ACRIN-4701 RESCUE: Randomized Evaluation of Patients With Stable Angina Comparing Utilization of Diagnostic Examinations
Phase: NA
Conditions: Chest Pain, Stable Angina Pectoris, CCS Class I to III, Angina Equivalent, Coronary Artery Disease
Sponsor: American College of Radiology

 
 
andomized valuation of Patients with table Angina  
omparing tilization of Diagnostic xaminations 
Arthur Stillman, MD, PhD 
Div of Cardiothoracic Imaging 
Emory University 
1364 Clifton Road NE 
Atlanta, GA 30322 
Phone: 404-712-7964 
Fax: 404-712-7777 
Email: aestill@emory.edu 
Pamela K. Woodard, MD 
Cardiovascular Imaging Laboratory 
Mallinckrodt Institute of Radiology, Washington 
Univ. School of Medicine 
510 S. Kingshighway Blvd.  
St. Louis, MO 63110 
Phone: 314-362-9989  
Fax: 314-747-3882 
Email: woodardp@mir.wustl.edu
Udo Hoffmann, MD, MPH  
Associate Prof. of Radiology,  
     Harvard Medical School 
Director, MGH Cardiac MR PET CT Program,  
     Massachusetts General Hospital, Boston 
165 Cambridge Street, Suite 400 
Boston, MA 02114  
Phone: 617-726-1255  
Fax: 617-724-4152  
Email: uhoffman@partners.org 
James E. Udelson, MD, FACC 
Chief, Division of Cardiology 
Director, Nuclear Cardiology Laboratory 
Tufts Medical Center 
750 Washington Street, Box 70 
Boston, MA 0211 
Phone: 617-636-8066 
Fax: 617-636-2276 
Email: judelson@tufts-nemc.org 
Constantine Gatsonis, PhD  
Center For Statistical Sciences  
Brown University, Box G-S121-7  
121 South Main Street  
Providence, RI 02912  
Phone: 401-863-9183  
Fax: 401-863-9182  
Email: gatsonis@stat.brown.edu 
Tao Liu, PhD 
Center For Statistical Sciences  
Brown University, Box G-121-7 
121 South Main Street  
Providence, RI 02912 
Phone: 401-863-6480 
Fax: 401-863-9182 
Email: tliu@stat.brown.edu 
 
Ilana Gareen, Ph.D. 
Center for Statistical Sciences 
Brown University, Box G-S121-7 
121 South Main Street  
Providence, RI 02912 
Phone: (401) 863-1758 
Fax: (401) 863-9182 
Email: igareen@stat.brown.edu 
November 5, 2010
February 16, 2011
May 4, 2011 
Includes Amendment 1 

2
May 4, 2011 
 
   
 
 
1.0 
Abstract..................................................................................................................................5 
 
2.0  
Background and Significance ................................................................................................6 
 
3.0 
Study Objectives/Specific Aims ............................................................................................10 
 
4.0 
Study Overview .....................................................................................................................11 
 
5.0 
Participant Selection/Eligibility Criteria................................................................................15 
 
6.0 
Site Selection .........................................................................................................................17 
 
7.0 
Data Management/Online Registration and Randomization .................................................21 
 
8.0 
Study Procedures ...................................................................................................................24 
 
9.0  
Imaging Protocol....................................................................................................................35 
 
10.0 
Adverse Events Reporting .....................................................................................................40 
 
11.0  Ethical Considerations ...........................................................................................................44 
 
12.0  Conflict of Interest.................................................................................................................45 
 
13.0  Publication Policy..................................................................................................................45 
 
14.0  Institutional Monitoring and Audits.......................................................................................45 
 
15.0 
Statistical Considerations ......................................................................................................48 
 
References..........................................................................................................................................57 
 
Appendix I: 
Informed Consent Form Template.............................................................................62 
 
Appendix II: Authorization to Release/Disclose Medical Records Template.................................76 
 
Appendix III: Supplemental Materials Available Online.................................................................78 
 
Appendix IV: Endpoints-Related Definitions...................................................................................79
 
 

3
May 4, 2011 
 
   
andomized valuation of Patients with table Angina  
omparing tilization of Diagnostic xaminations
(A Phase III, Multicenter, Randomized, Controlled, Comparative-Effectiveness Trial) 
 
 CCS, Canadian Cardiac Society; CCTA, coronary computed tomography angiography; SPECT, single 
photon emission tomography; MPI, myocardial perfusion imaging; TID, transient ischemic dilation; ECG, electrocardiogram; 
CAD, coronary artery disease; MACE, major adverse cardiac event; OMT, optimal medical therapy; ICA, invasive coronary 
angiography; LM Dz, left main disease (  50% stenosis). 
 
This randomized, controlled, diagnostic, multicenter trial will follow participants at 6-month intervals 
for up to 24 months to determine the incidence of MACE, defined as myocardial infarction (MI) or 
cardiac-related death, and cross-over to revascularization. (Some participants will be followed only up to 
12 months, dependent on when they join the trial and due to trial timeline completion limitations.) 
 

4
May 4, 2011 
 
   
The primary endpoint of the study is a combined endpoint of occurrence of MACE and 
revascularization. We will calculate differences in the combined MACE/revascularization endpoint 
between the CCTA and SPECT MPI/ICA arms.  
 
 CCTA may be used to direct patients with symptoms of stable angina or angina 
equivalent to OMT. The use of CCTA as a diagnostic tool for angina symptoms will be associated with 
no increase in MACE or revascularization, decreased cost, reduced risks (e.g., less radiation exposure), 
additional insights into alternate explanations of chest pain, and increased cost-effectiveness in 
comparison with use of SPECT MPI/ICA. 
 
 
Patients ages 40 or older presenting with symptoms of stable angina CCS Class I to III or angina 
equivalent, with or without known CAD, with planned non-invasive imaging for diagnosis. 
 
Patients will be excluded if they have/are: 
 Prior revascularization; 
 Renal insufficiency or renal failure;  
 History of allergy-like reaction to iodinated contrast; 
 Atrial fibrillation or significant arrhythmia judged to potentially limit quality of CCTA; 
 Acute ischemia; 
 Acute myocardial infarction;  
 Severe myocardial ischemia: known markedly positive exercise treadmill stress test (significant 
ST segment depressions or hypotensive response during stage I of the Bruce protocol); 
 Unable to suspend respiration for 15 seconds or to follow instructions to do so; 
 Unstable angina and symptoms refractory to maximal oral and intravenous medical therapy 
(persistent CCS Class IV); 
 History of known left ventricular ejection fraction < 45%; 
 Pulmonary edema or heart failure unresponsive to standard medical therapy; 
 Pacemaker; 
 Valvular heart disease likely to require surgery in the next 18 months; 
 Congenital heart disease or cardiomyopathy likely to affect prognosis during follow up; 
 Significant systemic hypertension (blood pressure > 200/100 mm Hg) unresponsive to medical 
therapy; 
Severe noncardiovascular comorbidity limiting survival (e.g., cancer or other life threatening 
illness for which the patient is expected to live less than 12 months); 
Prior imaging evaluation for this episode of symptoms (e.g., SPECT MPI or CCTA within the 
previous 72 hours); 
BMI > 40 kg/m2; 
 Pregnant. 
A total of 4300 patients will be randomized to CCTA or SPECT MPI/ICA for diagnostic assessment of 
angina at up to 80 institutions internationally. 

5
May 4, 2011 
 
 
This protocol for human research study is conducted according to United States and international 
standards of Good Clinical Practice (International Conference on Harmonisation [ICH] Guidelines), 
applicable government regulations (e.g. Title 45, Part 46 Code of Federal Regulations) and the 
American College of Radiology Imaging Network (ACRIN) research policies and procedures. 
 
Coronary computed tomography angiography (CCTA) represents a potentially disruptive technology in 
terms of its impact on the clinical evaluation and management of coronary artery disease (CAD). This 
was highlighted by its inclusion in the Consensus Report on Initial National Priorities for Comparative 
Effectiveness Research (CER) issued by the Institute of Medicine (IOM). Specifically, the report 
recommends: ³Compare the effectiveness of [CCTA] and conventional angiography in assessing 
coronary stenosis in patients at moderate pretest risk of [CAD].´ An additional IOM aim stated in the 
Consensus Report, most likely in response to the results of the Clinical Outcomes Utilizing 
Revascularization and Aggressive Drug Evaluation (COURAGE) trial, recommends research comparing 
the effectiveness of ³aggressive medical management and percutaneous coronary interventions [PCIs] in 
treating stable coronary disease for patients of different ages and with different comorbidities.´  
 
The results of the COURAGE trial suggest that patients with stable angina diagnosed with CAD and 
initially treated with pharmacologic therapy and lifestyle intervention, defined as optimal medical 
therapy (OMT), alone have no difference in outcomes in comparison to individuals treated with both 
OMT and PCI. CCTA, by explicitly identifying patients with potentially significant left main disease, 
can safely select patients for OMT without requiring diagnostic invasive coronary angiography (ICA). 
This is not the case for the more traditional single photon emission tomography myocardial perfusion 
imaging (SPECT MPI), where patients with a positive test for CAD will require diagnostic ICA to 
identify potential left main disease prior to the safe initiation of OMT. The proposed trial will compare 
these two diagnostic paradigms: CCTA versus SPECT MPI/ICA (SPECT MPI followed by diagnostic 
ICA) to determine extent of stenosis and subsequent therapeutic approach. 
 
The 
andomized valuation of Patients with 
table Angina 
omparing 
tilization of Diagnostic 
xaminations 
 is a multi-center randomized, controlled trial responding to the need for 
comparative analysis of these imaging technologies and the role of OMT in clinical care. This study 
builds on the results of the COURAGE trial by comparing CCTA and SPECT MPI/ICA integrated into a 
care paradigm featuring initial treatment with OMT for patients diagnosed with CAD without significant 
disease in the left main coronary artery. Participants will be followed for a composite endpoint of major 
adverse cardiac events (MACE) and cross-over to revascularization over a follow-up period up to two 
years (two to six time points depending on diagnostic results and time of enrollment into the trial). 
Participant outcomes will be assessed by age, gender, comorbidity, and angina classification class at 
presentation. Several comparative-effectiveness analyses will be performed. We hypothesize that the 
CCTA arm will be associated with no increase in MACE or revascularization, decreased cost, reduced 
risks (e.g., less radiation exposure), additional insights into or alternate explanations of chest pain, and 
increased cost-effectiveness in comparison with SPECT MPI/ICA. Findings are expected to result in 
validation of an evolving new standard of care for patients with stable angina that takes advantage of 
CCTA and OMT to more cost-effectively drive appropriate care while reducing the need for invasive 
diagnosis and increased radiation exposure with SPECT MPI/ICA. 

6
May 4, 2011 
 
 
 
In the United States, 9.8 million people have stable angina, with an annual incidence of 500,000.1
Although millions of individuals present with symptoms of stable angina or angina equivalent annually, 
it is estimated that only about one-third of these patients will have abnormal results from exercise 
SPECT MPI.2 Imaging plays a prominent role in establishing the diagnosis and, nationwide, represents a 
significant healthcare expense.  
 
Treatment of stable angina has traditionally been a combination of medical therapy and 
revascularization. The COURAGE trial recently showed that ³as an initial management strategy in 
patients with stable CAD, PCI did not reduce the risk of death, myocardial infarction [MI], or other 
major cardiovascular events when added to OMT.´3 This OMT-only paradigm as demonstrated in the 
COURAGE trial represents a substantial cost savings and is evolving into a new standard of care.  
 
CCTA accurately detects coronary atherosclerotic plaque and stenosis. CCTA, alone, has the potential to 
be less expensive than SPECT MPI followed by diagnostic ICA when the SPECT MPI test is positive, 
and represents an attractive alternative diagnostic approach.  
 
Guidelines for the diagnosis and management of patients with chronic stable angina have been 
published.4 The probability of CAD is estimated on the basis of patient age, gender, cardiovascular risk 
factors, and pain characteristics. Patients with intermediate or high probability of CAD will undergo 
additional risk stratification through further testing. For patients with low probability of CAD, the 
decision to have additional testing is made on a case-by-case basis.  
 
Exercise perfusion imaging, exercise echocardiography, or exercise ECG is recommended as the initial 
test for risk stratification in symptomatic patients who can exercise unless there are confounding factors 
on their ECG or the patients are taking digoxin. Pharmacologic stress imaging is recommended for the 
remainder of symptomatic patients. Patients with positive stress imaging demonstrating moderate to 
severe ischemia often undergo ICA to establish that the test was a true positive and to guide therapy 
including revascularization. Typically, on SPECT MPI,  10% of a reversible perfusion defect is defined 
as moderate to severe ischemia.5 Evidence of transient ischemic dilation (TID) accompanied by 
electrocardiogram (ECG) changes of ischemia identified during SPECT MPI should lead to ICA. 
 
The severity of symptoms of stable angina is generally graded by an angina class such as defined by the 
Canadian Cardiovascular Society (CCS).6 This is clinically based on the patient¶s symptoms at various 
levels of activity (Table 1). 

7
May 4, 2011 
 
 
Class I 
Ordinary physical activity does not cause angina, such as walking 
and climbing stairs. Angina with strenuous or rapid or prolonged 
exertion at work or recreation. 
Class II 
Slight limitation of ordinary activity. Walking or climbing stairs 
rapidly, walking uphill, walking or stair climbing after meals, or in 
cold, or in wind, or under emotional stress, or only during the few 
hours after awakening. Walking more than two blocks on the level 
and climbing more than one flight of ordinary stairs at a normal 
pace and in normal conditions. 
Class III 
Marked limitation of ordinary physical activity. Walking one to 
two blocks on the level and climbing one flight of stairs in normal 
conditions and at normal pace. 
Class IV 
Inability to carry on any physical activity without discomfort²
anginal syndrome may be present at rest. 
 
 
 
The landmark COURAGE trial recently showed that, ³as an initial management strategy in patients with 
stable CAD, PCI did not reduce the risk of death, MI, or other major cardiovascular events when added 
to OMT´.3 All of the participants in the study had a  70% stenosis in at least one epicardial coronary 
artery and documented objective evidence for myocardial ischemia. Another recent randomized trial 
studied participants with type 2 diabetes and stable CAD comparing treatments of OMT to OMT + 
revascularization.7 As in COURAGE, no significant difference in outcomes was found. Nevertheless, 
who will derive benefit from revascularization based on extent of patient ischemia remains unclear A 
small nuclear medicine substudy of participants in the COURAGE trial showed a greater reduction of 
ischemia treated by PCI + OMT over OMT alone for participants with larger reversible perfusion 
defects.5 While this substudy was not powered sufficiently to detect differences in outcomes, it suggests 
that patients with severe ischemia may benefit from PCI. Hachmanovitch et al showed in a non-
randomized single-center study that revascularization improved survival for participants with moderate-
severe ischemia, whereas participants with no or mild ischemia had better outcomes with OMT.8 
Certainly, the prognosis of patients with more ischemia is known to be worse.8,9  
 
A single center trial of participants in Brazil with stable 3-vessel disease and normal ventricular function 
(MASS II) randomized 611 patients into OMT alone or in combination with PCI or CABG.10,11 There 
was no significant difference in overall mortality in the three groups at either 5 or 10 years. 
Nevertheless, there was a higher incidence of acute MI, cardiac-related death, and subsequent 
revascularization due to refractory angina in the OMT alone group. While suggestive that OMT alone 
may be inferior to PCI and CABG for patients with 3-vessel disease, the study is limited by the single 
center design and relatively small number of participants in each arm. This result was not seen in 
COURAGE, but there were fewer patients with 3-vessel disease in COURAGE than MASS II. 
Participants with significant stenosis of their left main coronary artery did benefit from revascularization 
compared with medical therapy in the Veterans Administration Cooperative Study of Surgery for 
Coronary Arterial Occlusive Disease.12 This may be a particularly risky anatomy but the numbers of 

8
May 4, 2011 
 
 
participants in this study were relatively small (N=91), and there have been significant advances in 
medical therapy since this study was performed. 
A substudy of the COURAGE trial examined participants with stable CAD stratified by 
age and randomized to PCI + OMT or OMT alone. A total of 1381 participants younger 
than 65 years and 904 participants 65 years and older were followed. The addition of PCI 
to OMT did not improve or worsen clinical outcomes in participants 65 years and older 
during a median 4.6-year follow-up.13 In the TIME study (Trial of Invasive versus 
Medical therapy in Elderly), although early evaluation favored invasive therapy, 1-year 
follow-up of elderly participants ages 75 or older with CCS Class II or higher angina 
showed no significant difference in participants treated with OMT verses invasive 
therapy with regard to symptoms, quality of life (QoL), and death or non-fatal 
infarction.14 To our knowledge, no literature specifically addresses outcomes differences 
stratified by age in patients with stable angina treated by OMT as directed by the initial 
non-invasive imaging procedure of CCTA and imaging using SPECT MPI followed by 
diagnostic ICA.  
A substudy of the Euro Heart Survey of Stable Angina sought to determine gender 
differences in participant outcomes.15 A total of 3779 participants were included in the 
survey; 42% were female. In a multivariable model adjusted for age, abnormal left 
ventricular function, the presence of diabetes, and the severity of CAD defined as one-, 
two-, or three-vessel disease, female gender remained significantly predictive of death or 
MI, with women twice as more likely than men to die or have an MI during one-year 
follow up. Many other studies also have suggested gender differences in treatments and 
outcomes in patients with CAD.7,16,17 In RESCUE, we will also stratify outcomes by 
participant gender to identify any differences.  
A study by Sachdev et al assessed a cohort of 1471 participants with CAD who 
underwent cardiac catheterization and were followed for 10 to 15 years through the Duke 
Databank for Cardiovascular Diseases.18 The Charlson index,19 a widely used index of 
patient comorbidity, and a newly-created CAD-specific index18 were highly associated 
with long-term survival, almost equivalent to left ventricular ejection fraction. 
Components of the Charlson index with the greatest prognostic significance among 
patients with CAD were diabetes, renal insufficiency, chronic obstructive pulmonary 
disease, and peripheral vascular disease. As comorbid disease is strongly associated with 
long-term survival in patients with CAD, RESCUE will assess co-existing illnesses using 
these two indices to determine any impact of comorbidity upon differences in participant 
outcomes.  
 
Several myocardial jeopardy scores have been proposed to identify myocardium at risk. These generally 
take into consideration the location and extent of CAD. Three common scoring tools (Duke Prognostic 
Index),20 Myocardial Jeopardy Index described in the Bypass Angioplasty Revascularization 

9
May 4, 2011 
 
 
Investigation (BARI),21 Alberta Provincial Project for Outcome Assessment in Coronary Heart Disease 
(APPROACH)22 have been compared.23 All were found to be predictive of mortality and have been 
suggested as tools for cardiovascular outcome studies. The Duke index has the advantage of being the 
easiest to apply and most widely used. It also has been adapted for use with CCTA1 (Table 2) and for 
estimating the size of ischemic myocardium from ICA.24  
 
 
Subgroup 
Severity of CAD 
1 
< 50% Stenosis 
2 
> 2 Mild Stenoses With Proximal CAD  
in 1 Artery or 1 Moderate Stenosis 
3 
2 Moderate Stenoses or 1 Severe Stenosis 
4 
3 Moderate Stenoses, 2 Severe Stenoses,  
or Severe Stenosis in Proximal LAD 
5 
3 Severe Stenoses or 2 Severe Stenoses  
in Proximal LAD 
6 
> 50% Left Main Stenosis 
CCTA, coronary computed tomography angiography; CAD, coronary 
artery disease; LAD, left anterior descending coronary artery 
 
 
 
The importance of patient self-reported outcomes is widely recognized in the literature and by the US 
Food and Drug Administration.25,26 Global measures of health, such as the 36-Item Short Form Survey 
Instrument, version 2 (SF-36 v2), are useful to compare participant health status across studies of 
different health conditions27±30 as well as to derive health utilities for use in cost-effectiveness 
analyses.31 Disease-specific measures of participant health status, such as the Seattle Angina 
Questionnaire (SAQ), are useful to collect detailed information regarding the specific disease outcome 
of interest.32 Both the SF-36 and the SAQ have been used to assess health-related QoL in patients with 
angina and have been demonstrated to be internally consistent with good test-retest reliability.27±30,32 
Selected subscales from both tools have been correlated with patient angina severity measured using the 
CCS Classification (Table 1),32 and both of these tools have been used to measure participant health 
status in a prior large clinical trial of PCI and OMT interventions for patients with angina.33  
 
CCTA has been shown in recent multicenter studies to have high negative predictive value for 
obstructive CAD.34,35 Another multicenter study showed only moderate negative predictive value, but 
considered un-evaluable coronary artery segments to have no significant disease, which is contrary to 
common practice, and included these data in the trial analysis.36 All of these multicenter studies showed 
limited positive predictive value for obstructive CAD on a per-segment basis. Nevertheless, CCTA can 
be used effectively for prognosis, as was shown recently by Min et al.1 This study showed that the 
location and extent of CAD as assessed with a modified Duke coronary artery prognostic index (Table 

10
May 4, 2011 
 
 
2)37 may be used for predicting all-cause mortality. Larger scores represent poorer prognosis and were 
representative of greater myocardium ischemic risk.  
 
Given the linkage of the modified Duke coronary artery prognostic index to ischemic burden, it is 
reasonable to hypothesize that CCTA may be used as a primary tool to guide the clinical decision to 
prescribe OMT versus revascularization for patients with symptoms of stable angina. We note that the 
myocardial jeopardy score and angina variables were found to be the strongest predictors of 
revascularization in the Coronary Artery Surgery Study (CASS) registry.38 
 
A CCTA approach could provide considerable savings over the current common practice of SPECT MPI 
followed by diagnostic ICA when the SPECT MPI test is positive. The high negative predictive value of 
CCTA would exclude patients without CAD as a cause of their symptoms. The positive predictive value 
of CCTA for obstructive CAD on a per-patient basis is higher than that found for per-segment analyses 
and is more appropriate for guiding the patient to OMT. Moreover, the positive predictive value for the 
presence of plaque is high, as has been demonstrated in studies comparing CCTA to intravascular 
ultrasound. The major limitation of using CCTA to guide treatment is that some patients without 
obstructive CAD may be treated with OMT or may possibly be misdirected to coronary angiography to 
evaluate for revascularization because of suspected left main disease (  50% stenosis). However, it is 
anticipated that this cost should be more than offset by eliminating the current practice of SPECT MPI 
followed by diagnostic ICA in those patients who demonstrate myocardial ischemia. Even if plaque seen 
by CCTA is non-obstructive, the presence of plaque may indicate that microvascular disease is the cause 
of the symptoms, so OMT would be appropriate.  
 
The incidence of stable angina pectoris in the US is estimated to be 500,000 patients per year with a 
prevalence of 9.8 million.39 The diagnostic costs in evaluating these patients are substantial. Far more 
patients are evaluated for the presence of possible stable CAD as the cause of their symptoms. A recent 
study showed only about one-third of participants with symptoms of stable angina or anginal equivalent 
evaluated by SPECT MPI demonstrate evidence of ischemia.2 The high negative predictive value of 
CCTA can be expected to provide an effective filter to reduce the need for further evaluation for CAD. 
It has recently been suggested from an analysis of Medicare Category III transaction codes that 
substantial savings may be found using CCTA to establish the diagnosis.40
 
The primary endpoint of the study is a combined endpoint of occurrence of MACE, comprising cardiac-
related death or acute MI, and revascularization (see Appendix IV for definitions). We will calculate 
differences in the combined MACE/revascularization endpoint between the CCTA and SPECT 
MPI/ICA arms.  
 
  
To compare outcomes of participants with symptoms of stable angina or angina 
equivalent evaluated with an anatomic imaging strategy using CCTA as initial method of 
CAD diagnosis (Group A) to a combined functional and anatomic imaging strategy of 
SPECT MPI/ICA (Group B) as a guide to OMT. 

11
May 4, 2011 
 
 
To evaluate the ability of available prognostic indices to predict revascularization or 
MACE using CCTA information and to develop new indices using the RESCUE trial 
data. 
To determine the cost, effectiveness, and incremental cost-effectiveness of CCTA versus 
SPECT MPI/ICA in the evaluation of participants with symptoms of stable angina. 
To compare angina symptoms and self-reported health status of participants with 
symptoms of stable angina undergoing CCTA as initial method of CAD diagnosis to 
SPECT MPI/ICA as a guide to OMT.
The RESCUE study is designed as a phase III, randomized, controlled, diagnostic, multicenter trial. We 
will enroll 4300 participants at a maximum of 80 sites during an 18-month period. Patients with stable 
angina or anginal equivalent (nausea, dyspnea, syncope, etc) who consent and are enrolled in the trial 
will be randomized to CCTA (Group A) or SPECT MPI/ICA (Group B) as initial method of CAD-
symptom diagnosis. All participants diagnosed with CAD by either strategy will be treated initially by 
OMT unless there is evidence of significant left main CAD (  50% stenosis) or markedly abnormal 
stress test, in which case they will undergo ICA and possibly revascularization as is standard practice.  
 
Participants with CCTA or SPECT MPI/ICA findings of stenosis  50% in diameter will be treated with 
OMT unless the stenosis is in the left main coronary artery. Participants with moderate-severe ischemia 
by SPECT MPI (  10% reversible perfusion defect or evidence of TID accompanied by ECG changes of 
ischemia) will undergo diagnostic ICA to confirm no significant left main CAD (< 50% stenosis) and 
that the diagnosis is not a false positive. Participants with a stenosis  50% in diameter on diagnostic 
ICA will be directed to OMT. Un-evaluable proximal and mid segments will be regarded as being 
positive for CAD for the purposes of the study and the participant directed to OMT. Participants with 
left main CAD found on CCTA will undergo diagnostic ICA. Participants with CCTA findings of 
stenosis < 50% in diameter; SPECT MPI findings of reversible ischemia < 10% of the myocardium; or 
SPECT MPI findings of  10% reversible perfusion defect or evidence of TID accompanied by ECG 
changes of ischemia followed by ICA findings of < 50% stenosis will be treated per institutional 
standard of care or discharged and followed per protocol for MACE and revascularization.  
 
Both CCTA and SPECT MPI will be read locally at participating sites. Local-read results will be used to 
guide participants into additional diagnostic procedures (such as ICA in the SPECT MPI arm) and the 
various post-diagnostic arms of the study (Figure 1). All CCTA and SPECT MPI scans will be sent to 
the ACRIN core lab for archiving. The first two (2) scans from each site and a random subset of 10% of 
CCTA and SPECT MPI scans from each participating site will be reviewed centrally at the CCTA and 
SPECT MPI core labs for quality assurance. A modified Duke Prognostic Index will be calculated from 
the completed local-read CRF. The myocardial perfusion defect size will be determined for each SPECT 
MPI case locally both for determining participant direction to revascularization vs. OMT and for later 
prognostic analysis. Imaging recommendations have been suggested by ACRIN and the respective core 
labs and are available online at www.acrin.org/RESCUE_imagingmaterials.aspx.  
 
OMT includes antiplatelet therapy, aggressive lipid lowering targets,41 treatment for hypertension, 

12
May 4, 2011 
 
 
treatment for angina, diabetes control, smoking cessation, exercise, and nutritional/dietary and other 
lifestyle changes as was done in COURAGE.3 Changes to OMT by participants or by physician 
prescription will be tracked throughout trial follow up. (See Section 8.1.5.2 for OMT specifics.) 
Participants with persistent or worsening symptoms will be evaluated for revised therapeutic approaches 
and possible revascularization (see Section 8.1.5.3).   
 
Angina class (CCS Class I to III, Canadian Cardiovascular Society)6 will be assessed on entry into the 
study and at 6-month intervals for up to 24 months. Risk factors for CAD (including Diamond-
Forrester),42 Charlson Comorbidity Index,19 and CAD-specific Morbidity Index18 will be acquired at 
baseline only. The SAQ43 and SF-36 for QoL (quality-of-life) assessment will be administered by the 
site RA to all participants in the United States at baseline. A subset of US participants will complete the 
QoL questionnaires at 12 months; if necessary, telephone follow up will be used to encourage 
completion by mail or to conduct an interview to complete. Lifestyle questions will be administered by 
the site RA at baseline and be included during telephone follow up at 12-months only.  
 
Follow up at the site level will comprise telephone participant/proxy contact at 2 weeks and 2 months 
after enrollment 
 for participants who have positive cardiac findings on diagnostic CCTA or SPECT 
MPI. 
 participants (or their proxies) will be contacted by telephone for additional medical 
information at 6-month intervals after enrollment for up to 24 months. Number of time points and 
duration of follow up depend on diagnostic results and timing of enrollment, respectively. See Section 
8.2.1 for additional details.  
 
Medical records collection will be conducted for the subset of participants who self-report MACE, 
stroke, revascularization, cardiac-related visits, or visits related to incidental findings associated with the 
diagnostic tests. Procedures for medical record collection are dependent on site location and local 
standard practice in releasing participant protected health information (PHI). The schema of the trial is 
shown in Figure 1 below. Figure 2 below shows the selection process for medical record collection. 
 

13
May 4, 2011 
 
 
CCS, Canadian Cardiac Society; CCTA, coronary computed tomography angiography; SPECT, single 
photon emission tomography; MPI, myocardial perfusion imaging; TID, transient ischemic dilation; ECG, electrocardiogram; 
CAD, coronary artery disease; MACE, major adverse cardiac event; OMT, optimal medical therapy; ICA, invasive coronary 
angiography; LM Dz, left main disease (  50% stenosis). 

14
May 4, 2011 
 
 
No 
significant 
occlusion 
Incidental 
findings 
OMT 
Incidental 
findings 
No 
significant 
ischemia 
<50% 
stenosis 
50% 
stenosis 
Left main 
disease
10% reversible defect, 
evidence of TID with ECG 
changes of ischemia 
<10% reversible 
defect
Follow up: Contact participant or proxy up to 2 years after enrollment;  
time points dependent on diagnostic results and time of enrollment 
Recruit patients 
with symptoms 
of stable angina 
or angina CCS 
Class I to III 
CCTA 
SPECT MPI 
Randomly 
allocate 
Group A 
Group B 
CCS, Canadian Cardiac Society; CCTA, coronary computed tomography angiography; 
SPECT, single photon emission tomography; MPI, myocardial perfusion imaging; TID, transient ischemic 
dilation; ECG, electrocardiogram; MACE, major adverse cardiac event; OMT, optimal medical therapy; ICA, 
invasive coronary angiography; CTP, Current Procedural Terminology; ICD, International Classification of 
Diseases. 
MACE is defined as myocardial infarction or cardiac-related death. 
If participants  
in these groups 
do not report 
cardiac care,  
the site RA  
is required to 
investigate and 
determine why 
no medical care 
occurred 
Cardiac-related 
visits reported  
on telephone  
follow up 
MACE or 
revascularization
reported by 
participant/proxy; 
abstract MACE-
related visits 
Visits related to 
incidental 
findings reported 
on telephone 
follow up  
No MACE or 
revascularization 
No cardiac-
related care 
No abstraction
Abstraction for 
outcomes on 
study-specific 
and CPT/ICD 
code forms  
at the 6-month 
follow-up interval 
after initial report  
of event
Abstraction  
for outcomes  
on study-specific 
and CPT/ICD  
code forms 
Abstraction for 
outcomes on 
study-specific 
and CPT/ICD 
code forms 
Diagnostic 
ICA
Diagnostic 
ICA

15
May 4, 2011 
 
 
Patients ages 40 or older presenting with symptoms of stable angina CCS Class I to III or angina 
equivalent, with or without known CAD, with planned non-invasive imaging for diagnosis may enroll in 
the study. 
 
 Willing and able to provide a written informed consent; 
  40 years or older; 
Presentation with symptoms of stable angina (CCS Class I to III) or angina equivalent 
with or without known CAD;  
  Planned non-invasive imaging for CAD diagnosis; 
Able to tolerate CCTA or SPECT MPI per randomization as required by protocol, to be 
performed at an ACRIN-qualified facility with a RESCUE-qualified scanner. 
 
Prior revascularization; 
Not suitable to undergo CT with an iodinated contrast agent: 
Known allergy-like reaction to contrast media as defined by the American 
College of Radiology (ACR) (see www.acr.org/SecondaryMainMenuCategories/ 
quality_safety/contrast_manual.aspx for reaction definition) or moderate to severe 
allergic reactions to more than one allergen; 
Renal failure, as determined by glomerular filtration rate (GFR) < 30 
mL/min/1.73 m2 based on a serum creatinine level obtained within 28 days prior 
to registration;  
Renal insufficiency at the time of enrollment, as determined by GFR 30 to 60 
mL/min/1.73 m2 based on a serum creatinine level obtained within 28 days prior 
to registration, unless permitted by the institution¶s policy and/or ACR guidance 
for risk reduction strategies (see www.acr.org/SecondaryMainMenuCategories/ 
quality_safety/contrast_manual.aspx for guidance on contrast selection and pre-
treatment strategies); 
Atrial fibrillation or significant arrhythmia judged to potentially limit quality of CCTA; 
Acute ischemia; 
Acute myocardial infarction;  
 Severe myocardial ischemia: known markedly positive exercise treadmill stress test 
(significant ST segment depressions or hypotensive response during stage I of the Bruce 
protocol); 
Unable to suspend respiration for 15 seconds or to follow instructions to do so; 
Unstable angina and symptoms refractory to maximal oral and intravenous medical 
therapy (persistent CCS Class IV); 
 History of known left ventricular ejection fraction < 45%; 
Pulmonary edema or heart failure unresponsive to standard medical therapy; 

16
May 4, 2011 
 
 
Pacemaker;
Valvular heart disease likely to require surgery in the next 18 months; 
Congenital heart disease or cardiomyopathy likely to affect prognosis during follow up; 
Significant systemic hypertension (blood pressure > 200/100 mm Hg) unresponsive to 
medical therapy; 
Severe noncardiovascular comorbidity limiting survival (e.g., cancer or other life 
threatening illness for which the patient is expected to live less than 12 months); 
Prior imaging evaluation for this episode of symptoms (e.g., SPECT MPI or CCTA 
within the previous 72 hours); 
BMI > 40 kg/m2;
Pregnancy or intent to become pregnant (if a female is of childbearing potential²defined 
as a premenopausal female capable of becoming pregnant²a pregnancy test should be 
done prior to enrollment). 
Patients will be recruited from office-based clinical practices and from referrals to radiology 
departments and outpatient imaging centers where CCTA and SPECT MPI/ICA are performed. Patients 
presenting to the emergency department may be eligible for the trial as long as acute coronary syndrome 
is ruled out and all other eligibility criteria are met for trial participation. Informed consent will be 
obtained as soon as the potential participant is identified. Consent will be completed by an appropriate 
investigator-designated research staff.  
 
Referring physicians will need to be in agreement with the principles of the trial, 
A sheet describing possible OMT and a description of 
the trial will be sent to referring physicians.  
 
ACRIN will develop materials to aid participant recruitment. All materials used for participant 
recruitment will be reviewed and approved by each institution¶s Institutional Review Board (IRB).  
 
Subjects will not be excluded from entry based on sex or ethnicity. Training specific to inclusion of 
women and minorities will be provided at our Investigators Meeting. The sex and racial makeup of 
RESCUE will reflect the overall US population undergoing cardiovascular disease diagnosis. RESCUE 
will be conducted in compliance with the National Institutes of Health (NIH) Policy of Inclusion of 
Women and Minorities in Clinical Research, and with Federal Law PL 103-43 (NIH Revitalization Act 
of 1993). Minority groups are categorized according to the Revisions to the Standards for the 
Classification of Federal Data on Race and Ethnicity.  
 
As consecutive patients in need of receiving CCTA or SPECT MPI will be approached for participation 
in this trial, we anticipate that we will have commensurate representation from women and minorities in 
the study population. The trial results should therefore have broad generalizability and be in compliance 

17
May 4, 2011 
 
 
with NIH policy. In addition, as part of the secondary analyses, we will assess the effects of sex as well 
as race and ethnicity on the primary and secondary study outcomes. 
Both men and women and members of all ethnic groups are eligible for this trial. In conformance with 
the NIH Revitalization Act of 1993, with regard to inclusion of women and minorities in clinical 
research, the projected gender and minority accruals are shown below:
 
Hispanic or Latino
279 
409 
688 
Not Hispanic or Latino 
1462 
2150 
3612 
1741 
2559 
American Indian or Alaskan Native 
35 
51 
86 
Asian 
181 
266 
447 
Black or African American 
592 
870 
1462 
Native Hawaiian or other Pacific Islander 
10 
25 
26 
White 
923 
1356 
2279 
 
1741 
2559 
All 
sites 
must 
submit 
a 
Protocol 
Specific 
Application 
(PSA) 
(available 
online 
at 
www.acrin.org/RESCUE_protocol.aspx), which documents that the site has the necessary personnel, 
equipment, and referral base to carry out the requirements specific to the ACRIN 4701 RESCUE 
protocol. It will be reviewed and approved by the ACRIN Institutional Participant Committee. 
 
The potential sites for this study are cardiology or radiology institutions, including US Department of 
Veterans Affairs (VA) medical facilities, that meet qualifications for participating in this study (see 
below). See Section 9.0 for additional information regarding imaging qualification for this trial. 
 
The ACRIN core lab will work with the CCTA core lab, the Cardiovascular Imaging 
Core (CVIC) Laboratory at the Massachusetts General Hospital, to identify and 
implement criteria to qualify clinical and testing referral sites for RESCUE. 
 
Criteria for qualification of sites interested in participating will include:  
1) 
 64-slice multidetector CT technology for cardiac CT;  
2) Technologist expertise as defined by relevant certifying bodies for each test;  
3) At least minimum reader expertise defined as self attestation of:  

18
May 4, 2011 
 
 
a) Completed American College of Cardiology (ACC) Core Cardiology Training 
(COCATS) level II; 
b) ACR CCTA minimum proficiency as defined by the ACR CCTA Practice 
Guidelines (50 cases interpreted in previous 36 months);  
4) Intersocietal Commission for the Accreditation of Computed Tomography 
Laboratories (ICACTL) or ACR laboratory accreditation; and  
5) Adequate IT capabilities defined as compatibility of storage and transfer in DICOM 
format.  
 
The ACRIN core lab will work with the SPECT MPI core lab at Tufts Medical Center, to 
identify and implement criteria to qualify clinical and testing referral sites for RESCUE. 
SPECT myocardial perfusion studies will be performed in accordance with best practice 
standards as delineated in the imaging guidelines of the American Society of Nuclear 
Cardiology (ASNC) by appropriately credentialed physicians.  
 
The following minimal criteria will be used as guidelines for selecting sites:  
1) Use of standard equipment for exercise and pharmacologic testing and SPECT MPI 
as defined in current ASNC practice guidelines;44±46  
2) Technician expertise as defined by relevant certifying bodies for each test;  
3) Reader expertise defined as:  
a) Completed at least ACC COCATS II level training; 
 
b) Certification by the Certification Board of Nuclear Cardiology (CBNC); 
 
c) Board certification in Nuclear Medicine or Radiology;47  
4) Intersocietal Commission for the Accreditation of Nuclear Medicine Laboratories 
(ICANL), ACR, or Joint Commission laboratory accreditation; and 
5) Availability of standard commercial analytic software to calculate reversible and 
fixed defect size in order to determine % ischemia.   
 
One (1) test image in each modality (that is, one for CCTA and one for SPECT MPI) will 
be sent from the sites to ACRIN core lab to ensure that: the recommended protocols are 
followed; image quality is adequate; and that all technical issues related to image 
transmission and receipt are resolved. The CCTA test case will be assessed for adequate 
test protocol adherence, radiation exposure, image quality, data/image reconstruction, and 
transfer capability for final certification. Technical performance for CCTA and SPECT 
MPI will be judged by ACRIN technologists according to the criteria for each test listed 
in Table 4 below. Images that are technically challenging or where quality is considered 
borderline may be delivered electronically to the respective core labs for consultation 
with experts in each modality. For sites with inadequate studies, the ACRIN core lab will 
review the test protocol with the site in detail and request an additional study for the 
modality until the site fulfills all requirements.  
 

19
May 4, 2011 
 
 
CCTA  
1) Complete data set without major motion artifacts and sufficient 
contrast enhancement, additional data sets if motion artifacts are 
present (retrospective ECG gating), and protocol description with 
radiation dose details;  
2) Use of heart-rate lowering drug and retrospective ECG gating for 
heart rate > 65 bpm, unless a dual-source CCTA scanner is 
available.  
SPECT MPI  
1) High quality non attenuated-corrected AND attenuated-corrected 
(if attenuation-correction is used) raw rest and stress projection 
images with attention to minimal motion and acceptably low 
levels of hepatic and bowel uptake. 
2) Reconstructed files (short axis, vertical long axis, and horizontal 
short axis). 
3) Screen capture of quantitative analysis results page displaying 
³% of LV ischemia or ³% LV reversibility´ from a commercial 
quantitative software program (i.e., Emory Cardiac Toolbox,  
4D-MSPECT, QPS [Cedars Sinai], etc.). 
4) High quality gated SPECT MPI with Beat Length Histogram (if 
available). 
 
For site qualification questions or technical assistance on CCTA during the study from 
the ACRIN core lab, contact Cynthia Price, RT(R)(MR)(ARRT), via email or phone. 
 cprice@acr.org 
 215-940-8863 
 
For site qualification questions or technical assistance on SPECT MPI during the study 
from the ACRIN core lab, contact Rebecca Scaven, CNMT, via email or phone. 
 rscaven@acr.org 
 215-574-3175 
For CCTA questions related to image acquisition or interpretation, sites may contact the 
CCTA core lab at Massachusetts General Hospital via email or phone. 
 rescuehelp@partners.org 
 408-6RESCUE (408-673-7283) 
 
For SPECT MPI questions related to image acquisition or interpretation, sites may 
contact the SPECT MPI at Tufts Medical Center core lab via email, phone, or pager, to 
the attention of Deb Kinan, RTN. 
dkinan@tuftsmedicalcenter.org
 617-636-2357   
 
 
Images per protocol specifications must be reviewed and approved prior to participant 
enrollment. All scanner and image qualification materials are available at 

20
May 4, 2011 
 
 
www.acrin.org/RESCUE_protocol.aspx, and Section 9.0 provides additional information 
regarding the CCTA with iodinated contrast and SPECT MPI imaging recommendations.  
All regulatory documentation must be submitted to ACRIN Headquarters (via fax: 215-717-0936, 
ATTN: ACRIN Protocol Development and Regulatory Compliance Department). All institutions must 
have study-specific, initial full-board Institutional Review Board (IRB) approval for the protocol and 
informed consent form (ICF). An ICF Template is included in this protocol as Appendix I and may be 
adjusted for local IRB submission. Appendix II contains an Authorization to Release/Disclose Medical 
Records Template, which is designed for use by a site that will allow ACRIN to coordinate medical 
record collection for the trial. This document should be adjusted for local IRB submission, will be 
signed by the patient at time of consent, as it will be included in requests to outside healthcare providers 
that treat the participant during the trial follow-up timeline. Sites coordinating their own medical record 
collection, such as VA facilities, will not need to provide a local IRB-approved version of this document 
to ACRIN and will follow institutional protocols for medical record procurement and de-identification.  
 
The investigator and the investigator-designated research staff must follow OHRP-approved consent 
procedures (Title 45, Part 46 Code of Federal Regulations), as well as those set by the local IRB 
overseeing the study for the site. A copy of the IRB approval letter, a copy of the IRB-approved, site-
specific ICF and authorization document (as appropriate), ACRIN Statement of Investigator, 
Federalwide Assurance documentation, and evidence of completion of the Protecting Human Research 
Participants training from the NIH Office of Extramural Research (or institution-specific equivalent) 
must be delivered to the trial monitor to review the approved forms and keep on file at ACRIN 
Headquarters prior to activation of the study at the local site. 
 
 
The ACRIN Biostatistics and Data Management Center (BDMC) will monitor participant 
accrual. Total target accrual for this study is 4300 participants. During the first year, 
accrual will be reviewed monthly with the intention of discovering and resolving any 
recruitment barriers. 
The ACRIN Steering Committee regularly reviews the overall trial accrual and may 
request information about a trial¶s accrual performance to better understand general 
accrual barriers or issues. Accrual and safety information will be presented to the 
RESCUE Data and Safety Monitoring Committee (DSMC) at regularly scheduled 
meetings thereof; the RESCUE DSMC may, at its discretion, re-evaluate the study with 
respect to feasibility or the need for additional participating institutions. 
 
Monitoring of study-specific adverse events (AEs) and all primary endpoint events²
MACE and revascularization²will be conducted during the trial. ACRIN will centralize 
all AEs reporting for subsequent reporting to the RESCUE DSMC (and possibly to 
AHRQ). The medical monitor will review AEs on an on-going basis.  
 

21
May 4, 2011 
 
 
An adjudication committee will provide oversight for all reported MACE and 
revascularizations. Once MACE or revascularization has been reported, the site will be 
required to forward all medical and research records relating to these events to the 
ACRIN 4701 Lead Data Manager for review by the adjudication committee. An 
independent clinical event adjudication committee, comprising a minimum of three 
experts with clinical cardiovascular expertise, will be available to review and adjudicate 
medical records for all MACE and revascularization while blinded to study arm. The 
operation and procedures of the adjudication committee will be described in a separate 
document.  
 
The ACRIN web address is www.acrin.org. 
Data collection and management will be performed by the BDMC of ACRIN under the 
direction of Dr. Constantine Gatsonis. The Biostatistics Center (BC) is located at 
Center for Statistical Sciences at Brown University in Providence, RI, and the Data 
Management Center (DMC) is located at ACRIN in Philadelphia, PA. 
 
Participant enrollment and data collection occurs through a series of programmed 
screens accessed through the ACRIN web site to register/randomize participants, 
collect participant data, and maintain calendars of data submissions for each 
participant. By using the World Wide Web, ACRIN has made participant registration, 
data entry, and updated calendar information available to clinical sites 24 hours a day, 
seven days a week. Each successful case registration is confirmed through receipt of an 
e-mail containing a registration/randomization confirmation and a case-specific 
calendar identifying timelines for data and image submission. If the confirmation e-
mail is not received, the enrolling person should contact the DMC before attempting a 
re-registration. A DMC contact list is located on the ACRIN web site for each protocol.
 
Upon successful participant registration, a confirmation e-mail containing the 
registration and case-specific calendar is sent to the research staff enrolling the 
participant via the web. In addition, the investigator-designated research staff may 
download the participant specific data submission calendar, which lists all forms and 
designated reports required by protocol, along with the dates forms are due at the DMC. 
These calendars will be updated as the study proceeds to reflect data that have been 
received, deadlines to reply to queries about unclear data, deadlines for follow-up 
reports of AEs, or changes in the protocol that change the data being collected or the 
collection timeframe. Updated calendars for each participant can be obtained 24 hours a 
day from the ACRIN web site. The research associate (RA) may use the calendar as a 
case management tool for data submission and follow-up scheduling.  
 
The investigative site is required to submit data according to protocol as detailed on 
each participant¶s calendar, as long as the case status is designated as open/alive or 

22
May 4, 2011 
 
 
until the study is terminated. The case is closed when all data have been received, 
reviewed, and no outstanding data query exists for the case. 
 
To submit data via the ACRIN web site, the appropriate investigator-designated 
research staff will log onto the ACRIN web site and supply the pre-assigned user name 
and password. Case report forms (CRFs) will be available on the web site through a 
series of links. Each web form is separated into modules; each module must be 
completed sequentially in order for the internal programming to be accurate. The user 
selects the link to the appropriate form and enters data directly into the web-based 
form. As information is entered into the web form application, various logic checks will 
be performed. These logic checks look for data that are missing, data that are out of 
range, and data that are in the wrong format (e.g. character data in a field requiring 
numeric responses). Such errors will be detected as soon as the user attempts to either 
submit the form or move to the next data element. They must be corrected before the 
form is transmitted to the DMC. The user will not be able to finalize form transmission 
to the DMC until all data entered pass these logic checks. Forms that are not completed 
in one sitting can still be submitted and completed at a later date. The form will remain 
available on the web until the ³Complete Form Submission´ button is depressed.  
 
Once data entry of a form is complete, and the summary form is reviewed for 
completeness and accuracy, the investigator or the research staff presses the ³Complete 
Form Submission´ button on the form summary screen and the data are transferred into 
the clinical database. No further direct revision of the submitted data is allowed after 
this point. E-mail confirmation of web data entry is automatically generated and sent to 
the site investigator or RA listing all of the data generated and just submitted. Should a 
problem occur during transmission and the e-mail confirmation of data submission is 
not received, the investigator or RA should contact the DMC for resolution of the 
submission. 
 
If a temporary problem prevents access to the Internet, all sites are notified of the event 
and estimated down time through an ACRIN broadcast message. The investigative site 
should wait until access is restored to submit data. The site RA or investigator should 
notify the DMC of the problem and the DMC will give an estimated time when access 
will be restored. If access will be unavailable for an extended period, sites must seek 
another Internet Service Provider (ISP). On a short-term basis, the ACR can serve as an 
ISP. 
 
 
 
Once the patient has been found to be eligible to participate in the trial, the potential 
participant will be consented (see Informed Consent Form Template in Appendix I). 
Upon obtaining a signed ICF, the RA will register the participant by logging onto the 
ACRIN web site (www.acrin.org), and selecting the link for Data Center Login.  
After completing the registration, the system assigns a participant-specific case number. 
The system then moves to a screen, which confirms that the participant has been 

23
May 4, 2011 
 
 
successfully enrolled. This screen can be printed so that the registering site will have a 
copy of the registration for the participant¶s record. 
Any problems or questions regarding registration of participants should be directed to the 
ACRIN DMC. Never re-register a participant as this may lead to duplicate case numbers.  
 
Study participants will be randomized to the two study arms in equal proportions. 
Blocked randomization will be used, stratified by gender and participating institution. 
Randomization will be done at the time of study enrollment using the web site of the 
ACRIN DMC. In the unlikely event that the web-based system is unavailable, send a fax 
to ACRIN to the attention of ACRIN 4701 RESCUE Lead Data Manager at: 215-717-
0936. Please follow the fax with a call to the trial data manager at 215-574-3150 to help 
ensure the fax is seen as soon as possible. Should fax service be unavailable, call the 
ACRIN 4701 RESCUE Lead Data Manager at 215-574-3150 (assistance available 8:30 
am to 5 pm ET, Monday through Friday). 
 
The registration and data collection system has a built-in security feature that encrypts all data for 
transmission in both directions, preventing unauthorized access to confidential participant information. 
Access to the system will be controlled by a sequence of identification codes and passwords. 
Data received from the web-based forms are electronically stamped with the date and 
time of receipt by the ACRIN server. The data are then entered into the database. A 
protocol-specific validation program is used to perform more extensive data checks for 
accuracy and completeness. Complementary validation programs are initiated at the 
Brown BC and the DMC. The logic checks performed on the data at this point are more 
comprehensive than those built into the web-based data entry screens. They include 
checking that answers are logical, based on data entered earlier in the current form and 
the more thorough checks. Data elements that fail validation are followed up by the 
DMC. The validation program generated by BC produces a log of errors, which is sent 
to the DMC for resolution. The program is frequently updated to incorporate exceptions 
to rules so that subsequent validity checks minimize the time the DMC needs to spend 
resolving problems. Additional data review will take place once the data are transferred 
to the BC. The BC will run thorough cross-form validations, frequency distributions to 
look for unexpected patterns in data, and other summaries needed for study monitoring. 
Any errors found at the BC will be reported to the DMC for resolution. All BDMC 
communication with the participating sites is normally done through the DMC. 
 
If checks at DMC or BC detect missing or problematic data, the DMC personnel 
assigned to the protocol sends a Request for Information (Z1 query letter) to the site 
RA or investigator specifying the problem and requesting clarification. The DMC 
updates the participant¶s data submission calendar with the due date for the site RA or 
investigator¶s response.

24
May 4, 2011 
 
 
In addition to providing the investigator a data collection calendar for each case, the DMC periodically 
prompts institutions for timely submission of data through the use of a Forms Due Report. Distributed at 
intervals via the electronic mail system directly to both the RA and the investigator at each site, this 
report lists data items (e.g., forms, reports, and images) that are delinquent and those that will be due 
before the next report date. In addition to prompting clinicians to submit overdue data, the Forms Due 
Report helps to reconcile the DMC¶s case file with that of the RA and/or investigator. Future Due Forms 
Report may be sent on an as needed basis in addition to past due reports. The site investigator or RA 
may use the Forms Due and Future Due Reports as a case management tool. 
 
The BC at Brown University will maintain a study database at its site for monitoring 
data quality and for performing analyses. These data are drawn directly from the 
permanent database of the DMC. The transfer of data between the DMC and the BC 
has been validated through a series of checks consisting of roundtrip data verification in 
which data are sent back and forth to verify that the sent data are equivalent to the 
received data. These checks are repeated at random intervals during the course of a 
given study. Any discrepancies and other data quality issues will be referred to DMC 
for resolution, since only the DMC can correct the data file. No changes to the data 
will be made at the BC.  
 
A goal of the monitoring of data is to assess compliance with the protocol and to look 
for unforeseen trends that may be indicative of procedural differences among clinical 
sites. If patterns are discovered in the data that appear to arise from causes specific to 
an institution, the BDMC will apprise ACRIN Headquarters and the site of the 
problem, and work with the site, along with ACRIN Protocol Development and 
Regulatory Compliance (PDRC) department, until the problem has been resolved. If the 
BDMC, along with the PDRC, cannot find a resolution to the problem, it will be 
brought to the ACRIN Quality Assurance (QA) Committee for further discussion and 
resolution.  
Study-related procedures are detailed below. Important time points are:  
1) The initial study visit for consenting, eligibility review, baseline quality-of-life (QoL) (US sites only) 
and lifestyle questionnaires, registration, randomization, diagnostic imaging appropriate to assigned 
study group, AE assessment, and treatment; and  
2) Follow-up contacts²phone contact for participants with positive cardiac diagnostic findings at 2 
weeks and 2 months; phone contact for all participants at 6-month intervals from enrollment for up to 24 
months; and QoL assessment forms to a subset of participants²US sites only²at 12-months post-
randomization.  
 
Medical record collection will be required for adjudication for participants with a MACE or 
revascularization. Medical records will be abstracted for participants who report cardiac-related 
symptoms and care during follow±up contacts. In addition, medical records will be abstracted for those 

25
May 4, 2011 
 
 
participants with incidental findings on their CCTA or SPECT MPI examinations who self-report related 
care during trial follow up.  
Sections 8.5 and 8.6 provide study procedures tables specific to site and participant activities. Figures 1 
and 2 in Section 4.0 are flow charts of study procedures and medical records abstraction. Table 5 
outlines distinctions in procedures by site (non-VA US sites, US VA sites, and foreign sites). 
  Obtain a signed informed consent form; 
Perform baseline assessment to determine eligibility, comprising the following: 
Medical record review, especially to determine history of cardiac-related illness and 
testing²this may include a review of past medical history to determine cardiac or 
hypertensive tendencies at baseline; 
 Query to participant regarding history of reaction to iodinated contrast agent; 
 Query to participant regarding ability to hold breath for 15 seconds; 
 Complete pregnancy test for women of childbearing potential; 
 Collect blood for lab work to test renal sufficiency if not done within 28 days prior to 
enrollment; 
 Assess for angina classification (CCS Class I to III), risk factors for CAD, CAD-
specific morbidity, and comorbidity (Charlson Comorbidity); 
 Obtain contact information: two (2) phone numbers for participant (if possible), phone 
number for proxy, Social Security Number (for follow up access to Social Security 
Death Index [SSDI] as necessary), and self-addressed postcard completed by 
participant;  
 VA and foreign sites may be exempt from submitting PHI for study purposes, 
depending on their local policy. Other sites may request exemption and will be 
considered on a site-by-site basis.  See Sections 8.2 and 8.3 for additional details. 
 Collect ECG (originals are preferred, but color photocopies are sufficient; electronic 
submission or color photocopies by mail are sufficient), if performed within 30 days 
prior to diagnostic imaging; if not performed, unavailable, or completed within the 30 
days prior to diagnostic imaging, the ECG should be completed at the time of 
diagnostic imaging (e.g., in the case of ECG during SPECT MPI); 
 Collect laboratory results, only if available, including LDL, HDL, and HbA1c (previous 
28 days for each, or if available prior to diagnostic imaging) and highest-level troponin 
(previous 48 hours, or if available prior to diagnostic imaging); 
Administer SAQ and SF-36 for participant to complete (assistance should be limited; 
research staff will be trained on appropriate responses to participant queries)²US sites 
only. Foreign sites are exempt from the QoL component of the trial.  
Administer lifestyle questions (research staff will ask questions of participant to collect 
self-reported data). 
 

26
May 4, 2011 
 
 
  Register the eligible participant; 
 Receive randomization assignment to Group A (CCTA) or Group B (SPECT 
MPI/ICA); 
 Schedule CCTA or SPECT MPI/ICA to be completed within 2 weeks of consent. 
 Pre-treatment with heart-rate lowering drug and/or nitroglycerin depending on 
participant heart rate and imaging equipment (see Section 9.1.2.1); 
 Introduce intravenous (IV) catheter for contrast administration; 
Administer iodinated contrast agent; 
  Complete CCTA per protocol specifications (see Section 9.1); 
Assess for AEs. 
  Should the left main be un-evaluable, the CCTA will be considered positive for study 
analysis. The research team recommends and encourages rescanning with CCTA using 
an additional bolus of contrast if possible, and otherwise leaves it to the treating 
physician to determine further diagnostic assessment. Data from both imaging studies 
will be collected. 
 SPECT MPI and, if necessary based on extent of reversible defect, diagnostic ICA 
completed per institutional standard practices (see Section 9.2). 
 
  Should the examination be un-evaluable, the SPECT MPI will be considered positive 
for study analysis. The research team recommends and encourages reviewing rest and 
stress images post-acquisition for quality before the participant is released from the 
scanner and rescanned, if necessary. For STRESS Tl-201 imaging: If motion 
compromises a study, the benefit of rescanning is uncertain; the treating physician 
should determine further diagnostic assessment. Data from both imaging studies will be 
collected.
 Depending on diagnostic imaging study results, participant is prescribed OMT (see 
below), goes to diagnostic ICA for additional assessment, or may be discharged. All 
participants will be followed per Section 8.2. 
Participants with CCTA findings of a stenosis  50% in diameter will be treated 
with OMT unless the stenosis is in the left main coronary artery. 
Participants with moderate-severe ischemia by SPECT MPI (  10% reversible 
perfusion defect) or evidence of TID accompanied by ECG changes of ischemia 
will undergo diagnostic ICA to confirm no significant left main CAD (< 50% 

27
May 4, 2011 
 
 
stenosis) and that the diagnosis is not a false positive. Participants with a stenosis 
50% in diameter on diagnostic ICA will be directed to OMT. 
Un-evaluable proximal and mid segments will be regarded as being positive for 
CAD for the purposes of the study and the participant directed to OMT.  
Participants with left main CAD (  50% stenosis) found on CCTA will undergo 
diagnostic ICA.  
Participants with CCTA findings of stenosis < 50% in diameter; SPECT MPI 
findings of reversible ischemia < 10% of the myocardium; or SPECT MPI findings 
of  10% reversible perfusion defect or evidence of TID accompanied by ECG 
changes of ischemia followed by ICA findings of < 50% stenosis will be treated per 
institutional standard of care or discharged and followed per protocol for MACE 
and revascularization. 
 
See also Figure 1 in Section 4.0. 
OMT will be determined by the treating cardiologist, and a medical regimen to achieve 
OMT will be required. Specific medications, however, will not be required by the 
ACRIN 4701 RESCUE protocol. The following descriptions are based on the regimen 
used in the COURAGE trial3 and lipid lowering targets defined by the National Heart, 
Lung, and Blood Institute.41 The descriptions below should be considered a list of 
options to be applied to participants as appropriate to the individual participant¶s 
cardiac health requirements. The initial regimen and changes to the regimen (by 
participant or physician prescription) will be reported to ACRIN throughout the trial. 
1. An antiplatelet such as aspirin, 81 to 325 mg each day, and/or clopidogrel, 75 mg 
per day if participant is aspirin intolerant, or prasugrel. 
2. A statin such as atorvastatin, pravastatin, or rosuvastatin with target LDL 
cholesterol of 70 mg/dL.41  
3. An anti-hypertensive/anti-anginal beta blocker, such as metoprolol, carvedilol, or 
atenolol, with a blood pressure goal of < 130/80 mm Hg and reduced CCS angina 
class. 
4. An additional anti-hypertensive, such as amlodipine or an ACE-inhibitor, as 
needed. 
5. An additional anti-anginal, such as amlodipine or long-acting nitrate, as needed. 
6. An ACE-inhibitor (lisinopril) or angiotensin II receptor antagonist (Losartan) if 
ACE-inhibitor not tolerated, for all participants with left ventricular ejection 
fraction  40%. 
7. Attempt to raise HDL cholesterol, > 40 mg/dL in men and > 50 mg/dL in women, 
with exercise, extended release niacin, or fibrates alone or in combination once 
LDL level is at goal. 
8. Medications for diabetes control, with target HbA1c < 7%. 
9. Smoking cessation. 
10. Exercise regimen appropriate to diagnosis. 
11. Nutritional/dietary modification. 
Adherence to the OMT regimen will be documented on CRFs during participant follow 
up and from medical records, including those from referring physicians. 

28
May 4, 2011 
 
 
If a participant develops worsening or persistent angina after randomization, the 
following management guidelines will be used: 
a)  For all but CCS Class IV participants, intensify medical therapy (increase doses of 
anti-ischemic drugs and/or add additional agents as needed clinically); if the 
participant subsequently stabilizes to CCS Class I to II, continue medical therapy 
indefinitely; 
b)  If symptoms do not stabilize, or worsen to CCS Class III after 4 to 6 weeks of 
maximum medical therapy, it is recommended that the participant should undergo 
ICA for evaluation for revascularization. 
Follow up at the site level will comprise telephone participant/proxy contact at 2 weeks 
and 2 months after enrollment 
 for participants who have positive cardiac findings on 
diagnostic CCTA or SPECT MPI. 
 participants (or their proxies) will be contacted by 
telephone for additional medical information at 6-month intervals after enrollment for up 
to 24 months.  
 
Positive cardiac findings on diagnostic testing are defined as:  
1)   50% stenosis on CCTA or un-evaluable left main, or proximal and mid segments of 
all other epicardial arteries (right coronary artery, left anterior descending artery, or 
left circumflex artery); and  
2)   10% reversible defect on SPECT MPI or evidence of TID accompanied by ECG 
changes of ischemia. 
 
Participants with positive cardiac findings on diagnostic testing will be contacted a 
minimum of four (4) times (2 weeks, 2-, 6-, and 12-months after enrollment). All 
participants will be followed for a minimum of two (2) time points (6- and 12-months) 
and a maximum of six (6) time points (2-weeks, and then at 2-, 6-, 12-, 18-, and 24-
months) due to funding and trial timeline limitations. The following table presents this 
information again. 
 
 Participants With Positive Cardiac 
Findings on Diagnostic Testing 
2 Weeks, 2 Months, 6 Months,  
and 12 Months After Enrollment 
2 Weeks, 2 Months, 6 Months, 12 Months,  
18 Months, and 24 Months After Enrollment 
 Participants 
6 Months and 12 Months After 
Enrollment 
6 Months, 12 Months, 18 Months,  
and 24 Months After Enrollment 
Ideally, contact to complete each follow-up CRF should occur no later than 14 days after 
each time point. However, this is a timing guideline. The form related to 6-month follow 
up, for example, should not be completed until contact has been made (four [4] attempts) 
or other confirmation of participant¶s vital status (e.g., record review or known death) has 

29
May 4, 2011 
 
 
been verified. As research staff attempt to make contact, a follow-up contact log will be 
maintained to document attempted contact. 
Contact participant via telephone to obtain additional medical information. At each 
follow-up time point, the following information will be collected to assess angina, 
CAD, health status, and healthcare utilization: 
Canadian Cardiovascular Society Angina Status; 
Self-report for MACE, stroke, or revascularization; 
Adherence to OMT; 
Health status/medical utilization: 
 Outpatient providers; 
 Emergency departments; 
 Hospitals; 
 Specifically whether care was cardiac-related or related to care for 
incidental findings from the diagnostic assessment; 
Healthcare-related time and travel; 
Lifestyle questions (at 12-month follow-up only). 
If the participant or proxy reports MACE or revascularization, the site then will conduct 
a review of the participant¶s medical records or the SSDI. RAs will need to prepare 
medical records per institutional standard practice to be delivered to ACRIN for 
adjudication in cases of MACE and revascularization (see Section 6.3.3). 
Four (4) attempts should be made by research staff to contact the participant or proxy at 
each follow-up time point before completing the follow-up form. If participant vital 
status (e.g., known death) is verified, the site RA may complete the follow-up form. 
Attempts will be documented in a follow-up contact log. Participants should not be 
considered ³lost to follow up´ until the final month of follow up for the last participant 
who was enrolled. 
If a participant or proxy is not contacted at the 6-month time point, for example, but is 
contacted at the 12-month time point, health information will need to be queried for the 
entire time period. However, the exception is administration of the lifestyle 
questionnaire²if contact cannot be made at the 12-month follow-up time point, the 
lifestyle questionnaire will not be administered at the 18- or 24-month follow up. 
Medical record collection will be triggered by a combination of positive CCTA or 
SPECT MPI/ICA and/or participant self-report of MACE, stroke, revascularization, 
cardiac-related health care, or care for incidental findings from their study-related 
diagnostic evaluation. Medical record collection will be coordinated by the site RA or 
by ACRIN, depending on local institutional policy on release of PHI. Table 5 presents 
an overview by site type of the adjudication, abstraction, and QoL procedures. 

30
May 4, 2011 
 
 
 
Sites send  
de-identified medical 
records to ACRIN upon 
request from ACRIN Data 
Management 
Sites send  
de-identified medical 
records to ACRIN upon 
request from ACRIN Data 
Management 
Sites send  
de-identified medical 
records to ACRIN  
upon request from 
ACRIN Data 
Management 
Participant Contact 
Information sheets faxed 
to ACRIN. ACRIN 
obtains medical records 
from HIM departments  
or site coordinators,  
de-identifies, and  
prepares records for 
abstraction/coding 
Sites shall obtain their 
own medical records and 
those of outside providers 
and forward de-identified 
records to ACRIN for 
subsequent 
abstraction/coding  
Sites trained to abstract 
minimal required data 
themselves 
Participant Contact 
Information sheets faxed 
to Brown. Brown 
coordinates distribution 
and collection of QoL  
at 1-yr follow up 
VA sites may administer 
the QoL questionnaires to 
participants themselves. 
The VA sites will not be 
required to send Brown 
the Participant Contact 
Information sheets 
²foreign 
sites are exempt from 
conducting the QoL 
component of the trial 
SSN on Participant 
Contact Information 
sheets at ACRIN. Will be 
accessed only if needed 
for the cost-effectiveness 
analysis 
 
 
Depending on local policy for release of PHI, administration of the SAQ and SF-36 at 12 
months will be coordinated by the site or by the ACRIN Outcomes and Economics Unit 
(AOEU) located within the ACRIN Biostatistics Center at the Brown University Center 
for Statistical Sciences, Providence, RI. Foreign sites are exempt from the QoL (quality-
of-life) component of the trial. 
 
Sites coordinating the QoL component of the trial will be responsible for follow up with 
the participant to encourage completion. For participants whose questionnaires are 
administered by the AOEU, the AOEU will maintain a database to monitor accrual of 
study participants for the QoL studies and the receipt of mailed questionnaires and 
telephone contacts. The originals will remain at Brown University. 

31
May 4, 2011 
 
 
A random sample of US participants from each arm of the trial will be selected for 
accrual into the QoL sub-study and will be asked to complete the 12-month follow-up 
questionnaires.  
 Participant Contact Information Forms 
need to be faxed from the sites to the AOEU, where they will be received on a secure fax 
machine dedicated to studies conducted by the AOEU. The information will be entered in 
the AOEU database. AOEU personnel will contact the participant using participant 
contact information stored in the AOEU database.  
 site RAs may administer the 
questionnaires by mail (preferred; see procedures below), phone, or in-person. Site 
personnel will be responsible for management and administration of QoL tools if they 
choose not to have the AOEU assume this responsibility. 
 For participants whose questionnaires are administered by AOEU, AOEU personnel will 
mail copies of QoL tools to participants along with pre-addressed, stamped envelopes for 
return mailing to the AOEU. Participants will be provided with a toll-free number (which 
is answered by the AOEU or site RA) should they require assistance with reading 
questionnaires.  
 If the questionnaires are not received within 10 working days of the date of the mailing, 
the AOEU or site RA will telephone the participant to determine whether the 
questionnaires were received and completed. Participants who did not receive the 
questionnaires will have additional questionnaires sent by mail after confirming the 
correct mailing address. If questionnaires were received by the participant but never 
completed, the participant will be asked to complete and return them.   
 If questionnaires are not returned within 20 working days thereafter, the AOEU or site 
RA will attempt to complete the questionnaires in a telephone interview. Telephone 
interviews will be conducted only as a final measure to avoid any biases introduced by 
differences in the method of administration of the questionnaires, and the mode of 
administration of all such questionnaires will be documented in the trial database. The 
AOEU or site RA will not attempt to interpret a question; training will be provided to 
help ensure that the AOEU and site RAs facilitate completion of the QoL questionnaires 
in a standardized fashion.  
Medical chart abstraction will be triggered by participant responses during telephone 
follow up. The selection process is detailed in Figure 2 (see Section 4.0) and described 
below.  
All records relating to the following will be abstracted: 
1. MACE, stroke, and revascularization events; 
2. Medical care for cardiac issues; 
3. Medical care for OMT, to include any results of monitoring of targets for 
OMT, such as LDL/HDL, HbA1c, blood pressure, and heart rate, if 
available; 
4. ECG from follow-up cardiac-care visits (color photocopies are sufficient 
and may be submitted electronically or by mail); 

32
May 4, 2011 
 
 
5. Medical care related to incidental findings on the CCTA or SPECT MPI 
examinations. If during monitoring of the rate of incidental findings, the 
incidence is high, medical record abstraction may be conducted for only a 
subset of participants.  
A separate document will be provided to the sites to explain their responsibilities in the 
process of medical record abstraction. Medical records will be de-identified to protect the 
identity of the participant. Participant informed consent will be obtained prior to trial 
participation to allow research staff to procure any medical records that need to be 
abstracted from institutions outside of the consenting institution (e.g., collection of 
medical records from physicians treating incidental findings). 
 
Requests for medical records for adjudication and abstraction will be produced and 
mailed from ACRIN Headquarters based on response to follow-up contact and results of 
the diagnostic tests. 
Medical records abstraction and coding will be performed by a single central medical 
record abstraction company. Centralizing the abstraction process with a single group of 
abstractors simplifies quality control, ensuring consistent and reliable coding of medical 
conditions and care.  
All abstraction will be done directly onto electronic forms. These computer forms 
incorporate range checks and International Classification of Disease (ICD) and Current 
Procedural Terminology (CPT) look-ups which ensure that data are as error-free as 
possible.  
Foreign sites will be expected to abstract medical records pertaining to the primary aim 
and are exempt from the QoL questionnaires component of the trial. 
 
 
This is an intent-to-treat trial; should a participant be registered, randomized, and subsequently 
be unable to complete the diagnostic test for any reason, the reason will be captured and the 
participant will be treated per the decision of the treating cardiologist as appropriate to the 
circumstance. The participant will remain on trial and will be followed per protocol. 

33
May 4, 2011 
 
   
 
 

Informed Consent Form 
X
 
 
 
 
Screening/Eligibility Review 
X 
 
 
 
 
Medical History 
X 
 
 
 
 
CCS Classification 
X 
 
 
 
X 
Assess for CAD and Comorbidity  
X 
Pregnancy Test, as Appropriate 
X 
 
 
 
 
Serum Creatinine for GFR Measure (If Needed) 
X 
Collect Contact Information  
X 
 
 
 
X 
Collect or Perform ECG (ECG Can Be Completed at 
Baseline Within 30 Days Prior to Diagnostic Imaging 
or at the Time of Diagnostic Imaging) 
X 
 
 
 
X  
(If Performed During 
Follow-Up Cardiac Visits) 
Collect HbA1c, HDL, LDL, and Troponin Values 
(Only if Available; See Section 8.1.1.5) 
X 
 
 
 
X 
Administer Questionnaires (QoL at US Sites Only) 
X 
 
 
 
ACRIN Web Registration 
X 
Randomization to CCTA or SPECT MPI  
 
X 
 
 
 
 
 
 
 
         Pre-Medication, As Needed 
 
 
X 
 
         Intravenous Catheter and Iodinated Contrast   
         Agent Administration  
 
 
X 
 
         CCTA
 
X 
 
         SPECT MPI/ICA (per institutional standard)
X 
Prescribe Optimal Medical Therapy  
or Move to Invasive Coronary Angiography  
(as Appropriate to Diagnostic Results Per Protocol) 
 
 
 
X 
 
Contact Via Telephone (See Section 8.6 Below) 
 
 
 
 
X 
Subset of Participants Complete QoL Questionnaires 
 
 
 
 
X (at 12 Months) 
Assess for AEs 
 
 
X (CCTA Only) 
 
 

34
May 4, 2011 
 
   
 
 
*  
participants with positive cardiac findings on diagnostic assessment will be contacted at 2 weeks and 2 months. Questions during participant contact 
at 2 weeks and 2 months will be limited to MACE, stroke, and revascularization. 
 participants will be contacted at 6-month intervals after enrollment. The 
12-month follow-up contact will include an additional lifestyle questions. 
 
Medical record collection for abstraction of medical care utilization and information used to obtain costs will be performed based on participant self-report 
during 6-month interval telephone follow up for MACE, stroke, cross-over to revascularization, cardiac-related care, and care for incidental findings as 
outlined in Section 8.3.   
 
Á 
participants with positive cardiac findings on diagnostic assessment will be contacted at 2 weeks and 2 months. 
 participants will be 
contacted at 6-month intervals after enrollment.  
§ Questionnaires will be completed in person at baseline. Completion of questionnaires at 12-month follow up will be coordinated through the site or 
the ACRIN Outcomes and Economics Unit (see Section 8.2.2 for details) and will include only a subset of participants. Foreign sites are exempt from 
administering the QoL tools.
Á
Á
 
 
 
 
 
 
 
CCTA or SPECT MPI/ICA  
Within 2 Weeks After Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confirm Contact Information and Collect Contact 
Information for Treating Physicians 
X 
X 
X 
X 
X 
X 
X 
Canadian Cardiovascular Society Angina Status 
X 
 
 
X 
X 
X 
X 
Risk Factors for CAD 
X 
 
 
 
 
 
 
Diamond Forrester CAD Risk Analysis 
X 
 
 
 
 
 
 
Charlson Comorbidity 
X 
 
 
 
 
 
 
CAD-Specific Morbidity 
X 
 
 
 
 
 
 
MACE 
 
X 
X 
X 
X 
X 
X 
Stroke 
 
X 
X 
X 
X 
X 
X 
Revascularization 
 
X 
X 
X 
X 
X 
X 
Adherence/Changes to OMT 
 
 
 
X 
X 
X 
X 
Health Status/Medical Utilization 
 
 
 
X 
X 
X 
X 
Healthcare-Related Time and Travel 
X 
X 
X 
X 
§
SF-36 and Seattle Angina QoL Tools 
X 
 
X 
Lifestyle Questions 
X 
 
X 

35
May 4, 2011 
 
   
The CCTA core lab, the Cardiovascular Imaging (CVIC) Core Laboratory at the Massachusetts General 
Hospital, will assist ACRIN in the development of general and specific protocol recommendations. 
CCTA images from the first two study subjects at each site will be reviewed by the CCTA core lab, as 
well as a random sample of 10% of all cases thereafter. The ACRIN 4701 RESCUE Imaging Manual 
detailing imaging recommendations is available at www.acrin.org/RESCUE_imagingmaterials.aspx.   
During the 18-month enrollment period, clinical interpretation of all tests will be performed by qualified 
local readers at qualified testing sites. This interpretation will inform patient management decisions and 
will be captured on test-specific CRFs using national reporting guideline standards and multimodality 
common data elements.48,49
 
Participants will undergo contrast-enhanced CCTA following randomization to Group A 
for evaluation of suspected CAD. For CCTA, both retrospective and prospective ECG 
gating will be permitted. If retrospective ECG gating is performed, tube modulation is 
required. Calcium scoring is optional. 
 
 
 
The image acquisition protocol consists of the following two (2) steps: 
 
Image acquisition takes approximately 20 minutes; 
 
The participant will be transported to the CCTA suite and returned by qualified study 
personnel. 
Participants will be instructed and trained in breath holding. ECG electrodes will 
be mounted on the chest to enable co-registration of image acquisition and ECG 
signal. With the exception of sites with a dual-source CT (DSCT) scanner, all 
participants with a heart rate > 65 beats per minute will receive a heart-rate 
lowering drug (usually a beta blocker), intravenously and/or orally, to optimize 
image quality and sublingual nitroglycerin to maximally dilate the coronary 
arteries unless their systolic blood pressure is < 100 mm Hg or other 
contraindications are present. At sites with a DSCT scanner, due to the improved 
temporal resolution, heart-rate lowering drugs are not required, and participants 
may receive only sublingual nitroglycerin if there are no contraindications. 
 
 
 
All image acquisitions will be performed using a breath hold in inspiration. The 
CCTA imaging protocol will start with a topogram of the chest permitting the 
localization of the position of the heart. If standard care at the institution, a 
prospectively-gated low-dose non-contrast CT scan (120 kVp, 320 mA) to assess 
coronary calcium will be optional. Image acquisition will conclude with a 
contrast-enhanced CT scan to evaluate the presence of coronary atherosclerotic 
plaque and significant coronary artery stenosis.  
 

36
May 4, 2011 
 
   
For this scan, 80 mL of contrast, on average, will be injected as a bolus at a rate of 
5 mL/s to attenuate the lumen of the coronary arteries, the aorta, and the left 
ventricle. Appropriate timing of the contrast bolus will be ensured by either the 
determination of the transit time or the bolus trigger technique.  
 
Using ECG gating, the tube current will be reduced during systole according to 
each manufacturer¶s specific protocol to minimize radiation exposure. Sites may 
perform this with either prospective or retrospective ECG-gating. If retrospective 
gating is performed, the scan must be performed with radiation dose modulation 
or a minimum radiation dose protocol to reduce the tube current during systole.  
 
The effective radiation exposure is between 5 and 12 mSv for a contrast-enhanced 
scan. See Section 9.3.1.3 for a description of patient-safety monitoring for 
radiation exposure.  
 
 
 
At least one data set that demonstrates the least cardiac motion will be 
reconstructed (a minimum 0.8 mm thick axial images, 50% overlap) from the 
contrast-enhanced CCTA scan for the detection of coronary plaque and stenosis 
(pixel matrix: 512 x 512, FOV: 25 cm). 
 
The following should be included in the submitted data sets: 
 
Scout; 
 
Dose report; 
 
Calcium score series, if available; 
 
CCTA (1 or more phases); 
 
If retrospective ECG gating was used, a Multiphase series with 10 phases 
at 10% increments for single-source scanner or 20 phases at 5% 
increments for a dual-source scanner; 
 
If routinely reconstructed and assessed, a Full Field of View (FOV) series 
for incidental findings. 
 
 
Central CCTA reads will be performed in the first two (2) cases from each site and 
subsequently in a random sample of 10% of cases to assess for stenosis. Local 
interpretation of the CCTA examination will determine patient care. Assessment will 
include each of the major epicardial vessels (left main, left anterior descending, left 
circumflex, and right coronary artery) and their side branches. Local CCTA reading 
CRFs will be used later for calculation of a modified Duke Prognostic Index and other 
indices. Central reader interpretations at the CCTA core lab (10% of CCTA examinations 
will be read centrally) will be used to assess the quality of the data obtained from local 
CCTA interpretations. A modified Duke Prognostic Index and other myocardial jeopardy 
scores based on the local read will be used, along with the outcomes data, to create a 
revised jeopardy score as described in Section 15.2.1.  

37
May 4, 2011 
 
   
To allow a modified Duke Prognostic Index and other myocardial jeopardy/risk 
scores to be applied, stenoses²when present²will be graded as: 
None (0%); 
Very Mild (1% to 29% diameter); 
Mild (30% to 49% diameter); 
Moderate (50% to 69% diameter); or 
Severe (  70% diameter). 
Non-diagnostic coronary artery (proximal and mid) segments will be considered 
positive. 
 
For CCTA questions related to image acquisition or interpretation, sites may contact the 
CCTA core lab at Massachusetts General Hospital via email or phone. 
 rescuehelp@partners.org 
 408-6RESCUE (408-673-7283) 
The SPECT MPI core lab at Tufts Medical Center, will assist ACRIN in the development of general and 
specific protocol recommendations. SPECT MPI images from the first two study subjects at each site 
will be reviewed by the SPECT MPI core lab at Tufts Medical Center, as well as a random sample of 
10% of all cases thereafter. SPECT MPI studies will be performed per institutional standards in 
accordance with best practice standards, as delineated in the imaging guidelines of the American Society 
of Nuclear Cardiology (ASNC), by appropriately credentialed physicians. The ACRIN 4701 RESCUE 
SPECT 
MPI 
Imaging 
Acquisition 
Recommendations 
form 
is 
available 
online 
at 
www.acrin.org/RESCUE_imagingmaterials.aspx.  
 
During the 18-month enrollment period, clinical interpretation of all tests will be performed by qualified 
local readers at qualified testing sites. This interpretation will inform patient management decisions and 
will be captured on test-specific CRFs using national reporting guideline standards and multimodality 
common data elements.48,49  
 
 
All site protocols will be reviewed and approved by the ACRIN core lab prior to the 
enrollment period in order to ensure optimal imaging techniques are performed. 
Participants will undergo radionuclide SPECT MPI following randomization to Group B 
for evaluation of suspected CAD. All image acquisitions for a particular participant 
during one visit will be performed on the same camera/computer system.  
 
It is recognized that there are many appropriate ways to report findings for SPECT MPI, 
but in general it will be recommended that the report elements correlate with the 
following categories:  
1) Normal scan;  
2) Infarct (location) without inducible ischemia;  
3) Inducible ischemia < 10% myocardium (location);  
4) Inducible ischemia  10% myocardium (moderate to severe ischemia, location);  

38
May 4, 2011 
 
   
5) Left ventricular function with quantitative ejection fraction:  
Normal, global dysfunction, or regional dysfunction; 
6) Uninterpretable study. 
  
In order for the individual sites to interpret the SPECT MPI studies in accordance with 
the RESCUE guideline requiring cardiac catheterization for participants with  10% of 
the left ventricle with a reversible defect (inducible ischemia), it will be necessary for the 
sites to have one of the standard commercially available analytic software packages (e.g., 
Emory Toolbox, 4DM SPECT Corridor, Cedars-Sinai QPS, etc.).  
 
The ACRIN core lab will review one (1) sample SPECT MPI study from each site. 
Feedback from this sample study will be provided on an as-needed basis to discuss image 
quality issues or concerns. The feedback will occur via email and/or telephone call to the 
site¶s technologist during the study start-up period, prior to participant enrollment. 
During the trial, the SPECT MPI core lab at Tufts Medical Center will perform quality 
control on the first two (2) cases from each site and then a random sample of 10% of the 
SPECT MPI studies per site, with feedback provided as needed to the sites regarding 
image quality and analysis.  
 
For Secondary Aim I, Section 3.2.1, determining a predictive SPECT MPI index, local 
reads of the SPECT MPI examinations will be performed to determine the percent 
reversible perfusion defect.  
For SPECT MPI questions related to image acquisition or interpretation, sites may 
contact the SPECT MPI core lab at Tufts Medical Center via email, phone, or pager, to 
the attention of Deb Kinan, RTN. 
dkinan@tuftsmedicalcenter.org
 617-636-2357   
 
 ACRIN imaging research personnel will perform ongoing technical 
quality control (QC) review of all 4300 tests in RESCUE for quality and completeness of 
the diagnostic test dataset, adequate test protocol, proper data/image reconstruction, 
minimal radiation exposure for CCTA and SPECT MPI.  
 
Quality improvement communications to sites will occur on an 
ongoing basis.  
In addition, for participant safety, the 
ACRIN core lab will conduct a 100% QC of radiation exposure in CCTA and SPECT 
MPI. For the study-related CCTA imaging, sites will be contacted should radiation 
exposure exceed a mean of 15 mSv, to be assessed monthly by site and sites over the 
mean of 15 mSv based on the last 5 cases will be contacted by trial PIs. Sites whose 
performance repeatedly exceeds this criterion after repeated protocol review may be 
recommended to the ACRIN PDRC department for QA review and possible termination.  

39
May 4, 2011 
 
   
The CCTA and SPECT MPI core labs will perform expert 
central reads (blinded to the local interpretations) and review overall image quality in 
approximately 10% of participant cases. To ensure protocol compliance early on and to 
account for sites with low accrual, the first two studies and a random sample of 10% of 
the remaining studies from each site will be read in each modality to assess quality of 
local reads. These 10% will be selected by block randomization stratified by testing site 
and test modality.  
 
Feedback to sites will occur on two levels:  
1) Reports of site data benchmarked against all other sites including severity of 
disagreement; and  
2) Re-education and training of sites and readers as necessary.  
 
Each participating site is required to submit all acquired CCTA and SPECT MPI images of study 
participants to the ACRIN core laboratory. The image transfer method is via TRIAD-OA, a software 
application that includes a rich client and a site server (DICOM file cache). ACRIN will provide TRIAD 
software for electronic image submission and anonymization to participating institutions. Images can be 
transferred to the ACRIN central archive by inserting a CD or DVD in the drive of a PC with the 
TRIAD rich client installed. The TRIAD software anonymizes, encrypts, and applies lossless 
compression to the images before they are transferred to the ACRIN image archive in Philadelphia, PA. 
 
Prompt submission of all image data within five (5) days of completion of imaging is essential to ensure 
adequate QC. Images should be transmitted along with an Imaging Transmittal Worksheet (ITW) that 
can be found on the ACRIN 4701 RESCUE web site at: www.acrin.org/RESCUE_imagingmaterials 
.aspx. For support in sending the images via the Internet using TRIAD, contact the representatives of the 
core lab via email at Triad-Support@acr.org or by phone: 215-940-8820. 
 
Instructions for image submission and anonymization, as well as information regarding QC of images, 
are available at www.acrin.org/RESCUE_imagingmaterials.aspx. 

40
May 4, 2011 
 
   
 
An 
 is any untoward medical occurrence in a participant that does not necessarily 
have a causal relationship with the study intervention. An AE can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory or physiological finding), symptom, or disease 
temporally associated with the use of a medical treatment or procedure, regardless of whether it is 
considered related to the medical treatment or procedure (attribution of unrelated, unlikely, possible, 
probable, or definite). Abnormal results of diagnostic procedures are considered to be AEs if the 
abnormality: 
 Results in study withdrawal
 Is associated with a serious adverse event (SAE)
 Is associated with clinical signs or symptoms
 Leads to additional treatment or to further diagnostic tests
Is considered by the investigator to be of clinical significance
 is defined as any untoward medical occurrence that:  
 Results in death, or 
 Is life-threatening (at the time of the event), or  
 Requires inpatient hospitalization or prolongation of an existing hospitalization, or 
 Results in persistent or significant disability or incapacity, or
 Is a congenital anomaly/birth defect, or
 Requires intervention to prevent any of the above, per the investigator/sponsor.
A life-threatening AE is any adverse event that places the study 
participant, in the clinical opinion of the investigator, at immediate risk of death. 
Grade denotes the severity of the AE. An AE is graded using CTEP Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.0, or the following categories (if the term does NOT appear in the 
CTEP CTCAE v 4.0):  
 
1 ± Mild  
 
2 ± Moderate 
 
3 ± Severe 
 
4 ± Life-threatening or disabling 
 
5 ± Fatal 
Attribution determines whether an AE is related to a study treatment or procedure.  
 
Attribution categories are: 
Definite  ± AE 
 to the study treatment or procedure. 
Probable ± AE
 to the study treatment or procedure. 
Possible  ± AE 
 to the study treatment or procedure. 
Unlikely ± AE 
 to the study treatment or procedure. 
Unrelated ± AE 
 to the study treatment or procedure. 

41
May 4, 2011 
 
   
AEs may be 
 or 
:  
 
An 
 is one that is described in the protocol, the ICF, or the investigator¶s 
clinical brochure.  
 An 
 is one that has not been described in the protocol, the ICF, or the 
investigator¶s clinical brochure. 
 
Any AE that is a result of standard of care practice (e.g. related to stress testing or cardiac 
catheterization) will be reported and managed per the institution¶s policies and procedures.  
 
Only AEs that are considered 
or 
 related to the study-related CCTA scan 
procedures require reporting to ACRIN. Please refer to your local IRB¶s policies regarding AEs. 
 
Flushing; 
 
Pallor. 
 
 
Low-grade fever; 
 
Nausea; 
 
Vomiting; 
 
Hives; 
 
Rash; 
 
Extravasation. 
 
Kidney failure; 
 
Allergic-like reaction (including anaphylaxis or asthma). 
A history of contrast allergy excludes potential participants from this study. The injection 
may cause discomfort and irritation. The iodine-containing contrast used for CT scanning 
may cause significant contrast reactions in about one in a thousand (1:1,000) participants. 
Severe reaction is seen in as low as 4:10,000 to as high as 2:1,000 depending on the type 
of contrast used. Fatal reactions are exceedingly rare and have been reported in 1:170,000 
irrespective of the type of contrast used. The risk of death is less than 1:10,000. 
 
 
Hemorrhage (hematoma at the injection site); 
 
Infection (catheter related infection) at the injection site;  
 
Minor discomfort/pain; 
 
Fainting;  
 
Bleeding; 
 
Bruising.  
 

42
May 4, 2011 
 
   
The radiation dose from a  64 slice CCTA study of the coronary arteries varies widely 
depending upon patient size, scanner used, technique used (prospective triggering vs. 
retrospective gating), and the use of available methods for dose reduction.  All studies 
performed for this protocol will be performed with application of all available methods 
for dose reduction, including but not limited to: 
1. ECG-modulated tube current reduction during systole to at least 20% of the 
nominal value; 
2. Z-axis and in±plane topogram density modulated tube current variation (e.g. 
CareDose4D, SmartDose, etc.); 
3. Low kVp acquisition for smaller participants, if technique is available on 
scanner; 
4. Prospective ECG-triggered technique for selected patients at sites with relevant 
hardware, software, and experience with this technique. 
 
The radiation dose associated with this protocol will range from approximately 5 to 12 
mSv. Recent publications have modeled the risk of cancer induction related to this dose 
using the linear no-threshold assumption.  These studies have suggested that for young 
women who receive doses as the highest end of the range above, there would be an 
approximately 1% to 2% increase in their lifetime risk of cancer, with lower increases in 
cancer risk seen for older women and all men.  However, this range of doses is similar to 
that received during other studies performed for evaluation of suspected CAD, including 
coronary catheterization (4 to 10 mSv) and stress myocardial perfusion imaging using 
SPECT MPI (10 to 20 mSv).50,51 
 
 
Reactions to medications administered as part of the CCTA procedure (e.g., heart-rate 
lowering drugs, nitroglycerine), including hypotension, syncope, headache, 
arrhythmia, palpitations;
 
AEs related to procedures or treatments following incidental findings from the 
CCTA;
 
Malfunction of worn or implanted electronic medical devices. It has been 
reported by the FDA that CT scans may rarely cause the malfunction of electronic 
implanted medical devices, including drug pumps and pacemakers.
 
ACRIN will not collect any AEs related to standard-of-care SPECT MPI or ICA 
procedures.  Sites will follow institutional policies and procedures for any reported side 
effects for procedures other than the experimental CCTA component of the trial. 
 
Prompt reporting of AEs is the responsibility of each investigator, clinical RA, and/or nurse engaged in 
clinical research. Please refer to Sections 10.8 and 10.9 for specific details about reporting. Anyone 
uncertain about whether a particular AE should be reported should contact ACRIN Headquarters at 215-
574-3150 for assistance. However, an AE report should be submitted if there is a reasonable suspicion 
that the AE may be related to the study procedures. 
   

43
May 4, 2011 
 
   
 is defined as documentation of AEs on source documents and the AE CRF, and 
submission to ACRIN for preparation of a report for RESCUE DSMC review, and the final study report. 
 is defined as immediate notification of ACRIN within the specified timeframe 
outlined in the protocol.  Routine reporting requirements also apply. 
 
Information on all serious and non-serious, expected and unexpected AEs considered 
 and/or 
 related to the study components of the ACRIN 4701 RESCUE trial with the 
severity level of grades 3, 4, or 5 should be recorded immediately into the source document (e.g. AE 
Log and/or progress notes of the study participant¶s chart) and retained at the site. These AEs will also 
be recorded in the AE CRF and reviewed by the site principal investigator in real time to determine 
grade and attribution of the event. If the AE meets the criteria for serious and requires expedited 
reporting, an ACRIN SAE Report will be completed (refer to Section 10.9 for detailed instructions).  
 
AEs already documented in an AE CRF (i.e., at a previous assessment) and designated as µongoing,¶ 
should be reviewed at subsequent visits as necessary. If these have resolved, the documentation in the 
AE CRF should be completed including an end date for the event and not the date of the visit. If an 
adverse experience increases in frequency or severity during a study period, an up-to-date record of the 
experience will be documented. Each AE should be followed until resolution, stabilization, or until it has 
been determined that the study procedure or study participation is not the cause. Any SAE that occurs 
after the study period and is considered to be possibly related to the study procedures or study 
participation should be recorded and reported immediately. 
 
 
 
It is the responsibility of the investigator to document all AEs (as identified in Section 10.6) that occur 
during the course of the study including any unexpected AEs with grades 3, 4, and 5 with attributions of 
and 
 At each designated visit, the investigator will evaluate for any AEs. 
AEs not previously documented in the study will be recorded within the study participant¶s chart to 
identify any potentially related to any study procedures. The nature of each event, date and time (when 
appropriate) of onset, outcome, frequency, maximum intensity, action taken, and attribution will be 
recorded. 
You must use the following AE reporting criteria for all protocol-specific AEs/SAEs:  
Grade 3 unexpected AEs with hospitalization that are 
 or 
 require a complete SAE report to be submitted within 
 of first knowledge of the event. 
Grade 3 expected AEs with hospitalization that are 
or 
 will be reported by 
 
Grade 3 unexpected and expected AEs without hospitalization that are 
or 
 will be reported by 
 
Grade 4 unexpected and expected AEs that are 
 or 
 require a complete SAE report to be submitted within 

44
May 4, 2011 
 
   
 of first knowledge of the event. 
Grade 5 unexpected and expected AEs that are 
 or 
 will be reported via phone report within a 
time period to 
ACRIN by the investigator or investigator-designee. In addition, a complete 
SAE report is due within 
 of the initial 24-hour telephone 
report. 
Expedited AE reporting must be completed within 10 working days of first 
knowledge of the event.   
 
Assignment of grades and attribution for each AE/SAE must be completed by the site 
principal investigator. All AEs/SAEs should be documented in the study participant¶s 
chart and CRFs. For expedited SAE reports, a copy of the report must be kept at the site. 
Significant new information on any on-going SAE should be promptly reported to 
ACRIN.  
 
An expedited AE report requires submission to ACRIN using the ACRIN SAE Report.   
Completed expedited reports should be sent to: 
 
 
 
 
A copy of all SAE reports should be sent to ACRIN by fax at 215-940-8819.  All deaths 
should be reported by telephone within 24-hours of first knowledge of the event.  To 
make a telephone report to ACRIN, call 215-717-2763, available 24 hours a day 
(recorder available Monday through Friday from 4:30 PM to 8:00 AM Eastern Time and 
on weekends). 
All expedited AE reports should be sent to your local Institutional Review Board (IRB).  
Please refer to your local IRB¶s policies regarding AEs.   
This study is to be conducted according to International Conference of Harmonisation [ICH] guidelines, 
U.S. federal regulations, standards of Good Clinical Practice, and ACRIN research policies and 
procedures. 
 
This protocol and any amendments will be submitted to a properly constituted independent Ethics 
Committee (EC) or IRB for formal approval of the study conduct. The decision of the EC/IRB 
concerning the conduct of the study will be made in writing to the investigator and a copy of this 
decision will be provided to ACRIN before implementation of the study.  
 

45
May 4, 2011 
 
   
The investigator will provide ACRIN with the institution¶s Federalwide Assurance (FWA) number, 
along with the IRB approval letter and copy of the IRB-approved ICF. The investigator will provide a 
copy(s) of IRB approval letter(s) for any amendment(s) and copy(s) of annual renewal(s). 
 
All potential participants invited to join this study will be given an IRB-approved, site-specific ICF 
describing the study and providing sufficient information for participants to make informed decisions 
about their participation in this study (see Appendix I for an ICF template). The ICF will be submitted 
along with the protocol for review and approval by the EC/IRB. The study participant MUST be 
consented with the EC/IRB-approved ICF before the participant is subjected to any study procedures. 
The approved ICF MUST be signed and dated by the study participant or legally acceptable 
representative and the investigator-designated research staff obtaining the consent. Any revisions to the 
ICF at any time during the trial will need to be submitted to the local IRB for approval and to ACRIN 
PDRC for review and filing. 
 
Any investigator and/or research staff member who has a conflict of interest with this study (such as 
patent ownership, royalties, or financial gain greater than the minimum allowable by their institution) 
must fully disclose the nature of the conflict of interest in accordance with ACRIN Conflict of Interest 
policies and applicable federal, state, and local laws and regulations. 
Neither complete nor any part of the results of the study obtained under this protocol, nor any 
information provided to the investigator for the purposes of performing the study, will be published or 
passed on to any third party without the consent of the ACRIN Publications Committee. Any 
investigator involved in this study is obligated to provide ACRIN with complete test results and all 
clinical data obtained from the participants in this protocol. Investigators will follow the ACRIN 
Publication Policy (available online at www.acrin.org/PublicationsPolicy.aspx). 
 
The investigator will permit study-related monitoring and auditing inspections of all study-related 
documents by the EC/IRB, government regulatory agencies, and ACRIN. The investigator will ensure 
the capability for inspection of all participating sites¶ study-related facilities (e.g. imaging centers, 
satellite sites). The investigator will allocate adequate time for these activities, allow access to all study-
related documents and facilities, and provide adequate space to conduct these visits.  
 
  
Monitoring ensures protocol and regulatory compliance, participant¶s welfare and safety, and provides 
resources to sites for clarification to the protocol and guidance in completion of the CRFs. Monitoring of 
the protocol is implemented after the activation of the trial, and once participants have been enrolled into 
the study at each site. Each site will be informed when the monitoring of the protocol is implemented. 
Monitoring instructions will be sent to the site prior to the implementation of monitoring to aid in 
preparation for the monitoring. The instructions will specify regulatory documents and participant case 
records scheduled to be monitored. The ACRIN QA Monitor will review CRFs and source documents at 
several different time points: after first few participants enrolled and during the conduct of the trial, 
including staff changes at the participating sites. The QA Monitor will review the initial, annual, and any 

46
May 4, 2011 
 
   
revised regulatory documents during each monitoring phase. 
  
All participating institutions that enroll participants will be audited. The timing of the initial on-site audit 
will depend upon several factors, including the rate of accrual (both study-wide and site-specific), the 
number of evaluable participants enrolled at an individual site, the status of the protocol and pending 
amendments, and monitoring status. Generally, audits will be conducted after the number of evaluable 
participants reaches 10% of targeted accrual, either study-wide and/or site-specific. Audits are typically 
scheduled to occur at least 3 months after an institution has been monitored, providing that monitoring 
did not identify issues that mandate immediate auditing. This schedule may be altered in the event of 
pending protocol amendments. Closure of the study to accrual will trigger auditing of all participating 
institutions not yet audited. Additionally, site-specific circumstances may prompt an audit at any time. 
 
Subsequent audits will be scheduled per the outcome of the initial audit. The audits will be conducted 
per federally-mandated procedures established by the Department of Health and Human Services. 
Instructions for preparation for the audit visit will be sent to the site prior to the scheduled audit visit. 
These instructions will specify which participant case records will be reviewed during the audit. On-site 
records will be verified against the submitted form, and the findings will be recorded on specially-
prepared audit reports. Major discrepancies will be forwarded to the appropriate oversight body within 
ACRIN. IRB procedures, approvals, and ICFs will also be reviewed at the time of the audit visit. The 
ACRIN Audit Manual is available online at www.acrin.org. 
 
To help sites prepare for monitoring and audits and to assure that the investigator and the research staff 
maintain records appropriately, ACRIN Headquarters will offer training to sites. This training will cover 
all aspects of data collection, including special instructions to obtain and file the various source 
documents needed to verify the accuracy of submitted data for this trial.  
 
  
Source data are found in all information, original records of findings, observations, or other activities in 
a clinical trial necessary for the reconstruction and evaluation of the trial. Source data are contained in 
source documents. Source documents represent the first recording of any observations made or data 
generated about a study participant while he or she is enrolled in a clinical trial. Source documents for 
each study participant substantiate the data that are submitted to ACRIN. 
 
Source documents must verify the eligibility criteria and data submitted on all CRFs. If an item is not 
mentioned (e.g., history and physical examination alluding to a condition, but no mention of a 
psychological condition), it will be assumed it is not present. 
 
Research records for each case should contain copies of the source documents for the data collected and 
reported to ACRIN. If data are abstracted from medical charts that are not filed at the investigative sites 
(e.g. hospital charts), copies of these records should be filed in the research chart. Every attempt must be 
made to obtain all records/charts that were used to abstract any study data for this protocol. This will 
prevent any discrepancies and the inability to verify the document and the data reported.  
 

47
May 4, 2011 
 
   
CRFs, both web-based and paper forms, are the primary data collection instruments for the study. The 
paper CRFs are provided as tools to the sites; they are not mandated to be used on site. If sites do use 
ACRIN-supplied CRFs, then 1) make sure they are complete; 2) ensure medical records are copied even 
if data are extracted from the medical records; 3) and use ³N/D´ and ³N/A´ appropriately. All data 
requested on the CRFs must be recorded, and any missing data must be explained. If a space is left blank 
on paper CRFs because the procedure was not done or the question was not asked, ³N/D´ must be noted. 
If the item is not applicable to the individual case, ³N/A´ must be noted. All entries on paper CRFs must 
be printed legibly in black ink on the paper CRFs. In the event of any entry errors, corrections must be 
made by drawing a 
through the incorrect entry, writing
 when the correction is being made, and entering the correct 
data above the strike through. Do not use white out or an eraser. Please refer to ICH Good Clinical 
Practice Guidelines. 
 
Data elements that are extracted from the medical record (such as participant history or official clinical 
interpretations of images, pathology, or surgery results) and recorded on the CRFs will be reviewed 
against the appropriate component of the medical record. Data elements gathered from signed 
participant questionnaires must be available for review. Required study image interpretation data that are 
more detailed in information than the image and not typically documented in the standard radiology 
report may be documented on the CRF and are acceptable source documentation 
. At the time of audit, the auditor will verify the occurrence of the imaging examination, the 
reader, and the date of the exam(s) from the medical record(s).  
 
If the paper CRFs are to be used as source documentation at the time of data collection, then 1) a Note to 
File should indicate that the CRF is the source document and 2) the paper CRF must be signed and dated 
by the person who filled out the form. If data are directly entered into the electronic CRF, the 
confirmation sheet should be printed out, signed and dated by the person completing the electronic CRF, 
and filed as a source document. Any use of approved CRFs as source documentation require a signature 
and date on the CRF with a reference to the information source (participant questionnaire, CT, MR, 
etc.). Any use of CRFs as source documentation when the protocol has designated the source data will 
be medical record documentation will be considered a major protocol deficiency. 
Sites must obtain initial, full-board, local IRB approval to participate in ACRIN trials. Prior to 
participant registration, a copy of the IRB approval letter for the protocol and the ICF must be sent to 
ACRIN, along with a copy of the IRB-approved, site-specific ICF. Any study-related materials for 
patients must be IRB reviewed and approved prior to distribution; approval notifications and other IRB 
correspondence should be delivered to ACRIN PDRC. Investigator will provide a copy(ies) of IRB 
approval letter(s) for any amendment(s), and copy(ies) of annual renewal(s). International sites may use 
an Ethics Committee instead of an IRB. 

48
May 4, 2011 
 
   
A total of 4300 patients being evaluated for stable angina or angina equivalent will be randomized to 
either CCTA or SPECT MPI/ICA for diagnosis. All participants who are diagnosed as having 
obstructive CAD will be initially treated with OMT, allowing participants with persistent or worsening 
symptoms to later undergo revascularization. All participants will be followed for MACE and cross-over 
to revascularization (see Appendix IV for definitions), as well as cardiac-related care and care related to 
incidental findings from the diagnostic evaluations. QoL questionnaires will be administered at baseline 
and to a subset of participants at 12 months after enrollment. Lifestyle questions will be administered at 
baseline and 12-months among all participants contacted at that time point. Participant angina class will 
be assessed on entry into the study (CCS I±III, Canadian Cardiovascular Society)6 and at 6-month 
intervals for up to 24 months. The data will be analyzed in terms of non-inferiority. Sub analyses will be 
performed to assess outcomes by age, gender, co-morbidities, and angina class at presentation. 
 
Participants will be enrolled and randomized in equal proportions to the two study arms (Group A²
CCTA²and Group B²SPECT MPI/ICA). As noted earlier, randomization will be stratified by gender 
and participating institution. Participants will be enrolled over a period of 18 months. Participants with 
positive cardiac-related findings on their CCTA or SPECT/MPI will be followed a minimum of four 
times (at 2 weeks and 2, 6, and 12 months) and a maximum of six times over 24 months (adding 18 and 
24 months). For participants with negative cardiac-related findings on their CCTA or SPECT MPI, the 
first enrolled participants will be followed at four time points (6, 12, 18, and 24 months) and the last 
enrolled participants for two time points (6 and 12 months).  
. 
Time to the primary endpoint will be measured from 
randomization to the first occurrence of any of the component events. Definitive data 
regarding the primary endpoint will be collected via chart abstraction. All reports of 
MACE or revascularization will be reviewed by the outcomes adjudication committee 
(see Section 6.3). In order to account for the variable length of follow up of study 
participants, we will use methods from survival analysis to compare event rates in the 
two arms. Cases that have not reached the endpoint or have dropped before the end of the 
follow-up period will be considered as ³censored´.  
In the first step of the analysis, we will use graphical techniques to examine the 
distribution of time to the primary endpoint and will derive Kaplan±Meir curves for each 
arm, overall, and by subsets of interest (defined by gender, age, and major risk factors). 
The primary analysis will be conducted from an intent-to-treat perspective and will 
compare time to endpoint events in the two arms using a logrank test for the hypothesis 
of non-inferiority of the CCTA arm.52,53

49
May 4, 2011 
 
   
In secondary analyses, we will compare the two study arms separately on the basis of the 
two main components of the composite endpoint, namely MACE and revascularization. 
We also will use Cox regression models to examine the difference between the two arms 
in participant groups defined by characteristics of interest, including gender, age, major 
comorbidities, pre-existing CAD, and inpatient or ER status. Of primary interest in this 
regression analysis will be the interaction of participant covariates with the indicator of 
study arm. The Cox regression analysis will be performed for the composite primary 
endpoint and for MACE and revascularization separately. The results of these secondary 
analyses will be exploratory in nature and will be reported as such.  
 
To help with the clinical understanding of the comparisons in this aim, we will also 
perform a secondary analysis of data on angina symptom status assessed using the CCS 
Angina Status scale. The CCS Angina Status ordinal scale result will be assessed for each 
participant at baseline and at six-month intervals thereafter. We will first perform a 
graphical exploration of the data by examining the distribution of the results at each time 
point. We will use regression modeling for longitudinal ordinal data to compare the two 
arms and to examine potential effects of participant characteristics known at baseline, 
such as gender, race, and comorbidity.54 In these models, the interactions of covariates 
with indicator of study arm will be of primary interest. We will approach the handling of 
missing data and dropout using pattern mixture modeling, with sensitivity analysis to 
assess the effect of assumptions on patterns of missingness.55,56  
In this aim, we will examine the ability of indices to predict whether a study participant 
will experience MACE or will undergo revascularization within a period of 12 months 
from the time of study entry. For analysis purposes, the response will be a binary 
indicator of whether MACE or revascularization occurred in this 12-month period. Per 
study protocol, all participants will be followed for at least 12 months.  
 
In the first part of the analysis we will evaluate a modified Duke Prognostic Index to 
predict MACE or revascularization for participants in the CCTA arm. The index will be 
computed for each participant in the CCTA arm, and a receiver operating characteristic 
(ROC) curve will be developed with the reference standard being the binary indicator of 
whether the participant underwent revascularization or had MACE within 12 months 
from study entry as determined by the outcomes adjudication committee. We will 
develop next other new modifications of the Duke index adapted to the context of 
predicting MACE or revascularization using CCTA. We will use multivariate binary 
regression modeling to examine the relation between the binary response to the 
multidimensional vector of predictors used in a modified Duke index. Multiple 
imputation will be used to handle missing observations, if necessary. We will use cross-
validation to limit the potential for overfitting and to derive realistic estimates of the 
predictive performance of the model.57 We also will consider Ridge regressions, which 
impose penalty on the least squares to improve the predictive stability, to reduce the 
impact of collinearity in the predictors. The cross-validated area under the ROC curve for 

50
May 4, 2011 
 
   
the new index will be compared to the area under the curve estimated earlier for a 
modified Duke index. A non-parametric approach will be taken to the analysis of these 
ROCs.58 We will estimate and compare the areas under the curves using bootstrap 
methods, in order to account for the correlation in the index values arising from the fact 
that the indices will be evaluated on the same participants.  
 
In the second part of the analysis for this aim, we will use the CCTA assessments of the 
American Heart Association model of the coronary arteries to develop a new index for 
the prediction of revascularization or MACE. First, we will develop an index using the 
information of the maximum degree of stenosis (grade: none, very mild, mild, moderate, 
severe) in each segment. The analytic approach will be based on multivariate binary 
regression modeling as described above and will also incorporate clinical input and 
judgment for defining predictor variables. The cross-validated area under the ROC curve 
for the new index will be compared to the areas under the curve for the other indices 
discussed earlier in this section. We will also consider other, more recently developed 
measures of predictive performance based on reclassification.59  
The predictive index for SPECT MPI will be the measurement of size of the reversible 
perfusion defect on SPECT MPI. We will develop an ROC curve for this index as 
predictor of revascularization or MACE within 12 months and will estimate the area 
under the curve. We will use the ROC curve to estimate threshold values of the index that 
correspond to desirable values of sensitivity and specificity. We also will compare the 
areas under the ROC curves across the two arms using methods appropriate for 
independent curve comparisons.  
 
 
 
The analysis will be performed from the societal perspective. Costs will be measured in 
terms of US dollars while effectiveness will be measured in terms of life years and 
quality adjusted life years (QALYs). It is expected that the results from this study will 
provide the United States public and medical community with a scientific and economic 
basis for the production of imaging guidelines in the diagnosis and management of stable 
angina and will provide additional evidence for the evolution to initial treatment by OMT 
as the new standard of care. 
 
 
We will obtain information on health outcomes and health care utilization from 
medical records. Medical record abstraction will be coordinated centrally by 
staff at the Center for Statistical Sciences (CSS) at Brown University and at 
ACRIN. This group currently manages the chart abstraction process for the 
ACRIN arm of the National Lung Screening Trial (NLST). We will model our 
approach on that used for the NLST. In this multi-stage process to obtain 
medical records, study participants will complete a Health Status and Medical 
Utilization Questionnaire (in order to provide information on medical care 
received from outpatient providers, ERs, and hospitals) and a Patient and 
Caregiver Costs Related to Time and Travel Questionnaire (to document 

51
May 4, 2011 
 
   
healthcare-related time and travel since the last questionnaire completion) at 6-
month intervals for up to 24 months.  
Participants will be asked to provide information on whether the care was 
cardiac-related or related to medical follow-up of incidental findings on the 
CCTA or SPECT MPI examination, as well as contact information for each 
provider. Site RAs will obtain copies of the medical records based on 
information provided by the participant. Medical records abstraction will be 
performed by a central medical record abstraction company. Centralizing the 
abstraction process with a single group of abstractors simplifies quality control, 
ensuring consistent and reliable coding of medical conditions and care. All 
abstraction will be done directly onto electronic forms online. These computer 
forms incorporate range checks and ICD and CPT look-ups which ensure that 
data are as error-free as possible.   
 
 
We will perform a cost-effectiveness analysis (CEA) comparing the two arms 
within RESCUE using data from all participants recruited within the United 
States.60,61 We will attempt to access international medical records, and 
recognize that it may not be feasible at all participating international sites. The 
primary analysis will be performed assuming a societal perspective and lifetime 
time horizon.62 The effectiveness of each arm will be measured in terms of life 
years and QALY. In-trial life years and QALYs will be based on in-trial 
ascertainment of deaths and utilities. Utilities will be based on SF-36 
assessments at baseline and 12 months with conversion to Quality of Well 
Being scores.63 Life years beyond the trial will be based on Framingham 
survival estimates based on age, sex, and cardiovascular events.64 QALYs 
beyond the trial will be based on utilities assessed at 1 year, with downward 
adjustments to account for aging.  
 
The costs in each arm will be measured in terms of 2010 US dollars using the 
medical component of the consumer price index to adjust for the timing of the 
costs.65 The computation of costs will include direct and indirect medical costs, 
the latter of which will include time and travel expenses for participants and 
caregivers in each arm. Direct medical costs will be based on hospitalizations, 
outpatient care, and drugs assessed by medical chart abstraction blinded to 
randomization arm. Costs of hospitalizations will be based on diagnosis-related 
groups coding and average Medicare reimbursement rates obtained from the 
Medicare Part A (MEDPAR).66 Costs of outpatient care, including initial and 
subsequent cardiac testing and physician visits, will be based on current 
procedural terminology coding and the Medicare fee schedule67 while costs of 
cardiac drugs will be based on 
average wholesale prices. Finally, 
costs related to time and travel expenses for participants and caregivers will be 
based on in-trial questionnaires. Costs beyond the trial will be based on total 
annual personal age-specific healthcare costs per capita68 with adjustment for 
year.65  

52
May 4, 2011 
 
   
Life years, QALYs, and costs will be reported for both arms for in-trial, beyond 
trial, and lifetime time horizons. We will estimate incremental cost-
effectiveness ratios (ICERs) for life years and QALYs over the lifetime time 
horizon along with 95% confidence intervals for the ICERs using nonparametric 
bootstrapping methods.69 Uncertainty surrounding cost effectiveness will be 
displayed with scatter plots of incremental cost versus incremental effectiveness 
and cost-effectiveness acceptability curves.69 In addition, we will perform one-
way sensitivity analysis on key variables, including those used to project 
survival beyond the trial and various costs.  
 
 
The COURAGE study measured angina symptoms using the Seattle Angina 
Questionnaire (SAQ). In addition, Dougherty32 has reported that differences in 
angina severity were related to selected subscales of the Short Form-36 (SF-36). 
The SF-36 is useful because participant responses may be used to derive health 
utilities31 that may be used to inform cost-effectiveness analyses.  
 
In RESCUE, we propose to monitor angina symptoms and impact of those 
symptoms on participant QoL by administering the SAQ to all participants at 
baseline and to a subset of participants, stratified by diagnostic examination, at 
12 months after enrollment for all sites within the United States. The total time 
to complete both questionnaires is approximately 20 minutes.  
To establish a baseline for angina symptoms and the QoL 
assessment, all participants will be asked to independently complete the SAQ 
and the SF-36 at the baseline visit. QoL assessment at baseline will be 
completed prior to randomization.  
 Administration of the SAQ and the SF-36 at 12 months will be 
coordinated by the sites or ACRIN Outcomes and Economics Unit (AOEU) 
located within the ACRIN Biostatistics Center at the Brown University Center 
for Statistical Sciences, Providence, RI, for a subset of participants. See Section 
8.2.2 for details of administration procedures. 
 
We will use the SAQ to assess whether participants are angina-free at 12 
months, as well as to determine whether participants report a clinically 
meaningful improvement in any of the SAQ scales between the baseline and 12-
months assessments. Participants will be classified as angina-free if their SAQ 
score is 100, indicating no angina symptoms.  
 
We will use the SF-36 to derive eight profiles of functional health and well-
being. Physical health is measured by the Physical Functioning (PF), Role-
Physical (RP), Bodily Pain (BP), and General Health (GH) scales. Mental 
Health is described by the Vitality (VT), Social Functioning (SF) Role-

53
May 4, 2011 
 
   
Emotional (RE), and Mental Health (MH) scales.28,70 We will compare the 
change in each of these subscales between the baseline and the 12-month 
assessments for participants in each arm of the study.  
Measures of health status as measured by SAQ and SF-36 will be computed for 
selected participants. We will first perform a graphical exploration of the data 
by examining the distribution of each scale at the two time points and the 
change in the scale between the two time points. We will use regression 
modeling for longitudinal data to compare the two arms.54  
In these models, the interactions of covariates with indicator of study arm will 
be of primary interest. In addition to the overall comparison between the arms, 
the regression analysis will be used to examine potential effects of participant 
characteristics such as gender, race, and comorbidity. As described earlier in the 
analysis of the CCS longitudinal data on angina status, we will use pattern 
mixture models to address participant drop out and missing assessments. The 
clinical implications of potential effects identified in the analysis of the scale 
measures computed from SAQ and SF-36 will be examined using published 
guidelines.71  
The planned sample size is 4300 participants at up to 80 institutions, to be accrued over 18 months. 
We used reported data on MACE and revascularization from the COURAGE 
trial and combined this information with data from our clinical experience to 
formulate the range of necessary assumptions for sample size and power 
considerations for the primary endpoint. The computations were performed 
using the subroutine for logrank test for non-inferiority in the software package 
PASS.72  
 
In particular, we assumed that about 1% of participants will experience a 
MACE within 12 months from study entry and that an additional 5% will 
undergo revascularization within the same period. Thus we assumed a combined 
rate of 6% within 12 months for the primary endpoint (hazard rate=0.0052, 
assuming an exponential survival distribution). We also assumed that about 5% 
of participants will drop out during a 12-month period from each arm and about 
1% will switch from each arm to the other. The accrual time was set at 18 
months and the additional follow-up time at a minimum of 12 months. The 
following table shows the power of a test of non-inferiority for a test at level 
0.05 and the indicated non-inferiority hazard ratio.  

54
May 4, 2011 
 
   
0.7438  
4300  
1.25  
0.8548  
4300  
1.30  
0.9254  
4300  
1.35  
0.9651  
4300  
1.40 
The above computations of power are performed under the assumption that the 
actual hazard rates are identical in the two arms. The table indicates that if the 
hazard ratio for non-inferiority is 1.3 and above, a total sample size of 4300 
would be provide adequate power under the above assumptions about 12-month 
rate for the combined primary event rate, drop out, drop in, and non-
compliance. If the 12-month rate of MACE or revascularization is higher than 
6%, the power would increase. For example, if the 12-month event rate was 7% 
and all other assumptions were kept unchanged, the power is about 90% for 
hazard ratio equal to 1.3 and is about 80% for hazard ratio equal to 1.25.  
 
 
Statistical power for the comparison of areas under the ROC curves envisioned 
in this aim depends crucially on the relatively small number of participants 
expected to be revascularized or have MACE within 12 months. In line with 
information used in the primary aim, we assumed that about 6% (or 
approximately 129 participants) will have MACE or undergo revascularization 
with 12 months in each arm. We also assumed the correlation between index 
values is 0.5. The following table shows estimates of power to detect the 
indicated difference in areas under the curve, using a test of level 0.05. 
0.8147  
0.8000  
0.8700  
0.0700  
0.9087  
0.8000  
0.8800  
0.0800  
0.9624  
0.8000  
0.8900  
0.0900  
0.9873  
0.8000  
0.9000  
0.1000  
0.9965  
0.8000  
0.9100  
0.1100  
0.9992  
0.8000  
0.9200  
0.1200  
The power will decrease if control for multiple comparisons is implemented. 
For example, if the level of the test is set at 0.01, the minimum difference 
between the two areas under the curve needs to be at least 0.08 in order to 
achieve 80% power. Computations of power for these comparisons were made 
using PASS.72  

55
May 4, 2011 
 
   
 
We used data from the OMT arm of the COURAGE study33 to guide us in the 
choice of assumptions needed in the power computations for this aim. For 
example, for the QoL score from the SAQ, we assumed that the standard 
deviation at each time point is about 25 and the average, within arm, change 
between baseline and 12 months is about 20. The following table shows 
estimates of the power to detect a difference in the change from baseline 
between the two arms of the study using a two-sided test of the indicated level. 
The lower level was chosen to indicate power while control for multiple 
comparisons. Two values of the correlation were used and the sample size was 
adjusted for the projected drop out by 12 months. Computations were performed 
using the PASS software subroutine for means in repeated measures designs.72  
 
 
0.83542  
2.000  
0.500  
0.050  
0.99273  
3.000  
0.500  
0.050  
0.99995  
4.000  
0.500  
0.050  
0.77578  
2.000  
0.750  
0.050  
0.98287  
3.000  
0.750  
0.050  
0.99975  
4.000  
0.750  
0.050  
0.64055  
2.000  
0.500  
0.010  
0.96621  
3.000  
0.500  
0.010  
0.99951  
4.000  
0.500  
0.010  
0.55652  
2.000  
0.750  
0.010  
0.93334  
3.000  
0.750  
0.010  
0.99788  
4.000  
0.750  
0.010 
We performed similar computations for other subscales that will be computed in 
the study. Overall, the proposed design can provide adequate power to compare 
QoL changes in the two arms.  
Routine reports for this protocol will be included in the ACRIN Biostatistics Center Mid-
Year and Year-End Updates and will be provided to oversight bodies, including 
RESCUE DSMC for review during each of its twice-yearly meeting. 
 
 
Routine reports will include: 
 
Accrual and participant characteristics; 
 
Timeliness and completeness, eligibility and protocol compliance, and outcome data; 
 
All reported AEs. 
 

56
May 4, 2011 
 
   
Beside the data analysis as described in the analysis plan and standard monitoring for 
AEs and data quality at study terminal, we will conduct interim monitoring analyses at 6-
month intervals (i.e., at 12, 18, and 24 months) after the beginning of participant 
enrollment. Given the projected accrual rates at the three interim looks, we expect to have 
recruited 1075, 2150, and 3225 participants from whom we will have collected the 
baseline and at least one follow-up data. The interim analysis will assess efficacy and 
safety. The results will be presented to the RESCUE DSMC.  
 
Efficacy monitoring will be done by comparing the two arms on the basis of the 
time to occurrence of the primary endpoint, which is MACE, comprising 
cardiac-related death or acute MI, and revascularization. For the primary 
endpoint, a group sequential rule with a spending function corresponding to an 
O¶Brien-Fleming boundary will be used to determine the nominal significance 
levels to which interim p-values will be compared.73  
The RESCUE DSMC will review regular summary reports on AEs and more 
detailed information on SAEs. In addition the RESCUE DSMC will receive 
regular reports on events relevant to participant safety (including cardiac deaths 
or acute MIs). The timing and content of the reports will be decided during the 
first meeting of the RESCUE DSMC. The RESCUE DSMC may recommend 
special measures to be taken or the study to be stopped based on information 
about safety issues and other unanticipated concerns. 
 

57
May 4, 2011 
 
   
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62
May 4, 2011 
 
   
andomized valuation of Patients with table Angina  
omparing tilization of Diagnostic xaminations: RESCUE 
 
 
This is a clinical trial, a type of research study. Research staff will explain the clinical trial to you. 
Clinical trials include only people who choose to take part. Please take your time to make your decision 
about taking part. You may discuss your decision with your friends and family. You can also discuss it 
with your health care team. If you have any questions, you can ask your treating doctor, the study 
doctor, or other research staff for more explanation. If you decide to participate in this study, you will be 
asked to sign and date this form. 
 
You are being asked to be in this trial because you have symptoms of chest pain that your treating doctor 
thinks may be related to your heart health. Your treating doctor would like to perform some tests to find 
the cause of your pain. This trial will determine which diagnostic test you have and how you will be 
treated will depend on the results of the diagnostic test. 
 
Your treating doctor believes your symptoms are related to heart disease. If you decide to join the trial, 
you will be randomly assigned to either the current standard of care for diagnosis of your symptoms or 
to the study-related imaging for diagnosis. You should get information about the standard-of-care 
practice from your institution, but this informed consent form provides basic information since you will 
be randomly assigned to the standard-practice group or to the experimental group.  

63
May 4, 2011 
 
   
The current standard practice is a nuclear medicine cardiac stress test to see how your heart works 
during exercise or while using medications to excite the heart. You would undergo this cardiac stress 
test, or a similar study, even if you did not join the trial.  
 
The experimental group uses imaging is called coronary computed tomography (CT) angiography, 
which takes pictures of your heart after a dye is injected into your blood stream.  
 
If you are diagnosed with a heart condition, your treatment will depend on your diagnosis and amount of 
heart disease. You will either 1) be treated with medication and lifestyle change without additional 
procedures or 2) undergo testing that may involve additional procedures.
The purpose of this research is to:  
 Compare patient outcomes after diagnosis with either coronary CT or nuclear medicine cardiac 
stress test results; 
 Determine the appropriate use of medication and lifestyle change in clinical care; and 
 Compare costs associated with these approaches to care.  
 
The study doctors are hoping to be able to correctly diagnose heart disease and reduce the need for 
diagnostic tests and treatments while safely treating the condition. Previous research has shown that 
treatment with medicine and lifestyle change is safe and may reduce the need for additional diagnostic 
testing or surgery. 
 About Coronary CT Angiography (Group A) 
Coronary CT angiography is a heart-imaging technique that allows doctors to see your heart without 
having to put any tubes in the blood vessels near your heart (you will still need an arm vein IV). 
Coronary CT is a type of x-ray that can take as little as about 10 minutes. Your study doctor may wish to 
give you one or more medications to slow your heart rate and make the coronary arteries larger to 
improve the images. You will not be given these medications if you have any medical condition or are 
taking other medications that may cause problems. Please let your study doctor know if you have a 
history of asthma or other lung disease, allergic reactions to any medication, or if you have recently 
taken medications such as Viagra, Cialis, Levitra, or something similar. 
 
The coronary CT pictures show where blockages have built up in the coronary arteries. These materials, 
called plaques, can block the flow of blood needed to keep the heart healthy. If untreated, the muscle of 
the heart can be damaged or die. 
About Contrast Agents (Group A) 
 are liquid-like dyes that go into the body to help imaging machines create pictures of 
the body¶s organs and bones. The agent used with coronary CT in this trial contains iodine. If you have 
had a previous reaction to contrast agents with iodine, be sure to let your treating or study doctor know.
 About Nuclear Medicine Cardiac Stress Testing (Group B) 
Currently, people with symptoms like yours are evaluated using nuclear medicine stress testing. This test 
is used because it is good at accurately diagnosing and can be used in almost all patients. It involves 
gathering information about your heart health by having a scan of your heart at rest and another scan 
after you¶ve stressed your heart. In order to stress your heart, your heart rate is increased by either 

64
May 4, 2011 
 
   
walking on a treadmill, or if you are unable to walk on the treadmill, you can receive medications to 
increase your heart rate as if you¶ve been exercising.  
About Radiotracers (Group B) 
For nuclear medicine cardiac stress testing on a treadmill, a small amount of radioactive material, called 
a 
, is injected into the blood stream using an intravenous catheter that goes into a vein in your 
arm. The radiotracer gives off energy that can be collected to create a picture of how the heart is 
working. 
About Diagnostic Invasive Coronary Angiography (Group B)
You may need to have an additional diagnostic test called 
. It will depend 
on the results of your nuclear medicine cardiac stress test. This test is part of standard care. A catheter²
a small tube²is woven up from a blood vessel, usually in the upper thigh, through the body, and into 
the arteries that run outside of the heart. A dye made of iodine is injected through the catheter and makes 
pictures of the inside of the arteries. These pictures inform the doctors of where additional treatment 
may be needed.  
 
A total of 4300 people will take part in this study at up to 80 institutions internationally.  
 
You are being asked to join the study for up to two years (24 months). A member of the study staff will 
contact you or someone you designate (a proxy) by phone about your heart and other health up to six 
times, and you may be asked to complete questionnaires for the study.   
This trial is expected to end after all participants have completed the study-related follow-up calls and 
all information has been collected. This study may be stopped at any time by your study doctor, ACRIN, 
Food and Drug Administration (FDA), or Agency for Healthcare Research and Quality (AHRQ) without 
your consent because: 
 Your health or safety may be at risk; 
 You have not been following study instructions; 
 Of an administrative decision by ACRIN, the study doctor, FDA, or AHRQ. 
 
These actions do not require your consent, but you will be informed of any of these decisions if such a 
decision is made. 
 
You can stop participating at any time. However, if you decide to stop participating in the study, we 
encourage you to talk to the study doctor and your treating doctor first. Choosing to withdraw from the 
study will not interfere with your future care. 
If you take part in this study, you will have one of two diagnostic tests (either the coronary CT or the 
nuclear medicine cardiac stress test study) and your treatment will be determined by your diagnosis.  
 

65
May 4, 2011 
 
   
After one year, you may be asked to complete questionnaires related to your health and quality of life. 
You will be contacted by telephone up to six times, depending on your diagnosis and when you join the 
trial. 
 
The research staff will ask you questions about your health, including treatments related to your heart, 
care for non-heart-related findings from your diagnosis, visits to your treating doctor(s), and even the 
time and effort you have put into taking care of your heart (driving distances, amount of time). You may 
want to keep track of these details to make it easier for you to remember.  
 
The following tests and procedures will be performed to determine if you qualify to take part in 
this study: 
 
Review of your medical history including your history of heart-related illnesses, trends in 
heart health (such as your blood pressure), and recent blood test results. 
 
Blood collection to check your kidney health, if not checked within the past 28 days (this 
may mean a vial of blood has to be drawn for the test). 
 
Pregnancy test if you are a woman who may be able to become pregnant.  The result of the 
pregnancy test must show that you are not pregnant for you to qualify to participate in the 
study. 
 
You will be asked to sign a separate authorization to release some or all of your medical 
records for review and collection in this study. 
 
If you qualify to participate in this research study and if you decide to join the study, you will be 
asked to: 
 
Provide your contact information, including your mailing address, Social Security Number, 
and phone number(s), and the name of another person or doctor(s) we can contact who 
knows about your heart health should you be unavailable. 
 
Have an electrocardiogram (also called an ECG) at the time of your diagnostic imaging²but 
only if you have not had an ECG in the 30 days prior to diagnostic imaging that can be sent 
to ACRIN. 
 
Complete three (3) questionnaires that describe your health and quality of life. These 
questionnaires will take a total of about 25 minutes for you to complete them. 
If you qualify to participate in this research study, you will be randomly assigned by chance to 
one of the two following study groups: 
 
Experimental Group A:  The study-related coronary CT imaging for diagnosis of your 
symptoms.  (Your heart, blood pressure, and oxygen levels will be checked during the 
imaging study.) 
 
Standard Practice Group B:  The current standard care, nuclear medicine cardiac stress 
testing for diagnosis of your symptoms. 

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May 4, 2011 
 
   
You will have an equal 50/50 chance of being assigned to either of the study groups. Neither you 
nor the study doctor or study staff will choose what group you will be in. If you are randomized 
to a diagnostic test and cannot complete it, your study doctor and treating doctors will decide 
how to diagnose and treat your chest pain. You will still complete the study follow-up 
procedures. 
Depending on your diagnosis, your study and treating doctors have agreed to a specific treatment 
approach for this trial. You may be discharged from the hospital; receive a prescription for 
medication(s) and lifestyle changes; or you may need surgery for your condition. 
 
If you are diagnosed with heart disease during the study, a member of the study staff will contact 
you by telephone a minimum of four times (at 2 weeks, 2 months, 6 months, and 12 months after 
you join the study). You may also be contacted at 18 and 24 months after you join the study.  
 
If you are not diagnosed with heart disease during the study, a member of the study staff will 
contact you by telephone, a minimum of two times (at 6 months and 12 months after you join the 
study). You may also be contacted at 18 and 24 months after you join the study, for a possible 
total of 6 times that someone may contact you for the study. 
 
You will be asked to provide information about your heart-related and other health treatment and 
who has been treating you and where. With your permission and signed authorization of release 
of medical records form which you signed at the beginning of the study, the study staff will 
contact your treating doctors to request medical records for any treatment you may have 
received. 
 
You also will be asked about the time and effort you have put into taking care of your heart 
(driving distances, amount of time). You may want to keep track of these details to make it easier 
for you to remember. 
At 12 months after you join the trial, you may be asked to complete the same two questionnaires 
asking about your health and quality of life that you filled out at the beginning of the trial. People 
who receive the questionnaires will be randomly chosen. If you receive them, you will need to 
fill these out again and return them to research staff or in the envelope provided. These two 
questionnaires will take a total of about 20 minutes to complete. 
At the baseline assessment, your study doctor will ask you to sign a separate document called 
³authorization to disclose/release medical records´ to obtain some or all of your medical records 
from your doctor. A separate authorization is needed for the research doctors to collect and 
review the information regarding your heart health and treatments you have received. Your 
medical records will be collected and sent to ACRIN. The study staff will remove information 
that can identify you from your medical records. Your medical records will continue to be 
collected until the end of the study unless you withdraw your authorization in writing, as 
described in the separate authorization to release medical records. 

67
May 4, 2011 
 
   

68
May 4, 2011 
 
   
Read and sign the informed consent form; 
Provide contact information for yourself (your Social Security Number, 
mailing address, and phone number[s]) and for another person or doctor(s) 
who can be contacted regarding your heart health; 
 Provide medical history; 
 
Have a pregnancy test, as appropriate; 
 
Have about a vial of blood collected to check your kidney health, if not 
checked within the past 28 days before enrollment; 
 
Have an ECG if you have not had one within 30 days prior to diagnostic 
imaging; 
Complete three questionnaires (about 25 minutes total). 
After you join the trial, you will be randomly assigned to Group A  
(coronary CT) or Group B (nuclear medicine cardiac stress test) for diagnosis. 
 Receive pre-treatment medications, depending on your heart rate and the 
equipment being used at your institution;  
 Have an intravenous (IV) catheter placed; 
 Receive iodinated contrast agent; 
 Have a coronary CT. 
The nuclear medicine cardiac stress test will be performed per standard practice 
at 
. 
Depending on the results of your diagnostic test, you will: 
Be allowed to go home; 
Receive a prescription for medication(s) and lifestyle changes; 
Undergo surgery to further diagnose and/or treat your heart disease.  
 Provide medical information after 2 weeks and 2 months (
for positive 
cardiac findings) and (all participants) at 6 months and every six (6) months 
for up to 24 months (up to six times total) from the time of your initial visit. 
 
You will definitely receive follow-up phone calls at 6 and 12 months, 
but you may not be called at 18 and 24 months; the length of follow up depends 
on when you joined the trial. 
 Complete and return two (2) questionnaires (about 20 minutes total) that 
you may receive by mail at approximately 12 months after you join the 
study. Not everyone will receive this mailing. Some participants may be 
asked to complete the questionnaires at their institution or by phone. Those 
who do will be randomly chosen. 

69
May 4, 2011 
 
   
Depending on how you respond to follow-up questions about your heart health and treatment, research staff may 
need to access your medical records from other institutions and at facilities outside of this one. In order to request 
your medical records, these professionals will need access to your contact information. 
While on the study, you may be at risk for these side effects if you are randomly assigned to the study-
related coronary CT test. You should discuss these with your study and/or treating doctor(s). There may 
be other side effects that we cannot predict. Many side effects go away shortly after the coronary CT 
scan is stopped, but in some cases side effects can be serious, long lasting, or permanent.   
 
Minor discomfort; 
 Bruising; 
 Pain in the injection site. 
 
 Fainting; 
 Bleeding; 
 Infection. 
 Flushing; 
 Paleness. 
 
 Low-grade fever; 
 Nausea; 
 Vomiting; 
 Hives; 
 Rash; 
 Leaking from your IV into the soft tissue of your arm. 
 
 Allergic-type reaction; 
 Kidney failure. 
 
When you receive the contrast during the coronary CT scan, you may experience a warm or hot 
sensation and/or a metallic taste in your mouth. These are normal reactions and are not dangerous. 
 
If you experience an allergic-type reaction, with the coronary CT contrast agent, you will be treated for 
the reaction. If you have allergies or have had an allergic reaction to contrast in the past, please notify 
your treating doctor, the study doctor, and research staff. 

70
May 4, 2011 
 
   
   
 Headache, if nitroglycerin is given to you under your tongue. 
 
 
 Detection of abnormalities unrelated to your chest pain may occur in 10% to 20% of people 
undergoing coronary CT. Most often, small non-cancerous findings will be detected in the lung, and 
this could lead to an additional CT scan. Less likely, you will receive additional treatment. Your 
treating physician will be notified of any findings on imaging studies related and unrelated to your 
chest pain. 
 
 
 Malfunction of worn or implanted electronic medical devices; 
 Reaction to a medication given to you as part of the coronary CT procedure (such as a heart-rate 
lowering drug), including low blood pressure, passing out, headache, and abnormal or fast heart rate. 
 
If you wear or have electronic medical devices implanted such as a pacemaker or a drug pump, please 
make sure you tell your treating doctor, the study doctor, and research staff.  It was reported by the FDA 
that CT scans may cause the malfunction of electronic implanted medical devices.
 
 If you do not join this trial, you will be undergoing these or similar procedures as standard 
practice at your institution. 
 
 Minor discomfort; 
 Bruising; 
 Pain in the injection site. 
 
 Fainting; 
 Bleeding; 
 Infection. 
 Allergic-type reaction. 
 
If you experience an allergic-type reaction related to the radiotracer, you will be treated for the reaction. 
If you have allergies or have had an allergic reaction to radiotracers in the past, please notify your 
treating doctor, the study doctor, and research staff. 

71
May 4, 2011 
 
   
   
Fast heart rate; 
 Flushing; 
 Headache; 
 Chest pain; 
 Shortness of breath. 
 Low blood pressure; 
 Irregular heart rhythm; 
 Dizziness. 
 
 Difficulty breathing (bronchospasm); 
Transient (temporary) heart block; 
 Slow heart rate. 
 
 Death. 
   
 Chest pain. 
 Irregular heart rhythm. 
 
 Heart attack; 
 Dizziness; 
 Low blood pressure. 
 
 Death. 
 
Detection of abnormalities related to your chest pain is uncommon, but can happen during your nuclear 
medicine cardiac stress test examination. Your treating doctor will be notified of any findings on 
imaging studies related and unrelated to your chest pain. 
   
 Changes in your heart beat; 
 Heart attack; 
 Stroke; 

72
May 4, 2011 
 
   
 Bleeding. 
 
 Internal bleeding (retroperitoneal hematoma);
 Death. 
If you are assigned to the coronary CT, there are some risks from the scan used to 
evaluate your heart health in this study. This research study involves exposure to radiation from the 
coronary CT and therefore you will receive a radiation dose. Radiation dose associated with this study 
will range from approximately  to 
 mSv. At doses much higher than you will receive, radiation is 
known to increase the risk of developing cancer after many years. The dose that you will receive will 
very likely have no effects at all, but there is a very low risk that even at these doses, you may be at 
increase risk for developing cancer. Measures are taken to ensure that you are an appropriate candidate 
for these tests and that the risks to you are minimal. 
  If you are assigned to the nuclear medicine cardiac stress test, 
there are some risks from this test used to evaluate your heart health in this study. The nuclear medicine 
radiotracer in the trial will bring a small dose of radiation into your body. The radiation dose associated 
with this test will range from approximately 
 to 
 mSv. This test is currently one of the most widely 
used tests for diagnosing heart disease. At doses much higher than you will receive, radiation is known 
to increase the risk of developing cancer after many years. The dose that you will receive will very 
likely have no effects at all, but there is a very low risk that even at these doses, you may be at increase 
risk for developing cancer. Measures are taken to ensure you are an appropriate candidate for these tests 
and that the risks to you are minimal. 
Because possible exposure to radiation can damage an unborn baby, you will need to inform your study 
doctor or research staff if you are pregnant or suspect that you may be pregnant. If you are pregnant, you 
will not be able to participate in this study. If you are unsure, you will need to have a negative pregnancy 
result per the usual standard of care prior to enrolling and/or prior to imaging in this trial. 
For more information about risks and side effects, ask your study doctor. 
Taking part in this study may or may not make your health better. The results of your study-related 
diagnostic test will be shared with your treating doctor. The information from this study will help 
doctors decide diagnostic testing and treatment for people with chest pain in the future. The researchers 
hope the findings from this study will help reduce the need for a surgical procedure for some patients 
and will show the value of medical treatment before surgery.  

73
May 4, 2011 
 
   
You may choose not to take part in this study. If you choose not to participate, there will be no penalty 
and your treatment/medical care will not be affected. Your treating doctor can tell you the different 
available treatments for your chest pain or heart condition.  
 
We will do our best to make sure that your personal information will be kept private. However, we 
cannot guarantee total privacy. Your personal information may be given out if required by law. Records 
of your participation on this study, your progress, and images submitted (such as CCTA) while you are 
on the study will be kept in a confidential form at 
 and in a computer file at the 
headquarters of the American College of Radiology Imaging Network (ACRIN) in Philadelphia. All 
data sent to ACRIN over the Internet will be coded so that other people cannot read it. All personal 
identifiers are removed and replaced with a unique identifying number.  
 
You further understand and agree that authorized representatives of ACRIN, the FDA, AHRQ and its 
agents and contractors, the Institutional Review Board (IRB) of 
 and other groups or 
organizations that have a role in this study may, without obtaining additional consent from you, have 
access to and copy both your medical and research records, including the results of your participation in 
this study. This access is necessary to ensure the accuracy of the findings, the completion of the study, 
and your safety and welfare. If any publication or presentations result form this study, you will not be 
identified by name. Results will be reported in a summarized manner in which you cannot be identified. 
 
All personal identifiers will be removed and replaced with a unique identifying number to protect your 
identity. Your test results and clinical data important for the trial results will be kept permanently on file 
at ACRIN and may be used for future research. Any publications based on future research will not 
contain any identifying details or names. These images will not contain any identifying information and 
may be used for radiologist training and/or future research. 
 
You will receive no payment for taking part in this study. 
You will not be billed for the costs of any examinations or treatments that are considered part of the 
study and not part of standard care, such as the coronary CT and contrast agent used if you are randomly 
assigned to Group A. However, you and/or your health insurance will be charged for any portion of your 
care that is considered standard care (that is, if these expenses would have happened even if you were 
not in the study), such as the nuclear medicine cardiac stress test used in Group B. You may be 
responsible for any co-payments and deductibles that are standard for your insurance coverage. You 
and/or your insurance company will be billed for continuing medical care and/or hospitalization, 
including emergency medical care. 
 
It is important that you tell your study doctor, 
, if you feel that you have been injured 
because of taking part in this study or if any medical emergency, injury, or illness occurs during this 
study. You can tell the study doctor in person or call him/her at 
. 
 

74
May 4, 2011 
 
   
In the case of medical emergency, injury, or illness during this study, emergency medical treatment is 
available but will be provided at the usual charge. You and/or your insurance will be responsible for the 
cost of the medical care of that illness or injury. There is no financial compensation that has been set 
aside to compensate you in the event of injury. 
Taking part in this study is your choice. You may choose not to take part in the study. If you decide to 
participate, you are free to leave the study at any time. No matter what decision you make, there will be 
no penalty to you, and you will not lose any of your regular treatment and medical care options now or 
in the future. You can still get your medical care from our institution. 
 
During the study, we may find out more information that could be important to you. A Data and Safety 
Monitoring Committee (an independent group of experts) will be reviewing the data from this research 
throughout the study. This includes information that might cause you to change your mind about being 
in the study. If information becomes available from this or other studies that may affect your health, 
welfare, or willingness to stay in this study, we will tell you about it as soon as possible. 
 
This document explains your rights as a study participant. It you have any questions regarding your 
participation in this research study or you have any questions regarding your rights as a research 
participant, do not hesitate to speak with your treating doctor, the study doctor, or anyone listed below.  
 
You can talk to your treating doctor and the study doctor about any questions or concerns you have 
about this study. Contact the study doctor, 
, at 
. 
 
For additional information about your health or medical emergency, you may contact: 
 
 
 
 
 
 
Name 
 
 
Telephone Number 
 
For information about this study, you may contact: 
 
 
 
 
 
 
Name 
 
 
Telephone Number 
 
For questions about your rights while taking part in this study, call the 
 at 
 Institutional Review Board (a group of people who review 
the research to protect your rights) at 
. 
 
 
 
 
 
 
Name 
 
 
Telephone Number 
  

75
May 4, 2011 
 
   
More information on CT scans can be found in the ³Patients´ section of the ACRIN web site: 
www.acrin.org. You or your doctor can print a description of CT scans from this web site. 
When you sign this document, you are agreeing to take part in this study. This means you have read all 
the above information, asked questions regarding your participation, and received answers that you 
understand to all your questions. You also may have the opportunity to take this consent form home for 
review or discussion if you would like. A copy of the signed consent will be given to you.  
 
You willingly give your consent to participate in this study.  
 
 
 
 
  
  
 
Printed Name of Study Participant/ 
Signature 
Date 
Legal Representative 

76
May 4, 2011 
 
   
 
FROM:  American College of Radiology Imaging Network (ACRIN) 
  
 
  ACRIN 4701²Record Procurement Unit 
  
 
  1818 Market Street, Suite 1600 
  
 
     Philadelphia, PA 19103 
 
RE:  
Patient Name:  
  
 
Date of Birth:  
I authorize and request any and all of my healthcare providers to disclose my protected health 
information to ACRIN for the purpose of review and evaluation of the cost-effectiveness and healthcare 
utilization for diagnosis of cardiac-related symptoms for the ACRIN 4701 trial, entitled 
.  
 
I am authorizing release of all medical records pertaining to cardiac-related care and incidental findings 
care identified during trial-related diagnostic assessment and disclose full and complete protected 
medical information to ACRIN and its representatives.   
 
All medical records, meaning every page in my record, including but not limited to: office notes, 
face sheets, history and physical, consultation notes; inpatient, outpatient, and emergency room 
treatment; all clinical charts, reports, order sheets, progress notes, nurses¶ notes, clinic records, 
treatment plans, admission records, discharge summaries, requests for and reports of 
consultations; medication administration reports; documents, test results, statements, 
questionnaires/histories; and records received by other medical providers.  
 
All physical, occupational, and rehab requests and related consultations.  
 
All laboratory, histology, cytology, pathology, autopsy, immunohistochemistry records, and 
specimens reports; radiology records and images, including (but not limited to) CT, MRI, MRA, 
PET scans; echocardiogram and cardiac catheterization results.  
I understand the medical records to be released or disclosed may include information relating to sexually 
transmitted diseases, acquired immunodeficiency syndrome (AIDS), or human immunodeficiency virus 
(HIV), and alcohol and drug abuse and that this information will be used in the trial analysis only if they 
have any impact on my cardiac health. I have the option to refuse to release this type of medical 
information. I understand that if I check the ³Yes´ box below and add my initials, I am authorizing the 
release or disclosure of this type of information.  
 
 
Yes 
 
   (Initials) 
 No 

77
May 4, 2011 
 
   
I understand the following: See CFR §164.508(c)(2)(i-iii)  
a.  The healthcare providers who will receive this authorization are unknown at this time. 
b. By signing this authorization form, I am permitting the release of medical records to ACRIN by 
my treating doctors on past, present, and future treatments for the trial. 
c. ACRIN will contact my treating doctors with my permission to request and continue to collect 
my medical record until the trial is completed, regardless of whether I decide to actively 
participate or not to actively participate in the trial (called withdrawing from the study). 
d. I have a right to revoke this authorization at any time. I understand that to revoke this 
authorization, I must do so in writing and present my written revocation to ACRIN and the 
health care providers who previously received my authorization. I understand that the revocation 
will not apply to information that has already been released in response to this authorization.  
e. The information released will be de-identified and will be disclosed to other ACRIN 
representatives for the purpose of the clinical trial, or as required by law.  
f. My treatment or payment for my treatment will not be impacted by the signing of this 
authorization.  
g. I will receive a copy of this authorization. 
Any facsimile, copy or photocopy of the authorization shall authorize you to release the records 
requested herein to ACRIN and its representatives.  
Your organization will be reimbursed for copies of the medical record upon receipt of an invoice. If you 
require prepayment or have questions concerning reimbursement, please contact ACRIN at 
.
 
 
 
 
 
Printed Name of Patient or Legally Authorized Representative  
 
 
 
  
Signature of Patient or Legally Authorized Representative  
Date  
(See 45CFR § 164.508(c)(1)(vi))  
 
  
Name and Relationship of Legally Authorized Representative to Patient  
(See 45CFR §164.508(c)(1)(iv))  
 
 
Witness Signature 
 
 
 
 
 
 
Date  

78
May 4, 2011 
 
   
Supplemental materials that support the conduct of the trial are available on the ACRIN web site 
at the ACRIN 4701 RESCUE Protocol web page (www.acrin.org/RESCUE_protocol.aspx). 
Types of materials posted online include: 
 Application and protocol activation documents (General Qualifying and Protocol Specific 
Applications, Form FDA 1572, protocol activation checklist, etc.);  
 Data forms; 
 Imaging materials (Image Transmittal Worksheet, imaging parameter charts, image 
submission instructions, and scanning and image qualification instructions), available 
directly via www.acrin.org/RESCUE_imagingmaterials.aspx;  
 Recruitment and education materials; 
 Regulatory resources, available directly via www.acrin.org/pdrc.aspx; 
 Participating site list.  
 
For more information related to the trial, contact the ACRIN 4701 RESCUE Contact Personnel 
link on the above-mentioned web page for a list of protocol team members at ACRIN 
Headquarters and their roles. 
 
 
 

79
May 4, 2011 
 
   
1. Cardiac-related death; 
2. Acute myocardial infarction (AMI). 
Any sudden cardiac death, death due to AMI, and death due to heart 
failure/cardiogenic shock. In addition, any death without a clear non-cardiovascular cause or a death 
without known cause will be presumed cardiovascular death. Cardiac-related death is determined by 
adjudication of all-cause mortality. 
: Defined as evidence of myocardial necrosis/loss of viable 
myocardium in a clinical setting consistent with myocardial ischemia. MI events will be classified using 
the categories²type 1 to 5²defined by the 
.1 
1)  Spontaneous/non-procedure-related MI (types 1, 2):  
 
No recent cardiac intervention (e.g.: prior 72 hours). 
 
Abnormal levels of cardiac biomarkers, which are defined as values above the decision 
threshold considered diagnostic of MI at the local laboratory. Cardiac troponin is the 
preferred biomarker, and takes precedence over CK-MB. When troponin levels are 
unavailable, then CK-MB mass is the preferred biomarker and takes precedence over 
CK-MB activity. In the event that only CK-MB activity is available, abnormal is defined 
as total CK > 2 upper limit of normal and MB > 5% of total CK.  
AND one of the following: 
 
Ischemic symptoms within the prior 48 hours; 
 
Imaging evidence of loss of viable myocardium; 
 
New ECG findings (or presumed new if no prior ECG available as defined in the ACC 
Universal MI definitions).1  
2)  Procedure-related MI events (types 4, 5) will be considered a primary end-point and are 
further defined in ancillary documentation provided to the adjudication committee. 
 is defined as an attempted CABG and PCI, whether the procedure is successful or not, 
to include plain balloon angioplasty, stent placement, brachytherapy, atherectomy, laser, or rotational 
ablations. Coronary revascularization procedures for restenosis or as part of a staged PCI will be 
considered a subcategory of coronary revascularization. 
1. Thygesen K, Alpert JS, White HD, et al; the Joint ESC/ACCF/AHA/WHF Task for the Redefinition of Myocardial 
Infarction. Universal definition of myocardial infarction. Published jointly in: 
. 2007;28:2525±2528; 
. 2007;50:2173±2195; and 
. 2007;116:2634±2653.