Stress CMR Perfusion Imaging in the United States (SPINS) Study. A Society for Cardiovascular Magnetic Resonance (SCMR) Registry Study
Conditions: Myocardial Ischemia
Sponsor: Society for Cardiovascular Magnetic Resonance

                                          
 
 
 
 
 
 
 
 
Monday, July 4, 2022 
 
This document below is the Study Protocol including the Statistical Analysis of The Clinical Impact of 
Stress CMR Perfusion Imaging in the United States (SPINS): A Global CMR Registry Substudy 
(NCT03192891). 
 
 
Sincerely, 
 
Raymond Y. Kwong, MD MPH 
 
 
75 Francis Street,  
Boston, MA, 02115 
Tel: 857-307-1960, Fax: 857-307-1944 
Email: rykwong@bwh.harvard.edu 
 
Raymond Y. Kwong, M.D., M.P.H., F.A.C.C. 
Director of Cardiac Magnetic Resonance Imaging 
Brigham and Women's Hospital, Department of Medicine, 
Professor of Medicine, Harvard Medical School 

The Clinical Impact of Stress CMR Perfusion Imaging in the United States (SPINS): A Global 
CMR Registry Substudy  
 
Last approval date: October 29th, 2018 
 
Background 
Numerous single-center studies have indicated gadolinium-enhanced stress CMR perfusion imaging 
has excellent diagnostic accuracy for coronary artery disease and negative clinical event rates, with 
its diagnostic accuracy exceeding nuclear scintigraphy.  However, current prognostic evidence 
supporting clinical use of stress CMR is limited by study size, single-center settings with a 
predominance of academic centers, and a lack of "real-world" study design.  Large-scale multicenter 
real-world evidence from a registry will provide the much needed information to guide evidence-based 
clinical adaptation that benefits patient care. 
 
The Global Cardiac Magnetic Resonance Registry (GCMR) registry effort by the Society for 
Cardiovascular Magnetic Resonance (SMCR) constitutes the only current global effort that includes 
multiple international CMR programs that span academic, community hospital, and private practice 
settings (http://www.gcmr-scmr.org/).  This is also the only CMR registry that includes a large number 
of CMR sites in the United States. The GCMR is currently lead by Prof. Raymond Kwong under the 
direction of the SCMR Executive Committee, the Chief Executive Officer, and the Board of Trustees.  
This leadership structure within the SCMR guarantees continuity and consistent quality for many 
years into the future.  All of the data contributed by participating sites and the web database structure 
(http://www.gcmr-scmr.org/) are owned by the SCMR. 
 
Based on a recent survey of the current 68,500 studies contributed from US-based CMR programs in 
the GCMR, there have been approximately 10,700 stress CMR perfusion studies performed since 
2007.  The US sites and their investigators that contributed these studies are listed in Table 1.  
 
 
 

Investigating Team (this list may expand) 
Raymond Kwong (PI)(BWH), Rory Hachamovitch (CCF), Subha Raman (OSU), Andrew Arai (NIH), 
Scott Bingham (UCC), Ted Martin (OHI), Scott Flamm (CCF), Nat Reicheck (SFH), Chris Kramer 
(UVA), James Pottala PhD, PStat (USD - Statistician).   
 
Table 1 
Site 
Site Name 
PI 
stress 
CMR 
(estimated) 
BWH 
Brigham and Women's Hospital, Harvard 
University 
Kwong 
1,500 
OSU 
The Wexner Medical Center, The Ohio 
State University  
Raman/Simonetti 
2,000 
NIH 
National Institutes of Health  
Arai 
1,500 
UCC 
Central Utah Clinic Cardiology 
Bingham 
2,500 
OHI 
Oklahoma Heart Institute 
Martin 
1,000 
CCF 
Cleveland Clinic 
Flamm, 
Kwon, 
Hachamovitch 
1,000 
UVA 
University of Virginia School of Medicine 
Kramer 
700 
SFH 
Saint Francis Hospital, New York 
Reicheck 
500 
 
 
 
 
USD 
University of South Dakota 
Pottala (statistician) 
total number 
10,700 
 
Dr. Kwong has experience in developing web-based database infrastructures essential in conducting 
multicenter trials using CMR technology.  His lab in Boston currently serves as the CMR core 
laboratory for several large-scale NHLBI-funded international trials.  Dr. Kwong and the members of 
the investigating team have published key articles in the current literature about the clinical 
adaptation, strength and challenges, of stress CMR perfusion and they have extensive understanding 
of the needs and challenges of stress CMR perfusion in the US.  The ISCHEMIA trial is the largest 
(US$85M) clinical trial funded by the NIH/NHLBI currently using multimodality imaging to detect 
moderate-high risk patients to study for potential benefits of coronary revascularization.  Dr. Kwong 
has been intimately involved in the study design as well as the development and performance of the 
CMR core laboratory for the ISCHEMIA trial; he is extremely qualified to recommend the trial that best 
provides the needed evidence to clinically advance stress CMR perfusion in the US.  
 
Rationale and the Expected Deliverables of this Project 
This proposal (Project 1) aims to assess the clinical impact of stress CMR perfusion guided 
treatments on patient outcomes in a 2,200 consecutive multicenter patient cohort, referred for 
assessment of myocardial ischemia in the United States.   In the 3 specific aims presented below, we 
aim to obtain real-world evidence in patient outcomes including mortality and non-fatal cardiac 
outcomes, downstream cardiac procedures, invasive and non-invasive testing, costs in health care 
dollars based on national averages, and cardiac event-weighted quality adjusted life years (QALY).  
We believe these specific aims will provide the core evidence that medical insurance agencies and 
industries most sought after in making their reimbursement and payment decisions in the United 
States, towards the use of stress CMR perfusion imaging in patients with chest pain syndromes.  At 
the end of the funding period, we expect multiple publications to result from each of the 3 specific 
aims which represent these core evidence. 
 
Study Cohort and Enrollment Criteria 
Consecutive patients who underwent stress CMR perfusion imaging for evaluation of myocardial 
ischemia between 2008-2013.                            

Inclusion Criteria: all of the following at time of imaging:  
a) male or female at age 35-85 years,  
b) presence of either of the following sign/symptom that led to stress CMR imaging 
1) Symptoms suspicious of ischemia, or 
2) abnormal ECG with a suspicion of coronary artery disease 
c) Intermediate or high risk of significant coronary disease based on at least 2 of the following 
conditions: 
a. patient age > 50 for male, 60 for female 
b. Diabetes: by either history or medical treatment 
c. Hypertension: by either history or medical treatment 
d. Hypercholesterolemia: by either history or medical treatment 
e. family history of premature coronary disease: first degree relative at age <= 55 male 
and <=65 female 
f. Body mass index > 30 
g. Any medical documentation of peripheral artery disease 
h. Any history of myocardial infarction or percutaneous coronary intervention 
Exclusion Criteria: any of the following at time of imaging:  
a) Prior history of coronary artery bypass surgery (CABG) 
b) Acute myocardial infarction within the past 30 days prior to CMR 
c) any significant non-coronary cardiac conditions confirmed by medical documentation 
a. severe valvular heart disease,  
b. non-ischemic cardiomyopathy with LVEF <40%,  
c. infiltrative cardiomyopathy,  
d. hypertrophic cardiomyopathy,  
e. pericardial disease with significant constriction, or  
d) active pregnancy,  
e) any competing conditions leading to an expected survival of < 2 years 
f) Known inability to follow-up due to logistical reasons (e.g. patient lives in another country 
where follow-up is not feasible) 
 
 
Study Endpoints and Hypotheses to Test 
Study Endpoints 
Primary outcomes include all-cause mortality, acute myocardial infarction (AMI), and late coronary 
revascularization (PCI or CABG beyond 60 days after CMR).   
Secondary outcomes include non-fatal cardiac events (including cardiac hospitalizations for unstable 
angina or heart failure, heart transplant, significant ventricular arrhythmias, and strokes), alteration of 
diagnostic and therapeutic decision, and cardiac event-weighted QALY. 
The specific aims of this project are listed below: 
Specific Aim 1 – Association of CMR ischemic burden with clinical outcomes in the real-world 
To test the hypothesis that stress CMR perfusion imaging adds predictive stratification of clinical 
outcomes over known risk factors for patients presenting with chest pain syndromes, at moderate 
pre-test risk, in a multicenter real-world setting in the US.  Endpoints of interests include both primary 
and secondary outcomes.  This aim is important because it provides the prognostic association of key 
CMR variables of ischemia with the observed primary and secondary events without and with 
adjustments to known clinical markers of patient risks, annualized event rates of primary and 
secondary outcomes either annualized across the entire study period or at specific intervals of study 
follow-up (e.g. first, second, third year of follow-up etc), net reclassification index by CMR metrics of 
ischemia towards current guideline-supported treatments, and potential alteration of diagnostic and 
therapeutic thinking. 
 

Specific aim 1 will assess the prognostic association of presence of ischemia and percent ischemic 
myocardium (both by CMR) with the primary and secondary clinical outcomes.   In the multi-variable 
analyses, key known risk markers such as patient age, patient sex, left ventricular and systolic 
volume (LVESV), validated pretest coronary disease probability, and validated risk score (Diamond 
and Forrester) will be considered for inclusion in a multivariable model, and then presence or extent 
of ischemia by stress CMR will be added to the model to test the null hypothesis that CMR 
assessment of ischemia do not add prognostic value, versus the alternative hypothesis that stress 
CMR assessment of ischemia do add predictive value.  A significance level of 0.05 will be used.  
Since CMR findings will affect patient management, which in turn, will affect the clinical outcomes, in 
a secondary analysis, cardiac treatment (e.g. revascularization) received within 60 days of the CMR 
will be added to the above model to account for treatment effects on the relationship between extent 
of ischemia and outcome. Annualized event rates of the primary and secondary outcomes, stratified 
by CMR ischemia (present or absent), and CMR ischemic burden (mild, moderate, high), will be 
determined, both unadjusted and adjusted for cardiac treatments received.   We also plan to calculate 
net reclassification index of these CMR metrics to event-free survival (primary and secondary 
outcomes).  
 
Interim analysis at the end of the 2-year study period 
The study investigators agree with collaborators from Siemens and Bayer that an interim analysis at 
the end of the 2-year study period, of the proposed N=2,200, will inform the magnitude of the risk 
reduction rate.  We firmly believe that the current proposed study of N=2,200 will lead to important 
and publishable results and we plan to publish manuscripts based on results obtained from the cohort 
of 2,200 patient subjects.  However, this interim analysis will help to infer towards the planning of 
future studies and preparation of manuscripts that will provide key additional evidence regarding the 
clinical impact of stress CMR in the US.  These actions include the possibility of proposing another 
study aiming at a larger sample size. 
 
Specific Aim 2 – Assessment of the impact of CMR-guided invasive coronary 
revascularization, compared with medical therapy, on primary outcomes 
Sub-aim 2.1  
Using a propensity score-matching analysis, test the hypothesis that in real-world 
clinical practice that stress CMR perfusion imaging-guided use of invasive coronary revascularization 
(INT) (defined by INT performed within 60 days after CMR) offers AMI-free, coronary 
revascularization-free, survival benefits over medical therapy (MED) in patients with suspected 
ischemia.  We will estimate the # lives saved per 100 patients treated with INT versus MED (based on 
predicted primary outcome rate amongst MED)−(predicted primary outcome rate amongst INT) 
Sub-aim 2.2  
Using a propensity score-matching analysis, test the hypothesis that in real-world 
clinical practice that stress CMR perfusion imaging-guided use of INT offers survival benefits free of 
primary or secondary outcomes over MED in patients with suspected ischemia.   
Sub-aim 2.3  
The preferred initial treatment for patients with stable ischemic heart disease 
(SIHD) is the best available medical therapy. The benefits of using physiologic ischemia-based 
guidance to performing INT has been shown in the FAME and FAME-2 trials where fraction-flow-
reserve was used to assess physiological significance of coronary stenosis. In FAME (multi-vessel 
SIHD) and FAME 2 (single or multi-vessel SIHD) trials: a 29% and 66% relative risk reduction of 
primary outcome at 2-years were reported, respectively. CMR perfusion assessment had 
demonstrated remarkable correlation to FFR based assessment of coronary physiologic significance.  
For sub-aim 2.3, test the hypothesis that comparing to the FAME-2 primary outcome rate of patients 
managed by medical management alone, CMR-guided INT patients have a relative risk reduction of 
2-year primary outcomes >= 30%. 
 
Specific Aim 3 – Cost-effectiveness analysis  
 
 

Using a propensity score-matching analysis, test the hypothesis that in real-world clinical practice that 
stress CMR perfusion imaging-guided use of INT offers cost-effectiveness benefits over MED in 
patients with suspected ischemia.   
 
Database Infrastructure of Database and DICOM Storage 
A HTTP secure web database focusing on collecting clinical data in CMR (CMR Cooperative)  
(https://cmrcoop.partners.org/) has been established and collecting CMR data since 2008.  There are 
currently 45 US centers using this web-based HIPAA compatible database which allows complete de-
identification of all patient information, multicenter research, and DICOM anonymized linkage and 
storage.  In addition, this web-tool was designed to facilitate detailed but simple-to-use interface in 
collecting all data (below) relevant to this multicenter study.  Several pages of this web-tool are 
displayed in the Appendix Section. 
 
 
Data to Collect 
a) Patient Demographics  
Basic patient demographic data including age, gender, cardiac and non-cardiac medical 
history, and medications in use at the time of imaging.  Detailed collection of cardiac symptoms 
and reasons for imaging referral including the Diamond and Forrester symptom scores, New 
York Heart Association Grade, pre-test CAD risk scores will be determined.  Key demographic 
variables (amongst others) are shown in Appendix A2. 
b) CMR Imaging  
Detailed contrast uses including types, brands, dosages, and methodology of contrast 
injections will be collected.   Retrospective review of site-reported extent of myocardial 
ischemia by CMR, based on a 17-segment AHA nomenclature, as "mild" (<=3 segments), 
"moderate" (4-7 segments), or "severe" (>=8 segments).  CMR based LVEF, infarct location 
and number of segments with LGE.  Please refer to Appendix A3 for subset of the examples of 
the web-based data collection. 
c) Clinical Outcomes within 4 years after CMR 
Primary outcomes: a) All-cause including cardiac mortality, b) new acute MI, within 4 years 
after CMR imaging, and c) late coronary revascularization (PCI or CABG beyond 60 days after 
CMR);  
Secondary outcomes: heart failure hospitalization, unstable angina hospitalization, heart 
transplantation, significant ventricular arrhythmias, and strokes, within 4 years after CMR. 
Times to all of the above events will be collected. Other supportive data: angiographic reports 
including PCI details, CABG operative reports.  Repeat events of all non-fatal outcomes will be 
collected using our web-based data structures (Appendix A4). 
d) Costs 
Please see the attached word file figure 3 and the excel file budget (GCMR stress perfusion 
budget).   
All costs of imaging tests, medical care, and cardiac procedures will be based on regional 
national average inflated to the year of study analysis.            
Imaging: Initial and downstream performance of any imaging studies (stress CMR, stress 
nuclear imaging including SPECT or PET, coronary CTA, stress echocardiography, and stress 
treadmill exercise test without imaging).       
Medical care: any treatment of acute MI, heart failure or unstable angina admissions, and heart 
transplantation.             
Cardiac procedures: coronary angiography with and without intervention, CABG, ICD and 
pacemaker implantation.   
e) Effectiveness                                                             
Quality-adjusted life years (QALY) over a 4-year period calculated by validated utility-weighting 
(www.cearegistry.com).   

 
Core Lab DICOM Reads 
 
Participating sites will be asked to provide DICOM images for a random sample of trial-eligible CMR 
studies (10% of eligible cases at the site). The core lab will review rest perfusion, stress perfusion, 
and LGE images. The purpose of the DICOM reads is to assess the quality of images and not to 
dispute the site’s interpretation of cases. 
DICOM images read by the core lab will be shared with the vendors (Siemens and Bayer). 
 
Number of Sites 
It is expected that a range of 6-15 US centers will participate.  Each site will be screened by a sample 
survey and is required to provide a limited dataset to verify the existence of the stress CMR studies, 
completeness of key pulse sequences (cardiac function, stress perfusion, and LGE imaging), and 
diagnostic quality for ischemia assessment.  To qualify for the study, a site needs to demonstrate: 
a) Willingness/ability to provide a screening dataset 
b) Can contribute at least 100 studies 
c) <10% of the consecutive cohort were deemed diagnostic inadequate by the site 
                                                          
 
Sample Size 
For sub-aim 1: 
The rate of cardiac hard events (death and acute MI) is estimated based on reported evidence of 
0.5% and 6% per year for patients who have absence and presence of ischemia on CMR perfusion 
imaging, respectively.  We plan to collect follow-up events for a 4-year period after CMR.  Based on 
prior evidence, prevalence of ischemia on CMR perfusion was 23% in referred patients.  
With a sample size of 2,200 patients, 506 (23%) are assumed to be with presence of ischemia and 
1694 (77%) with absence of ischemia. With incidences of 6% and 0.5% per year and a 4-year follow-
up, a total of 124 of 506 patients with ischemia and 36 of 1694 patients with no ischemia are 
expected to experience an event, i.e. a total of 150 patients with event.  
 
A sample size of 2,200 patients overall and 150 patients with event in a 4-year follow-up is regarded 
sufficient to run multivariable analysis with up to 10 variables.  
 
With regards to the sample size considerations on the time-to-event analysis, the following settings 
and assumptions were used:  
- 
Power = 80% 
- 
Level of significance (two-sided) = 5% 
- 
Assumed proportion in control group (i.e. no revascularization)= 77% 
- 
Total sample size = 2,200 patients 
- 
Number of events = 150 in total sample 
-  
4-year follow-up for all patients available 
- 
The hazard ratio is estimated by a Cox proportional hazard model 
 
With a sample size of 2,200 patients and an event rate of 124 in group 1 and 36 in group 2, a hazard 
ratio of 0.59 can be detected with the above mentioned settings and assumptions (i.e. 41% risk 
reduction rate).  
 
 
For sub-aim 2.3 (comparison to the historical FAME 2 study 
As reported in published data (own BWH dataset and Hachamovitch et al Circulation 2011 Apr 
12;123(14):1509-18), the event rate of patients who underwent revascularization guided by CMR 
ischemia (i.e. CMR physiologic guidance) is about 5% per year, i.e. 10% in a 2-year follow-up. In the 

historic fame-2 study, the 2-year event rate of patients who did not use physiological guidance 
(N=441), was 19.5%. With a power of 80%, a two-sided alpha of 5% and an assumed difference 
under H1 of -9.5%, the sample size of patients in this registry needs to be at least 180 patients.  
 
 
Bias considerations  
The minimization of biases and confounding are major tasks when conducting a cohort study. By the 
nature of this type of study, randomization cannot be introduced to minimize these. Therefore, in the 
patient selection, major efforts have to be taken to minimize any type of bias. Special care has to be 
taken with regard to selection bias, i.e. the selection process to decide whether a patient is eligible for 
the study entry.  
 
In order to minimize selection bias and treatment bias over time across the centers, we plan to select 
the 2,200 consecutive cases from GCMR registry using a search criteria of stress CMR studies 
performed between 2008-2012.  We plan to restrict the contribution from each of the sites to between 
100-500 consecutive studies.  Unsuccessful cases (technical failures or patient factors) during the 
same time interval will also be recorded for the purpose of a separate analysis of study success rate.    
 
A large selection of possible confounders will be collected to assess any differences between the two 
groups of patients (patients with and without ischemia) to assess any differences between the groups 
with regard to e.g. medical history, demographics and baseline characteristics.   
 
 
Statistical Analyses 
Specific aim 1 
Unadjusted and multivariable survival analyses associating presence of ischemia and percent 
ischemic myocardium (both by CMR), with the primary and secondary clinical outcomes will be 
performed.   In the multi-variable analyses, key known risk markers such as age, patient sex, left 
ventricular and systolic volume (LVESV), validated pretest coronary disease probability, and validated 
risk score (Diamond and Forrester) will be modeled, and then extent of ischemia by stress CMR 
studies will be added to the model to test the null hypothesis that CMR findings do not add predictive 
value, versus the alternative hypothesis that stress CMR findings do add predictive value.  A 
significance level of 0.05 will be used.  Since CMR findings will affect patient management, which in 
turn, will affect the clinical outcomes, in a secondary analysis, cardiac treatment (e.g. 
revascularization) received within 60 days of the CMR will be added to the above model to account 
for treatment effects on the relationship between extent of ischemia and outcome. Annualized event 
rates of the primary and secondary outcomes, stratified by CMR ischemia (present or absent), and 
CMR ischemic burden (mild, moderate, high), will be determined, both unadjusted and adjusted for 
cardiac treatments received.   We also plan to calculate net reclassification index of these CMR 
metrics to event-free survival (primary and secondary outcomes). In addition, we will examine the 
annual event rates of primary and secondary outcomes in each of these subgroups and perform 
corresponding comparative analyses. 
 
Interim analysis at the end of the 2-year study period 
The study investigators agree with collaborators from Siemens and Bayer that an interim analysis at 
the end of the 2-year study period, of the proposed N=2,200, will inform the magnitude of the risk 
reduction rate.  In addition, it will provide reasonable guidance to what actions will be appropriate, if 
necessary, to further evaluate specific aim 1.  These actions include the possibility of proposing 
another study aiming at a larger sample size. 
 
Specific aim 2 (2 separate analyses for sub-aims 2.1 and 2.2, respectively) 

We structured the present study’s analysis of observational data to mimic a randomized clinical trial: a 
patient’s assignment to a treatment was based on the therapy selected in the first 60 days after stress 
CMR perfusion study and nonrandomized treatment adjusted for via a propensity score. This time 
point of 60 days was selected from previous work indicating that revascularization performed within 
this timeframe resulted from the noninvasive imaging study, whereas referrals after 60 days tended to 
be attributable to worsening clinical status.   Based on our pilot data, approximately 10-15% of 
patients undergo early coronary revascularization within the first 60 days after CMR. We therefore 
anticipate that 85-90% of the study cohort received MED whereas 10-15% received INT. 
 
We plan to examine the assumptions of proportional hazards in each of the Cox models.   In addition, 
performance of the propensity score model will be tested by comparing the prognostic associations 
between treatment and clinical outcomes, without and with that propensity score matching.     Key risk 
markers will be compared between the treatment groups, without and with inclusion of the propensity 
score matching. 
 
Step 1: Propensity Score to Treatment   We plan to structure the study analysis of observational data 
in SA1 to mimic a randomized clinical trial: a) assignment of coronary intervention (INT) vs. medical 
therapy (MED) is based on the therapy selected in the initial 60 days after imaging and b) 
nonrandomized treatment adjusted for via a propensity score.  Either PCI or CABG will define 
coronary revascularization.   Follow-up time begins at the time of the index stress CMR imaging.  To 
adjust for non-randomization of treatment, a single propensity score will be developed using logistic 
regression to model the decision to refer to revascularization considering all factors known to 
influence the referral decision.  This single composite propensity score represents the probability of 
treatment assignment, which will be included in all subsequent survival models (step 2) associating 
stress CMR perfusion guided-treatment with the respective endpoints in each of the 3 sub-aims.   
This adjustment reduces the bias introduced by nonrandomized referral to INT in practice.   While all 
factors known to influence this referral decision will be considered for entry into this logistic regression 
model, based on existing literature, the most likely predictors of referral to INT include % ischemic 
myocardium (% myocardial mass based on number of segments, by CMR),  typical angina symptoms 
(yes if positive response to 2 of 3 Diamond and Forrester qualities, else no), infarct size (LGE size, 
grams of myocardial mass), ischemic ST changes on rest ECG (yes/no), pre-test coronary disease 
probability (ordinal), and prior cardiac catheterization (yes/no).2   We anticipate that 10-15% of 
patients (~n=300) received INT so model over-fitting will not occur when constructing this logistic 
regression model. 
Step 2: Multivariable survival analyses for treatment’s impact incorporating the propensity score (sub-
aims 2.1 and 2.2).   A Cox proportional hazards model will be used to assess the association of 
treatment with the primary outcome (sub-aim 2.1) and secondary outcome-free survival (sub-aim 2.2).  
For each of sub-aim 2.1 and 2.2, we plan to build a survival model using Cox proportional hazards 
regression to control for the effects of baseline patient differences.  Key known risk markers to be 
included in these models are age, sex, diabetes, and % ischemic myocardium.  Major Treatment (INT 
or MED) and the propensity score will then be entered into the model to assess for any survival 
advantage from INT vs MED adjusting for the nonrandomized referral pattern.  Any potential impact 
by any covariate in the model onto the survival benefit from INT, will be tested by adding an 
interaction term between treatment and the covariate of interest.  
Specific aim 3 
A decision analysis will be performed and it compares stress CMR perfusion imaging based on all 
cost and outcome data obtained in this study, against the current cost-effectiveness data from 
SPECT imaging and coronary CTA.  It has been shown recently that coronary CTA-only strategy 
demonstrated a favorable incremental cost effectiveness ratio (ICER) of $20,429 per QALY, which is 

both cheaper and more effective than SPECT imaging (dominated) for evaluation of intermediate-risk 
chest pain patients without known coronary artery disease.   
Using CMR data collected from the current proposal study, we anticipate that a base-case model (a 
55 year-old male with 30% CAD prevalence) of comparative cost-effectiveness analysis can be 
constructed using published diagnostic performance of CAD diagnosis from other modalities: 
coronary CTA (95% sensitivity, 83% specificity, equivocal rate 0.12), SPECT (87% sensitivity, 73% 
specificity, equivocal rate 0.09), and invasive coronary angiography (100% sensitivity, 100% 
specificity).3   
We plan to perform a decision analysis and compare the following strategies (a) coronary CT 
angiography followed by invasive coronary angiography for positive or equivocal findings for CAD at 
coronary CT angiography (coronary CT angiography only), (b) coronary CT angiography followed by 
invasive coronary angiography for positive findings for CAD at coronary CT angiography and 
myocardial perfusion SPECT for equivocal findings for CAD at coronary CT angiography (coronary 
CT angiography first), (c) myocardial perfusion SPECT followed by invasive coronary angiography for 
positive or equivocal findings for CAD at myocardial perfusion SPECT (myocardial perfusion SPECT 
only), (d) stress CMR perfusion followed by invasive coronary angiography for positive or equivocal 
findings for CAD at CMR perfusion (myocardial perfusion CMR only), and (e) direct invasive coronary 
angiography.  Using costs and QALY data we collect from the current proposed study, a base-case 
model (55 year-old male with 30% CAD prevalence) of cost-effectiveness analysis can be 
constructed using published diagnostic performance of CAD diagnosis: coronary CTA (95% 
sensitivity, 83% specificity, equivocal rate 0.12), SPECT (87% sensitivity, 73% specificity, equivocal 
rate 0.09), and invasive coronary angiography (100% sensitivity, 100% specificity).  From published 
meta-analyses, stress CMR perfusion had reported a 89-92% sensitivity, and 80-90% specificity. 
 
 
 

Project Period 
12/01/2016 - 11/30/2018 (2 years) 
 
Potential Impact 
If stress CMR performs in this large observational real-world cohort as well as predicted by previous 
single-center trials, this study will provide robust evidence that stress CMR perfusion should become 
standard of care world-wide. 
 
 
 

References 
 
 
1: Wagner A, Bruder O, Schneider S, Nothnagel D, Buser P, Pons-Lado G, Dill T, Hombach V, 
Lombardi M, van Rossum AC, Schwitter J, Senges J, Sabin GV, Sechtem U, Mahrholdt H, Nagel E. 
Current variables, definitions and endpoints of the European cardiovascular magnetic resonance 
registry. J Cardiovasc Magn Reson. 2009 Nov 5;11:43. doi: 10.1186/1532-429X-11-43. PubMed 
PMID: 19891768; PubMed Central PMCID: PMC2779181. 
 
 
2: Hachamovitch R, Hayes SW, Friedman JD, Cohen I, Berman DS. Comparison of the short-term 
survival benefit associated with revascularization compared with medical therapy in patients with no 
prior coronary artery disease undergoing stress myocardial perfusion single photon emission 
computed tomography.  Circulation. 2003 Jun 17;107(23):2900-7. Epub 2003 May 27. PubMed PMID: 
12771008. 
 
 
3: Min JK, Gilmore A, Budoff MJ, Berman DS, O'Day K. Cost-effectiveness of coronary CT 
angiography versus myocardial perfusion SPECT for evaluation of patients with chest pain and no 
known coronary artery disease. Radiology. 2010 Mar;254(3):801-8. doi: 10.1148/radiol.09090349. 
PubMed PMID: 20177094. 
 

Appendix Section 
 
A1: Diamond and Forrester Chest Pain Prediction Score to restrict enrollment to intermediate 
(moderate) to high risk pre-test likelihood of disease. 
 
 
 

A2: Collection of patient demographic Data  
 
 
 
 
 

A3: Database display of hemodynamic and ventricular functional parameters 
 
 
 
 
 

A4: Collection of patient clinical outcomes 
 
 
 
 

A5: Collection of Segmental Analyses Data 
 
 
 
 
 

A6: Collection of Downstream Cardiac Tests