortening. 
The patients will be positioned on standard L recumbent position. 
Transthoracic echocardiography will be performed using the Vivid E9 (GE 
Healthcare, Milwaukee, Wisconsin). 
The same system will be used to acquire all echocardiograms. All 
echocardiograms will be analyzed in our laboratory. LVEF will be calculated 
from the apical 4- and 2-chamber views using a modified Simpson’s biplane 
method by single investigator.  
To measure myocardial strain, 2-dimensional grayscale images will be obtained 
in the parasternal short-axis view at the mid-papillary and apical levels; as well 
as the 3 standard apical views (apical 4-, 3- and 2-chamber views). 
The timing of aortic valve closure will be obtained using pulsed-wave Doppler 
traces in the apical 3 or 5 views (using the more direct angle). Peak systolic 
radial and circumferential strain will be measured by averaging the peak 
systolic strain values in all 6 segments of the parasternal short-axis view 
(EchoPAC; GE Healthcare).   
Summary of views: All ReSTE images will be obtained at rest and at peak 
hyperemia (between 2-4 min period post regadenoson injection). 
1. Apical 4 view, at highest possible frame rate (>40fps) 
2. Apical 3, at highest possible frame rate (>40fps) 
3. Apical 2, at highest possible frame rate (>40fps) 
4. Base SAX view, for torsion analysis 
5. Apex SAX view (pass the insertion of the papillary muscles), for torsion  
 
analysis 
6. One full 3D loop, at least 2 beats. 
7. All images must be sent to ECHO-PAC system (internal disk). 
 
In light of several publications (8,9) supporting the state of peak hyperemia 
with regadenoson at the 2-4 min after injection interval, including a study used 
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for perfusion echocardiography (10), we will obtain these images after the 2nd 
minute and expect to complete by the 4th minute. 
SPECT protocol will be performed as the current MDACC standard.  
ReSTE will be performed concomitantly with SPECT as planned by ordering 
clinician. Therefore the same dose of regadenoson will be in effect used for 
both tests. We anticipate the potential need for ReSTE re-imaging of 
approximately 10% of participants to ensure that images are adequate for 
research quality measurements. In this event, an additional dose of regadenoson 
will be given after nuclear imaging is complete so that ReSTE peak hypermia 
images can be redone. 
Data management and consent 
Consent will be obtained by designated personnel who will be well informed 
about the purpose of the study and potential risks prior to patient enrollment.  
Detailed information regarding the purpose of the study and potential risks will 
be discussed with the patient.  An opportunity will be provided to patients to 
address any questions or concerns related to participation.  Patients will be 
informed that participation is voluntary and consent and participation may be 
withdrawn at any time. Patients will also be informed that there is no 
compensation for participation. 
Provisions taken to maintain confidentiality of specimens/data: 
Unique study numbers will be assigned and all identifiers will be removed. Data 
will be stored in PDMS to ensure CFR Title 21 Part 11 compliance. Paper 
records will be kept locked in file cabinet and secured in locked office. Only 
study collaborators and Cardiology department personnel will have access to 
the data. Study records and data files will be disposed of in accordance to 
institutional policies after study is completed.  
Security plan for data:  
Collection of Identifiers:   
Identifiers (name, medical record number) will be collected but will be replaced 
by study numbers.  The key linking these numbers will be retained in a locked 
file by the investigator designated personnel. 
 
Breaking of Blind: 
The PI will remain blinded to the nuclear results obtained during the ReSTE 
until strain interpretation is completed to prevent bias. Breaking of the blind 
will not be necessary for safety as no clinical decision making will be based 
upon the strain results. 
 
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Training of personnel:  Only MDACC personnel designated by the Principal 
investigator will have access to study records.  These personnel will be fully 
trained to maintain the patient health information confidentiality. 
 
Data Storage:  Patient information and relevant data will be stored on 
password-protected institution computers behind the institution firewall. Data 
will not be transferred to laptop computers that are removed from the 
institution.   
Data Sharing:  Study data will not be shared with any individuals or entities 
that are not involved in the study. 
Final disposition of study records:  These data will be used only for this 
research study.  Study data will be retained by the PI and will be disposed of in 
accordance to institutional policies after study is completed. No more than 5 
years after manuscript publication. 
Sample Size: 300 patients.  
Criteria for Removal (If indicated): Any time, at patient request.  
 
5.0 Reporting Requirements 
 
Adverse Events 
 All serious adverse events related to regadenoson will be documented  and 
reported to Astellas Pharm Inc. The use of aminophylline as an antidote will be 
reserved for severe adverse events experienced due to regadenoson per 
MDACC protocol. 
 
6.0 Statistical Considerations 
 
Statistical analysis: 
Design and sample size/power 
This is a 1-arm trial in cancer patients who are considered in the Department of 
Cardiology for stress testing. The primary objective of the study is to evaluate 
the ability of ReSTE (novel screening method) to identify patients with 
ischemia with as much accuracy as the conventional method, SPECT. Due to 
budgetary and other constraints (see below), the evaluation will be conducted 
among SPECT positive patients (Grp 1). 
A total of 300 eligible patients will be enrolled into this trial. Each patient will 
undergo both SPECT and ReSTE stress testing for the diagnosis of ischemia. 
The gold standard test for the diagnosis of ischemia is angiography. However 
not all of the 300 patients will receive an angiogram due to patient’s availability 
(many patients’ primary concerns will be cancer related), current practice 
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guidelines as well as financial limitations. Currently, only those who are 
SPECT positive may potentially receive an angiogram. We expect 210 (70%) of 
the 300 patients will be SPECT positive. Out of those 210 patients, 178 (85%) 
will actually undergo an angiography (Grp 1).  
Since not all of the 300 patients will receive an angiogram, we will not be able 
to demonstrate directly the non-inferiority of ReSTE with regard to its accuracy 
of identifying ischemia when compared to SPECT imaging. However if ReSTE 
is truly as accurate as SPECT in its ability of identifying ischemia, then among 
those who are SPECT positive and also undergo an angiogram test, we expect 
minimum discordance between the angiogram and the ReSTE. Therefore, we 
aim at demonstrating that the angiogram and the ReSTE are equivalent in 
classifying ischemia among the SPECT positive patients; this corresponds to 
test if ReSTE is as accurate as SPECT in the diagnosis of ischemia at least 
among SPECT positive patients. Assuming that the true respective ischemia 
rates diagnosed by angiogram and ReSTE are P0 and P1, we will perform 
equivalence test to test the following hypotheses: 
 
 
 
 
 
H0: |P1-P0|>0.05; 
 
 
 
 
 
H1: |P1-P0|≤0.05; 
If we observe a 7% discordance rate (equivalent to 12 of the 178 patients) 
between the angiogram and ReSTE results, and we were to allow a +/-5% 
tolerance limit, we would have 80% power to declare equivalence using a one-
sided paired test of equivalence in proportion (alpha of 0.05), i.e. we will reject 
the null hypothesis that |P1-P0| >0.05 and accept the alternative hypothesis that 
|P1-P0| ≤0.05. Lower discordance rates would yield higher power, so this 
estimate of power is rather conservative. The sample size calculation was 
performed using nQuery Advisor 7.0. 
Analysis Plans 
Patients’ demographic and clinical characteristics will be summarized using 
descriptive statistics such as mean, standard deviation, median, interquartile 
range (IQR), frequency where appropriate. We will apply Student t-
test/Wilcoxon test and Kruskal-Wallis test/ANOVA to compare continuous 
variables, and the chi-square test or the Fisher’s exact test (14) to compare 
categorical variables in different patient groups (Grp 1).  
As the primary analysis, we will use a paired test of equivalence for proportions 
proposed by Tango (11) to test the equivalence of the two ischemia tests among 
the SPECT positive patients. 
Among the SPECT positive patients, Standard measures of clinical performance 
of ReSTE including sensitivity, specificity and positive and negative predictive 
values (12) will be estimated first. Additionally, the corresponding 2-sided 95% 
CI of binomial proportion will be calculated. We will use Receiver operating 
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characteristic (ROC) curve analysis (13) to assess the best cut-off for the 
ReSTE test, and calculate the area under the ROC curve to assess the 
performance of different cut-offs of ReSTE for the group. 
For the secondary endpoints including cardiac event rates at Day 30 post-
operation, we will provide estimates along with 95% confidence intervals (Grp 
2). Univariate and multivariate logistic regression models will be fit to identify 
risk factors associated with the Day 30 events. Specifically, we will assess 
whether or not ReSTE adds predictive information above and beyond SPECT in 
predicting the Day 30 events. We hypothesize that patients who are positive on 
both SPECT and ReSTE have the highest Day 30 cardiac complication rates 
while those who are negative on both tests have the lowest cardiac complication 
rates. We will test whether the difference in statistical predictive accuracy 
between different logistic regression models (with or without ReSTE in the 
models) is significant (14). The predictive accuracy of the various logistic 
regression models will be quantified by C statistic, which provides the area 
under the receiver operating characteristics curve (13,14). To protect against 
over-fitting in the stepwise regression, we will use a bootstrap procedure to 
obtain an unbiased estimate of the C-index. These analyses will be performed 
using all patients for whom we have available data. 
 
7.0 Study Timeline 
 
Our numbers are estimated based on the actual cardiac catheterizations 
performed in our lab. The cardiac catheterization lab opened in November 
2009. It is the only full service cath lab in any cancer center. There were 250 
angiograms performed in the first 12 months and the annual number has 
continued to increase annually. The percentage of angiograms performed in our 
cancer population is different than the population in any general cardiac center 
since our patients often find themselves in the position of needing a complete 
cardiac evaluation in order to proceed with anti-cancer therapies.  
Final disposition of the data: in accordance to MD Anderson institutional 
policies after the study is completed. 
 
8.0 Figures 
 
Figure 1. ReSTE = Regadenoson Speckle tracking Echocardiogram. Yellow 
fill is Group 1, Blue is 2 
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9.0 References  
 
 
1. ICRP PUBLICATION 120: Radiological Protection in Cardiology. C. 
Cousins, D.L. Miller, et al; http://dx.doi.org/10.1016/j.icrp.2012.09.001 
2. Noninvasive evaluation of ischemic heart disease: myocardial perfusion 
imaging or stress echocardiography? Schinkel A, Bax J, Geleijnse M, Boersma 
E, Elhendy A, Roelandt J, et al. Eur Heart J 2003;24:789-800. 
3. American Society of Echocardiography Recommendations for Performance, 
Interpretation, and Application of Stress Echocardiography. Pellikka P, Nagueh 
S. JASE; Volume 20 (9). Sept 2007; pp. 1021-1041. 
SPECT  & consent for ReSTE
N ≈ 300
Positive for Ischemia 
n ≈ 210
Negative for Ischemia 
n ≈ 90
Angiogram or 
CT Angio
n ≈ 178
(Grp 1)
If ReSTE
Negative = 
True Negative
No Angiogram 
or CT Angio
n ≈ 32
If ReSTE is 
Positive = 
False Positive
Abnormal 
Coronaries
Normal 
Coronaries
ReSTE
Positive will 
be 
considered 
a True 
Positive and 
indicates 
ReSTE
accuracy
ReSTE
Negative 
may be a 
False 
positive 
and could 
question  
accuracy of 
both SPECT 
and ReSTE
ReSTE
Positive 
True False 
Positive and 
indicates 
inaccuracy 
of ReSTE
ReSTE
Negative 
True 
Negative 
and 
indicates 
accuracy of 
ReSTE
If this is a surgery patient will  need to use 30d post-p event rate for prognosis
(Grp 2)
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4. Non-Doppler Two-dimensional Strain Imaging by Echocardiography–From 
Technical Considerations to Clinical Applications. Perk G, Tunick PA, 
Kronzon I. JASE 2007; 20:234-243. 
5. Current and Evolving Echocardiographic Techniques for the Quantitative 
Evaluation of Cardiac Mechanics: ASE/EAE Consensus Statement on 
Methodology and Indications Endorsed by the Japanese Society of 
Echocardiography. Mor-Avi V, Lang R, et al. JASE; 2011; 24:277-313. 
6. Prediction of All-Cause Mortality from Global Longitudinal Speckle Strain, 
Comparison with Ejection Fraction and Wall Motion Scoring. Stanton T, Leano 
R., Marwick TH. Circ Cardiovasc Imaging 2009; 2; 356-364. 
7. 2009 ACCF/AHA Focused Update on Perioperative Beta Blockade 
Incorporated Into the ACC/AHA 2007 Guidelines on Perioperative 
Cardiovascular Evaluation and Care for Noncardiac Surgery. A Report of the 
American College of Cardiology Foundation/American Heart Association Task 
Force on Practice Guidelines. Fleisher et al. JACC Vol. 54, No. 22, 2009: e13–
118. 
8. Initial clinical experience with regadenoson, a novel selective A2A agonist 
for pharmacologic stress single-photon emission computed tomography 
myocardial perfusion imaging. Hendel RC, Bateman TM, Cerqueira MD, 
Iskandrian AE, Leppo JA, Blackburn B, Mahmarian JJ. JACC 2005 Dec 6; 
46(11):2069-75. Epub 2005 Nov 9. 
9. Novel short-acting A2A adenosine receptor agonists for coronary 
vasodilation: inverse relationship between affinity and duration of action of 
A2A agonists. Gao Z, Li Z, Baker SP, Lasley RD, Meyer S, Elzein E, Palle V, 
Zablocki JA, Blackburn B, Belardinelli L. J Pharmacol Exp Ther. 2001 Jul; 
298(1):209-18. 
10. Real-Time Perfusion during Regadenoson Stress. Porter et al. Circ 
Cardiovasc Imaging. 2011; 4:628-635. 
11. Tango T, Equivalence test and confidence interval for the difference in 
proportions for the paired-sample design. Statist Med. 1998, 17, 891-908. 
12. Woolson RF, Clarke WR. Statistical Methods for the Analysis of 
Biomedical Data, 2nd Edition. Wiley, New York, 2002. 
13. Hanley, JA, McNeil, BJ. The meaning and use of the area under a receiver 
operating characteristic (ROC) curve. Radiology 1982, 143, 29–36. 
14. Harrell F. Regression modeling strategies. New York: Springer-Verlag; 
2001. 
 
 
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