Prospective Randomized Trial of the Optimal Evaluation of Cardiac Symptoms and Revascularization
Phase: NA
Conditions: Coronary Artery Disease
Sponsor: HeartFlow, Inc.

This supplement contains the following items for: Douglas PS, Nanna MG, Kelsey MD, et al. 
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Original protocol, final protocol, and summary of amendments

Table of Contents
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Original Protocol  
Final Protocol
Summary of Protocol Amendments 

PRECISE Protocol
CP-907-001-A
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 CONFIDENTIAL  
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The PRECISE Protocol 
Prospective Randomized Trial of the Optimal Evaluation of Cardiac 
Symptoms and Revascularization  
Study Objective 
The primary objective of the PRECISE trial is to assess clinical 
outcomes, decision making regarding noninvasive testing and invasive 
angiography, and costs using a precision evaluation strategy as 
compared to a usual care strategy in participants with stable symptoms 
suggestive of coronary artery disease. The precision evaluation 
strategy will be based on a pre-test risk assessment and will 
incorporate cCTA with selective FFRCT and guideline-recommended 
care with symptom and risk factor management and no immediately 
planned testing.  
Study Design 
The study will be a prospective, pragmatic, randomized clinical trial of 
the comparative effectiveness of diagnostic evaluation strategies for 
stable CAD, to be performed in outpatient settings, including primary 
care and cardiology practices. Qualifying patients presenting with new 
symptoms suspicious for clinically significant CAD (and without known 
CAD), who are recommended for diagnostic testing and did not receive 
any cardiovascular testing within the past 12 months, will be 
randomized to an initial strategy of either precision care or usual care.  
All subsequent decisions in the usual care arm regarding additional 
testing, medications, and/or procedures will be at the discretion of the 
responsible clinical care team. 
Study Principal 
Investigator 
Pamela S. Douglas, MD 
Duke University 
Durham, NC 27701 
USA 
Sponsor 
HeartFlow, Inc. 
1400 Seaport Blvd., Building B 
Redwood City, CA 94063 
Campbell Rogers, MD 
Chief Medical Officer 
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Investigator Protocol Signature Page 
I have read and understand the protocol and agree that it contains all the ethical, legal, and 
scientific information necessary to conduct this study. I will personally conduct the study as 
described. I will provide copies of the protocol to all assigned physicians, nurses, and other 
professional personnel who will participate in the study and will be responsible for their 
compliance and adherence to the study protocol. I am aware that this protocol must be 
approved by the Institutional Review Board or Ethics Committee. I agree to adhere strictly to 
the attached protocol. I agree that clinical data entered on case report forms by me and my 
staff will be supplied to HeartFlow and may be utilized by HeartFlow in various ways, such 
as for submission to governmental regulatory authorities and/or in combination with clinical 
data gathered from other research sites, whenever applicable. I agree to allow HeartFlow 
monitors and auditors and their designees full access to all medical records at the research 
facility for participants screened or randomized in the study. I agree to provide all participants 
with informed consent forms and will ensure adequate informed consent is obtained, as 
required by government regulations and International Conference on Harmonization 
guidelines.   
Version Date: Jun 29, 2018 
 
__________________________________   
__________________________ 
 Site Name 
Site Number 
 
__________________________________   
__________________________ 
 Principal Investigator (print name) 
 
Date 
__________________________________   
__________________________ 
 Pamela Douglas, MD, Trial PI 
 
Date 
__________________________________   
__________________________ 
Campbell Rogers, MD, HeartFlow CMO  
Date
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Protocol Version and Amendment Tracking  
  
Version Number/Amendment  
Approval Date  
1.0 
Jun-29, 2018 
 
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TABLE OF CONTENTS 
I. STUDY SYNOPSIS .................................................................................................................... 
II. INTRODUCTION ...................................................................................................................... 
II.A. Primary Hypothesis 
 
II.B. Signifance of the Study  
III. BACKGROUND AND STUDY RATIONALE ............................................................................ 
III.A. Prior Literature and Studies 
 
III.B. Rationale for the Current Study: A Precision Approach to Chest Pain Evaluation 
 
IV. STUDY OVERVIEW AND OBJECTIVES ................................................................................ 
IV.A. Overview of PRECISE  
IV.B. Primary Objective and Endpoints 
 
IV.C. Secondary Endpoints 
 
IV.D. Rationale for the Selection of Outcome Measures 
 
IV.E. Rationale for the Selection of Testing in Each Arm 
 
IV.F. Participant Randomization 
 
IV.G. Diagnostic Evaluations and Subsequent Care  
V. STUDY PROCEDURES ........................................................................................................... 
V.A. Participant Screening For Eligibility 
 
V.B. Participant Randomization and Enrollment 
 
V.C. Participant Cohort Assignment  
V.D. Participant Follow-Up 
 
V.E. Cross Over Participants  
V.F. Participant Withdrawal  
V.G. Schedule of Assesments 
 
VI. ADDITIONAL ASSESMENTS AND SUBSTUDIES ................................................................. 
VI.A. Quality of Life Assesments 
 
VI.B. Economic and Resource Utilization Assesments 
 
VI.C. Imaging and other Cardiac Assessments 
VII. ENDPOINT DETERMINATION, SAFETY AND MONITORING .............................................. 
VII.A. Primary Endpoint Definitions  
VII.B. Secondary Endpoint Definitions 
 
VII.C. Testing Complications and Reporting  
VII.D. Independent Clinical Event Adjudication Committee  
VII.E. Data and Safety Monitoring Board 
 
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VIII. STATISTICAL PLAN ............................................................................................................. 
VIII.A. Sample Size Determination and Statistical Power 
 
VIII.B. Statistical Analysis Plan 
 
IX. ETHICAL CONSIDERATIONS AND RISK ANALYSIS ........................................................... 
IX.A. Ethical Considerations  
IX.B. Study Risks and Benefits 
 
X. DATA HANDLING AND QUALITY ASSURANCE ................................................................... 
X.A.  Completing and Signing Case Report Forms  
X.B.  Clinical Data Management 
 
X.C.  Archiving of Data 
 
XI. STUDY MONITORING, AUDITING, AND INSPECTING ......................................................... 
XI.A.  Study Monitoring 
 
XI.B.  Auditing and Inspecting 
 
XII. REFERENCES ....................................................................................................................... 
 
 
 
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TABLE OF ABBREVIATIONS 
 
ACC  
American College of Cardiology  
AHA  
American Heart Association  
BMI  
body mass index  
BP  
blood pressure  
CAD  
coronary artery disease  
CV 
cardiovascular 
CCC  
Clinical Coordinating Center  
CI  
confidence interval  
CK-MB  
creatinine kinase-myocardial band  
CMS 
Centers for Medicare & Medicaid Services 
COCATS   
Core Cardiology Training Symposium  
cCTA  
coronary computed tomographic angiography  
DCRI 
Duke Clinical Research Institute 
DECISION 
Decisive Evaluation of Cardiac Ischemia, Symptoms and 
Revascularization 
DSMB  
Data and Safety Monitoring Board  
ECG  
electrocardiogram  
Echo  
echocardiogram  
EDC 
electronic data capture 
EQ-5D-5L 
A standardized instrument developed by the EuroQol Group as a 
measure of health-related quality of life. 
eCRF  
electronic case report form  
FFR 
fractional flow reserve 
FS 
Finkelstein and Schoenfeld statistical method 
FFRCT 
non-invasive technique using cCTA to determine FFR 
g/L  
grams per liter  
HDL  
high-density lipoprotein  
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ICA 
invasive coronary angiography 
IRB  
institutional review board  
IVUS 
intravascular ultrasound 
IXRS  
interactive voice/web response system  
LDL  
low-density lipoprotein  
LV  
left ventricular   
MACE 
major adverse cardiovascular event 
MAR  
missing at random   
MDCT 
multidetector computed tomography 
MI  
myocardial infarction  
MOP  
manual of procedures  
mSv  
milliSievert  
NICE 
National Institute for Health and Care Excellence 
(In the United Kingdom’s National Health Service) 
NHPR 
non hyperemic pressure ratio  
PAD  
peripheral arterial disease  
PCI  
percutaneous coronary intervention  
PI  
principal investigator  
PLATFORM Prospective LongitudinAl Trial of FFRCT: Outcome and Resource 
Impacts study 
PRECISE  
Prospective Randomized Trial of the Optimal Evaluation of 
Cardiac Symptoms and Revascularization 
PROMISE  
PROspective Multicenter Imaging Study for Evaluation of Chest 
Pain randomized clinical trial 
QoL  
quality of life  
ROC  
receiver operating characteristic  
SAQ  
Seattle Angina Questionnaire  
SCOT-
HEART 
Scottish Computed Tomography of the HEART randomized clinical 
trial 
ULN 
upper limit of normal  
  
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I. STUDY SYNOPSIS 
 
Protocol Title 
PRECISE: Prospective Randomized Trial of the Optimal Evaluation of 
Cardiac Symptoms and Revascularization 
Investigational Strategy 
Precision diagnostic evaluation as the initial strategy for suspected CAD in 
patients with stable symptoms 
Study Principal 
Investigator 
Pamela S Douglas, MD 
Duke Clinical Research Institute, Duke University, Durham NC 
Academic Research 
Organizations 
Duke Clinical Research Institute (DCRI), Durham, NC, USA  
Cardiovascular Research Foundation (CRF), New York, NY, USA 
Clinical Research 
Organization 
Medpace Research, Inc. 
Sponsor 
HeartFlow Inc.  
1400 Seaport Blvd 
Redwood City, CA 94063 
Participants and Study 
Centers 
Approximately 2100 participants randomized at approximately 100 outpatient 
sites in the US and outside of the US 
Planned Study Duration 
Approximately 48 months 
Primary Study Objective 
To assess clinical outcomes, decision making regarding noninvasive testing 
and invasive angiography, and costs using a precision evaluation strategy as 
compared to a usual care strategy in participants with stable symptoms 
suggestive of coronary artery disease. The precision evaluation strategy will 
be based on a pre-test risk assessment, and will incorporate cCTA with 
selective FFRCT and guideline-recommended care with symptom and risk 
factor management and no immediately planned testing. 
Primary Hypotheses 
In stable participants with a clinical recommendation for testing to evaluate 
suspected coronary artery disease (CAD) a precision evaluation strategy, 
incorporating a risk-based assignment to guideline recommended medical 
management without planned testing for selected low risk participants and 
cCTA with selective FFRCT in elevated risk participants, will result in improved 
clinical outcomes of death/MI and a lower rate of catheterization without 
obstructive CAD as compared to usual care strategy. 
Population 
Stable patients who have a clinical recommendation for testing (noninvasive 
or invasive) for suspected coronary artery disease 
Study Design and 
Methods 
Prospective, pragmatic, randomized clinical trial of diagnostic evaluation 
strategies for stable CAD, to be performed in outpatient settings, including 
primary care and cardiology practices. Qualifying patients presenting with 
new symptoms suspicious for clinically significant CAD (and without known 
CAD), who are recommended for diagnostic testing and did not receive any 
cardiovascular testing within the past 12 months, will be randomized to an 
initial strategy of either precision care or usual care of the site’s choosing. All 
subsequent decisions in the usual care arm regarding additional testing, 
medications, and/or procedures will be at the discretion of the responsible 
clinical care team; the use of cCTA as the initial diagnostic strategy is not 
allowed in the usual care arm. 
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Precision evaluation: Participants randomized to a precision strategy will 
be assigned to either guideline-recommended care without immediately 
planned testing (low risk) or cCTA with selective FFRCT (elevated risk) using 
a risk tool based on pre-test clinical characteristics derived from the 
PROMISE trial and validated in SCOT-HEART trial. Participants assigned to 
guideline-recommended care without planned testing will be treated with 
preventive and antianginal medical treatment per guideline 
recommendations and clinical judgment and followed without testing. 
Participants and their providers will be provided informational resources 
explaining the safety and rationale of this strategy based on pre-test 
probabilities and the PROMISE Minimal Risk Score. Participants with 
documented intractable symptoms despite maximal medical management 
may undergo cCTA with selective FFRCT at the participant’s or site clinician’s 
discretion.  
 
Usual Care: For participants randomized to usual care, the participant’s care 
team will select the specific noninvasive stress test (exercise 
electrocardiogram, stress nuclear imaging [including PET], stress MR, or 
stress echocardiogram); OR invasive test: (direct to diagnostic 
catheterization). The use of cCTA as the initial diagnostic strategy is 
explicitly excluded in this arm. 
 
In both arms, the participant’s care team will be provided with physician and 
patient informational resources summarizing current recommendations for 
test interpretation and preventive care. Optimal medical management will be 
recommended but not mandated in either arm. 
Randomization and 
Stratification 
Participants will be randomized using a 1:1 randomization scheme via an 
interactive web or voice-based system (IXRS). Randomization will be 
stratified by intended first test if randomized to usual care, low vs. elevated 
pre-test risk, and site. 
Enrollment in the strata of intended noninvasive test first (vs. intended 
invasive angiography first) will be capped at 90%. 
Primary Endpoint 
 
Time to a composite of: MACE (all cause death, non-fatal MI) or invasive 
cardiac catheterization without obstructive CAD (obstructive CAD defined as 
diameter stenosis ≥50% according to clinical site interpretation, FFR≤0.80, or 
NHPR<0.90) at one year (intention to treat) 
Secondary Effectiveness 
Endpoints 
Endpoints will be assessed at 45 days, 6 months, 1 year, and 2 years. 
1. Hierarchical analysis (Finkelstein and Schoenfeld (FS) or Pocock’s win 
ratio) of primary endpoint 
2. Resource use patterns (all patients) and medical costs (US patients) to 
12 months 
3. QoL: measured by the Seattle Angina Questionnaire (SAQ) to assess 
angina-specific Quality of Life  and the EuroQoL 5D (EQ-5D-5L) survey 
to assess overall (generic) health status  
4. Death: All-cause, cardiovascular, non-cardiovascular 
5. Myocardial infarction: All, procedural, spontaneous MI 
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6. Hospitalizations: All, cardiovascular, non-cardiovascular, and for 
progressive or unstable angina  
7. Preventive medication use (ASA, statins) in participants with clinical 
indication for use: eg: hyperlipidemia, diabetes, documented CAD 
8. Cumulative radiation exposure at 1 year  
9. PRECISE primary endpoint at 24 months 
10. MACE, defined as all-cause death myocardial infarction, or ischemia-
driven revascularization at 24 months (DECISION co-primary end point) 
11. All-cause death, MI, all follow-up unplanned revascularization 
procedures, cardiac catheterizations without actionable findings at 24 
months (DECISION co-primary end point) 
12. Proportion of invasive cardiac catheterization patients who undergo 
revascularization (PCI or CABG) within 6 months of enrollment 
Pre-specified subgroup 
analyses 
1. Low risk vs. elevated risk by PROMISE score 
2. Intended initial test: functional stress test vs. invasive (direct to cath) 
3. Clinical factors: Sex, age, diabetes  
4. Presentation: Primary symptom (chest pain vs. other), SAQ angina 
frequency score 
Inclusion Criteria 
Inclusion criteria (all must be present):  
1. Age ≥18 years 
2. Stable typical or atypical symptoms suspicious for coronary artery disease 
with further non-emergent testing or elective catheterization recommended 
to evaluate the presence of suspected coronary artery disease  
3. Safe performance of cCTA: 
x 
Creatinine clearance ≥45 ml/min  
x 
For a female participant of childbearing potential, a pregnancy test 
must be performed with negative results known within 7 days prior to 
randomization 
4. Willingness to comply with all aspects of the protocol, including 
adherence to the assigned strategy and follow-up visits  
5. Ability to provide written informed consent 
Exclusion criteria 
Exclusion criteria (all must be absent): 
1. Acute chest pain 
2. Unstable clinical status   
3. Noninvasive or invasive CV testing for CAD within 1 year 
4. Lifetime history of any obstructive CAD (no prior CABG or PCI, stenosis 
≥50%), or known EF ≤40% or moderate to severe valvular or congenital 
cardiac disease 
5. Contraindications to cCTA including but not limited to estimated 
creatinine clearance (GFR) <45 ml/min measured within 90 days 
6. Exceeds local weight or size limit for cCTA or cardiac catheterization 
7. Any condition leading to possible inability to comply with the protocol 
procedures or follow-up 
8. Any condition that might interfere with the study procedures or follow-up 
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9. Enrolled in an investigational trial that involves a non-approved cardiac 
drug or device which has not reached its primary endpoint 
10. Life expectancy less than 2 years due to non-cardiovascular 
comorbidities 
Study Follow-up 
Participant follow-up will be done at 45 days, 6 months, 1 year, and 2 years. 
Sample Size 
Considerations 
Primary superiority testing hypothesis of all cause death/MI or invasive 
cardiac catheterization without obstructive CAD (diameter stenosis ≥50% or 
FFR≤0.80/ or NHPR<0.90) at one year (intention to treat, time to first event 
analysis): Assuming an 8% event rate at 1 year in the usual care group and 
5% in the precision care group (3% absolute [37.5% relative] effect 
magnitude). Assumed rates are based on 30% assigned to guideline-
recommended care with symptom management and no planned testing 
(within which 30% will cross over to cCTA with selective FFRCT); and overall 
10% will not receive assigned testing; enrolling 1050 participants per group 
(2100 total participants) would provide at least 90% power to demonstrate 
superiority accounting for 10% attrition rate. 
 
 
 
 
 
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II. INTRODUCTION 
 
II.A. Primary Hypotheses 
The overarching goal of the Prospective Randomized Trial of the Optimal Evaluation of Cardiac 
Symptoms and Revascularization (PRECISE) research program is to assess clinical outcomes, 
decision making regarding noninvasive testing and invasive angiography, and costs using a 
precision evaluation strategy as compared to a usual care strategy in participants with stable 
symptoms suggestive of coronary artery disease. The precision evaluation strategy will be based 
on a pre-test risk assessment, and will incorporate cCTA with selective FFRCT and guideline-
recommended care with symptom management and no planned testing. 
 
The primary hypothesis of PRECISE is: in stable participants with a clinical recommendation for 
testing to evaluate suspected coronary artery disease (CAD) a precision evaluation strategy will 
result in improved clinical outcomes of death/MI and a lower rate of catheterization without 
obstructive CAD as compared to a usual care strategy. 
 
An important secondary hypothesis is that the precision evaluation strategy will result in improved 
patient-reported outcomes, reflected in the SAQ angina frequency and quality of life scores. We 
also expect the precision strategy to result in reduced resource utilization and net cost savings 
compared to usual care evaluation.  
 
The usual care arm participants will undergo either noninvasive stress testing, with the specific 
modality at the discretion of the participant’s clinician, or invasive cardiac catheterization (ICA) as 
the initial test.  
 
The precision evaluation arm starts with the use of the PROMISE Risk Tool to categorize patient 
risk for CAD and events.  The PROMISE Risk Tool is a validated risk model that has been shown 
to accurately identify chest pain patients who are unlikely to benefit from non-invasive testing (i.e. 
have minimal or no atherosclerosis and likely to have no events within two years). The lowest risk 
group in the precision arm identified using this model will be assigned to guideline-recommended 
care focused on symptom and risk factor management without planned cardiac diagnostic testing. 
The remaining participants, who will be of elevated risk, will be initially evaluated with cCTA with 
selective FFRCT.  
 
I.B. Significance of the Study 
The goal of PRECISE is to define the optimal evaluation and management strategy of stable, 
symptomatic participants with suspected CAD. If the hypotheses of PRECISE are supported by 
the results of the trial, PRECISE will form the core of a compelling body of evidence supporting 
important changes in clinical practice guidelines and clinical care that will both improve outcomes 
for patients and reduce the use of unnecessary (low yield) testing and associated medical costs. 
Chest pain is one of the most common symptoms that bring patients into the health care system 
and one of the most difficult for providers to address confidently.  The variability of current practice 
and the frequent overuse of testing derive from the lack of consensus among experts and among 
guidelines about how best to achieve a secure diagnosis and appropriate management plan.  The 
results of PRECISE will have major implications for all health systems where stable chest pain is 
a common reason for subjects to seek care. 
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III. BACKGROUND AND STUDY RATIONALE 
 
III.A. Prior Literature and Studies 
 
Unmet need to develop novel approaches for the diagnostic evaluation in stable chest pain 
patients  
 
Coronary artery disease is an extremely common diagnosis worldwide and results in significant 
morbidity and mortality1, 2. Among the common presentations, stable symptoms of chest pain or 
exertional dyspnea can be diagnostically puzzling and often require diagnostic testing or 
angiography to be certain of the diagnosis and treatment. Current US, EU and UK guidelines 
recommend risk stratification using presentation characteristics and risk factors to determine 
which patients require noninvasive testing or should be referred directly to invasive 
catheterization3. However, in the current era, the results of using these recommended strategies 
are unsatisfactory. The population undergoing noninvasive testing has a low rate of obstructive 
CAD (10-20%) and very low annual event rates (~1-2%/year) 4, 5, while patients undergoing 
invasive angiography frequently don’t have actionable CAD6. These patterns of care have 
resulted in high costs without accompanying clinical benefit7. A new approach to the risk 
stratification and subsequent diagnostic evaluation and management of patients with stable 
symptoms suggestive of CAD is urgently needed. 
 
Uncertainty Regarding the Optimal First Test for Detection and Exclusion of Coronary Artery 
Disease: Evidence For cCTA  
 
While a number of functional and anatomic non-invasive tests are available for the evaluation of 
stable chest pain patients, the optimal evaluation strategy for patients with stable chest pain is 
uncertain, and recommendations in current guidelines differ markedly. In a recent attempt to 
address these issues systematically, two large multicenter, open-label, randomized controlled 
trials explored the diagnostic evaluation of patients with symptoms that may represent coronary 
artery disease. The SCOT-HEART (Scottish Computed Tomography of the HEART)4 and 
PROMISE (PROspective Multicenter Imaging Study for Evaluation of chest pain)5 trials sought to 
address evidence gaps in noninvasive testing in stable chest pain, an area in which few 
randomized trials had previously been conducted. 
 
Key findings from SCOT-HEART and PROMISE: The overall results and important similarities 
and differences between the two trials have been recently described8. The SCOT-HEART study 
enrolled 4,146 patients with stable chest pain to cCTA in addition to usual care (which generally 
included electrocardiogram [ECG] stress testing) or to usual care alone. The trial used an 
upstream primary endpoint related to diagnostic thinking: managing clinician certainty of the 
diagnosis of angina secondary to CAD, which showed an increase in the cCTA group (RR: 1.79; 
95% confidence interval [CI]: 1.62 to 1.96), as did the secondary endpoint of certainty of diagnosis 
of CAD (RR: 2.56; 95% CI: 2.33 to 2.79). The clinical outcomes-related secondary endpoint of 
the rate of cardiovascular death or nonfatal myocardial infarction (MI) appeared to be reduced in 
the cCTA group at 20 months (RR: 0.62, 95% CI: 0.38 to 1.01; p=0.0527), although the overall 
event rates were low in both arms, reflecting the inclusion of a large number of patients without 
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CAD. Of note, a landmark analysis excluding the 7 week delay to receiving a cCTA yielded a 
hazard ratio of 0.50 for CV death and MI9.  
 
The larger PROMISE trial randomly assigned 10,003 symptomatic, stable outpatients requiring 
evaluation for suspected CAD to either initial cCTA or functional stress testing (exercise treadmill 
testing [ETT], nuclear stress testing, or stress echocardiography), with a median follow-up of 25 
months. The event related composite primary endpoint (death, MI, hospitalization for unstable 
angina, or major cardiovascular procedural complication) occurred at similar rates in the cCTA 
and functional testing groups (3.3% and 3.0%), which was lower than previously established 
historical rates. More patients in the cCTA group underwent cardiac catheterization within 90 days 
after randomization (12.2% vs. 8.1%), but the secondary endpoint of the frequency of 
catheterization showing no obstructive CAD was significantly lower in the cCTA group (3.4% vs. 
4.3%, p=0.02) as was the rate of death and MI at 12 months (HR 0.66; p=0.049). Furthermore, 
among patients randomized to an intended nuclear testing strategy, the mean cumulative 
radiation exposure was lower in the cCTA group compared with the functional testing group (12.0 
- 8.4 mSv vs. 14.1 - 7.6 mSv). This encompassed all downstream radiation within 90 days, 
including that associated with cardiac catheterization, and is particularly intriguing because more 
cCTA patients received cardiac catheterization.  
 
In addition to improving triage to the cardiac catheterization lab and potentially reducing radiation 
exposure, mounting evidence has demonstrated that use of cCTA, compared to functional testing, 
yields improved preventive medical treatment and better prognostic information4, 5, 10. Patients in 
the PROMISE trial who underwent cCTA experienced greater uses of indicated cardio-protective 
medications such as aspirin and statins10. This increase is prognostically important, as data from 
the CONFIRM registry (Coronary CT Angiography Evaluation for Clinical Outcomes International 
Multicenter) demonstrated that baseline statin therapy among patients with non-obstructive CAD11 
identified on cCTA was associated with a reduction in mortality compared to non-use12, while 
statin therapy among patients with obstructive CAD identified on cCTA was associated with a 
reduction in MACE13.  
 
The identification of non-obstructive CAD with high risk plaque characteristics can only be 
accomplished non-invasively by cCTA and is an important prognostic indicator, with even mild 
abnormalities conferring nearly three times the risk of death, MI and unstable angina compared 
to patients with a normal study14, 15. Furthermore, cCTA leads to higher yield of positive results 
with actionable or obstructive CAD, among patients undergoing cardiac catheterization5. This is 
in line with data from the CONFIRM registry, where investigators demonstrated that cCTA could 
be used as an effective gatekeeper prior to invasive coronary angiography16.  
 
Most importantly, a recent meta-analysis largely based on PROMISE and SCOT-HEART data 
showed a clear benefit in ‘hard’ cardiovascular outcomes to a cCTA first strategy, with a 29% 
reduction in MI17. This was potentially driven by the increase in medication utilization in the cCTA 
arm of the study as well as more catheterization and revascularization17.   
 
To summarize, there are several practical and clinical implications of SCOT-HEART and 
PROMISE which inform the proposed design of PRECISE: 
x 
Contemporary patients with stable chest pain are at low risk of clinical events. Therefore, a 
strategy to test only those with an elevated likelihood of having obstructive CAD or risk for 
events, while instituting optimal medical care including deferring testing in those unlikely to 
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benefit (i.e. using the PROMISE Risk Score), may be feasible, clinically important and 
efficient. 
x 
cCTA is a reasonable first test for routine assessment of patients with stable chest pain, and 
when compared to functional testing, is associated with an increase in preventive medication 
use and a reduction in myocardial infarction.  
x Future trials investigating the optimal evaluation of patients with stable chest pain should 
include the evaluation of clinical outcomes and other measures of testing efficiency (i.e., 
cardiac catheterization without obstructive CAD).  
 
The Case for the Use of cCTA with selective FFRCT as the Optimal First Test 
 
The current noninvasive diagnostic testing strategies using functional testing have relatively poor 
accuracy given the low disease prevalence in this population, leading to high rates of false-
positive results18. Specifically, current diagnostic strategies lead to high rates (~50%) of cardiac 
catheterization without significant obstructive disease or need for revascularization5, 7. As 
described above, incorporating cCTA into testing strategies can reduce the frequency of cardiac 
catheterization without obstructive disease but tends to increase rates of invasive angiography 4, 
5. 
 
Non-invasive computationally-derived FFRCT has been developed using resting coronary CT 
images without the administration of adenosine or change in underlying cCTA protocols18-21. The 
methodology has been previously described elsewhere. 22 In short, FFRCT uses the accurate 
anatomical model of the coronary arteries and myocardium obtained with conventional cCTA and 
applies the physical laws that govern flow, microcirculatory resistance, coronary branching, and 
simulated hyperemia. The Navier-Stokes equations that solve for velocity, resistance and 
pressure for all Newtonian fluids are applied to provide a 3-dimensional pressure map across the 
coronary tree. This use of computational fluid dynamics generates FFR values from 0 to 1, with 
<0.80 considered hemodynamically significant. The values are congruent with invasive FFR, as 
shown in several prospective validation studies18-20. Finally, the anatomical modeling has been 
improved by the use of advanced deep and machine learning techniques applied to the large data 
sets acquired via central analysis. 
 
The addition of FFRCT may reduce a potential limitation of a cCTA-first approach, excess invasive 
angiography, by providing both functional and anatomic data. Specifically, FFRCT markedly 
reduces in the false positive rate of cCTA alone vs. invasive FFR adjudicated ischemia with 68% 
of false positive CT interpretations in the NXT Trial reclassified as true negative. A retrospective 
analysis from the PROMISE trial in 181 patients with cCTA, cardiac catheterization and FFRCT 
revealed that FFRCT was a better predictor of revascularization and events than cCTA alone. 
Modelling of the incorporation of FFRCT into catheterization decision making suggested a 
reduction in catheterization rate with cCTA from 12.2% to 7.8% while reducing the rate of 
catheterization without obstructive CAD from 27% to 15% and increasing the yield of 
catheterization leading to revascularization from 49% to 61%23. Given that PCI of lesions with 
negative FFR is associated with worse outcomes24, 25, while treatment of FFR positive lesions with 
PCI vs. optimal medical therapy results in improved clinical outcomes, the potential clinical value 
of adding FFRCT to a cCTA based diagnostic strategy is evident.  
 
 
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The safety and utility of a CT/ FFRCT strategy were further tested in the PLATFORM Study 
(Prospective LongitudinAl Trial of FFRCT: Outcome and Resource Impacts) which evaluated rates 
of invasive catheterization without obstructive CAD in patients undergoing invasive evaluation. 
Patients in 2 sequential non-overlapping cohorts of patients referred for ICA were assigned to 
either undergo ICA or cCTA/ FFRCT with ICA use based on the results of the cCTA and FFRCT. 
The cCTA/FFRCT strategy resulted in a significant reduction in the rate of cath lab finding of no 
obstructive disease, from 73 to 12%7. Furthermore, ICA was deferred in 61% of cCTA/FFRCT 
strategy patients. A follow-up at one year demonstrated that cCTA with selective FFRCT strategy 
yielded similar clinical outcomes and quality of life, at a substantially reduced cost. 
 
While much of the early focus has been on a reduction in referral for ICA in the absence of 
actionable CAD, more recently there has been growing interest in using FFRCT to enhance 
catheterization lab efficiency by increasing the proportion of catheterizations that include 
revascularization (ICA/PCI ratio) and providing guidance regarding revascularization strategies 
before the invasive angiogram. Importantly, in this case FFRCT is not being used only in a binary 
fashion but rather to provide a richer understanding of the pattern and degree of pressure loss 
across the epicardial coronary system and its connection to the extent of ischemia present.  
The value of cCTA and FFRCT has been recognized by The National Institute for Health and Care 
Excellence (NICE) in their advisory for stable chest pain (Clinical Guidance 95) and technical 
evaluation of FFRCT, as well as by establishment of reimbursement standards by the Centers for 
Medicare and Medicaid Services (CMS) 26, 27. The 2016 NICE guidance recognized the difficulties 
with risk stratification in an era of reduced obstructive CAD prevalence in the population 
undergoing evaluation and the importance of anatomical assessment of CAD26, 27. In response, it 
recommends coronary cCTA as the first-line investigation for patients presenting with new-onset 
chest pain felt to be due to CAD based on its superior clinical diagnostic utility and cost-
effectiveness26, 27. Further, based on the results of the PLATFORM trial, the NHS recommends 
addition of FFRCT to cCTA as a cost savings measure26.  In the United States, CMS approved a 
New Technology Ambulatory Payment Classification (APC) for HeartFlow FFRCT analysis on 
January 1, 201828. The acknowledgement of FFRCT by CMS is a critical step toward increasing 
the availability of the technology to patients who may benefit. However, other organizations’ 
standards documents have not yet been revised to incorporate the emerging evidence base 
supporting CCTA and FFRCT, indicating that there is still a need for additional evidence to support 
the routine use of FFRCT in clinical practice. 
 
Rationale and Evidence for Incorporation of a Strategy of Guideline-recommended Care without 
Planned Testing in Low Risk patients 
 
Given the low prevalence of obstructive CAD (10-20%) and very low annual event rates (~1-
2%/year) among stable chest pain patients undergoing non-invasive testing, combined with the 
high cost of testing4, 5, prospective evaluation of the safety and efficacy of an approach of 
guideline-recommended care without planned testing has become a necessity. Although there 
are no data regarding outcomes and costs of a guideline-recommended care without planned 
testing in symptomatic patients, it is possible to define in principle a cohort in whom deferred 
testing might be the optimal strategy. The argument for testing this is further strengthened by the 
equivalence of medical and invasive strategies in preventing cardiovascular events in stable CAD, 
as several trials have shown no benefit of revascularization over optimal medical treatment 29, 30. 
It is reasonable to hypothesize that this may be especially true for those at lowest risk, in whom 
noninvasive testing is even less likely to lead to outcomes-improving revascularization, thereby 
removing the need for testing as a gateway to the catheterization laboratory.  
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The COURAGE trial (Clinical Outcomes Utilizing Revascularization and Aggressive Drug 
Evaluation) demonstrated no significant difference in a composite of death, myocardial infarction, 
and stroke between patients with objective evidence of myocardial ischemia and significant CAD 
on medical therapy vs. those undergoing PCI (19.5% vs. 20.0%, p=0.62)29. The more recent 
ORBITA trial (Percutaneous coronary intervention instable angina) randomized 200 patients with 
stable angina and a single-vessel stenosis to optimal medical therapy + PCI vs. optimal medical 
therapy plus a sham procedure, with a primary endpoint of difference in exercise time during a 6-
week follow-up period30. The authors found no significant difference in improvement in exercise 
time (+28.4 seconds in PCI group vs. +11.8 seconds in sham group, p=0.2), nor any significant 
change in the secondary outcome of Seattle Angina Questionnaire (SAQ)-angina frequency from 
baseline (14.0 in PCI group vs. 9.6 in sham group, p=0.26)30. The ongoing improvements in 
medical management of CAD risk, angina and established coronary artery disease further 
emphasize the need for diagnostic strategies that minimize unnecessary invasive angiography 
and revascularization by emphasizing guideline-recommended care in patients at very low risk 
for obstructive disease. 
 
These studies support the development of a patient-centric strategy to identify those who may 
derive minimal benefit from testing, a strategy which carries several desirable implications for 
patients, clinicians, and clinical practice in general. For patients, this process can mean a 
reduction in use of testing from which they would not benefit, thereby saving time, anxiety, and 
cost, as well as potential reductions in radiation exposure and false-positive test results that could 
lead to more invasive, unnecessary procedures. For clinicians, a tool identifying the lowest risk 
patients has the potential to help optimize office-based decision making. From a practice and 
societal perspective, in an era in which practitioners are increasingly held accountable for costs 
and quality, the ability to confidently identify patients highly unlikely to benefit from potentially 
expensive testing and who may therefore be managed conservatively has many potential 
economic and process-of-care advantages.  
 
The PROMISE Risk Tool was expressly developed to identify low-risk patients with stable chest 
pain who are unlikely to benefit from non-invasive testing, and for whom guideline-recommended 
medical management alone may be safe. Current guidelines recommend using a version of the 
Diamond and Forrester risk score for pretest likelihood of obstructive CAD, but multiple 
investigators have found that this tool grossly over estimates actual presence of disease5, 31, 32. 
The consequence is an imprecise evaluation strategy for millions of patients, resulting in unhelpful 
testing of lower risk individuals. For a significant portion of these, a false positive functional testing 
leads them to have invasive cardiac catheterizations to rule out the disease they do not have. The 
Risk Tool developed using the PROMISE cohort employs 10 readily available clinical variables 
and has been validated in the SCOT-HEART population33, 34. This risk tool identifies patients with 
stable chest pain who have no coronary plaque or calcification by cCTA and no cardiac events 
over 2 years, and who therefore would be predicted to derive minimal or no value from 
noninvasive testing33, 34. Testing whether this risk tool can be employed prospectively to safely 
and effectively risk stratify low risk patients into a strategy of guideline-recommended care with 
symptom and risk factor management and without diagnostic testing is one of the core secondary 
objectives of the PRECISE research program. 
  
 
III.B. Rationale for the Current Study: A Precision Approach to Chest Pain Evaluation 
 
 
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Despite the high-burden of stable chest pain in the U.S., and the enormous research literature 
reporting on the comparative effectiveness of different options, no single diagnostic strategy has 
emerged with a broad consensus of support. Each testing community continues to favor its own 
technology and the clinicians who must select the testing approach to use for their patients are 
caught in the middle, unable to resolve the controversies that have characterized this area of 
cardiovascular medicine for decades. The situation is complicated by the heterogeneity of the 
current population’s burden of disease. More than a quarter (27%) of the PROMISE cohort had 
no coronary plaque whatsoever, while high-risk CAD, defined as left main stenosis (≥50% 
stenosis) or either (a) ≥50% stenosis ‘[50]’ or (b) ≥70% stenosis ‘[70]’ of 3 vessels or 2-vessel 
CAD involving the proximal left anterior descending artery was identified in 6.6% [50] and 2.4% 
[70] of patients. Thus, the first goal of any optimal management strategy for stable symptoms in 
patients with suspected CAD is determination of an individual patient’s risk. Using the PROMISE 
Risk Tool to accurately assess patient risk33, 34, we will prospectively test the hypothesis that low 
risk patients can be correctly identified with only baseline clinical data and that emphasizing 
guideline-recommended care while deferring testing in these patients improves chest pain 
decision making by reducing unnecessary invasive angiography without leading to an increase in 
MACE, and by reducing cost.  
 
Among patients in whom contemporary risk evaluation suggests an elevated risk for obstructive 
CAD, the observational data suggest that cCTA with selective FFRCT may improve appropriate 
triage to invasive angiography5, 23, while reducing cost9.  
 
Thus, the case for an adequately powered randomized clinical trial with a pragmatic design, 
comparing clinical outcomes following testing strategies regularly used in current clinical practice 
to a precision evaluation strategy is compelling. PRECISE is designed to be that trial  
 
If the findings of PRECISE are positive as hypothesized, it is expected that the trial will lead to 
updates in appropriate use criteria, clinical practice guidelines, and payer policies such that cCTA 
with selective FFRCT receives a class IA recommendation for stable chest pain patients to improve 
outcomes and reduce costs. PRECISE will identify those chest pain patients for whom non-
invasive testing may be safely deferred and simultaneously improve the efficiency of testing for 
elevated risk patients. The results of this study will shift the paradigm of clinical thinking in this 
area from the current approach of identifying a single best test for all, to incorporating a patient-
centric risk-based evaluation and management strategy for stable chest pain patients. 
 
IV. STUDY OVERVIEW AND OBJECTIVES  
 
IV.A. Overview of PRECISE  
 
PRECISE is a multicenter, randomized, trial that will enroll approximately 2100 participants in a 
comparison of a risk-based precision evaluation strategy of guideline-recommended medical 
management without planned testing (in minimal risk participants) and cCTA with selective FFRCT 
(in elevated risk participants) with usual care in stable symptomatic patients with suspected CAD.  
 
Location 
Participants will be enrolled at approximately 100 outpatient sites in the US and outside of the 
US.  No center may enroll more than 315 (15%) participants in the trial. 
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Participant Population and Selection 
Participants will be symptomatic patients with suspected CAD and a stable clinical course who 
are recommended by their managing clinician to have a non-invasive diagnostic test or ICA. 
Subjects will be excluded if they have any history of documented CAD (including 
revascularization, myocardial infarction or any degree of CAD proven by imaging) or have had 
diagnostic cardiovascular testing for suspected CAD within the last year. Subjects will also be 
excluded if their symptoms are not clearly stable or if their managing clinician feels testing is 
needed on an urgent or emergent basis. 
 
Diagnostic testing for the assessment of CAD symptoms is ordered by physicians and other 
clinicians from many specialties and is performed in multiple settings, including physician offices, 
hospital outpatient departments, and diagnostic testing facilities. A trial, such as PRECISE, that 
seeks to improve the management of non-acute chest pain must incorporate this diversity in order 
to be broadly relevant to the target population under study. PRECISE site selection will seek to 
encompass this diversity.  
 
Study duration 
The anticipated total duration of the PRECISE study will be approximately 48 months for start-up, 
enrollment, follow up, and close out. Participants will be followed for 24 months after enrollment.   
 
Study design 
The figure below represents a diagrammatic representation of the trial design. 
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Non-acute CP patients; No history of CAD or recent testing <1 year
Recommended for non-emergent NI test or ICA: N= 2100
Specify usual care
preferred 1st test
Data entered for
PROMISE risk calculator
R
Usual care evaluation
Strategy selected by
site clinician
Precision evaluation
Strategy assigned
by PROMISE risk strata
Composite Primary Endpoint: Effective CP Evaluation at 12 months
MACE (death/MI), Cath w/o obs CAD (stenosisш50%, FFRч0.80, NHPR<0.90)
Secondary Endpoints
Hierarchical analysis of primary endpoint; Resource use; QOL; Death/MI/CV hospitalizations;
Preventive med use; Primary at 24 mo; Radiation; Co-Primary endpoints of DECISION; Cath efficiency
Guideline rec medical
management w/o
planned testing
Functional testing OR
Direct to cath
cCTA +/- FFRCT
IV.B. Primary Objective and Endpoints
The primary objective of the PRECISE study is to assess clinical outcomes, patient-reported 
outcomes, decision making regarding noninvasive testing and invasive angiography, and costs 
using a precision evaluation strategy as compared to a usual care strategy in participants with 
stable symptoms suggestive of coronary artery disease. The precision evaluation strategy will be 
based on a pre-test risk assessment and will incorporate cCTA with selective FFRCT and 
guideline-recommended care with symptom and risk factor management and no immediately 
planned testing. We hypothesize that in stable patients with a clinical recommendation for testing 
to evaluate suspected CAD the proposed precision evaluation strategy will improve outcomes 
and reduce costs compared to usual care evaluation. 
The primary endpoint is a composite of: MACE (all cause death and non-fatal MI) or invasive 
cardiac catheterization without CAD (no coronary stenosis ≥50%, or with FFR≤0.80, or non-
hyperemic pressure ratio (NHPR) <0.90). The primary study hypothesis will be tested at one year
using an intention to treat analysis.
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IV.C. Secondary Endpoints 
 
Endpoints will be assessed at 45 days, 6 months, 1 year, and 2 years. Secondary endpoints 
include: 
1. Hierarchical analysis (Finkelstein and Schoenfeld (FS) or Pocock’s win ratio) of primary 
endpoint (gives priority to clinical importance of the components of the composite outcome 
rather than time to event) 
2. Resource use patterns (all participants) and medical costs (US participants): resources to be 
assessed include index testing, follow up testing, diagnostic and other cardiac procedures 
and hospitalizations. Primary comparisons will be made at 12 months.  
3. QoL: the Seattle Angina Questionnaire (SAQ)  will be used to assess angina-specific Quality 
of Life; the EuroQoL 5D (EQ-5D-5L) survey will be used for a brief assessment of overall 
(generic) health status; patient satisfaction with diagnostic process will be assessed once at 
45 days using a 4-item instrument created for this trial.  
4. Death: All-cause, cardiovascular, non-cardiovascular 
5. Myocardial infarction: All, procedural, spontaneous MI 
6. Hospitalizations: All, cardiovascular, non-cardiovascular, and for progressive or unstable 
angina  
7. Rates of preventive medication use (ASA, statins) in participants with clinical indication for 
use: hyperlipidemia, diabetes, documented CAD 
8. Cumulative radiation exposure at 1 year  
9. PRECISE primary endpoint at 24 months 
10. MACE, defined as all-cause death myocardial infarction, or ischemia-driven 
revascularization at 24 months (DECISION co-primary end point) 
11. All-cause death, MI, all follow-up unplanned revascularization procedures, cardiac 
catheterizations without actionable findings at 24 months (DECISION co-primary end point) 
12. Proportion of invasive cardiac catheterization patients who undergo revascularization (PCI 
or CABG) within 6 months of enrollment (catheterization efficiency) 
 
IV.D. Rationale for the Selection of Outcome Measures 
 
Rationale for Clinical Assessments 
Major adverse cardiovascular events (MACE) are a primary concern for clinicians and patients 
presenting with stable chest pain. The primary composite endpoint of MACE at 12 months (all 
cause death, non-fatal MI), invasive cardiac catheterization without obstructive CAD (diameter 
stenosis ≥50%, FFR≤0.80 or NHPR<0.90)) is clinically relevant and, the components taken 
together, represent a sound measure of an effective diagnostic chest pain evaluation4, 5, 35, 36. The 
selection of 12 months is based on the rationale that the longer the duration between the 
evaluation strategy and an eventual outcome, the less likely it is that the evaluation strategy is 
directly related to the outcome of interest. In PROMISE, there was a significant reduction in death 
and MI in the cCTA arm compared to the usual care arm at 12 months, which was no longer 
significant after a median 25 months of follow-up5. The use of this composite clinical endpoint will 
be critical to assessing the PRECISE hypothesis that a precision evaluation strategy with cCTA 
and selective FFRCT and guideline-recommended medical management without planned testing 
will yield superior outcomes at lower cost compared with a usual care testing strategy. 
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Rationale for Economic and Quality of Life (QoL) Assessments in PRECISE 
Non-invasive diagnostic testing for the evaluation of stable chest pain represents a significant 
cost to the U.S. and other healthcare systems. In the past when payers in the US have attempted 
to control costs by reducing the reimbursements provided for diagnostic testing, clinicians 
responded by increasing the number of tests obtained. An emphasis on generating evidence for 
cost-savings via a safer and more efficient approach is critical in enhancing value while reducing 
the financial burden on patients, providers, and the system alike. In addition, this precision-based 
approach to diagnostic evaluations in CAD participants may result in improvements in the quality 
of care of our participants. Further, since there has been no prospective trial of guideline-
recommended care without planned testing, the ability of such an approach to provide equivalent 
symptom relief compared with usual care is of great importance and critical to the evaluation of 
this approach. For these reasons, the potential impact of a precision-based approach on resource 
use and QoL must be evaluated in PRECISE.  
 
IV.E. Rationale for Selection of Testing in Each Arm 
 
Usual Care Arm 
Functional stress testing with stress nuclear, stress echocardiography, and exercise ECG for the 
diagnosis of CAD is well-established in clinical practice (ACC/AHA 2012 Stable Ischemic Heart 
Disease guidelines, class I, Level of Evidence (LOE) B)37.  While stress CMR is less commonly 
used, it also receives a class IIa, LOE B recommendation in patients who are unable to exercise37 
and is used in some centers. In contrast, it is common for patients to be referred direct to 
diagnostic angiography without undergoing a functional test. This group represents up to 50% of 
elective catheterization populations and is thus an important usual care approach to suspected 
CAD35, 38, 39.   In order to accurately capture the wide variety of testing strategies available to and 
used by community clinicians and real-world practice patterns, a usual care strategy arm with site 
clinician decision-making should include all of the above options. This will improve the 
generalizability of the trial while accurately capturing the potential impact of the implementation 
of a precision approach. Use of cCTA as the initial diagnostic strategy is specifically excluded in 
the usual care strategy arm. 
 
Precision Evaluation Arm 
PRECISE will evaluate whether a precision evaluation strategy that combines contemporary risk 
stratification using the PROMISE Risk Tool with functional and anatomic non-invasive evaluation 
with cCTA with selective FFRCT can improve outcomes over usual care in stable chest pain 
patients while safely deferring further testing in low-risk patients and reducing cost overall. While 
current guidelines recommend the non-invasive and invasive initial testing approaches for 
patients with stable chest pain37, current practice is known to lead to high rates of ICA without 
obstructive CAD6, 40.  Further, although guidelines also recommend no testing in the lowest risk 
groups (pre-test probability of obstructive CAD <10 or 15%), currently available risk tools result in 
many clinicians appearing to ignore this recommendation: current patterns of care using available 
risk stratification tools results in testing populations with a prevalence of obstructive CAD of only 
10-20%, and a prevalence of no coronary plaque of >25%4, 5. The intervention in PRECISE will 
triage patients into two risk groups who will be assigned to receive either guideline-recommended 
medical management without planned testing or cCTA with selective FFRCT. The PROMISE Risk 
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Tool can identify low-risk patients with stable chest pain that would be expected to derive minimal 
value from noninvasive testing and is superior to either Framingham Risk Score or Diamond and 
Forrester assessments33, 34. cCTA with selective FFRCT represents a combined functional and 
anatomic testing modality that can lower the frequency of finding no obstructive CAD at 
catheterization and thus reduce costs7, 41.  
 
IV.F. Randomization Method 
 
Participants who meet all inclusion criteria and none of the exclusion criteria will be randomized 
in a ratio of 1:1 within a clinical center to either a precision evaluation strategy or usual care 
using an interactive web or voice-based system (IXRS). Randomization will be stratified by 
intended first test if randomized to usual care and by classification as minimal vs. elevated risk 
by the minimal risk model. The randomization scheme within a clinical center will be carried out 
by the method of random permuted block design with variable block size.  
Enrollment in the randomization strata of intended first test being noninvasive (vs. direct to 
catheterization) will be capped at 90% of the sample size. 
Risk will be classified by a risk tool using pre-test clinical characteristics derived in the PROMISE 
trial and validated in SCOT-HEART. Participants randomized to follow a precision strategy group 
will be assigned to either guideline-recommended care with symptom and risk factor management 
and no immediately planned testing (low risk group) or cCTA with selective FFRCT (elevated risk 
of obstructive coronary disease and/or events). Participants randomized to precision evaluation 
and risk stratified into the low risk group and their providers will be provided informational 
materials explaining the rationale for this decision and the safety of this strategy based on 
outcomes of similar participants in the PROMISE trial. 
Participants randomized to usual care will undergo either noninvasive stress testing or invasive 
testing (direct to diagnostic catheterization), as recommended by their managing clinician and 
agreed to by the participant. Acceptable noninvasive testing options will include exercise 
electrocardiogram, stress nuclear imaging (including PET), stress MR or stress echocardiogram. 
The use of cCTA is explicitly excluded as the initial diagnostic strategy in this arm. 
In both arms, all subsequent decisions regarding additional testing, medications, and/or 
procedures will be at the discretion of the responsible clinical care team. Each care team will be 
provided with informational materials summarizing current standards for test interpretation and 
preventive care.  However, specific medical treatment will not be mandated by the study. 
 
IV.G. Diagnostic Evaluations and Subsequent Care 
 
Description of Evaluations to be performed 
Participants will be assessed per the individual clinicians’ routine approach to patients presenting 
with stable chest pain. Initial evaluation will include an appropriate medical history, physical 
examination, resting 12-lead ECG, and other routine blood work. A pregnancy test will be required 
for female participants of childbearing potential, and a creatinine blood test will be required for 
participants without a recent normal value (within previous 90 days).  
 
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At the time of randomization, the site clinician will specify the preferred first diagnostic strategy 
(noninvasive stress test vs. direct to catheterization) if randomized to the usual care arm and this 
choice will be used to stratify randomization. Also part of the randomization process, every 
participant will undergo risk stratification with the PROMISE risk calculator although sites will be 
blinded to results. Participants randomized to the precision evaluation arm, will be assigned to 
either no planned testing vs cCTA/FFRCT based on results.  
 
Sites will be provided with informational materials outlining standards of care for all noninvasive 
test interpretation and guideline recommendations for care and symptom and risk factor 
management. Participant-friendly versions of these material will also be provided to sites, and 
may be used as handouts.  
 
Symptoms and Quality of Life (QoL) will be assessed by the EuroQoL 5D (EQ-5D-5L) survey to 
assess overall (generic) health status and the Seattle Angina Questionnaire (SAQ) to assess 
angina-specific Quality of Life. 
 
Equipment, Protocols & Interpretation  
All participating sites will use standard equipment and procedures for usual care testing, including 
diagnostic angiography, stress echocardiography, stress nuclear perfusion imaging, stress CMR, 
and exercise ECG as defined by current practice guidelines42-49. Sites must also use at least 64-
slice temulti-detector computed tomography (MDCT) for coronary cCTA49, 50. All testing protocols 
will be in accordance with current best-practice standards42-48, 50.  
 
Interpretation 
The interpretation of all diagnostic tests will be performed in a timely fashion and will capture the 
presence and extent of findings including diagnosing or excluding CAD (diagnostic angiography), 
fixed or inducible LV perfusion and wall motion abnormalities (stress echo, cMR and stress 
nuclear), and functional capacity (in the case of exercise ECG, exercise echo and exercise 
nuclear). The site interpretation and clinical report of all diagnostic tests, including noninvasive 
stress testing, cCTA and invasive angiography, will be uploaded through the EDC. 
 
cCTA study interpretation will be carried out by physicians with at least ACC COCATS (Core 
Cardiology Training Symposium) level 2 training, Society of Cardiovascular Computed 
Tomography level 2, recognized by the Certification Board of Computed Cardiovascular 
Tomography,  or equivalent50. Certification by the Certification Board of Nuclear Cardiology or 
Board Certification in nuclear medicine or radiology will be considered satisfactory for 
interpretation of stress nuclear imaging studies. Stress echo and cMR readers also be at least 
COCATS level 2 trained or equivalent. Prior to being opened to participant enrollment, sites will 
be certified to ensure that quality cCTA images can be obtained. 
 
Referral of precision evaluation cCTA participants for FFRCT determinations 
Participants randomized to the precision evaluation arm who are determined to be at elevated 
risk will undergo cCTA as the initial diagnostic strategy according to current best practice 
standards. Image sets showing at least one 30-90% stenosis in epicardial vessels of 2mm 
diameter or greater will be promptly sent to HeartFlow for analysis of FFRCT. Results will be 
returned to sites in < 24 hours to enable rapid incorporation into clinical decision making, 
 
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Subsequent Care 
Subsequent care will be provided by the individual site clinicians at their own discretion, with 
encouragement to follow guideline-based approaches. Information will be provided to the 
individual sites on diagnostic test interpretation and subsequent management approaches for the 
various imaging modalities, including relevant guideline recommendations for primary and 
secondary prevention.  
 
Need for testing in low risk participants randomized to the precision care arm 
Participants randomized to the precision evaluation arm and determined to be at low risk will be 
treated for symptoms and risk factor management according to current guideline 
recommendations. While it is expected that this will resolve symptoms in nearly all cases it is 
recognized that chest pain will persist in some despite medical treatment. In some cases, 
additional non-cardiac diagnostic testing may be pursued. In other cases, the site clinician may 
decide that further cardiac testing is warranted, in which case a cCTA followed by selective FFRCT 
should be performed. Details regarding such decision making will be captured in the case report 
form.     
 
V. STUDY PROCEDURES  
V.A. Patient Screening for Eligibility 
 
Patients will be screened by site personnel for eligibility and provided information about the study. 
Patients not meeting inclusion and or having exclusion criteria will be documented as being 
excluded. Patients meeting inclusion and not meeting any exclusion criteria will be provided an 
informed consent form to review and sign prior to being randomized into the study. 
 
Screening visit (in-person) 
At the screening visit, patients will undergo the following: 
x 
Review consent form and have all questions appropriately answered. 
x 
Provide consent by signing the Informed Consent Form 
x 
Review of medical history 
x 
Review of concomitant medications 
x 
Pregnancy test (for females of child-bearing potential) 
x 
Creatinine test (if not done in last 90 days) 
x 
Resting 12-lead ECG (optional, clinical care only) 
 
Inclusion Criteria 
1. Age ≥18 years 
2. Stable typical or atypical symptoms suggesting possible coronary artery disease (CAD) 
with further non-emergent testing or elective catheterization recommended to evaluate the 
presence of suspected CAD  
3. Safe performance of cCTA: 
a. Creatinine clearance ≥45 ml/min  
b. For a female participant of childbearing potential, a pregnancy test must be 
performed with negative results known within 7 days prior to randomization 
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4. Willingness to comply with all aspects of the protocol, including adherence to the assigned 
strategy and follow-up visits  
5. Ability to provide written informed consent 
 
Exclusion Criteria 
1. Acute chest pain 
2. Unstable clinical status   
3. Noninvasive CV testing within 1 year (for suspected CAD) 
4. History of known obstructive CAD (prior myocardial infarction, CABG or PCI, stenosis 
≥50%), known EF≤40% or other moderate to severe valvular or congenital disease 
5. Contraindications to cCTA including but not limited to estimated creatinine clearance 
(GFR) <45 ml/min 
6. Any condition leading to possible inability to comply with the protocol 
7. Exceeds the weight or size limit for cCTA or cardiac catheterization at the site 
8. Life expectancy less than 2 years due to non-cardiovascular comorbidities 
9. Enrolled in an investigational trial that involves a non-approved cardiac drug or device 
which has not reached its primary endpoint 
10. Any condition that might interfere with the study procedures or follow-up 
 
Assessment of CAD risk will be performed during screening to ensure eligibility. It will include:  
x 
General medical history   
x 
Cardiovascular risk factors and comorbidities as well as prior testing or events 
x 
Physical exam  
x 
Laboratory testing  
The following major cardiac risk factors will be assessed: 
x 
Age 
x 
Sex 
x 
BP/hypertension 
x 
Diabetes  
x 
Cholesterol (including low-density lipoprotein [LDL], high-density lipoprotein [HDL]), if 
available 
x 
Smoking status 
x 
Family history  
x 
Sedentary life style  
x 
Obesity (BMI, waist hip ratio) 
x 
Cerebrovascular and peripheral arterial disease (PAD)  
x 
Ankle brachial index (ABI) 
 
V.B. Randomization and Enrollment 
 
Once a participant has consented to participate in the trial, participant information will be entered 
into the database.  If a patient is a screen failure, the data that has been collected up until this 
point for the patient for screening purposes will be entered into the case report forms (CRF) in the 
electronic data capture (EDC) system.  No additional information will be collected after this point 
for such a patient.  
 
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For eligible participants, medical history data will be captured in the EDC. In addition, sites will 
need to specify the intended first test which would be performed if the participant is randomized 
to the usual care arm.  The participant will then be randomized to either the usual care arm or the 
precision evaluation arm.  Once randomization occurs, the participant is considered enrolled in 
the study. If randomized to the precision evaluation arm, participants will be further assigned to 
guideline-recommended without planned testing or cCTA with selective FFRCT. 
 
V.C. Participant Cohort Assignment 
 
Participant will be randomized to either the usual care arm or the precision evaluation arm within 
14 days of screening. 
 
Usual Care Arm 
Participants randomized to the usual care arm will undergo either noninvasive stress testing 
(exercise electrocardiogram, stress nuclear imaging including PET, stress MR, or stress 
echocardiogram), with the specific modality at the discretion of the participant’s clinician, or 
invasive catheterization. Performance of cCTA as the initial test is excluded in this arm. 
 
Precision Evaluation Arm 
Participants randomized to the precision evaluation arm will be assigned a management approach 
based on their PROMISE Risk Score, a risk model based on pre-test clinical characteristics 
derived from the PROMISE trial and validated in SCOT-HEART34. Participants will be assigned 
to either guideline-recommended medical management without planned testing (low risk) or cCTA 
with selective FFRCT (elevated risk). Participants assigned to the strategy of guideline-
recommended medical management without planned testing will be treated with risk-appropriate 
preventive care and symptom control (including therapeutic trials of anti-anginal medications). 
Participants and their providers will be provided informational materials demonstrating the safety 
of this strategy based on pre-test probabilities and the PROMISE Risk Score. Participants with 
intractable symptoms despite maximal medical management whose clinicians opt for further 
testing (crossovers) will undergo cCTA with selective FFRCT. 
 
Participants undergoing cCTA as the initial test (both assigned or crossover) should have FFRCT 
analysis ordered if cCTA shows at least one 30-90% stenosis in epicardial vessels of 2mm 
diameter or greater. Image sets will be sent promptly to HeartFlow for analysis and results will 
be returned to sites in < 24 hours to enable rapid incorporation into clinical decision making. 
 
V.D. Participant Follow-Up 
 
Participants will be followed up at 45 (+/-14) days and at 6, 12, and 24 months (+/- 30 days) after 
enrollment. For North American participants, follow-up after the 45 day visit will be done by phone 
interviews conducted by the DCRI Outcomes Call Center. For participants outside North America, 
follow-up will be conducted by the site coordinators.  
 
Activities to be conducted at each follow up contact are described below and in the Schedule of 
Events. 
 
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45(+/-14) day follow-up visit (in-person) 
At the 45-day follow-up visit, participants will be asked the following: 
x 
Assessment if any MACE has occurred since enrollment 
x 
CV Update: Review and documentation of any cardiovascular diagnostic test, 
cardiovascular procedure, or hospitalizations/clinic visits due to cardiovascular 
symptoms and complications since enrollment 
x 
Review and documentation of concomitant medication changes since enrollment 
x 
Complete the following 3 questionnaires: 
o Seattle Angina Questionnaire 
o EQ-5D-5L Questionnaire 
o Participant Satisfaction Questionnaire 
x 
Collection of  
o Any cardiovascular test – both written report and test output 
o Any cardiovascular imaging – both written report and image file 
 
6 months (+/-30 days) follow-up contact 
At the 6-month follow-up contact, participants will be asked the following: 
x 
Assessment if any MACE has occurred since the 45-day visit 
x 
CV Update: Review and documentation of any cardiovascular diagnostic test, 
cardiovascular procedure, or hospitalizations/clinic visits due to cardiovascular symptoms 
and complications since last visit 
x 
Review and documentation of concomitant medication changes since enrollment 
x 
Complete the following 2 questionnaires: 
o Seattle Angina Questionnaire 
o EQ-5D-5L Questionnaire 
x 
Collection of (may also be done centrally) 
o Any cardiovascular test – both written report and test output 
o Any cardiovascular imaging – both written report and image file 
 
12 months (+/-30 days) follow-up contact 
At the 12-month follow-up visit, participants will be asked the following:  
x 
Assessment if any MACE has occurred since the 6-month visit/phone call 
x 
CV Update: Review and documentation of any cardiovascular diagnostic test, 
cardiovascular procedure, or hospitalizations/clinic visits due to cardiovascular symptoms 
and complications since last visit 
x 
Review and documentation of concomitant medication changes since enrollment 
x 
Complete the following 2 questionnaires: 
o Seattle Angina Questionnaire 
o EQ-5D-5L Questionnaire 
x 
Collection of (may also be done centrally) 
o Any cardiovascular test – both written report and test output 
o Any cardiovascular imaging – both written report and image file 
 
24 months (+/-30 days) follow-up contact 
At the 24-month follow-up visit, participants will be asked to report the following: 
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x 
Assessment if any MACE has occurred since the last visit/phone call 
x 
CV Update: Review and documentation of any cardiovascular diagnostic test, 
cardiovascular procedure, or hospitalizations/clinic visits due to cardiovascular symptoms 
and complications since  last visit 
x 
Review and documentation of concomitant medication changes since enrollment 
x 
Complete the following 2 questionnaires: 
o Seattle Angina Questionnaire 
o EQ-5D-5L Questionnaire 
 
V.E. Cross-over in precision evaluation arm participants 
 
While precision evaluation participants determined to be at very low risk and assigned to the 
strategy of guideline-recommended medical management with no immediately planned testing 
are highly unlikely (by definition) to have significant obstructive CAD, their managing clinicians 
will be encouraged to treat them with guideline recommended preventive care and other medical 
therapy as deemed appropriate to their clinical circumstances. This is expected to control or 
eliminate symptoms in most participants. However, additional testing may be warranted for those 
with intractable or accelerating symptoms despite reasonable medical treatment or other 
compelling reasons for testing. The reasons for this will be carefully documented in the eCRF. 
Unless there are urgent or emergent indications to proceed with invasive testing, all such 
participants who require testing will have a cCTA followed by selective FFRCT rather than either 
stress testing or elective invasive catheterization.  
 
V.F. Participant Withdrawal 
 
In accordance with the Declaration of Helsinki, each participant is free to withdraw from the study 
at any time. Investigator(s) also have the right to withdraw participants from the study in the event 
of illness or other reasons concerning the health or wellbeing of the participant, or in the case of 
lack of cooperation. Should a participant decide to withdraw or should the investigator(s) decide 
to withdraw the participant, all efforts will be made to complete and report the observations up to 
the time of withdrawal as thoroughly as possible. If possible, a complete final evaluation at the 
time of the participant’s withdrawal should be made.  The reason for withdrawal must be noted in 
the eCRFs. 
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V.G. Schedule of Assessments 
 
Screening 
Randomization 
Day 1 
Day 45 
(
 +/-14 d) 
6-mo. 
 (+/- 30d) 
12-mo. 
(+/- 30d) 
24-mo. 
 (+/- 30d) 
Informed consent 
X 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
Cardiovascular update 1 
 
 
X 
X 
X 
X 
Concomitant medications 
X 
 
X 
X 
X 
X 
Cardiovascular Risk factors (including PROMISE risk 
tool data entry for randomization) 
X 
 
 
 
 
 
Pregnancy test
2 
X 
 
 
 
 
 
Creatinine
3 
X 
 
 
 
 
 
Resting 12-lead ECG
4 
X 
 
 
 
 
 
QoL evaluation: SAQ, EQ5D-5L 
X 
 
X 
X 
X 
 
Participant Satisfaction Questionnaire 
 
 
X 
 
 
 
Randomization 
 
X 
 
 
 
 
Initial diagnostic invasive or noninvasive test 
performed (if assigned)  
 
Prior to 45 day 
visit 
 
 
 
 
 
Cardiac imaging/testing clinical report  and image 
collection 
 
 
X 
X 
X 
 
Interval assessment for CV events and testing 
 
 
X 
X 
X 
X 
Endpoint assessments 
 
 
X 
X 
X 
X 
1. 
During cardiovascular update, if participants have received an additional diagnostic test, a cardiovascular procedure or have been hospitalized since the 
last visit, additional data will be collected  
2. 
For a female participant of childbearing potential, a pregnancy test must be performed with negative results known within 7 days prior to randomization 
3. 
Creatinine blood draw required only for participants without a recent normal value (within previous 90 days) 
4. 
Resting 12-lead ECG preferred in last 30 days (optional, clinical care only) 
5. 
Use of specific medications such as beta blockers, ACE inhibitors/ARBs, statins, aspirin, and antiplatelet agent
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VI.ADDITIONAL ASSESSMENTS AND SUBSTUDIES 
 
VI.A. Quality of Life Assessments 
 
A short battery of instruments will be used to provide a relevant assessment of health-related 
quality of life that will capture the most likely health benefits to be associated with the precision 
strategy while not being burdensome to study participants. Quality of life (QoL) assessments will 
be conducted at baseline, 45 days, 6 months, and 12 months. Chest pain specific QOL will be 
assessed with the Seattle Angina Questionnaire (SAQ). While the full instrument has 19 items 
covering 5 dimensions of the impact of chest pain on QoL, we will use the scales for physical 
limitations, angina frequency, and disease perception/quality of life (14 items total) 1. These three 
scales will also allow calculation of the recently described 7-item short SAQ2. The SAQ has been 
used as the primary disease-specific QoL outcome measure in a number of major clinical trials 
(including COURAGE, PROMISE, and ISCHEMIA) and is useful for this trial because it assesses 
chest pain and its impact on functioning and well-being regardless of whether the symptoms are 
due to coronary disease or are non-coronary. Since many participants in this study will be found 
not to have significant coronary disease and will be provided with that reassuring finding, the SAQ 
will allow us to assess the extent to which such information is associated with changes in the 3 
dimensions noted above.  
Overall health status will be assessed briefly using the EQ-5D-5L, a standardized generic 
measure that can also be used to link specific health states to general population-based utilities5. 
The EQ-5D-5L consists of two parts: (1) a descriptive assessment of five dimensions (mobility, 
self-care, usual activities, pain/discomfort, anxiety/depression), each of which can take one of five 
responses corresponding to the level of severity within each dimension, and (2) a self-rating 0-
100 "thermometer" of current health-related quality of life.  
 
VI.B. Economic and Resource Utilization Assessments  
 
The primary economic analyses in PRECISE will be performed from the perspective of the US 
health care system. Detailed information regarding the quantity and cost of health care services 
received by participants in each treatment group will be collected prospectively as part of the trial. 
Relevant health care resource consumption during initial testing through 2-year follow-up will be 
collected on the clinical trial electronic case report form (eCRF). (The cost of acute and non-acute 
hospital care will be derived from billing data collected from patients enrolled at US sites.) 
Physician and other outpatient care reported in the eCRF will be valued using secondary sources. 
Primary resource use and cost comparisons will be based on participants enrolled in the US. 
Secondary analyses will examine the consistency of treatment related differences in resource use 
in the US with the sites outside the US. 
 
VI.C. Imaging and other Cardiac Assessments  
 
For all participants in either arm in whom an invasive coronary angiogram is performed within the 
first 12 months, procedural reports and angiographic images will be uploaded via the electronic 
data capture (EDC) system to create an angiographic image repository. In addition the report, as 
well as imaging and / or graphic data from any procedures performed to assess stenosis 
significance or severity such as, FFR, NHPR, IVUS, OCT should be uploaded. Similarly, for all 
participants receiving cCTA imaging within the first 12 months, the cCTA images and reports will 
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be uploaded via the EDC system to create an image repository.  A core lab may be added to 
analyze these images. Data collection for these elements will be coordinated by the DCRI 
Outcomes Group for North American patients followed by the call center and by site coordinators 
for all other sites.  
 
VII. ENDPOINT DETERMINATION, SAFETY, AND MONITORING 
 
VII.A. Primary Endpoint Definitions   
 
Major Adverse Cardiovascular Events (all cause death, non-fatal myocardial infarction) 
All cause death 
All cause death is defined as death resulting from any cause. In addition, the cause of death 
will be adjudicated, including cardiovascular death defined as death due to myocardial 
infarction, sudden cardiac death, heart failure, stroke, cardiovascular procedures, 
cardiovascular hemorrhage, or death due to other cardiovascular causes 51.  
  
Myocardial infarction   
Acute myocardial infarction (MI) is defined as having evidence of myocardial necrosis in a 
clinical setting consistent with myocardial ischemia51. Specifically, MI is defined as having: 
 1) Typical rise and/or gradual fall in cardiac biomarker level (cardiac troponin preferred) 
with values exceeding the 99th percentile of the institutional upper limit of normal (ULN) 
(generally 2x the ULN) 
 AND either:  
2) Clinical presentation defined as typical cardiac ischemic type pain/discomfort or 
dyspnea felt to be due to ischemia and consistent with the diagnosis of myocardial 
ischemia and infarction  
Or  
3) ECG manifestations of acute myocardial ischemia (in absence of left ventricular 
hypertrophy and left bundle branch block) including evolving ST elevation, ST depression, 
T-wave changes, new pathological Q-waves (R waves in V1-2) in at least two consecutive 
leads or new left bundle branch block.  
A complete definition of the criteria for MI can be found in the 2017 Cardiovascular and 
Stroke Endpoint Definitions for Clinical Trials51. Peri-procedural infarctions are defined as 
greater than 3x ULN for serum CK-MB for PCI and greater than 5x ULN for CABG.   
Cardiac catheterization without obstructive coronary artery disease (diameter stenosis <50%, 
any FFR >0.80 or NHPR ≥0.90) 
Cardiac catheterization without obstructive coronary artery disease will be defined as the 
absence of any >50% stenosis or hemodynamic indication of significance in any major 
epicardial vessel including side branches ≥2 mm in diameter, as determined by the clinical 
site interpretation.  
 
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VII.B. Secondary Endpoint Definitions  
 
Hierarchical analysis  
Finkelstein and Schoenfeld (FS) or Pocock’s win ratio analysis of primary endpoint is 
defined in section VII B Statistical Analysis Plan. 
 
Resource use 
Resource use is defined as counts and types of baseline testing, follow up testing, 
diagnostic and therapeutic procedures, and both inpatient and outpatient care at 12 months.  
Costs from the US perspective will be estimated.  
 
Quality of Life Metrics 
 
Quality of Life assessments to be completed by the participants are the Seattle Angina 
Questionnaire and the EQ-5D-5L.  
 
Death  
  
Death will be categorized as all-cause, cardiovascular, non-cardiovascular. 
 
Myocardial infarction 
Myocardial infarction will be characterized according to Universal MI definition subtypes as 
Type 1, 2, 3, 4a, 4b, 4c and 5. 
 
Hospitalizations  
All, cardiovascular, non-cardiovascular, and for progressive or unstable angina. Urgent and 
unscheduled hospitalizations for other cardiovascular causes that do not meet the criteria for the 
specific events listed above will be classified as hospitalization for other cardiovascular causes 
(e.g., hospitalization for cardiac chest pain that does not meet the criteria for MI, hospitalization 
for arrhythmias, hospitalization for pulmonary embolism). Non-cardiovascular hospitalization are 
defined as any hospitalization whose primary cause is not thought to be CV in nature. 
 
Preventive medication use  
Information on preventive medication use will be acquired at study entry and 45 days. 
Participants with a clear clinical indication for use of ASA/antiplatelet agents and or, statins eg: 
hyperlipidemia, diabetes, documented CAD, will be characterized according to use/nonuse for 
each medication class. 
 
DECISION co-primary end point  
MACE, defined as all-cause death myocardial infarction, or ischemia-driven 
revascularization at 24 months as defined by the DECISION trial. 
 
DECISION co-primary end point 
All-cause death, MI, all follow-up unplanned revascularization procedures, cardiac 
catheterizations without actionable findings at 24 months as defined by the DECISION trial. 
  
 
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PRECISE primary endpoint at 24 months 
 The PRECISE primary endpoint will be determined at 24 months. 
 
Radiation safety endpoint – cumulative dose at 1 year 
The cumulative radiation exposure over the 12 months following enrollment will be 
calculated based on the participant’s exposure to radiation for cardiovascular care from one or 
more of the following modalities. For cCTA, the administered radiation dose (computed 
tomography dose index volume and dose length product for cCTA) will be recorded by the 
individual sites. For stress nuclear imaging, the radiotracer dose(s) will be collected and 
converted to equivalent radiation doses for comparison to cCTA. For ICA, the radiation dose from 
fluoroscopy administered will be recorded by sites and converted using standardized approaches 
to allow for comparison to radiation from cCTA.  In instances in which the information required to 
assess actual dose is not available, a standard dose based on accepted average exposures will 
be imputed for that form of testing. Cumulative radiation exposure from additional cardiac testing 
and procedures during the entire follow-up period will also be collected.   
 
Catheterization efficiency 
The proportion of invasive cardiac catheterization patients who undergo revascularization 
(PCI or CABG) within 6 months of enrollment will be determined. 
 
VII.C Testing Complications and Reporting 
 
The study intervention is the implementation of a precision evaluation strategy compared to usual 
care evaluation in non-acute chest pain participants with no history of CAD or recent testing 
whose clinicians recommend non-emergent non-invasive testing or ICA. Since all trial 
procedures represent standard of care for the eligible study population, there are no specific 
safety events associated with investigative procedures in this trial. However, there are known 
complications from these clinically recommended tests and procedures which are outlined below. 
These complications will be reported by site personnel.  
 
For Precision Evaluation Strategy 
 
For Guideline-recommended Medical Management 
While participants assigned to the guideline-recommended care with no planned testing arm will 
have exceedingly low risk of events and are predicted to derive minimal or no value from 
noninvasive testing33, 34, there is a very small risk of missing left main or 3-vessel disease for 
which revascularization may be life-prolonging.  
 
For cCTA with selective FFRCT:   
Mild contrast reaction such as rash and hives. 
1. Severe contrast reactions including anaphylaxis or death occurring within 24 hours of 
contrast administration. 
2. Extravasation of contrast into the surrounding tissue of the extremity where contrast 
was administered intravenously.  
3. Symptomatic bradycardia or hypotension in relation to beta blockade or nitrates 
administered for cCTA.  
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4. Acute bronchospasm following beta blockade administered for cCTA.  
 
For Usual Care (noninvasive or invasive testing)  
For exercise testing including during stress echo or stress nuclear (including PET):  
1. Hypotension defined as systolic BP less than 80 mmHg or fall in systolic BP >20 
mmHg  
2. Stress-induced symptoms or ECG changes that do not resolve within 20 minutes  
3. Rapid atrial fibrillation that does not slow or convert with standard interventions 
4. Ventricular tachycardia  
5. Hospital admission not otherwise captured by pre-specified study endpoints, due to 
one of the above 
  
For stress nuclear (including PET):  
1. Any adverse reactions potentially related to the use of vasodilators such as 
adenosine, regadenoson, or dipyridamole   
  
For stress echo:  
1. Any stress-induced wall motion abnormality that does not resolve within 20 minutes 
2. Any adverse reaction to echo contrast 
3. Any adverse reaction to dobutamine, including sustained ventricular tachycardia or 
other tachyarrhythmias  
 
For stress cardiac MRI:  
1. Any adverse reactions potentially related to the use of vasodilators such as 
adenosine, regadenoson, or dipyridamole   
2. Any adverse reaction to MRI contrast agents, including gadolinium-based agents 
 
      For cardiac catheterization: 
1. Any adverse reactions potentially related to the use of sedatives, local anesthetics, 
contrast agent or other medication’s 
2. Any adverse reactions potentially related to arterial puncture and wire/catheter 
introduction 
3. Any adverse reaction to coronary catheterization including dissection, embolization, 
stroke, malignant arrhythmias and asystole, and death 
 
VII.D. Independent Clinical Event Adjudication Committee  
 
An independent clinical event committee (CEC) will be responsible for the blinded review and 
adjudication of the primary endpoint. The CEC will settle any disputes with committee review and 
discussion. Any uncertainty regarding the finding of cardiac catheterization without obstructive 
disease will prompt review of the original cardiac catheterization images for further independent 
adjudication. Collection of medical records and other documentation required for CEC reviews 
will be coordinated by the DCRI call center for North American participants and by site 
coordinators for participants in all other regions. 
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VII.E. Data and Safety Monitoring Board  
 
An independent Data and Safety Monitoring Board (DSMB) will be appointed to monitor 
participant safety and to review study performance. The DSMB will periodically review the study 
data and assess participant safety and adherence to the study protocol. The DSMB will define 
the operating guidelines and processes for study evaluation, interim analyses, event triggers for 
unscheduled review; these will be agreed upon at the initial meeting of the DSMB. Periodic 
reports will be prepared by HeartFlow (or its designee) for the DSMB on based on the operational 
plan outlined by the DSMB charter. The DSMB will make its recommendations to the study 
Steering Committee and the sponsor following their meeting. Details on statistical stopping rules 
guidelines will be provided in the DSMB charter.  
VIII. Statistical Methods 
Separate, complete Statistical Analysis Plan (SAP) documents will be prepared for the clinical 
outcome analyses and the economics and quality of life (EQOL) outcomes. 
 
VIII.A. Sample Size Determination and Statistical Power  
 
Sample size and power calculations for this study are based on the hypothesis that the precision 
evaluation arm is superior to the usual care arm on the time-to-first event of the composite MACE 
endpoint (defined as: all-cause death, non-fatal MI) or invasive cardiac catheterization without 
obstructive CAD (obstructive CAD defined as diameter -stenosis ≥50%, FFR≤0.80 or NHPR 
<0.90). Time to event analysis will use the date of the event, including the date of catheterization 
which is used to determine the absence of obstructive CAD. Assuming 10% of usual care 
participants will receive angiography as a first test results in an 8% primary endpoint event rate 
at 1 year in the usual care group and 5% (absolute) event rate in the precision care group (i.e., 
37.5% relative effect size) with 30% assigned to guideline-recommended care with symptom 
management and no planned testing. Assumptions used in the primary endpoint event rate 
calculations (i.e. 8% vs. 5%) were: an overall 10% will not receive randomized testing and within 
the precision evaluation arm, 30% of those assigned to guideline-recommended care will cross 
over to cCTA with selective FFRCT. 
 
Enrolling 1050 patients per group (2100 total participants) would provide at least 90% power to 
detect a relative risk reduction of 37.5% in the precision evaluation arm. Sample size calculations 
are based on the log-rank test 52 with 12-month accrual period, a minimum 12-month follow-up 
(i.e., last participant will be followed for at least 12-months), 10% attrition rate (i.e., lost to follow-
up, dropouts) and a two-sided type I error rate of 0.05.  
Table shows total number 
of participants needed for 
85%, 90% and 95% power.  
Although, this is not an 
event-driven study, the 
table below also provides 
total number of MACE 
needed.  
1-yr event rate in 
precision 
evaluation arm 
Power 
Total 
number of 
participants 
needed 
Total number 
of MACE 
events 
needed 
 5%   
 
(37.5% effect size) 
85% 
1792 
173 
90% 
2096 
202 
95% 
2592 
250 
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Power curves (Figure: Long-Rank for Two Survival Curves) provide total sample size needed for 
several relative effect size (i.e., 1-hazard ratio) scenarios. 
 
Figure: Long-Rank for Two Survival Curves 
 
VIII.B. Statistical Analysis Plan 
Analysis of the Primary Endpoint 
The primary endpoint of this study is based on time-to-first occurrence of any of the MACE 
components, which is defined as a composite of all-cause death, non-fatal MI or invasive cardiac 
catheterization without obstructive CAD (obstructive CAD defied as diameter stenosis ≥50%, 
FFR≤0.80, or NHPR<0.90). The time from randomization to the first event among the components 
of the MACE endpoint will be measured (in days) for those who experienced an event and 
calculated as the date of the first event minus the date of randomization.  For participants who do 
not experience any of the MACE component events or who withdraw consent or drop out of the 
study before experiencing an event, time from randomization to the date of last contact will be 
used in the analysis, and those participants will be considered as censored observations in the 
time-to-event analysis.    
The primary and secondary endpoint comparisons between the randomized groups in this study 
will be performed according to the principle of "intention-to-treat" (ITT); that is, participants will be 
analyzed according to the treatment arm to which they were randomized, regardless of 
subsequent crossover or post-randomization strategy.   
The log-rank test53 will be the primary analytic tool for statistically assessing outcome differences 
between the two randomized treatment strategies with respect to the primary composite endpoint. 
Cox proportional hazards model54 will be used to estimate the hazard ratio (HR) and 95% 
confidence interval (CI) summarizing the difference in outcome between the two randomized 
arms, using treatment as the only predictor in the model.  Proportionality assumption in the Cox 
model (i.e., constant hazard over time) will be checked and tested. 
 
Cumulative event rates will be calculated according to the method of Kaplan and Meier55 for each 
randomized arm as a function of time from randomization, and the estimated event probabilities 
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will be displayed graphically.  Adjusted HR and its 95% CI will be estimated using Cox proportional 
hazards model by including pre-specified baseline risk factors as covariates in the model.  
 
A sensitivity analysis for the primary composite MACE endpoint will be conducted using the 
method of “win-ratio”56.  The win-ratio method of Pocock et al is an extension of Finkelstein and 
Schoenfeld rank-test method57 which order-rank composite endpoints based on their clinical 
importance. More details on primary, secondary and sensitivity analyses will be provided in the 
complete Statistical Analysis Plan (SAP). 
 
Subgroup analyses 
If there is an overall difference in MACE outcome between treatment strategies, subgroup 
analyses will be performed to assess whether the intervention effect is consistent across all 
participants, or whether it varies according to specific participant characteristics.  In particular, 
these analyses will focus on whether the relative intervention effect compared to usual care differs 
according to the following baseline variables: 
x 
Low risk vs. elevated risk by PROMISE Risk score 
x 
Intended first test: functional vs. invasive 
x 
Sex (male vs. female) 
x 
Age (<65, 65 to 74, and >75 years)  
x 
History of diabetes  
x 
Presentation: primary symptom (chest pain vs. other), SAQ angina score (daily/weekly 
angina at baseline versus less frequent) 
x 
Geographic region (US, Canada, Europe, Other Regions) 
These analyses will utilize the Cox model and will be accomplished by testing for interactions 
between the randomized treatment strategy and the specific baseline variables listed above.  In 
addition to the formal assessment of treatment by covariate interactions, the effect of the 
treatment strategy characterized by a hazard ratio and 95% confidence interval will be calculated 
and displayed using a forest plot for the subgroups of participants defined by the variables listed 
above. These descriptive hazard ratios will be carefully interpreted in conjunction with the formal 
interaction tests.   
The effect of the treatment strategy may also be examined in other subgroups of clinical interest 
in addition to those listed above.   
 
Analysis of the Secondary Endpoints 
The secondary endpoints listed in section III.C. Secondary Endpoints that are measured as time-
to-event will be analyzed using the same statistical methods used for the primary efficacy endpoint 
(Section VI.A. Primary Endpoint Definitions). Specifically, the log-rank test will be the primary 
analytic tool for statistically assessing mortality differences between the two randomized 
treatment strategies. A hazard ratio and 95% confidence interval summarizing the difference in 
outcome between the two randomized arms will be computed using the Cox model.   
Participant deaths will be classified by the Clinical Events Committee (CEC) as to whether the 
mode of death was due to a cardiovascular (CV) cause.  If insufficient source documents are 
obtained to allow CEC adjudication of the cause of death, and the CEC classifies the cause of 
death as “unknown,” then the site-reported cause of death (if available) will be used.  If neither 
the site nor the CEC can provide a classification of the cause of death, the death will not be 
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considered as a cardiovascular death. As supplemental analyses, however, this endpoint will also 
be examined using (a) only the deaths classified by the CEC as cardiovascular, and (b) using 
deaths classified by the CEC as cardiovascular, but also including any deaths in the 
cardiovascular category that are classified as unknown by the CEC.    
Competing risks methodology of Fine and Gray58, where death due to a non-cardiovascular cause 
is considered as a competing risk. This methodology, rather than treating non-cardiovascular 
death as a censoring event, makes incidence use of the cumulative function, and is performed 
within the proportional hazards framework using the marginal failure sub-distribution associated 
with the event of interest (cardiovascular death). Similar analyses will be conducted for time-to-
event endpoints in which death is not part of the endpoint of interest. 
Analysis of Resource Use Endpoints 
For the Economics outcomes, we will compare resource use at 12 months between treatment 
arms by intention-to-treat. All-cause hospitalizations, cardiovascular hospitalizations, ER visits 
not resulting in hospitalization, and major outpatient procedures will be enumerated. In addition, 
we will examine length of stay by intensity of care, numbers of CTAs, noninvasive stress tests 
(stress perfusion imaging, stress echocardiography, exercise electrocardiography, stress 
cardiac magnetic resonance imaging), invasive tests (invasive coronary angiography, invasive 
fractional flow reserve or equivalent, optical coherence tomography, intravascular ultrasound), 
coronary revascularization procedures (coronary artery bypass graft surgery (CABG), 
percutaneous coronary intervention (PCI), number of coronary stents), and cardiac medications 
(beta blockers, aspirin, statins, antiplatelet medications). 
Confidence intervals for differences will be estimated using the bootstrap approach. Differences 
in resource use will be interpreted in the context of the trial clinical results, looking for both 
consistency and plausibility. Descriptive comparisons of intensity of care/resource consumption 
according to clinical variables defining subgroups of interest will be performed. The primary 
economic analyses will focus on the US enrollment and in secondary analyses, resource use 
patterns for all patients enrolled in the trial will be compared by intention-to-treat to develop an 
understanding of the degree to which treatment related differences in the trial are region 
dependent. 
 
Analyses of Medical Costs (US participants) 
To compare medical costs between treatment arms, we must: 1) assign costs to all medical 
resources consumed during the study period; 2) compute mean costs by treatment group 
(defined by the principle of intention-to-treat); and 3) calculate the difference in mean costs 
between treatment arms and generate confidence intervals. 
A) Derivation of Cost Estimates. 
The cost of US hospital-based care will be estimated by applying hospital-specific, revenue 
center level cost-to-charge ratios to empirical billing data collected during the study. This 
approach, which has been used successfully in numerous previous clinical trials including the 
PROMISE trial takes advantage of the objective, detailed account in hospital bills of services 
provided to patients, and recalibrates hospital charges to more closely reflect costs. Based on 
experience in similar studies, we anticipate having complete billing data for 95% of patients 
treated in hospitals that generate bills. For the small percentage of patients without billing data, 
we will impute costs using a generalized linear model developed using study data. In this model, 
the dependent variable will be defined as total cost, and independent variables will include 
resource use elements available in the case report form, such as number of hospitalized nights 
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by intensity of care and number of relevant high cost procedures. Coefficients for model 
parameters will be estimated using study data of patients with complete costs and then used to 
predict costs for patients without billing information. 
The cost of stays at non-acute care facilities will be estimated by multiplying the length of stay 
by the corresponding per-diem/reimbursement rate.  
Costs for physician services will be estimated by mapping major inpatient and outpatient 
procedures and services recorded on the case report form to appropriate CPT codes in the 
Medicare Fee Schedule. We will also assign rounding fees for inpatient stays based on type of 
unit.  
Costs for diagnostic testing procedures done in an outpatient or standalone facility will be 
derived from secondary sources available to the DCRI Outcomes Group at the time of study 
analysis. 
The cost of medications of interest/relevance will be estimated on the basis of medication use 
recorded in the eCRF and unit costs by medication type and class, based on current estimates 
of acquisition cost.  
B) Cost Comparisons 
Primary statistical comparisons of costs between the two treatment groups will be performed 
using the intention-to-treat principle in the US cohort. A nonparametric partitioned estimator will 
be used to estimate diagnostic strategy-specific, 2-year medical costs with 8 partitions 
corresponding to 3-month intervals following randomization. Comparisons between the two 
testing strategies will be made using a normal approximation with standard errors estimated 
using the bootstrap approach. Bootstrapping will be performed using 10,000 repetitions, with 
percentile-based confidence intervals reported. The primary cost comparison will be made for 
cumulative costs at 12 months. The primary effect size will be the mean cost difference between 
the two arms with 95% confidence intervals. P values will be calculated for selective 
comparisons, with a “significant” p value equivalent to a 95% confidence interval that excludes 
0. No adjustment in significance levels for multiple comparisons will be used.  
Differences in cost will be interpreted in the context of the trial clinical results, looking for both 
consistency and plausibility. Costs will be presented both overall and by category (e.g., inpatient 
hospitalization, outpatient procedures, concomitant medications, non-acute institutional care). 
Hospitalizations will be classified as cardiovascular or non-cardiovascular by the Clinical Events 
Committee. For illustrative purposes, we will use bootstrap methods to plot the probability of a 
difference in total costs greater than arbitrary thresholds of interest (such as $500, $750, or 
$1000).  
C) Cost Sensitivity Analyses 
In secondary sensitivity analyses, we will apply US unit costs to all resource use of all patients 
and compare costs between treatment groups across all patients enrolled in the trial. While US 
unit costs may not reflect the absolute or relative costs of health care services internationally, 
their application to all patients will permit a weighted aggregation and comparison of resource 
use in the total trial population. In this manner, the effect of overall patterns of resource use in 
the US cohort versus ex-US on cost differences by treatment group can be assessed. We will 
also perform a per protocol analysis of costs. 
 
Analyses of Quality of Life Outcomes 
For each of the QOL measures examined in this study, we will provide simple descriptive and 
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comparative analyses by intention-to-treat. To address the multiple comparisons problem 
arising from testing each individual scale and time point separately, we propose two 
complementary approaches. First, we will pre-specify the angina frequency scale from the SAQ 
as the primary QOL comparison of interest and assign all other comparisons to a secondary 
(supportive) status. Second, we will use a repeated-measures mixed model with the baseline 
score as a covariate, Day 45, Month 6, Month 12, Month 18, and Month 24 responses included 
as outcome variables, and time as a fixed variable. Restricted maximum likelihood estimation 
will be used to model all available data from each subject without imputing missing values. An 
unstructured covariance matrix will be used. 
 
Point estimates for each diagnostic strategy arm and strategy arm mean differences (precision 
strategy – usual care) with 95% confidence intervals (CIs) will be generated for each time 
point. The primary assessment will be based on the strategy arm difference at Month 12. 
Additional analyses will examine the intervention effect at the other contact time points. 
Additionally, the intervention effect will be averaged across all the follow-up time points. The 
estimated intervention difference and 95% CIs will be obtained using the ESTIMATE 
Statement in SAS PROC MIXED. 
 
We expect to have analyzable data on t95% of survivors at each follow-up interview, and, with 
90%+ data collection (945+ patients per treatment group), consistent with our past performance 
in trials of this size and complexity and using similar methods, even accounting for loss of data 
due to death or incapacity, we should have 90% or greater statistical power to detect clinically 
significant differences in our major QOL measures. 
 
Major QOL subgroups to be examined will be those prespecified for the clinical analysis of this 
trial. In addition, we will use baseline angina frequency from the SAQ to create a subgroup of 
subjects with daily or weekly chest pain versus those with less frequent symptoms.  
 
IX. ETHICAL CONSIDERATIONS AND RISK ANALYSIS  
IX.A. Ethical Considerations 
 
PRECISE will be conducted in accordance with the recommendations for human research from 
the 18th World Medical Assembly, Helsinki 1964.  All potential sites will obtain Institutional Review 
Board (IRB) or Ethics Committee (EC) approval of the protocol, the associated consent form and 
any participant facing recruitment tools. Written informed consent will be obtained from each 
patient before any study procedures are performed.  Patients will have the option to consent for 
the study after receiving a full explanation of the risks, benefits, and available diagnostic options, 
with the right to refuse participation. Clinicians will have the option to pursue alternative diagnostic 
pathways if they deem it to be in the best interest of the patient, with the reason for study protocol 
deviation documented. Participants can withdraw from the study at any time.  
 
IX.B. Study Risks and Benefits 
 
Potential Risks 
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Participation in PRECISE does not present any extra risks other than the risks associated with 
the clinically indicated care recommended by the participant’s treating physicians to evaluate and 
treat symptoms suggestive of CAD. As all approaches included in the trial are recognized as 
standard of care, the risk associated with the trial can be described in detail by the treating 
physician.  
Noninvasive diagnostic imaging is generally considered a safe and effective diagnostic approach. 
FFRCT does not pose any additional risk to participants beyond the performance of cCTA itself. 
It does offer the potential benefit to participants of the recognition of hemodynamically significant 
lesions (FFR <0.80 or NHPR <0.90) that may not demonstrate anatomic significance (<50% 
diameter stenosis) and avoidance of unnecessary revascularization of >50% lesions that are not 
hemodynamically significant (FFR>0.80).  
The risks of guideline-recommended care without planned testing in the lowest risk participants 
has not been extensively studied prospectively. However, validation of the PROMISE Risk Tool 
in SCOT-HEART indicate that participants in this risk category have a CV death/MI event rate 
<1%/year, similar to the event rate observed in an age and sex matched US population. While 
the risk of guideline-recommended care without planned testing in the precision evaluation arm 
has not been quantified prospectively it is not expected to differ from the excellent outcomes 
noted above in such patients who do undergo testing. Further, participants with continued 
symptoms not controlled by medications will be permitted to cross over to the precision strategy 
arm and receive, cCTA with selective FFRCT.  
 
Potential Loss of Confidentiality  
 In any clinical trial, there is a possible risk of loss of confidentiality. To prevent this from occurring, 
HeartFlow has strict procedures in place to ensure that all study data are confidential and 
anonymized except as required for centralized follow-up data collection for North America, which 
will be performed by the DCRI Outcomes Call Center. For all data transferred from enrolling sites 
or from the Call Center, participants will be identified only by unique patient identifiers. Data 
transmitted will not contain any protected health information  and participants will be identified 
only by unique patient identifiers. Data transmitted will not contain any protected health 
information.  All applicable study data will be transferred in a secure manner and in accordance 
with applicable regulations.  
 
Potential Benefits 
 The PRECISE results should improve the care of future patients recommended for additional 
evaluation for suspected CAD. In addition, the trial will deliver high-quality data on radiation 
exposure, incidental findings, and other clinically important “side effects” of the evaluation and 
management strategies that will be examined in a large real-world experience. All participants 
may benefit from increased contact with health care providers due to study-required visits. 
 
X. 
DATA HANDLING AND QUALITY ASSURANCE  
 
X.A. Completing and Signing Case Report Forms 
 
Electronic CRFs will be employed. Trained site personnel or the trained DCRI Outcomes Group 
will enter data into the eCRFs. Data changes and corrections should be done within the 
electronic system. The audit trail will record all changes made, the date and time of the 
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correction, the person making the change and a reason for the change. The appropriate 
electronic signature will be provided by the investigator as indicated. 
 
X.B. Clinical Data Management 
 
The sponsor or its designees will be responsible for the handling, processing, and quality control 
of the data in compliance with all applicable regulatory guidelines. 
 
The training of clinical site personnel and the DCRI Outcomes Group on eCRF completion will 
be the responsibility of the sponsor or its designees. To ensure uniform data collection, a Case 
Report Form Guide will be created to assist with eCRF completion. All clinical site research 
coordinators will undergo site initiation training to become thoroughly familiar with the protocol, 
case report forms, and with methods of data verification. 
 
X.C. Archiving of Data 
 
All study documentation at the investigator site and sponsor site will be archived in accordance 
with ICH GCP. It is HeartFlow’s policy to retain the data collected in this clinical study for a 
minimum of 5 years after termination of the study. Clinical sites will be asked to retain the data for 
at least 2 years following completion of the study or longer as required by local laws. 
 
XI. STUDY MONITORING, AUDITING, AND INSPECTING  
 
HeartFlow or its designees will monitor this clinical study to check the adequacy of clinical site 
staff and facilities, and to ensure adherence to the protocol, study procedures, and applicable 
regulations. In accordance with ICH E6 GCP guidelines, the clinical site monitor will also assess 
proper eCRF completion and source document retention. The investigator and clinical site staff 
are expected to provide adequate space for monitoring visits and to allocate sufficient time to 
permit adequate review of the study’s progress. The investigator will permit study-related 
monitoring, audits, IRB review, and regulatory inspection(s), providing direct access to source 
data/documents and study-related facilities (e.g., pharmacy, diagnostic testing and laboratories). 
 
 
 
XI.A. Study Monitoring 
 
Study monitoring will be performed in accordance with ICH E6GCP, this protocol, and applicable 
local regulations.  A Clinical Monitoring Plan will be written at the outset of the study to provide 
project-specific operational guidelines for the clinical monitoring process and procedures, define 
responsibilities of the Site Management/Monitoring Team, which will in turn ensure the quality and 
integrity of data collected.  
 
XI.B. Auditing and Inspecting 
 
 
HeartFlow quality assurance personnel and/or their designee(s) may conduct audits at the study 
site(s). Audits may include, but not be limited to: audit trail of data handling and processes, SOPs, 
presence of required documents, the informed consent process, and comparison of case report 
forms/database with source documents. The investigator agrees to accommodate and participate 
in audits conducted at a reasonable time in a reasonable manner, as needed. 
 
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XII. References 
 
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Longenecker CT, Lutsey PL, Mackey JS, Matchar DB, Matsushita K, Mussolino ME, Nasir 
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33. Adamson PD, Fordyce CB, McAllister DA, Udelson JE, Douglas PS and Newby DE. 
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computed tomography angiography: An external validation of the PROMISE minimal-risk 
tool. International journal of cardiology. 2018;252:31-34. 
34. Fordyce CB, Douglas PS, Roberts RS, Hoffmann U, Al-Khalidi HR, Patel MR, Granger CB, 
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Deriving Minimal Value From Noninvasive Testing: The PROMISE Minimal-Risk Tool, A 
Secondary Analysis of a Randomized Clinical Trial. JAMA Cardiol. 2017;2:400-408. 
35. Douglas PS, Pontone G, Hlatky MA, Patel MR, Norgaard BL, Byrne RA, Curzen N, Purcell I, 
Gutberlet M, Rioufol G, Hink U, Schuchlenz HW, Feuchtner G, Gilard M, Andreini D, Jensen 
JM, Hadamitzky M, Chiswell K, Cyr D, Wilk A, Wang F, Rogers C and De Bruyne B. Clinical 
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37. Fihn SD, Gardin JM, Abrams J, Berra K, Blankenship JC, Dallas AP, Douglas PS, Foody JM, 
Gerber TC, Hinderliter AL, King SB, 3rd, Kligfield PD, Krumholz HM, Kwong RY, Lim MJ, 
Linderbaum JA, Mack MJ, Munger MA, Prager RL, Sabik JF, Shaw LJ, Sikkema JD, Smith 
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patients with stable ischemic heart disease: a report of the American College of Cardiology 
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38. Bradley SM, Spertus JA, Kennedy KF, Nallamothu BK, Chan PS, Patel MR, Bryson CL, 
Malenka DJ and Rumsfeld JS. Patient selection for diagnostic coronary angiography and 
hospital-level percutaneous coronary intervention appropriateness: insights from the 
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39. Lin GA, Dudley RA, Lucas FL, Malenka DJ, Vittinghoff E and Redberg RF. Frequency of 
stress testing to document ischemia prior to elective percutaneous coronary intervention. 
JAMA : the journal of the American Medical Association. 2008;300:1765-73. 
40. Patel MR, Dai D, Hernandez AF, Douglas PS, Messenger J, Garratt KN, Maddox TM, 
Peterson ED and Roe MT. Prevalence and predictors of nonobstructive coronary artery 
disease identified with coronary angiography in contemporary clinical practice. American 
heart journal. 2014;167:846-52.e2. 
41. Colleran R, Douglas PS, Hadamitzky M, Gutberlet M, Lehmkuhl L, Foldyna B, Woinke M, 
Hink U, Nadjiri J, Wilk A, Wang F, Pontone G, Hlatky MA, Rogers C and Byrne RA. An FFRCT 
diagnostic strategy versus usual care in patients with suspected coronary artery disease 
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analysis of the PLATFORM (Prospective Longitudinal Trial of FFRCT: Outcome and 
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43. Pellikka PA, Nagueh SF, Elhendy AA, Kuehl CA and Sawada SG. American Society of 
Echocardiography Recommendations for Performance, Interpretation, and Application of 
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45. Henzlova MJ, Duvall WL, Einstein AJ, Travin MI and Verberne HJ. ASNC imaging guidelines 
for SPECT nuclear cardiology procedures: Stress, protocols, and tracers. Journal of nuclear 
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guidelines for SPECT nuclear cardiology procedures: Stress, protocols, and tracers. Journal 
of nuclear cardiology : official publication of the American Society of Nuclear Cardiology. 
2016;23:640-642. 
47. Dilsizian V, Bacharach SL, Beanlands RS, Bergmann SR, Delbeke D, Dorbala S, Gropler 
RJ, Knuuti J, Schelbert HR and Travin MI. ASNC imaging guidelines/SNMMI procedure 
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48. Hundley WG, Bluemke DA, Finn JP, Flamm SD, Fogel MA, Friedrich MG, Ho VB, Jerosch-
Herold M, Kramer CM, Manning WJ, Patel M, Pohost GM, Stillman AE, White RD and 
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49. Leipsic J, Abbara S, Achenbach S, Cury R, Earls JP, Mancini GJ, Nieman K, Pontone G and 
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50. Abbara S, Blanke P, Maroules CD, Cheezum M, Choi AD, Han BK, Marwan M, Naoum C, 
Norgaard BL, Rubinshtein R, Schoenhagen P, Villines T and Leipsic J. SCCT guidelines for 
the performance and acquisition of coronary computed tomographic angiography: A report 
of the society of Cardiovascular Computed Tomography Guidelines Committee: Endorsed 
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51. Hicks KA, Mahaffey KW, Mehran R, Nissen SE, Wiviott SD, Dunn B, Solomon SD, Marler 
JR, Teerlink JR, Farb A, Morrow DA, Targum SL, Sila CA, Thanh Hai MT, Jaff MR, Joffe HV, 
Cutlip DE, Desai AS, Lewis EF, Gibson CM, Landray MJ, Lincoff AM, White CJ, Brooks SS, 
Rosenfield K, Domanski MJ, Lansky AJ, McMurray JJV, Tcheng JE, Steinhubl SR, Burton P, 
Mauri L, O'Connor CM, Pfeffer MA, Hung HMJ, Stockbridge NL, Chaitman BR and Temple 
RJ. 2017 Cardiovascular and Stroke Endpoint Definitions for Clinical Trials. Journal of the 
American College of Cardiology. 2018;71:1021-1034. 
52. Collet D. Modeling survival data in medical research (2nd edition). London: Chapman & Hall; 
2003. 
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53. Kalbfleisch JD, Prentice RL. The Statistical Analysis of Failure Time Data. 2nd edition.  2002, 
John Wiley & Sons, Inc. Hoboken, New Jersey. 
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B (Methodological). 1972;34:187-220. 
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of the American Statistical Association. 1958;53:457-481. 
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of composite endpoints in clinical trials based on clinical priorities. Eur Heart J. 2012;33:176-
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57. Finkelstein DM and Schoenfeld, DA. Combining mortality and longitudinal measures in 
clinical trials. Statistics in Medicine. 1999;18:1341-1354. 
58. Fine JP and Gray RJ. A Proportional Hazards Model for the Subdistribution of a Competing 
Risk. Journal of the American Statistical Association. 1999;94:496-509. 
 
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The PRECISE Protocol 
 
Prospective Randomized Trial of the Optimal Evaluation of 
Cardiac Symptoms and Revascularization 
 
 
 
Study Objective 
The primary objective of the PRECISE trial is to assess clinical 
outcomes, decision making regarding noninvasive testing and 
invasive angiography, and costs using a precision evaluation 
strategy as compared to a usual care strategy in participants with 
stable symptoms suggestive of significant coronary artery disease. 
The precision evaluation strategy will be based on a pre-test risk 
assessment and will incorporate cCTA with selective FFRCT and 
guideline-recommended care with symptom and risk factor 
management and no immediately planned testing. 
 
Study Design 
The study will be a prospective, pragmatic, randomized clinical trial 
of the comparative effectiveness of diagnostic evaluation strategies 
for stable suspected CAD, to be performed in outpatient settings, 
including primary care and cardiology practices. Qualifying patients 
presenting with new symptoms suspicious for clinically significant 
CAD (and without known CAD), who are recommended for 
diagnostic testing and did not receive any cardiovascular testing 
within the past 12 months, will be randomized to an initial strategy of 
either precision care or usual care. All subsequent decisions in the 
usual care arm regarding additional testing, medications, and/or 
procedures will be at the discretion of the responsible clinical care 
team. 
 
Study Principal 
Investigator 
Pamela S. Douglas, MD 
Duke University 
Durham, NC 27701 
USA 
 
Sponsor 
HeartFlow, Inc. 
1400 Seaport Blvd., Building B 
Redwood City, CA 94063 
Campbell Rogers, MD 
Chief Medical Officer 
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Investigator Protocol Signature Page 
 
I have read and understand the protocol and agree that it contains all the ethical, legal, and 
scientific information necessary to conduct this study. I will personally conduct the study as 
described. I will provide copies of the protocol to all assigned physicians, nurses, and other 
professional personnel who will participate in the study and will be responsible for their 
compliance and adherence to the study protocol. I am aware that this protocol must be 
approved by the Institutional Review Board or Ethics Committee. I agree to adhere strictly to 
the attached protocol. I agree that clinical data entered on case report forms by me and my 
staff will be supplied to HeartFlow and may be utilized by HeartFlow in various ways, such 
as for submission to governmental regulatory authorities and/or in combination with clinical 
data gathered from other research sites, whenever applicable. I agree to allow HeartFlow 
monitors and auditors and their designees full access to all medical records at the research 
facility for participants screened or randomized in the study. I agree to provide all participants 
with informed consent forms and will ensure adequate informed consent is obtained, as 
required by government regulations and International Conference on Harmonization 
guidelines. 
 
 
Version Date: Oct 15, 2019 
 
 
 
Site Name 
Site Number 
 
 
 
Principal Investigator (print name) 
 
 
 
 
Principal Investigator (Signature)  
Date 
 
 
 
 
 
 
 
 
 
Manesh Patel, MD, Trial Co-Principal Investigator  
Date 
 
 
Campbell Rogers, MD, HeartFlow CMO 
 
Date 
 
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Protocol Version and Amendment Tracking 
 
Version Number/Amendment 
Approval Date 
1.0 
Jun 29, 2018 
1.1 
Jul 31, 2018 
1.2 
Sept 10, 2018 
1.3 
Nov 21, 2018 
1.4 
Feb 1, 2019 
1.5 
Oct 15, 2019 
 
 
 
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Amendment from version 1.4 dated February 1, 2019 to version 1.5 dated October 15, 2019 
 
Section 
Version 1.4 
Version 1.5 
Investigator Protocol 
Signature Page 
NA 
Included separate line for PI signature 
Table of Abbreviations
NA 
AG: Agatston units 
Table of Abbreviations
DECISION: Decisive Evaluation of 
Cardiac Ischemia, Symptoms and 
Revascularization 
Removed 
Table of Abbreviations
HU: Hounsfield units 
Removed 
IV. Study Overview and 
Objectives - Study 
duration 
The anticipated total duration of the 
PRECISE study will be approximately 
48 months for start-up, enrollment, 
follow up, and close out. Participants 
will be followed for 24 months after 
enrollment. 
Overall study duration reduced to 36 month 
and patient follow up to 12 month after 
enrollment. 
“The anticipated total duration of the 
PRECISE study will be approximately 36 
months for start-up, enrollment, follow up, and 
close out. Participants will be followed for 12 
months after enrollment.” 
IV.A. Overview of 
PRECISE – figure of 
the trial design 
 
 
 
Figure updated to remove 24 month and co-primary 
endpoints of DECISION. Arrows leading to GRMT or 
cCTA annotated “low risk” and “elevated risk” 
respectively. Patients with known nonobstructive 
coronary plaque or extensive coronary calcium 
randomized to the precision arm are mandated to 
undergo cCTA +/- FFRCT, independent from 
PROMISE risk score strata. 
IV.B. Primary Objective 
and Endpoints 
Per the exclusion criteria, any previous 
noninvasive or invasive CV diagnostic 
testing for suspected CAD must have 
been >1 year prior to enrollment. 
Patients with known obstructive CAD 
(prior myocardial infarction, CABG or 
PCI, any stenosis ≥50%) are ineligible 
for PRECISE. 
Replaced with: 
“Patients with known nonobstructive coronary 
plaque or extensive coronary calcium 
randomized to the precision arm are mandated 
to undergo cCTA +/- FFRCT, independent from 
their PROMISE risk score strata.” 
IV.C. Secondary 
Endpoints 
Endpoints will be assessed at 45 days, 6 
months, 1 year and 2 years. 
Removed secondary endpoint assessment at 2 
years: 
“Endpoints will be assessed at 45 days, 6 months 
and 1 year.” 
IV.C. Secondary 
Endpoints 
9. PRECISE primary endpoint at 24 
month 
Removed PRECISE primary endpoint at 24 
month 
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Section 
Version 1.4 
Version 1.5 
IV.C. Secondary 
Endpoints 
10. MACE, defined as all-cause death 
myocardial infarction, or ischemia-driven 
revascularization at  24 months 
(DECISION co-primary end point) 
 
Removed DECISION co-primary endpoint 
IV.C. Secondary 
Endpoints 
11. All-cause death, MI, all follow-up 
unplanned revascularization procedures, 
invasive coronary angiograms without 
actionable findings at 24 months 
(DECISION co-primary end point) 
 
Removed DECISION co-primary endpoint 
V.A. Patient Screening 
for Eligibility – Inclusion 
Criteria 
 
NA 
Added inclusion criteria #3 
 
“3. If prior CV testing has occurred, it must have 
been performed greater than one year prior 
to randomization, and the following must be 
met: 
a) cCTA or invasive coronary angiography 
(ICA) with stenosis < 50% 
b) Quantified coronary artery calcium 
(CAC) < 100 AG  
 
V.A. Patient Screening 
for Eligibility – 
Exclusion Criteria 
 
3. Noninvasive or invasive CV testing within 
1 year (for suspected CAD).  CV testing 
for CAD refers to any stress tests, ICA, 
and cCTA (including calcium scoring) 
only. 
Resting 
ECG 
and 
resting 
echocardiogram are not exclusionary.  
 
Including resting CMR (MRI) as not 
exclusionary: 
 
“3. Noninvasive or invasive CV testing for CAD 
within 1 year. CV testing for CAD refers to 
any stress tests, 
invasive coronary 
angiography (ICA), and cCTA (including 
calcium scoring) only. 
a) 
Resting ECG, resting 
echocardiogram and resting CMR 
(MRI) are not exclusionary 
regardless of when they were 
performed. 
 
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Section 
Version 1.4 
Version 1.5 
V.D. Participant Follow-
Up 
 
24 months (+/-30 days) follow-up contact 
At the 24-month follow-up visit, participants 
will be asked to report the following: 
x Assessment if any MACE has occurred 
since the last visit/phone call 
x CV Update: Review and documentation of 
any cardiovascular diagnostic test, 
cardiovascular procedure, or 
hospitalizations/clinic visits due to 
cardiovascular symptoms and complications 
since last visit 
x Review and documentation of concomitant 
cardiovascular medication changes since 
enrollment 
x Complete the following 2 questionnaires: 
o Seattle Angina Questionnaire 
o EQ-5D-5L Questionnaire 
x Collection of the following: 
o Any cardiovascular test – both written 
report and test output 
o Any cardiovascular imaging – both written 
report and image file 
Removed 
participant 
follow-up 
requirement at 24 month 
VII.A. Primary Endpoint 
Definitions – 
Myocardial infarction 
 
The exception will be for peri procedural 
myocardial infarctions, which are defined 
as biomarker elevation ≥10 times the 
upper reference limit (URL) for creatine 
kinase MB (CKMB) and/or ≥70 URL for 
troponin as outlined in the most recent 
SCAI definition60. 
 
Reference 60 (Moussa ID, Klein LW, et al) 
removed and updated with reference 51 
(Thygesen K, Alpert JS, et al) 
 
“This definition will be followed for spontaneous 
as well as periprocedural MIs, for which the 
elevation in cTn must be at least cTn values >5 
times the 99th percentile URL for PCI and >10 
times for CABG related infarctions51” 
VIII.B. Statistical 
Analysis Plan – 
Analysis of the Primary 
Endpoint 
A sensitivity analysis for the primary 
composite MACE endpoint will be 
conducted using the method of “win-
ratio”56. The win-ratio method of Pocock 
et al is an extension of Finkelstein and 
Schoenfeld rank-test method57 which 
order-rank composite endpoints based 
on their clinical importance. 
A sensitivity analysis for the primary composite 
MACE (all cause death and non-fatal MI) or 
invasive cardiac catheterization without CAD 
(no coronary stenosis ≥50% according to QCA 
by core-lab adjudication or site interpretation if 
QCA is not available, or with FFR≤0.80, or 
instantaneous wave free ratio (iFR) ≤0.89) 
endpoint will be conducted using the method of 
“win-ratio”
56 and Finkelstein and Schoenfeld  
rank-test method
57. 
 
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TABLE OF CONTENTS 
 
I. STUDY SYNOPSIS 
12 
II. INTRODUCTION 
16 
II.A. Primary Hypothesis 
II.B. Significance of the Study 
III. BACKGROUND AND STUDY RATIONALE 
17 
III.A. Prior Literature and Studies 
III.B. Rationale for the Current Study: A Precision Approach to Chest Pain Evaluation 
IV. STUDY OVERVIEW AND OBJECTIVES 
22 
IV.A. Overview of PRECISE 
IV.B. Primary Objective and Endpoints 
IV.C. Secondary Endpoints 
IV.D. Rationale for the Selection of Outcome Measures 
IV.E. Rationale for the Selection of Testing in Each Arm 
IV.F. Participant Randomization 
IV.G. Diagnostic Evaluations and Subsequent Care 
V. STUDY PROCEDURES 
30 
V.A. Participant Screening for Eligibility 
V.B. Participant Randomization and Enrollment 
V.C. Participant Cohort Assignment 
V.D. Participant Follow-Up 
V.E. Testing in precision evaluation arm for participants assigned to no immediate testing 
V.F. Participant Withdrawal 
V.G. Schedule of Assessments 
VI. ADDITIONAL ASSESMENTS AND SUBSTUDIES 
36 
VI.A. Quality of Life Assessments 
VI.B. Economic and Resource Utilization Assessments 
VI.C. Imaging and other Cardiac Assessments 
VII. ENDPOINT DETERMINATION, SAFETY AND MONITORING 
37 
VII.A. Primary Endpoint Definitions 
VII.B. Secondary Endpoint Definitions 
VII.C. Testing Complications and Reporting 
VII.D. Independent Clinical Event Adjudication Committee 
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VII.E. Data and Safety Monitoring Board 
VIII. STATISTICAL METHODS 
41 
VIII.A. Sample Size Determination and Statistical Power 
VIII.B. Statistical Analysis Plan 
IX. ETHICAL CONSIDERATIONS AND RISK ANALYSIS 
46 
IX.A. Ethical Considerations 
IX.B. Study Risks and Benefits 
X. DATA HANDLING AND QUALITY ASSURANCE 
47 
X.A. Completing and Signing Case Report Forms 
X.B. Clinical Data Management 
X.C. Archiving of Data 
XI. STUDY MONITORING, AUDITING, AND INSPECTING 
48 
XI.A. Study Monitoring 
XI.B. Auditing and Inspecting 
XII. REFERENCES 
49 
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TABLE OF ABBREVIATIONS 
 
ACC 
American College of Cardiology 
ACS 
acute coronary syndrome 
AHA 
American Heart Association 
AG 
Agatston units 
BMI 
body mass index 
BP 
blood pressure 
CAC 
Coronary Artery Calcium 
CAD 
coronary artery disease 
CV 
Cardiovascular 
CI 
confidence interval 
CK-MB 
creatine kinase-myocardial band 
CMS 
Centers for Medicare & Medicaid Services 
COCATS 
Core Cardiology Training Symposium 
cCTA 
coronary computed tomographic angiography 
CP 
chest pain 
cTn 
cardiac troponin 
DCRI 
Duke Clinical Research Institute 
DSMB 
Data and Safety Monitoring Board 
ECG 
Electrocardiogram 
Echo 
Echocardiogram 
EDC 
electronic data capture 
EQ-5D-5L 
a standardized instrument developed by the EuroQol Group as a 
measure of health-related quality of life. 
eCRF 
electronic case report form 
FFR 
fractional flow reserve 
FS 
Finkelstein and Schoenfeld statistical method 
FFRCT 
non-invasive technique using cCTA to determine FFR 
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g/L 
grams per liter 
 
HDL 
high-density lipoprotein 
ICA 
invasive coronary angiography 
iFR 
instantaneous wave free ratio 
IRB 
institutional review board 
IVUS 
intravascular ultrasound 
IXRS 
interactive voice/web response system 
LDL 
low-density lipoprotein 
LV 
left ventricular 
MACE 
major adverse cardiovascular event 
MAR 
missing at random 
MDCT 
multidetector computed tomography 
MI 
myocardial infarction 
MOP 
manual of procedures 
MPI 
myocardial perfusion imaging 
mSv 
milliSievert 
NI 
non-invasive 
NICE 
National Institute for Health and Care Excellence (In the 
United Kingdom’s National Health Service) 
NHPR 
non-hyperemic pressure ratio 
OCT 
 optical coherence tomography 
PAD 
peripheral arterial disease 
PCI 
percutaneous coronary intervention 
PI 
principal investigator 
PLATFORM Prospective LongitudinAl Trial of FFRCT: Outcome and Resource Impacts 
study 
PRECISE 
Prospective Randomized Trial of the Optimal Evaluation of Cardiac 
Symptoms and Revascularization 
PROMISE 
PROspective Multicenter Imaging Study for Evaluation of Chest Pain 
randomized clinical trial 
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QCA 
quantitative coronary angiography 
QoL 
quality of life 
ROC 
receiver operating characteristic 
SAQ 
Seattle Angina Questionnaire 
SCAI 
Society for Cardiovascular Angiography and Interventions 
SCOT- 
HEART 
Scottish Computed Tomography of the HEART randomized clinical trial 
ULN 
upper limit of normal 
URL 
upper reference limit 
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I. STUDY SYNOPSIS 
 
 
Protocol Title 
PRECISE: Prospective Randomized Trial of the Optimal 
Evaluation of Cardiac Symptoms and Revascularization 
Investigational Strategy 
Precision diagnostic evaluation as the initial strategy for suspected 
significant CAD in patients with stable symptoms 
Study Principal 
Investigator 
Pamela S Douglas, MD 
Duke Clinical Research Institute, Duke University, Durham NC 
Academic Research 
Organizations 
Duke Clinical Research Institute (DCRI), Durham, NC, USA 
Cardiovascular Research Foundation (CRF), New York, NY, USA 
Clinical Research 
Organization 
Medpace Research, Inc. 
Sponsor 
HeartFlow, Inc. 
1400 Seaport Blvd 
Redwood City, CA 94063 
Participants and Study 
Centers 
Approximately 2100 participants randomized at approximately 100 sites 
in the US and outside of the US 
Planned Study Duration 
Approximately 36 months 
Primary Study Objective 
To assess clinical outcomes, decision making regarding noninvasive 
testing and invasive angiography, and costs using a precision 
evaluation strategy as compared to a usual care strategy in participants 
with stable symptoms suggestive of significant coronary artery disease. 
The precision evaluation strategy will be based on a pre-test risk 
assessment and will incorporate cCTA with selective FFRCT and 
guideline-recommended care with symptom and risk factor 
management and no additional immediately planned testing. 
Primary Hypotheses 
In stable participants with a clinical recommendation for testing to 
evaluate suspected significant CAD a precision evaluation strategy, 
incorporating a risk-based assignment to guideline recommended 
medical management without planned testing for selected low risk 
participants or cCTA with selective FFRCT in elevated risk participants, 
will result in improved clinical outcomes of death/MI and a lower rate of 
catheterization without obstructive CAD as compared to usual care 
strategy. 
Population 
Stable patients who have a clinical recommendation for testing 
(noninvasive or invasive) for suspected significant CAD 
Study Design and 
Methods 
Prospective, pragmatic, randomized clinical trial of diagnostic evaluation 
strategies for stable suspected significant CAD, to be performed in 
outpatient settings, including primary care and cardiology practices. 
Qualifying patients presenting with new symptoms suspicious for 
clinically significant CAD (and without known obstructive CAD), who are 
recommended for diagnostic testing and did not receive any 
cardiovascular testing within the past 12 months, will be randomized to 
an initial strategy of either precision care or usual care of the site’s 
choosing. All subsequent decisions in the usual care arm regarding 
additional testing, medications, and/or procedures will be at the 
discretion of the responsible clinical care team; the use of cCTA as the 
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initial diagnostic strategy is not allowed in the usual care arm and is 
prohibited as a subsequent test for the first 45 days after randomization. 
 
Precision evaluation: Participants randomized to a precision strategy 
will then be assigned to either guideline-recommended care without 
immediately planned testing (low risk) or cCTA with selective FFRCT 
(for those with elevated risk or known non-obstructive atherosclerosis) 
using a risk tool based on pre-test clinical characteristics derived from 
the PROMISE trial and validated in SCOT-HEART trial. As is 
recommended for all participants, those assigned to guideline-
recommended care without planned testing will be treated with 
preventive and antianginal medical treatment per guideline 
recommendations and clinical judgment and followed without testing. 
Participants and their providers will be provided informational resources 
explaining the safety and rationale of this strategy based on pre-test 
probabilities and the PROMISE Minimal Risk Score. Participants with 
documented intractable symptoms despite maximal medical 
management may undergo cCTA with selective FFRCT at the 
participant’s or site clinician’s discretion. 
 
Usual Care: For participants randomized to usual care, the 
participant’s care team will select the specific noninvasive stress test 
(exercise electrocardiogram, stress nuclear imaging [including PET], 
stress MR, or stress echocardiogram); OR invasive test: (direct to 
diagnostic catheterization). The use of cCTA as the initial diagnostic 
strategy is explicitly excluded in this arm and prohibited as a 
subsequent test for the first 45 days after randomization. 
 
In both arms, the participant’s care team will be provided with physician 
and patient informational resources summarizing current 
recommendations for test interpretation and preventive care. Optimal 
medical management will be recommended but not mandated in either 
arm. 
Randomization 
and Stratification 
Participants will be randomized using a 1:1 randomization scheme via 
an interactive web or voice-based system (IXRS). Randomization will 
be stratified by intended first test if randomized to usual care, low vs. 
elevated pre-test risk, and site. 
Enrollment in the strata of intended noninvasive test first (vs. intended 
invasive angiography first) will be capped at 90%. 
Primary Endpoint 
Time to a composite of: MACE (all cause death, non-fatal MI) or 
invasive cardiac catheterization without obstructive CAD (obstructive 
CAD defined as diameter stenosis ≥50% according to core-lab 
adjudicated quantitative coronary angiography (QCA), FFR≤0.80, or 
iFR≤0.89) at one year (intention to treat) 
Secondary 
Effectiveness 
Endpoints 
Endpoints will be assessed at 45 days, 6 months, and 1 year. 
1. Hierarchical analysis (Finkelstein and Schoenfeld (FS) and 
Pocock’s win ratio) of primary endpoint 
2. Resource use patterns and medical costs 
3. QoL: measured by the Seattle Angina Questionnaire (SAQ) to 
assess angina-specific Quality of Life and the EuroQoL 5D (EQ-
5D-5L) survey to assess overall (generic) health status 
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4. Death: All-cause, cardiovascular, non-cardiovascular 
5. Myocardial infarction: All, procedural, spontaneous MI 
6. Hospitalizations: All, cardiovascular, non-cardiovascular, 
and for progressive or unstable angina 
7. Preventive medication use (ASA, statins) in participants with 
clinical indication for use: e.g.: hyperlipidemia, diabetes, 
documented CAD 
8. Cumulative radiation exposure at 1 year 
9. Proportion of invasive coronary angiogram patients who undergo 
revascularization (PCI or CABG) within 6 months of enrollment 
Pre-specified 
subgroup 
analyses 
1. Low risk vs. elevated risk by PROMISE score or pre-existing non-
obstructive CAD 
2. Intended initial test: functional stress test vs. invasive (direct to cath) 
3. Clinical factors: sex, age, diabetes 
4. Presentation: primary symptom (chest pain vs. other), SAQ angina 
frequency score 
Inclusion Criteria 
Inclusion criteria (all must be present): 
1. Age ≥18 years 
2. Stable typical or atypical symptoms suggesting possible significant 
coronary artery disease (CAD) with further non-emergent testing or 
elective catheterization recommended to evaluate the presence of 
suspected significant CAD.  Stable chest pain (or equivalent) includes 
those who have fully been ruled out for Acute Coronary Syndrome 
(ACS) and for whom elective testing is recommended, regardless of 
the venue in which they are seen. 
3. If prior CV testing has occurred, it must have been performed greater 
than one year prior to randomization, and the following must be met: 
a. 
cCTA or invasive coronary angiography (ICA) with 
stenosis < 50% 
b. 
Quantified coronary artery calcium (CAC) < 100 AG 
4. Safe performance of cCTA: 
a. 
Creatinine clearance ≥45 ml/min per most recent 
measurement within 90 days 
b. 
For a female participant of childbearing potential (those 
who have not been surgically sterilized or are not 
postmenopausal), a pregnancy test must be performed 
with negative results known within 7 days prior to 
randomization 
5. Willingness to comply with all aspects of the protocol, 
including adherence to the assigned strategy and follow-
up visits 
6. Ability to provide written informed consent 
 
Exclusion criteria 
Exclusion criteria (all must be absent): 
1. Acute chest pain (in patients who have not been ruled out for ACS) 
2. Unstable clinical status 
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3. Noninvasive or invasive CV testing for CAD within 1 year. CV testing 
for CAD refers to any stress tests, invasive coronary angiography 
(ICA) and cCTA (including calcium scoring) only. 
a. 
Resting ECG, resting echocardiogram and resting CMR 
(MRI) are not exclusionary regardless of when were 
performed 
4. Lifetime history of known obstructive CAD (prior myocardial infarction, 
CABG or PCI, stenosis ≥50%), known EF ≤40% or other moderate to 
severe valvular or congenital cardiac disease 
5. Contraindications to cCTA including but not limited to 
creatinine clearance (GFR) <45 ml/min as per most recent 
measurement taken within 90 days 
6. Exceeds the site’s weight or size limit for cCTA or cardiac 
catheterization 
7. Any condition leading to possible inability to comply with the 
protocol procedures or follow-up 
8. Any condition that might interfere with the study procedures or 
follow-up 
9. Enrolled in an investigational trial that involves a non-approved 
cardiac drug or device which has not reached its primary 
endpoint 
10. Life expectancy less than 2 years due to non-cardiovascular 
comorbidities 
 
Study Follow-up 
Participant follow-up will be done at 45 days, 6 months, and 1 year. 
Sample Size 
Considerations 
Primary superiority testing hypothesis of all cause death/MI or invasive 
cardiac catheterization without obstructive CAD (diameter stenosis 
≥50% or FFR≤0.80/ or iFR≤0.89) at one year (intention to treat, time to 
first event analysis): Assuming an 8% event rate at 1 year in the usual 
care group and 5% in the precision care group (3% absolute [37.5% 
relative] effect magnitude). Assumed rates are based on estimated 
~20% assigned to guideline- recommended care with symptom 
management and no planned testing (within which 30% will cross over 
to cCTA with selective FFRCT); and overall 10% will not receive 
assigned testing; enrolling 1050 participants per group (2100 total 
participants) would provide at least 90% power to demonstrate 
superiority accounting for 10% attrition rate. 
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II. INTRODUCTION 
 
II.A. Primary Hypotheses 
The primary goal of the Prospective Randomized Trial of the Optimal Evaluation of Cardiac Symptoms 
and Revascularization (PRECISE) research program is to assess clinical outcomes, decision making 
regarding noninvasive testing and invasive angiography, and costs using a precision evaluation 
strategy as compared to a usual care strategy in participants with stable symptoms suggestive of 
significant coronary artery disease. The precision evaluation strategy will be based on a pre-test risk 
assessment and the presence or absence of known non-obstructive atherosclerosis; participants in 
this arm will undergo either cCTA with selective FFRCT or no immediately planned testing. All 
participants are encouraged to have guideline- recommended care with symptom management. 
 
The primary hypothesis of PRECISE is: in stable participants with a clinical recommendation for testing 
to evaluate suspected significant coronary artery disease (CAD), a precision evaluation strategy will 
result in improved clinical outcomes of death/MI and a lower rate of catheterization without obstructive 
CAD as compared to a usual care strategy. 
 
An important secondary hypothesis is that the precision evaluation strategy will result in improved 
patient-reported outcomes, reflected in the SAQ angina frequency and quality of life scores. We also 
expect the precision strategy to result in reduced resource utilization and net cost savings compared 
to usual care evaluation. 
 
The usual care arm participants will undergo either noninvasive stress testing, with the specific 
modality at the discretion of the participant’s clinician, or invasive coronary angiography (ICA) as the 
initial test. 
 
The precision evaluation arm starts with the use of the PROMISE Risk Tool to categorize patient risk 
for CAD and events. The PROMISE Risk Tool is a validated risk model that has been shown to 
accurately identify chest pain patients who are unlikely to benefit from non-invasive testing (i.e. have 
minimal or no atherosclerosis and likely to have no events within two years). The lowest risk group in 
the precision arm identified using this model will be assigned to guideline-recommended care focused 
on symptom and risk factor management without planned cardiac diagnostic testing. Those participants 
who are identified to be of elevated risk or those with known non-obstructive coronary atherosclerosis 
(regardless of risk score results) will be initially evaluated with cCTA with selective FFRCT.   
I.B. Significance of the Study 
The goal of PRECISE is to define the optimal evaluation and management strategy of stable, 
symptomatic participants with suspected significant CAD. If the hypotheses of PRECISE are supported 
by the results of the trial, PRECISE will form the core of a compelling body of evidence supporting 
important changes in clinical practice guidelines and clinical care that will both improve outcomes for 
patients and reduce the use of unnecessary (low yield) testing and associated medical costs. Chest 
pain is one of the most common symptoms that bring patients into the health care system and one of 
the most difficult for providers to address confidently. The variability of current practice and the frequent 
overuse of testing derive from the lack of consensus among experts and among guidelines about how 
best to achieve a secure diagnosis and appropriate management plan. The results of PRECISE will 
have major implications for all health systems where stable chest pain is a common reason for 
participants to seek care. 
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III. BACKGROUND AND STUDY RATIONALE 
 
III.A. Prior Literature and Studies 
 
Unmet need to develop novel approaches for the diagnostic evaluation in stable chest pain 
patients 
 
CAD is an extremely common diagnosis worldwide and results in significant morbidity and mortality1, 
2. Among the common presentations, stable symptoms of chest pain or exertional dyspnea can be 
diagnostically puzzling and often require diagnostic testing or angiography to be certain of the 
diagnosis and treatment. Current US, EU and UK guidelines recommend risk stratification using 
presentation characteristics and risk factors to determine which patients require noninvasive testing 
or should be referred directly to invasive catheterization3. However, in the current era, the results of 
using these recommended strategies are unsatisfactory. The population undergoing noninvasive 
testing has a low rate of obstructive CAD (10-20%) and very low annual event rates (~1-2%/year) 4, 
5, 59, while patients undergoing invasive angiography frequently don’t have actionable CAD6. These 
patterns of care have resulted in high costs without accompanying clinical benefit7. A new approach 
to the risk stratification and subsequent diagnostic evaluation and management of patients with 
stable symptoms suggestive of CAD is urgently needed. 
 
Uncertainty Regarding the Optimal First Test for Detection and Exclusion of Coronary Artery 
Disease: Evidence For cCTA 
 
While a number of functional and anatomic non-invasive tests are available for the evaluation of 
stable chest pain patients, the optimal evaluation strategy for patients with stable chest pain is 
uncertain, and recommendations in current guidelines differ markedly. In a recent attempt to address 
these issues systematically, two large, multicenter, open-label, randomized controlled trials explored 
the diagnostic evaluation of patients with symptoms that may represent coronary artery disease. 
The SCOT-HEART (Scottish Computed Tomography of the HEART)4, 59 and PROMISE 
(PROspective Multicenter Imaging Study for Evaluation of chest pain)5 trials sought to address 
evidence gaps in noninvasive testing in stable chest pain, an area in which few randomized trials 
had previously been conducted. 
 
Key findings from SCOT-HEART and PROMISE: The overall results and important similarities and 
differences between the two trials have been recently described8. The SCOT-HEART study enrolled 
4,146 patients with stable chest pain to cCTA in addition to usual care (which generally included 
electrocardiogram [ECG] stress testing) or to usual care alone. The trial used an upstream primary 
endpoint related to diagnostic thinking: managing clinician certainty of the diagnosis of angina 
secondary to CAD, which showed an increase in the cCTA group (RR: 1.79; 95% confidence interval 
[CI]: 1.62 to 1.96), as did the secondary endpoint of certainty of diagnosis of CAD (RR: 2.56; 95% CI: 
2.33 to 2.79). The clinical outcomes-related secondary endpoint of the rate of cardiovascular death 
or nonfatal myocardial infarction (MI) appeared to be reduced in the cCTA group at 20 months (RR: 
0.62, 95% CI: 0.38 to 1.01; p=0.0527), although the overall event rates were low in both arms, 
reflecting the inclusion of a large number of patients without 
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CAD. Of note, a landmark analysis excluding the 7 week delay to receiving a cCTA yielded a hazard 
ratio of 0.50 for CV death and MI9. 
 
The larger PROMISE trial randomly assigned 10,003 symptomatic, stable outpatients requiring 
evaluation for suspected CAD to either initial cCTA or functional stress testing (exercise treadmill 
testing [ETT], nuclear stress testing, or stress echocardiography), with a median follow-up of 25 
months. The event related composite primary endpoint (death, MI, hospitalization for unstable 
angina, or major cardiovascular procedural complication) occurred at similar rates in the cCTA and 
functional testing groups (3.3% and 3.0%), which was lower than previously established historical 
rates. More patients in the cCTA group underwent cardiac catheterization within 90 days after 
randomization (12.2% vs. 8.1%), but the secondary endpoint of the frequency of catheterization 
showing no obstructive CAD was significantly lower in the cCTA group (3.4% vs. 4.3%, p=0.02) as 
was the rate of death and MI at 12 months (HR 0.66; p=0.049). Furthermore, among patients 
randomized to an intended nuclear testing strategy, the mean cumulative radiation exposure was 
lower in the cCTA group compared with the functional testing group (12.0 
- 8.4 mSv vs. 14.1 - 7.6 mSv). This encompassed all downstream radiation within 90 days, including 
that associated with cardiac catheterization, and is particularly intriguing because more cCTA 
patients received cardiac catheterization. 
 
In addition to improving triage to the cardiac catheterization lab and potentially reducing radiation 
exposure, mounting evidence has demonstrated that use of cCTA, compared to functional testing, 
yields improved preventive medical treatment and better prognostic information4, 5, 10. Patients in the 
PROMISE trial who underwent cCTA experienced greater uses of indicated cardio-protective 
medications such as aspirin and statins10. This increase is prognostically important, as data from the 
CONFIRM registry (Coronary CT Angiography Evaluation for Clinical Outcomes International 
Multicenter) demonstrated that baseline statin therapy among patients with non-obstructive CAD11 
identified on cCTA was associated with a reduction in mortality compared to non-use12, while statin 
therapy among patients with obstructive CAD identified on cCTA was associated with a reduction in 
MACE13. 
 
The identification of non-obstructive CAD with high risk plaque characteristics can only be 
accomplished non-invasively by cCTA and is an important prognostic indicator, with even mild 
abnormalities conferring nearly three times the risk of death, MI and unstable angina compared to 
patients with a normal study14, 15. Furthermore, cCTA leads to higher yield of positive results with 
actionable or obstructive CAD, among patients undergoing cardiac catheterization5. This is in line 
with data from the CONFIRM registry, where investigators demonstrated that cCTA could be used 
as an effective gatekeeper prior to invasive coronary angiography16. 
 
Most importantly, a recent meta-analysis largely based on PROMISE and SCOT-HEART data 
showed a clear benefit in ‘hard’ cardiovascular outcomes to a cCTA first strategy, with a 29% 
reduction in MI17. This was potentially driven by the increase in medication utilization in the cCTA 
arm of the study as well as more catheterization and revascularization17. 
 
To summarize, there are several practical and clinical implications of SCOT-HEART and PROMISE 
which inform the proposed design of PRECISE: 
x 
Contemporary patients with stable chest pain are at low risk of clinical events. Therefore, a 
strategy to test only those with an elevated likelihood of having obstructive CAD or risk for 
events, while instituting optimal medical care including deferring testing in those unlikely to 
benefit (i.e. using the PROMISE Risk Score), may be feasible, clinical important and efficient. 
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x 
cCTA is a reasonable first test for routine assessment of patients with stable chest pain, and 
when compared to functional testing, is associated with an increase in preventive medication 
use and a reduction in myocardial infarction. 
x 
Future trials investigating the optimal evaluation of patients with stable chest pain should 
include the evaluation of clinical outcomes and other measures of testing efficiency (i.e., 
cardiac catheterization without obstructive CAD). 
 
The Case for the Use of cCTA with selective FFRCT as the Optimal First Test 
The current noninvasive diagnostic testing strategies using functional testing have relatively poor 
accuracy given the low disease prevalence in this population, leading to high rates of false- positive 
results18. Specifically, current diagnostic strategies lead to high rates (~50%) of cardiac 
catheterization without significant obstructive disease or need for revascularization5,7. As described 
above, incorporating cCTA into testing strategies can reduce the frequency of cardiac 
catheterization without obstructive disease but tends to increase rates of invasive angiography 4, 5. 
 
Non-invasive computationally-derived FFRCT has been developed using resting coronary CT images 
without the administration of adenosine or change in underlying cCTA protocols18-21. The 
methodology has been previously described elsewhere.22 In short, FFRCT uses the accurate 
anatomical model of the coronary arteries and myocardium obtained with conventional cCTA and 
applies the physical laws that govern flow, microcirculatory resistance, coronary branching, and 
simulated hyperemia. The Navier-Stokes equations that solve for velocity, resistance and pressure 
for all Newtonian fluids are applied to provide a 3-dimensional pressure map across the coronary 
tree. This use of computational fluid dynamics generates FFR values from 0 to 1, with 
<0.80 considered hemodynamically significant. The values are congruent with invasive FFR, as 
shown in several prospective validation studies18-20. Finally, the anatomical modeling has been 
improved by the use of advanced deep and machine learning techniques applied to the large data 
sets acquired via central analysis. 
 
The addition of FFRCT may reduce a potential limitation of a cCTA-first approach, excess invasive 
angiography, by providing both functional and anatomic data. Specifically, FFRCT markedly reduces 
the false positive rate of cCTA alone vs. invasive FFR adjudicated ischemia with 68% of false 
positive CT interpretations in the NXT Trial reclassified as true negative. A retrospective analysis 
from the PROMISE trial in 181 patients with cCTA, cardiac catheterization and FFRCT revealed that 
FFRCT was a better predictor of revascularization and events than cCTA alone. Modelling of the 
incorporation of FFRCT into catheterization decision making suggested a reduction in catheterization 
rate with cCTA from 12.2% to 7.8% while reducing the rate of catheterization without obstructive 
CAD from 27% to 15% and increasing the yield of catheterization leading to revascularization from 
49% to 61%23. Given that PCI of lesions with negative FFR is associated with worse outcomes24, 25, 
while treatment of FFR positive lesions with PCI vs. optimal medical therapy results in improved 
clinical outcomes, the potential clinical value of adding FFRCT to a cCTA based diagnostic strategy 
is evident. 
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The safety and utility of a CT/ FFRCT strategy were further tested in the PLATFORM Study 
(Prospective LongitudinAl Trial of FFRCT: Outcome and Resource Impacts) which evaluated rates of 
invasive catheterization without obstructive CAD in patients undergoing invasive evaluation. Patients 
in 2 sequential non-overlapping cohorts of patients referred for ICA were assigned to either undergo 
ICA or cCTA/ FFRCT with ICA use based on the results of the cCTA and FFRCT. The cCTA/FFRCT 
strategy resulted in a significant reduction in the rate of cath lab finding of no obstructive disease, 
from 73 to 12%7. Furthermore, ICA was deferred in 61% of cCTA/FFRCT strategy patients. A follow-
up at one year demonstrated that cCTA with selective FFRCT strategy yielded similar clinical 
outcomes and quality of life, at a substantially reduced cost. 
 
While much of the early focus has been on a reduction in referral for ICA in the absence of actionable 
CAD, more recently there has been growing interest in using FFRCT to enhance catheterization lab 
efficiency by increasing the proportion of catheterizations that include revascularization (PCI or 
CABG / ICA ratio) and providing guidance regarding revascularization strategies before the invasive 
angiogram. Importantly, in this case FFRCT is not being used only in a binary fashion but rather to 
provide a richer understanding of the pattern and degree of pressure loss across the epicardial 
coronary system and its connection to the extent of ischemia present. 
The value of cCTA and FFRCT has been recognized by The National Institute for Health and Care 
Excellence (NICE) in their advisory for stable chest pain (Clinical Guidance 95) and technical 
evaluation of FFRCT, as well as by establishment of reimbursement standards by the Centers for 
Medicare and Medicaid Services (CMS) 26, 27. The 2016 NICE guidance recognized the difficulties 
with risk stratification in an era of reduced obstructive CAD prevalence in the population undergoing 
evaluation and the importance of anatomical assessment of CAD26, 27. In response, it recommends 
coronary cCTA as the first-line investigation for patients presenting with new-onset chest pain felt to 
be due to CAD based on its superior clinical diagnostic utility and cost- effectiveness26, 27. Further, 
based on the results of the PLATFORM trial, the NHS recommends addition of FFRCT to cCTA as a 
cost savings measure26. In the United States, CMS approved a New Technology Ambulatory 
Payment Classification (APC) for HeartFlow FFRCT analysis on January 1, 201828. The 
acknowledgement of FFRCT by CMS is a critical step toward increasing the availability of the 
technology to patients who may benefit. However, other organizations’ standards documents have 
not yet been revised to incorporate the emerging evidence base supporting CCTA and FFRCT, 
indicating that there is still a need for additional evidence to support the routine use of FFRCT in clinical 
practice. 
 
Rationale and Evidence for Incorporation of a Strategy of Guideline-recommended Care without 
Planned Testing in Low Risk patients 
 
Given the low prevalence of obstructive CAD (10-20%) and very low annual event rates (~1- 
2%/year) among stable chest pain patients undergoing non-invasive testing, combined with the high 
cost of testing4, 5, prospective evaluation of the safety and efficacy of an approach of guideline-
recommended care without planned testing has become a necessity. Although there are no data 
regarding outcomes and costs of a guideline-recommended care without planned testing in 
symptomatic patients, it is possible to define in principle a cohort in whom deferred testing might be 
the optimal strategy. The argument for testing this is further strengthened by the equivalence of 
medical and invasive strategies in preventing cardiovascular events in stable CAD, as several trials 
have shown no benefit of revascularization over optimal medical treatment 29, 30. It is reasonable to 
hypothesize that this may be especially true for those at lowest risk, in whom noninvasive testing is 
even less likely to lead to outcomes-improving revascularization, thereby removing the need for 
testing as a gateway to the catheterization laboratory. 
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The COURAGE trial (Clinical Outcomes Utilizing Revascularization and Aggressive Drug 
Evaluation) demonstrated no significant difference in a composite of death, myocardial infarction, 
and stroke between patients with objective evidence of myocardial ischemia and significant CAD 
on medical therapy vs. those undergoing PCI (19.5% vs. 20.0%, p=0.62)29. The more recent 
ORBITA trial (Percutaneous coronary intervention instable angina) randomized 200 patients with 
stable angina and a single-vessel stenosis to optimal medical therapy + PCI vs. optimal medical 
therapy plus a sham procedure, with a primary endpoint of difference in exercise time during a 6- 
week follow-up period30. The authors found no significant difference in improvement in exercise 
time (+28.4 seconds in PCI group vs. +11.8 seconds in sham group, p=0.2), nor any significant 
change in the secondary outcome of Seattle Angina Questionnaire (SAQ)-angina frequency from 
baseline (14.0 in PCI group vs. 9.6 in sham group, p=0.26)30. The ongoing improvements in medical 
management of CAD risk, angina and established coronary artery disease further emphasize the 
need for diagnostic strategies that minimize unnecessary invasive angiography and 
revascularization by emphasizing guideline-recommended care in patients at very low risk for 
obstructive disease. 
 
These studies support the development of a patient-centric strategy to identify those who may 
derive minimal benefit from testing, a strategy which carries several desirable implications for 
patients, clinicians, and clinical practice in general. For patients, this process can mean a reduction 
in use of testing from which they would not benefit, thereby saving time, anxiety, and cost, as well 
as potential reductions in radiation exposure and false-positive test results that could lead to more 
invasive, unnecessary procedures. For clinicians, a tool identifying the lowest risk patients has the 
potential to help optimize office-based decision making. From a practice and societal perspective, 
in an era in which practitioners are increasingly held accountable for costs and quality, the ability 
to confidently identify patients highly unlikely to benefit from potentially expensive testing and who 
may therefore be managed conservatively has many potential economic and process-of-care 
advantages. 
 
The PROMISE Risk Tool was expressly developed to identify low-risk patients with stable chest 
pain who are unlikely to benefit from non-invasive testing, and for whom guideline-recommended 
medical management alone may be safe. Current guidelines recommend using a version of the 
Diamond and Forrester risk score for pretest likelihood of obstructive CAD, but multiple 
investigators have found that this tool grossly over estimates actual presence of disease5, 31, 32. The 
consequence is an imprecise evaluation strategy for millions of patients, resulting in unhelpful testing 
of lower risk individuals. For a significant portion of these, a false positive functional testing leads 
them to have invasive cardiac catheterizations to rule out the disease they do not have. The Risk 
Tool developed using the PROMISE cohort employs 10 readily available clinical variables (such as 
tobacco usage, ethnicity/race, and age) and has been validated in the SCOT-HEART population33, 
34. This risk tool identifies patients with stable chest pain who have no coronary plaque or 
calcification by cCTA and no cardiac events over 2 years, and who therefore would be predicted to 
derive minimal or no value from noninvasive testing33, 34. Testing whether this risk tool can be 
employed prospectively to safely and effectively risk stratify low risk patients into a strategy of 
guideline-recommended care with symptom and risk factor management and without diagnostic 
testing is one of the core secondary objectives of the PRECISE research program. 
 
 
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III.B. Rationale for the Current Study: A Precision Approach to Chest Pain Evaluation 
 
Despite the high-burden of stable chest pain in the U.S., and the enormous research literature 
reporting on the comparative effectiveness of different options, no single diagnostic strategy has 
emerged with a broad consensus of support. Each testing community continues to favor its own 
technology and the clinicians who must select the testing approach to use for their patients are 
caught in the middle, unable to resolve the controversies that have characterized this area of 
cardiovascular medicine for decades. The situation is complicated by the heterogeneity of the 
current population’s burden of disease. More than a quarter (27%) of the PROMISE cohort had no 
coronary plaque whatsoever, while high-risk CAD, defined as left main stenosis (≥50% stenosis) or 
either (a) ≥50% stenosis ‘[50]’ or (b) ≥70% stenosis ‘[70]’ of 3 vessels or 2-vessel CAD involving 
the proximal left anterior descending artery was identified in 6.6% [50] and 2.4% 
[70] of patients. Thus, the first goal of any optimal management strategy for stable symptoms in 
patients with suspected CAD is determination of an individual patient’s risk. Using the PROMISE 
Risk Tool to accurately assess patient risk33, 34, we will prospectively test the hypothesis that low 
risk patients can be correctly identified with only baseline clinical data and that emphasizing 
guideline-recommended care while deferring testing in these patients improves chest pain decision 
making by reducing unnecessary invasive angiography without leading to an increase in MACE, and 
by reducing cost. 
 
Among patients in whom contemporary risk evaluation suggests an elevated risk for obstructive 
CAD, the observational data suggest that cCTA with selective FFRCT may improve appropriate 
triage to invasive angiography5, 23, while reducing cost9. 
 
Thus, the case for an adequately powered randomized clinical trial with a pragmatic design, 
comparing clinical outcomes following testing strategies regularly used in current clinical practice to 
a precision evaluation strategy is compelling. PRECISE is designed to be that trial. 
 
If the findings of PRECISE are positive as hypothesized, it is expected that the trial will lead to 
updates in appropriate use criteria, clinical practice guidelines, and payer policies such that cCTA 
with selective FFRCT receives a class IA recommendation for stable chest pain patients to improve 
outcomes and reduce costs. PRECISE will identify those chest pain patients for whom non- invasive 
testing may be safely deferred and simultaneously improve the efficiency of testing for elevated risk 
patients. The results of this study will shift the paradigm of clinical thinking in this area from the 
current approach of identifying a single best test for all, to incorporating a patient- centric risk-based 
evaluation and management strategy for stable chest pain patients. 
 
 
IV. STUDY OVERVIEW AND OBJECTIVES 
 
IV.A. Overview of PRECISE 
 
PRECISE is a multicenter, randomized, trial that will enroll approximately 2100 participants in a 
comparison of a risk-based precision evaluation strategy of guideline-recommended medical 
management without planned testing (in minimal risk participants) and cCTA with selective FFRCT 
(in elevated risk participants) with usual care in stable symptomatic patients with suspected 
significant CAD. 
 
Location 
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Participants will be enrolled at approximately 100 sites in the US and outside of the US. No center 
may enroll more than 315 (15%) participants in the trial. 
 
Participant Population and Selection 
Participants will be symptomatic patients with suspected significant CAD and a stable clinical 
course who are recommended by their managing clinician to have a non-invasive diagnostic test 
or ICA. Patients will be excluded if they have any history of documented CAD (including 
revascularization, myocardial infarction or any degree of CAD proven by imaging) or have had 
diagnostic cardiovascular testing for suspected CAD within the last year. Patients will also be 
excluded if their symptoms are not clearly stable or if their managing clinician feels testing is needed 
on an urgent or emergent basis. 
 
Diagnostic testing for the assessment of CAD symptoms is ordered by physicians and other 
clinicians from many specialties and is performed in multiple settings, including physician offices, 
hospital outpatient departments, and diagnostic testing facilities. A trial, such as PRECISE, that 
seeks to improve the management of non-ACS chest pain must incorporate this diversity in order to 
be broadly relevant to the target population under study. PRECISE site selection will seek to 
encompass this diversity. 
 
Study duration 
The anticipated total duration of the PRECISE study will be approximately 36 months for start-up, 
enrollment, follow up, and close out. Participants will be followed for 12 months after enrollment. 
 
Study design 
The figure below represents a diagrammatic representation of the trial design. 
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IV.B. Primary Objective and Endpoints 
 
The primary objective of the PRECISE study is to assess clinical outcomes, patient-reported 
outcomes, decision making regarding noninvasive testing and invasive angiography, and costs 
using a precision evaluation strategy as compared to a usual care strategy in participants with 
stable symptoms suggestive of significant coronary artery disease. The precision evaluation 
strategy will be based on a pre-test risk assessment which will be used to assign participants to 
either  cCTA with selective FFRCT or guideline-recommended care with symptom and risk factor 
management and no immediately planned testing. In addition, patients with known mild coronary 
plaque without obstructive stenosis or extensive coronary calcium randomized to the precision 
evaluation arm are mandated to undergo cCTA +/- FFRCT, independent of their PROMISE risk 
score strata. We hypothesize that in stable patients with a clinical recommendation for testing to 
evaluate suspected significant CAD, the proposed precision evaluation strategy will improve 
outcomes and reduce costs compared to usual care evaluation. 
 
The primary endpoint is a composite of: MACE (all cause death and non-fatal MI) or invasive 
cardiac catheterization without CAD (no coronary stenosis ≥50% according to QCA by core-lab 
adjudication or site interpretation if QCA is not available, or with FFR≤0.80, instantaneous wave 
free ratio (iFR) ≤0.89) or other validated NHPR. The primary study hypothesis will be tested at one 
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year using an intention to treat analysis. 
IV.C. Secondary Endpoints 
 
Endpoints will be assessed at 45 days, 6 months, and 1 year. Secondary endpoints include: 
1. Hierarchical analysis (Finkelstein and Schoenfeld (FS) and Pocock’s win ratio) of primary 
endpoint (gives priority to clinical importance of the components of the composite outcome 
rather than time to event) 
2. Resource use patterns (all participants) and medical costs (US participants): resources to be 
assessed include index testing, follow up testing, diagnostic and other cardiac procedures and 
hospitalizations. Primary comparisons will be made at 12 months. 
3. QoL: the Seattle Angina Questionnaire (SAQ) will be used to assess angina-specific Quality of 
Life; the EuroQoL 5D (EQ-5D-5L) survey will be used for a brief assessment of overall (generic) 
health status; patient satisfaction with diagnostic process will be assessed once at 45 days 
using a 4-item instrument created for this trial. 
4. Death: All-cause, cardiovascular, non-cardiovascular 
5. Myocardial infarction: All, procedural, spontaneous MI 
6. Hospitalizations: All, cardiovascular, non-cardiovascular, and for progressive or unstable 
angina 
7. Rates of preventive medication use (ASA, statins) in participants with clinical indication for use: 
hyperlipidemia, diabetes, documented CAD 
8. Cumulative radiation exposure at 1 year 
9. Proportion of invasive coronary angiogram patients who undergo revascularization (PCI or 
CABG) within 6 months of enrollment (catheterization efficiency) 
 
 
IV.D. Rationale for the Selection of Outcome Measures 
 
Rationale for Clinical Assessments 
Major adverse cardiovascular events (MACE) are a primary concern for clinicians and patients 
presenting with stable chest pain. The primary composite endpoint of MACE at 12 months (all cause 
death, non-fatal MI), invasive cardiac catheterization without obstructive CAD (diameter stenosis 
≥50% by QCA, FFR≤0.80 or iFR≤0.89) is clinically relevant and, the components taken together, 
represent a sound measure of an effective diagnostic chest pain evaluation4, 5, 35, 36. The selection of 
12 months is based on the rationale that the longer the duration between the evaluation strategy 
and an eventual outcome, the less likely it is that the evaluation strategy is directly related to the 
outcome of interest. In PROMISE, there was a significant reduction in death and MI in the cCTA arm 
compared to the usual care arm at 12 months, which was no longer significant after a median 25 
months of follow-up5. The use of this composite clinical endpoint will be critical to assessing the 
PRECISE hypothesis that a precision evaluation strategy with cCTA and selective FFRCT and 
guideline-recommended medical management without planned testing will yield superior outcomes 
at lower cost compared with a usual care testing strategy. 
 
Rationale for Economic and Quality of Life (QoL) Assessments in PRECISE 
Non-invasive diagnostic testing for the evaluation of stable chest pain represents a significant cost 
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to the U.S. and other healthcare systems. In the past when payers in the US have attempted to 
control costs by reducing the reimbursements provided for diagnostic testing, clinicians responded 
by increasing the number of tests obtained. An emphasis on generating evidence for cost-savings 
via a safer and more efficient approach is critical in enhancing value while reducing the financial 
burden on patients, providers, and the system alike. In addition, this precision-based approach to 
diagnostic evaluations in CAD participants may result in improvements in the quality of care of our 
participants. Further, since there has been no prospective trial of guideline- recommended care 
without planned testing, the ability of such an approach to provide equivalent symptom relief 
compared with usual care is of great importance and critical to the evaluation of this approach. For 
these reasons, the potential impact of a precision-based approach on resource use and QoL must 
be evaluated in PRECISE. 
 
IV.E. Rationale for Selection of Testing in Each Arm 
 
Usual Care Arm 
Functional stress testing with stress nuclear, stress echocardiography, and exercise ECG for the 
diagnosis of CAD is well-established in clinical practice (ACC/AHA 2012 Stable Ischemic Heart 
Disease guidelines, class I, Level of Evidence (LOE) B37. While stress CMR is less commonly used, 
it also receives a class IIa, LOE B recommendation in patients who are unable to exercise37 and is 
used in some centers. In contrast, it is common for patients to be referred direct to diagnostic 
angiography without undergoing a functional test. This group represents up to 50% of elective 
catheterization populations and is thus an important usual care approach to suspected CAD35, 38, 39. 
In order to accurately capture the wide variety of testing strategies available to and used by 
community clinicians and real-world practice patterns, a usual care strategy arm with site clinician 
decision-making should include all of the above options. This will improve the generalizability of the 
trial while accurately capturing the potential impact of the implementation of a precision approach. 
Participants with history of known obstructive CAD (prior myocardial infarction, CABG or PCI, 
stenosis ≥50%) are excluded from enrollment into the trial. In all participants in the usual care arm, 
cCTA is prohibited as a subsequent test for the first 45 days after randomization. 
 
 
Precision Evaluation Arm 
PRECISE will evaluate whether a precision evaluation strategy that combines contemporary risk 
stratification using the PROMISE Risk Tool with functional and anatomic non-invasive evaluation 
with cCTA with selective FFRCT can improve outcomes over usual care in stable chest pain patients 
while safely deferring further testing in low-risk patients and reducing cost overall. While current 
guidelines recommend the non-invasive and invasive initial testing approaches for patients with 
stable chest pain37, current practice is known to lead to high rates of ICA without obstructive CAD6, 
40. Further, although guidelines also recommend no testing in the lowest risk groups (pre-test 
probability of obstructive CAD <10 or 15%), currently available risk tools result in many clinicians 
appearing to ignore this recommendation: current patterns of care using available risk stratification 
tools results in testing populations with a prevalence of obstructive CAD of only 10-20%, and a 
prevalence of no coronary plaque of >25%4, 5. The intervention in PRECISE will triage patients into 
two risk groups who will be assigned to receive either guideline-recommended medical management 
without planned testing  or cCTA with selective FFRCT. The PROMISE Risk Tool can identify low-
risk patients with stable chest pain that would be expected to derive minimal value from noninvasive 
testing and is superior to either Framingham Risk Score or Diamond and Forrester assessments33, 
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34. cCTA with selective FFRCT represents a combined functional and anatomic testing modality that 
can lower the frequency of finding no obstructive CAD at catheterization and thus reduce costs7, 41. 
 
 
IV.F. Randomization Method 
 
Participants who meet all inclusion criteria and none of the exclusion criteria will be randomized in 
a ratio of 1:1 within a clinical center to either a precision evaluation strategy or usual care using an 
interactive web or voice-based system (IXRS). Randomization will be stratified by intended first test 
(if randomized to usual care) and by classification as low vs. elevated risk by the minimal risk model. 
Participants with known non-obstructive plaque will be included in the elevated risk strata 
regardless of risk score. The randomization scheme within a clinical center will be carried out by 
the method of random permuted block design with variable block size. 
 
Enrollment in the randomization strata of intended first test being noninvasive (vs. direct to 
catheterization) will be capped at 90% of the sample size. 
 
Risk will be classified by a risk tool using pre-test clinical characteristics (including tobacco usage, 
ethnicity, and age) derived in the PROMISE trial and validated in SCOT-HEART or by the presence 
of non-obstructive plaque/CAC < 100 AU. Participants randomized to follow a precision strategy 
group will be assigned to either guideline-recommended care with symptom and risk factor 
management and no immediately planned testing (low risk group) or cCTA with selective FFRCT 
(elevated risk of obstructive coronary disease and/or events). Participants randomized to precision 
evaluation and risk stratified into the low risk group and their providers will be provided informational 
materials explaining the rationale for this decision and the safety of this strategy based on outcomes 
of similar participants in the PROMISE trial. 
 
Participants randomized to usual care will undergo either noninvasive stress testing or invasive 
testing (direct to diagnostic catheterization), as recommended by their managing clinician and 
agreed to by the participant. Acceptable noninvasive testing options will include exercise 
electrocardiogram, stress nuclear imaging (including PET), stress MR or stress echocardiogram. 
The use of cCTA is explicitly excluded as the initial diagnostic strategy in this arm and prohibited 
as a subsequent test for the first 45 days after randomization. 
 
In both arms, all subsequent decisions regarding additional testing, medications, and/or procedures 
will be at the discretion of the responsible clinical care team. Each care team will be provided with 
informational materials summarizing current standards for test interpretation and preventive care. 
However, specific medical treatment will not be mandated by the study. 
 
IV.G. Diagnostic Evaluations and Subsequent Care 
 
Description of Evaluations to be performed 
Participants will be assessed per the individual clinicians’ routine approach to patients presenting 
with stable chest pain. Initial evaluation will include an appropriate medical history, physical 
examination, resting 12-lead ECG, and other routine blood work. A pregnancy test will be required 
for female participants of childbearing potential (those who have not been surgically sterilized or 
are not postmenopausal), and a creatinine blood test will be required for participants without a 
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recent normal value (most recent measurement taken within previous 90 days).  At the time of 
randomization, the site clinician will specify the preferred first diagnostic strategy (noninvasive 
stress test vs. direct to catheterization) if randomized to the usual care arm and this choice will be 
used to stratify randomization. Also part of the randomization process, every participant will 
undergo risk stratification with the PROMISE risk calculator although sites will be blinded to results. 
Participants randomized to the precision evaluation arm will be assigned to either no planned 
testing vs cCTA/FFRCT based on risk score results and the presence of known non-obstructive 
coronary atherosclerosis.  
 
Sites will be provided with informational materials outlining standards of care for all noninvasive 
test interpretation. Guideline recommendations for care and informational materials on symptom 
and risk factor management will also be provided. These are intended to be followed for all 
participants. Participant-friendly versions of these materials will be provided to sites and may be 
used as handouts. 
 
Symptoms and Quality of Life (QoL) will be assessed by the EuroQoL 5D (EQ-5D-5L) survey to 
assess overall (generic) health status and the Seattle Angina Questionnaire (SAQ) to assess 
angina-specific Quality of Life. 
 
Equipment, Protocols & Interpretation 
All participating sites will use standard equipment and procedures for usual care testing, including 
diagnostic angiography, stress echocardiography, stress nuclear perfusion imaging, stress CMR, 
and exercise ECG as defined by current practice guidelines42-49. Sites must also use at least 64- 
slice multi-detector computed tomography (MDCT) for coronary cCTA49, 50. All testing protocols will 
be in accordance with current best-practice standards42-48, 50. 
 
Interpretation 
The interpretation of all diagnostic tests will be performed in a timely fashion and will capture the 
presence and extent of findings including diagnosing or excluding CAD (diagnostic angiography), 
fixed or inducible LV perfusion and wall motion abnormalities (stress echo, cMR and stress 
nuclear), and functional capacity (in the case of exercise ECG, exercise echo and exercise nuclear). 
The site interpretation and clinical report of all diagnostic tests, including noninvasive stress testing, 
cCTA and invasive angiography, will be uploaded through the EDC. 
 
cCTA study interpretation will be carried out by site physicians with at least ACC COCATS (Core 
Cardiology Training Symposium) level 2 training, Society of Cardiovascular Computed Tomography 
level 2, recognized by the Certification Board of Computed Cardiovascular Tomography, or 
equivalent50. Certification by the Certification Board of Nuclear Cardiology or Board Certification in 
nuclear medicine or radiology will be considered satisfactory for interpretation of stress nuclear 
imaging studies. Stress echo and cMR readers also be at least COCATS level 2 trained or 
equivalent. Prior to being opened to participant enrollment, sites will be certified to ensure that 
quality cCTA images can be obtained. 
 
Referral of precision evaluation cCTA participants for FFRCT determinations 
Participants randomized to the precision evaluation arm who are either 1) determined to be at 
elevated risk or 2) have known non-obstructive coronary atherosclerosis will undergo cCTA as the 
initial diagnostic strategy according to current best practice standards. Image sets showing at least 
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one 30-90% stenosis in epicardial vessels of 2mm diameter or greater should be promptly sent to 
HeartFlow for analysis of FFRCT. Results will be returned to sites in < 24 hours to enable rapid 
incorporation into clinical decision making.  
Subsequent Care 
Subsequent care will be provided by the individual site clinicians at their own discretion, with 
encouragement to follow guideline-based approaches. Information will be provided to the individual 
sites on diagnostic test interpretation and subsequent management approaches for the various 
imaging modalities, including relevant guideline recommendations for primary and secondary 
prevention. 
For patients in the Precision Evaluation Arm, ICA should not be performed unless at least one of 
the following criteria are met: 
x 
Any stenosis ≥90% identified by cCTA 
x 
Left Main stenosis ≥30% identified by cCTA 
x 
Plaque rupture identified by cCTA 
x 
Lesion-specific FFRCT ≤0.85 in vessels with reference vessel diameter of 2.0mm or greater   
 
Need for testing in low risk participants randomized to the precision care arm 
Participants randomized to the precision evaluation arm and determined to be at low risk will be 
treated for symptoms and risk factor management according to current guideline recommendations. 
While it is expected that this will resolve symptoms in nearly all cases it is recognized that chest 
pain will persist in some despite medical treatment. In some cases, additional non-cardiac 
diagnostic testing may be pursued. In other cases, the site clinician may decide that further cardiac 
testing is warranted, in which case a cCTA followed by selective FFRCT should be performed. Details 
regarding such decision making will be captured in the case report form. 
 
 
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V. STUDY PROCEDURES 
V.A. Patient Screening for Eligibility 
 
Patients will be screened by site personnel for eligibility and provided information about the study. 
Patients’ not meeting inclusion and or having exclusion criteria will be documented as being 
excluded. Patients meeting inclusion and not meeting any exclusion criteria will be provided an 
informed consent form to review and sign prior to being randomized into the study. 
 
Inclusion Criteria 
 
1. 
Age ≥18 years 
2. 
Stable typical or atypical symptoms suggesting possible significant coronary artery disease 
(CAD) with further non-emergent testing or elective catheterization recommended to evaluate the 
presence of suspected significant CAD.  Stable chest pain (or equivalent) includes those who 
have fully been ruled out for Acute Coronary Syndrome (ACS) and for whom elective testing is 
recommended, regardless of the venue in which they are seen.  
3. 
If prior CV testing has occurred, it must have been performed greater than one year prior to 
randomization, and the following must be met: 
a) 
cCTA or invasive coronary angiography (ICA) with stenosis < 50% 
b) 
Quantified coronary artery calcium (CAC) < 100 AG 
4. 
Safe performance of cCTA: 
a) 
Creatinine clearance ≥45 ml/min per most recent measurement within 90 days 
b) 
For a female participant of childbearing potential (those who have not been surgically 
sterilized or are not postmenopausal), a pregnancy test must be performed with 
negative results known within 7 days prior to randomization 
5. 
Willingness to comply with all aspects of the protocol, including adherence to the assigned 
strategy and follow-up visits regardless of actual testing performed 
6. 
Ability to provide written informed consent 
 
Exclusion Criteria 
 
1. 
Acute chest pain (in patients who have not been ruled out for ACS) 
2. 
Unstable clinical status 
3. 
Noninvasive or invasive CV testing for CAD within 1 year. CV testing for CAD refers to any 
stress tests, invasive coronary angiography (ICA), and cCTA (including calcium scoring) only. 
a) Resting ECG, resting echocardiogram and resting CMR (MRI) are not exclusionary 
regardless of when they were performed. 
4. 
Lifetime history of known obstructive CAD (prior myocardial infarction, CABG or PCI, stenosis 
≥50%), known EF≤40% or other moderate to severe valvular or congenital cardiac disease 
5. 
Contraindications to cCTA including but not limited to creatinine clearance (GFR) <45 ml/min 
as per most recent measurement taken within 90 days 
6. 
Exceeds the site’s weight or size limit for cCTA or cardiac catheterization  
7. 
Any condition leading to possible inability to comply with the protocol procedures and follow-up  
8. 
Any condition that might interfere with the study procedures or follow-up 
9. 
Enrolled in an investigational trial that involves a non-approved cardiac drug or device which 
has not reached its primary endpoint 
10. Life expectancy less than 2 years due to non-cardiovascular comorbidities 
 
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Screening visit (in-person) 
 
Participant will be randomized to either the usual care arm or the precision evaluation arm within 
14 days of screening. 
 
At the screening visit, patients will undergo the following: 
x 
Review consent form and have all questions appropriately answered. 
x 
Provide consent by signing the Informed Consent Form 
x 
Review of medical history 
x 
Review of concomitant medications 
x 
Pregnancy test (for females of child-bearing potential – those who have not been surgically 
sterilized or are not postmenopausal) 
x 
Creatinine test (if not done in last 90 days) 
Resting 12-lead ECG (optional, clinical care only) Assessment of CAD risk will be performed during 
screening to ensure eligibility. It will include: 
x 
General medical history 
x 
Cardiovascular risk factors and comorbidities as well as prior testing or events 
x 
Physical exam 
x 
Laboratory testing 
The following major cardiac risk factors will be assessed: 
x 
Age 
x 
Sex 
x 
BP/hypertension 
x 
Diabetes 
x 
Cholesterol (including low-density lipoprotein [LDL], high-density lipoprotein [HDL]), if 
available 
x 
Smoking status 
x 
Family history 
x 
Sedentary life style 
x 
Obesity (BMI, waist hip ratio) 
x 
Cerebrovascular and peripheral arterial disease (PAD) 
x 
Ankle brachial index (ABI) 
 
V.B. Randomization and Enrollment 
 
Once a participant has consented to participate in the trial, participant information will be entered 
into the database. If a patient is a screen failure, the data that has been collected up until this point 
for the patient for screening purposes will be entered into the case report forms (CRF) in the 
electronic data capture (EDC) system. No additional information will be collected after this point for 
such a patient. 
For eligible participants, medical history data will be captured in the EDC. In addition, sites will need 
to specify the intended first test which would be performed if the participant is randomized to the 
usual care arm. The participant will then be randomized to either the usual care arm or the precision 
evaluation arm. Once randomization occurs, the participant is considered enrolled in the study. If 
randomized to the precision evaluation arm, participants will be further assigned to guideline-
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recommended without planned testing or cCTA with selective FFRCT. 
 
V.C. Participant Cohort Assignment 
 
Participant will be randomized to either the usual care arm or the precision evaluation arm within 
14 days of screening. 
 
Usual Care Arm 
Participants randomized to the usual care arm will undergo either noninvasive stress testing 
(exercise electrocardiogram, stress nuclear imaging including PET, stress MR, or stress 
echocardiogram), with the specific modality at the discretion of the participant’s clinician, or invasive 
catheterization. In all participants in the usual care arm, cCTA is prohibited as a subsequent test 
for the first 45 days after randomization. 
 
Precision Evaluation Arm 
Participants randomized to the precision evaluation arm will be assigned a management approach 
based on their PROMISE Risk Score, a risk model based on pre-test clinical characteristics derived 
from the PROMISE trial and validated in SCOT-HEART34 or the presence of known non- obstructive 
atherosclerosis. Participants will be assigned to either 1) guideline-recommended medical 
management without planned testing (low risk) or 2) cCTA with selective FFRCT (elevated risk or 
those with known plaque. independent of the PROMISE Risk Tool assessment).  Participants 
assigned to the strategy of guideline-recommended medical management without planned testing 
will be treated with risk-appropriate preventive care and symptom control (including therapeutic 
trials of anti-anginal medications). Participants and their providers will be provided informational 
materials demonstrating the safety of this strategy based on pre-test probabilities and the 
PROMISE Risk Score. Participants with intractable symptoms despite maximal medical 
management whose clinicians opt for further testing (crossovers) will undergo cCTA with selective 
FFRCT. 
 
Participants undergoing cCTA as the initial test (both assigned or crossover) should have FFRCT 
analysis ordered if cCTA shows at least one 30-90% stenosis in epicardial vessels of 2mm diameter 
or greater. Image sets will be sent promptly to HeartFlow for analysis and results will be returned 
to sites in < 24 hours to enable rapid incorporation into clinical decision making. 
 
V.D. Participant Follow-Up 
 
Participants will be followed up at 45 (+/-14) days and at 6 and 12 months (+/- 30 days) after 
enrollment. For US participants, follow-up at 45 days and at 6 and 12 months will be done by phone 
interviews conducted by the DCRI Outcomes Call Center, unless not allowed by their enrolling site. 
For participants outside of the US, follow-up will be conducted by the site coordinators. 
 
Activities to be conducted at each follow up contact are described below and in the Schedule of 
Events. 
45 (+/-14) day follow-up visit (in-person, portions may be done by phone) At the 45-day follow-up 
visit, participants will be asked the following: 
x 
Assessment if any MACE has occurred since enrollment 
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x 
CV Update: Review and documentation of any cardiovascular diagnostic test, 
cardiovascular procedure, or hospitalizations/clinic visits due to cardiovascular symptoms 
and complications since enrollment 
x 
Review and documentation of concomitant cardiovascular medication changes since 
enrollment 
x 
Complete the following 3 questionnaires: 
o Seattle Angina Questionnaire 
o EQ-5D-5L Questionnaire 
o Participant Satisfaction Questionnaire 
x 
Collection of the following: 
o Any cardiovascular test – both written report and test output 
o Any cardiovascular imaging – both written report and image file 
 
6 months (+/-30 days) follow-up contact 
At the 6-month follow-up contact, participants will be asked the following: 
x 
Assessment if any MACE has occurred since the 45-day visit 
x 
CV Update: Review and documentation of any cardiovascular diagnostic test, 
cardiovascular procedure, or hospitalizations/clinic visits due to cardiovascular symptoms 
and complications since last visit 
x 
Review and documentation of concomitant cardiovascular medication changes since 
enrollment 
x 
Complete the following 2 questionnaires: 
o Seattle Angina Questionnaire 
o EQ-5D-5L Questionnaire 
x 
Collection of the following: 
o Any cardiovascular test – both written report and test output 
o Any cardiovascular imaging – both written report and image file 
 
12 months (+/-30 days) follow-up contact 
At the 12-month follow-up visit, participants will be asked the following: 
x 
Assessment if any MACE has occurred since the 6-month visit/phone call 
x 
CV Update: Review and documentation of any cardiovascular diagnostic test, 
cardiovascular procedure, or hospitalizations/clinic visits due to cardiovascular symptoms 
and complications since last visit 
x 
Review and documentation of concomitant cardiovascular medication changes since 
enrollment 
x 
Complete the following 2 questionnaires: 
o Seattle Angina Questionnaire 
o EQ-5D-5L Questionnaire 
x 
Collection of the following: 
o Any cardiovascular test – both written report and test output 
o Any cardiovascular imaging – both written report and image file 
 
V.E. Testing in precision evaluation arm for participants assigned to no immediate testing 
Precision evaluation participants determined to be at very low risk and assigned to the strategy of 
guideline-recommended medical management with no immediately planned testing are highly 
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unlikely (by definition) to have significant obstructive CAD. The managing clinician is encouraged 
to treat them with guideline-recommended preventive care, anti-anginal medications and other 
medical therapy as deemed appropriate to their clinical circumstances. This is expected to control 
or eliminate symptoms in most participants.  In the unlikely event that symptoms are intractable or 
accelerating, despite reasonable medical treatment or if other compelling reasons for additional 
evaluation are present, testing may be warranted.  
Unless there are urgent or emergent indications to proceed with invasive testing, all such 
participants requiring testing should have a cCTA followed by selective FFRCT rather than stress 
testing or elective invasive catheterization. cCTA with selective FFRCT should only be pursued if 
the participant is having: 
1. Unstable/accelerating symptoms (i.e. no longer falls into stable angina cohort) 
2. Continued stable symptoms despite risk factor modification including: 
a) Optimized blood pressure control with goal <130/80 mmHg 
b) Optimized lipid management with high-intensity statin in appropriate patients 
c) Optimized diabetes management with blood glucose control in appropriate patients 
d) Antiplatelet therapy in appropriate patients 
e) Tobacco cessation in patients who smoke 
f) Lifestyle counseling regarding diet exercise and stress reduction 
g) Anti-anginal therapy including utilization of beta-blockers, calcium channel blockers, 
short and long-acting nitrates, and/or ranolazine 
The assignment to no immediate testing is not time limited and is valid for the duration of the 
participant’s enrollment in the trial. Testing in such participants should be infrequent and the reasons 
for this will be carefully documented and monitored. 
 
V.F. Participant Withdrawal 
 
In accordance with the Declaration of Helsinki, each participant is free to withdraw from the study at 
any time. Investigator(s) also have the right to withdraw participants from the study in the event of 
illness or other reasons concerning the health or wellbeing of the participant, or in the case of lack of 
cooperation. Should a participant decide to withdraw or should the investigator(s) decide to withdraw 
the participant, all efforts will be made to complete and report the observations up to the time of 
withdrawal as thoroughly as possible. If possible, a complete final evaluation at the time of the 
participant’s withdrawal should be made. The reason for withdrawal must be noted in the eCRFs. 
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PRECISE Protocol 
  
 
 
  CP-907-001-A 
Oct 11, 2019 v1.5 
 
V.G. Schedule of Assessments 
 
 
 
Screening 
Randomization 
Day 1 
Day 45 
( +/-14 d) 
6-mo. 
(+/- 30d) 
12-mo. 
(+/- 30d) 
Informed consent 
X 
 
 
 
 
Medical history 
X 
 
 
 
 
Cardiovascular update 1 
 
 
X 
X 
X 
Concomitant cardiovascular medications 
X 
 
X 
X 
X 
Cardiovascular risk factors (including PROMISE 
minimal risk score data entry for randomization) 
X 
 
 
 
 
2 
Pregnancy test 
X 
 
 
 
 
3 
Creatinine 
X 
 
 
 
 
4 
Resting 12-lead ECG 
X 
 
 
 
 
QoL evaluation: SAQ, EQ5D-5L 
X 
 
X 
X 
X 
Participant Satisfaction Questionnaire 
 
 
X 
 
 
Randomization 
 
X 
 
 
 
Initial diagnostic invasive or noninvasive test 
performed (if assigned) 
 
Prior to 45 day 
visit 
 
 
 
Cardiac imaging/testing clinical report and image 
collection 
 
 
X 
X 
X 
Interval assessment for CV events and testing 
 
 
X 
X 
X 
Endpoint assessments 
 
 
X 
X 
X 
1. 
During cardiovascular update, if participants have received an additional diagnostic test, a cardiovascular procedure or have been hospitalized since the 
last visit, additional data will be collected 
2. 
For a female participant of childbearing potential, a pregnancy test must be performed with negative results known within 7 days prior to randomization 
3. 
Creatinine blood draw required only for participants without a recent normal value (most recent within previous 90 days) 
4. 
Resting 12-lead ECG preferred in last 30 days (optional, clinical care only) 
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VI. ADDITIONAL ASSESSMENTS AND SUBSTUDIES 
VI.A. Quality of Life Assessments 
 
A short battery of instruments will be used to provide a relevant assessment of health-related quality 
of life that will capture the most likely health benefits to be associated with the precision strategy 
while not being burdensome to study participants. Quality of life (QoL) assessments will be 
conducted at baseline, 45 days, 6 months, and 12 months. Chest pain specific QOL will be assessed 
with the Seattle Angina Questionnaire (SAQ). While the full instrument has 19 items covering 5 
dimensions of the impact of chest pain on QoL, we will use the scales for physical limitations, angina 
frequency, and disease perception/quality of life (14 items total)1. These three scales will also allow 
calculation of the recently described 7-item short SAQ2. The SAQ has been used as the primary 
disease-specific QoL outcome measure in a number of major clinical trials (including COURAGE, 
PROMISE, and ISCHEMIA) and is useful for this trial because it assesses chest pain and its impact 
on functioning and well-being regardless of whether the symptoms are due to coronary disease or 
are non-coronary. Since many participants in this study will be found not to have significant coronary 
disease and will be provided with that reassuring finding, the SAQ will allow us to assess the extent 
to which such information is associated with changes in the 3 dimensions noted above. 
Overall health status will be assessed briefly using the EQ-5D-5L, a standardized generic measure 
that can also be used to link specific health states to general population-based utilities5. The EQ-5D-
5L consists of two parts: (1) a descriptive assessment of five dimensions (mobility, self-care, usual 
activities, pain/discomfort, anxiety/depression), each of which can take one of five responses 
corresponding to the level of severity within each dimension, and (2) a self-rating 0- 100 
"thermometer" of current health-related quality of life. 
 
VI.B. Economic and Resource Utilization Assessments 
 
The primary economic analyses in PRECISE will be performed from the perspective of the US health 
care system. Detailed information regarding the quantity and cost of health care services received 
by participants in each treatment group will be collected prospectively as part of the trial. Relevant 
health care resource consumption during initial testing through 1-year follow-up will be collected on 
the clinical trial electronic case report form (eCRF). (The cost of acute and non-acute hospital care 
will be derived from billing data collected from patients enrolled at US sites.) Physician and other 
outpatient care reported in the eCRF will be valued using secondary sources. Primary resource use 
and cost comparisons will be based on participants enrolled in the US. Secondary analyses will 
examine the consistency of treatment related differences in resource use in the US with the sites 
outside the US. 
 
VI.C. Imaging and other Cardiac Assessments 
 
For all participants in either arm in whom an invasive coronary angiogram is performed, procedural 
reports and angiographic images will be uploaded via the electronic data capture (EDC) system to 
create an angiographic image repository. In addition, the report, as well as imaging and / or graphic 
data from any procedures performed to assess stenosis significance or severity such as, FFR, iFR, 
IVUS, OCT should be uploaded. Similarly, for all participants receiving cCTA imaging, the cCTA 
images and reports will be uploaded via the EDC system to create an image repository. Invasive 
angiography will be evaluated by a core lab for QCA; other core lab(s) may be added to analyze 
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additional images. 
VII. ENDPOINT DETERMINATION, SAFETY, AND MONITORING
VII.A. Primary Endpoint Definitions 
Major Adverse Cardiovascular Events (all cause death, non-fatal myocardial infarction) All cause 
death 
All cause death is defined as death resulting from any cause. In addition, the cause of death will 
be adjudicated, including cardiovascular death defined as death due to myocardial infarction, 
sudden cardiac death, heart failure, stroke, cardiovascular procedures, cardiovascular 
hemorrhage, or death due to other cardiovascular causes51. 
Myocardial infarction 
Acute myocardial infarction (MI) is defined as having evidence of myocardial necrosis in a 
clinical setting consistent with myocardial ischemia. Specifically, the Fourth Universal 
Definition51 of type I MI is defined as: 
Detection of a rise and/or fall of cTn values with at least 1 value above the 99th percentile URL and 
with at least 1 of the following: 
x
Symptoms of acute myocardial ischemia;
x
New ischemic ECG changes;
x
Development of pathological Q waves;
x
Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality
in a pattern consistent with an ischemic etiology;
x
Identification of a coronary thrombus by angiography including intracoronary imaging or by
autopsy.*
cTn indicates cardiac troponin; ECG, electrocardiogram; URL, upper reference limit. 
*Postmortem demonstration of an atherothrombus in the artery supplying the infarcted myocardium,
or a macroscopically large circumscribed area of necrosis with or without intramyocardial hemorrhage,
meets the type 1 MI criteria regardless of cTn values.
A complete definition of the criteria for MI can be found in the Fourth Universal Definition of 
Myocardial Infarction (2018). This definition will be followed for spontaneous as well as 
periprocedural MIs, for which the elevation in cTn must be at least cTn values >5 times the 99th 
percentile URL for PCI and >10 times for CABG related infarctions51.  
Cardiac catheterization without obstructive coronary artery disease (diameter stenosis <50%, any 
FFR >0.80 or iFR >0.89) 
Cardiac catheterization without obstructive coronary artery disease will be defined as the 
absence of any >50% stenosis or hemodynamic indication of significance in any major 
epicardial vessel including side branches ≥2 mm in diameter, as determined by core-lab 
adjudicated QCA. The Steering Committee may consider the use of other validated NHPRS as 
they become clinically available. Equivalent cut points for each approved test will be determined 
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at that time.  
VII.B. Secondary Endpoint Definitions 
 
Hierarchical analysis 
Finkelstein and Schoenfeld (FS) and Pocock’s win ratio analysis of primary endpoint is defined 
in section VII B Statistical Analysis Plan. 
 
Resource use 
Resource use is defined as counts and types of baseline testing, follow up testing, diagnostic 
and therapeutic procedures, and both inpatient and outpatient care. Costs from the US perspective 
will be estimated. 
 
Quality of Life Metrics 
Quality of Life assessments to be completed by the participants are the Seattle Angina 
Questionnaire and the EQ-5D-5L. 
 
Death 
Death will be categorized as all-cause, cardiovascular, non-cardiovascular. 
 
Myocardial infarction 
Myocardial infarction will be characterized according to the 4th Universal MI definition for both 
spontaneous and for periprocedural MI51 MIs. 
 
Hospitalizations 
All, cardiovascular, non-cardiovascular, and for progressive or unstable angina. Urgent and 
unscheduled hospitalizations for other cardiovascular causes that do not meet the criteria for the 
specific events listed above will be classified as hospitalization for other cardiovascular causes (e.g., 
hospitalization for cardiac chest pain that does not meet the criteria for MI, hospitalization for 
arrhythmias, hospitalization for pulmonary embolism). Non-cardiovascular hospitalization are 
defined as any hospitalization whose primary cause is not thought to be CV in nature. 
 
Preventive medication use 
Information on preventive medication use will be acquired at study entry and 45 days. 
Participants with a clear clinical indication for use of ASA/antiplatelet agents and or, statins eg: 
hyperlipidemia, diabetes, documented CAD, will be characterized according to use/nonuse for each 
medication class. 
 
Radiation safety endpoint – cumulative dose at 1 year 
The cumulative radiation exposure over the 12 months following enrollment will be calculated 
based on the participant’s exposure to radiation for cardiovascular care from one or more of the 
following modalities. For cCTA, the administered radiation dose (computed tomography dose index 
volume and dose length product for cCTA) will be recorded by the individual sites. For stress nuclear 
imaging, the radiotracer dose(s) will be collected and converted to equivalent radiation doses for 
comparison to cCTA. For ICA, the radiation dose from fluoroscopy administered will be recorded by 
sites and converted using standardized approaches to allow for comparison to radiation from cCTA. 
In instances in which the information required to assess actual dose is not available, a standard 
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dose based on accepted average exposures will be imputed for that form of testing. Cumulative 
radiation exposure from additional cardiac testing and procedures during the entire follow-up period 
will also be collected. 
 
Catheterization efficiency 
The proportion of invasive cardiac catheterization patients who undergo revascularization (PCI 
or CABG) within 6 months of enrollment will be determined. 
 
VII.C Testing Complications and Reporting 
 
The study intervention is the implementation of a precision evaluation strategy compared to usual 
care evaluation in non-acute chest pain participants with no history of CAD or recent testing whose 
clinicians recommend non-emergent non-invasive testing or ICA. Since all trial procedures represent 
standard of care for the eligible study population, there are no specific safety events associated with 
investigative procedures in this trial. However, there are known complications from these clinically 
recommended tests and procedures which are outlined below. These complications will be reported 
by site personnel. 
 
For Precision Evaluation Strategy 
 
For Guideline-recommended Medical Management 
While participants assigned to the guideline-recommended care with no planned testing arm will 
have exceedingly low risk of events and are predicted to derive minimal or no value from noninvasive 
testing33, 34, there is a very small risk of missing left main or 3-vessel disease for which 
revascularization may be life-prolonging. 
 
For cCTA with selective FFRCT: 
Mild contrast reaction such as rash and hives. 
1. Severe contrast reactions including anaphylaxis or death occurring within 24 hours of 
contrast administration. 
2. Extravasation of contrast into the surrounding tissue of the extremity where contrast was 
administered intravenously. 
3. Symptomatic bradycardia or hypotension in relation to beta blockade or nitrates 
administered for cCTA. 
4. Acute bronchospasm following beta blockade administered for cCTA. 
 
For Usual Care (noninvasive or invasive testing) 
For exercise testing including during stress echo or stress nuclear (including PET): 
1. Hypotension defined as systolic BP less than 80 mmHg or fall in systolic BP >20 mmHg 
2. Stress-induced symptoms or ECG changes that do not resolve within 20 minutes 
3. Rapid atrial fibrillation that does not slow or convert with standard interventions 
4. Ventricular tachycardia 
5. Hospital admission not otherwise captured by pre-specified study endpoints, due to one 
of the above 
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For stress nuclear (including PET): 
1. Any adverse reactions potentially related to the use of vasodilators such as adenosine, 
regadenoson, or dipyridamole 
 
For stress echo: 
1. Any stress-induced wall motion abnormality that does not resolve within 20 minutes 
2. Any adverse reaction to echo contrast 
3. Any adverse reaction to dobutamine, including sustained ventricular tachycardia or 
other tachyarrhythmias 
 
For stress cardiac MRI: 
1. Any adverse reactions potentially related to the use of vasodilators such as adenosine, 
regadenoson, or dipyridamole 
2. Any adverse reaction to MRI contrast agents, including gadolinium-based agents 
 
For cardiac catheterization: 
1. Any adverse reactions potentially related to the use of sedatives, local anesthetics, 
contrast agent or other medication’s 
2. Any adverse reactions potentially related to arterial puncture and wire/catheter 
introduction 
3. Any adverse reaction to coronary catheterization including dissection, embolization, 
stroke, malignant arrhythmias and asystole, and death 
 
VII.D. Independent Clinical Event Adjudication Committee 
 
An independent clinical event committee (CEC) will be responsible for the blinded review and 
adjudication of the primary endpoint. The CEC will settle any disputes with committee review and 
discussion. Any uncertainty regarding the finding of cardiac catheterization without obstructive 
disease will prompt review of the original cardiac catheterization images for further independent 
adjudication. Collection of medical records and other documentation required for CEC reviews will 
be coordinated by the DCRI call center for US participants and by site coordinators for participants 
in all other regions. 
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VII.E. Data and Safety Monitoring Board 
 
An independent Data and Safety Monitoring Board (DSMB) will be appointed to monitor participant 
safety and to review study performance. The DSMB will periodically review the study data and 
assess participant safety and adherence to the study protocol. The DSMB will define the operating 
guidelines and processes for study evaluation, interim analyses, event triggers for unscheduled 
review; these will be agreed upon at the initial meeting of the DSMB. Periodic reports will be prepared 
by HeartFlow (or its designee) for the DSMB on based on the operational plan outlined by the DSMB 
charter. The DSMB will make its recommendations to the study Steering Committee and the sponsor 
following their meeting.  
 
VIII. Statistical Methods 
Separate, complete Statistical Analysis Plan (SAP) documents will be prepared for the clinical 
outcome analyses and the economics and quality of life (EQOL) outcomes. 
 
VIII.A. Sample Size Determination and Statistical Power 
 
Sample size and power calculations for this study are based on the hypothesis that the precision 
evaluation arm is superior to the usual care arm on the time-to-first event of the composite MACE 
endpoint (defined as: all-cause death, non-fatal MI) or invasive cardiac catheterization without 
obstructive CAD (obstructive CAD defined as diameter -stenosis ≥50%, FFR≤0.80 or iFR 
≤0.89). Time to event analysis will use the date of the event, including the date of catheterization 
which is used to determine the absence of obstructive CAD. Assuming 10% of usual care 
participants will receive angiography as a first test results in an 8% primary endpoint event rate at 1 
year in the usual care group and 5% (absolute) event rate in the precision care group (i.e., 37.5% 
relative effect size) with an estimated ~20% assigned to guideline-recommended care with symptom 
management and no planned testing. Assumptions used in the primary endpoint event rate 
calculations (i.e. 8% vs. 5%) were: an overall ~10% will not receive randomized testing and within 
the precision evaluation arm, 30% of those assigned to guideline-recommended care will cross over 
to cCTA with selective FFRCT. 
 
Enrolling 1050 patients per group (2100 total participants) would provide at least 90% power to 
detect a relative risk reduction of 37.5% in the precision evaluation arm. Sample size calculations are 
based on the log-rank test52 with 12-month accrual period, a 12-month follow-up in all participants , 
10% attrition rate (i.e., lost to follow- up, dropouts) and a two-sided type I error rate of 0.05. 
Table shows total number 
of participants needed for 
85%, 90% and 95% power. 
 
event-driven study, the 
table also provides total 
number 
of 
cath 
and 
MACE needed. 
Although, this is not an 
1-yr event rate 
in precision 
evaluation arm 
 
Power 
Total 
number of 
participants 
needed 
Total number 
of cath and 
MACE  
needed 
5% 
 
(37.5% effect 
size) 
85% 
1792 
173 
90% 
2096 
202 
95% 
2592 
250 
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Power curves (Figure: Long-Rank for Two Survival Curves) provide total sample size needed for 
several relative effect size (i.e., 1-hazard ratio) scenarios. 
Figure: Long-Rank for Two Survival Curves 
 
VIII.B. Statistical Analysis Plan 
Analysis of the Primary Endpoint 
The primary endpoint of this study is based on time-to-first occurrence of any of the  components, 
which is defined as a composite of MACE (all-cause death, non-fatal MI) or invasive cardiac 
catheterization without obstructive CAD (obstructive CAD defied as diameter stenosis ≥50%, 
FFR≤0.80, or iFR≤0.89) over 12-month follow-up. The time from randomization to the first event 
among the components of the primary endpoint will be measured (in days) for those who 
experienced an event and calculated as the date of the first event minus the date of randomization. 
For participants who do not experience any of the primary endpoint component events or who 
withdraw consent or drop out of the study before experiencing an event, time from randomization 
to the date of last contact will be used in the analysis, and those participants will be considered as 
censored observations in the time-to-event analysis. 
The primary and secondary endpoint comparisons between the randomized groups in this study 
will be performed according to the principle of "intention-to-treat" (ITT); that is, participants will be 
analyzed according to the treatment arm to which they were randomized, regardless of subsequent 
crossover or post-randomization strategy. 
The log-rank test53 will be the primary analytic tool for statistically assessing outcome differences 
between the two randomized treatment strategies with respect to the primary composite endpoint. 
Cox proportional hazards model54 will be used to estimate the hazard ratio (HR) and 95% 
confidence interval (CI) summarizing the difference in outcome between the two randomized arms, 
using treatment as the only predictor in the model. Proportionality assumption in the Cox model 
(i.e., constant hazard over time) will be checked and tested. 
 
Cumulative event rates will be calculated according to the method of Kaplan and Meier55 for each 
randomized arm as a function of time from randomization, and the estimated event probabilities 
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will be displayed graphically. Adjusted HR and its 95% CI will be estimated using Cox proportional 
hazards model by including pre-specified baseline risk factors as covariates in the model. 
 
A sensitivity analysis for the primary composite MACE (all cause death and non-fatal MI) or invasive 
cardiac catheterization without CAD (no coronary stenosis ≥50% according to QCA by core-lab 
adjudication or site interpretation if QCA is not available, or with FFR≤0.80, or instantaneous wave 
free ratio (iFR) ≤0.89) endpoint will be conducted using the method of “win-ratio”56 and Finkelstein 
and Schoenfeld  rank-test method57.  More details on primary, secondary and sensitivity analyses 
will be provided in the complete Statistical Analysis Plan (SAP). 
 
Subgroup analyses 
Subgroup analyses will be performed to assess whether the intervention effect is consistent across 
all participants, or whether it varies according to specific participant characteristics. In particular, 
these analyses will focus on whether the relative intervention effect compared to usual care differs 
according to the following baseline variables: 
x 
Low risk vs. elevated risk by PROMISE Risk score or presence of known non-obstructive 
atherosclerosis 
x 
Intended first test: functional vs. invasive 
x 
Sex (male vs. female) 
x 
Age (<65, 65 to 74, and >75 years) 
x 
History of diabetes 
x 
Presentation: primary symptom (chest pain vs. other), SAQ angina score (daily/weekly angina 
at baseline versus less frequent) 
x 
Geographic region (US, Canada, Europe, Other Regions) 
These analyses will utilize the Cox model and will be accomplished by testing for interactions 
between the randomized treatment strategy and the specific baseline variables listed above. In 
addition to the formal assessment of treatment by covariate interactions, the effect of the treatment 
strategy characterized by a hazard ratio and 95% confidence interval will be calculated and 
displayed using a forest plot for the subgroups of participants defined by the variables listed above. 
These descriptive hazard ratios will be carefully interpreted in conjunction with the formal 
interaction tests. 
The effect of the treatment strategy may also be examined in other subgroups of clinical interest in 
addition to those listed above. 
 
Analysis of the Secondary Endpoints 
The secondary endpoints listed in section III.C. Secondary Endpoints that are measured as time- 
to-event will be analyzed using the same statistical methods used for the primary efficacy endpoint 
(Section VI.A. Primary Endpoint Definitions). Specifically, the log-rank test will be the primary 
analytic tool for statistically assessing mortality differences between the two randomized treatment 
strategies. A hazard ratio and 95% confidence interval summarizing the difference in outcome 
between the two randomized arms will be computed using the Cox model. 
Participant deaths will be classified by the Clinical Events Committee (CEC) as to whether the 
mode of death was due to a cardiovascular (CV) cause. If insufficient source documents are 
obtained to allow CEC adjudication of the cause of death, and the CEC classifies the cause of 
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death as “unknown,” then the site-reported cause of death (if available) will be used. If neither the 
site nor the CEC can provide a classification of the cause of death, the death will not be considered 
as a cardiovascular death. As supplemental analyses, however, this endpoint will also be examined 
using (a) only the deaths classified by the CEC as cardiovascular, and (b) using deaths classified 
by the CEC as cardiovascular, but also including any deaths in the cardiovascular category that 
are classified as unknown by the CEC. 
Competing risks methodology of Fine and Gray58, where death due to a non-cardiovascular cause 
is considered as a competing risk. This methodology, rather than treating non-cardiovascular death 
as a censoring event, makes incidence use of the cumulative function, and is performed within the 
proportional hazards framework using the marginal failure sub-distribution associated with the 
event of interest (cardiovascular death). Similar analyses will be conducted for time-to- event 
endpoints in which death is not part of the endpoint of interest. 
Analysis of Resource Use Endpoints 
For the Economics outcomes, primary comparison will be at 12 months between treatment arms 
by intention-to-treat. All-cause hospitalizations, cardiovascular hospitalizations, ER visits not 
resulting in hospitalization, and major outpatient procedures will be enumerated. In addition, we 
will examine length of stay by intensity of care, numbers of CTAs, noninvasive stress tests (stress 
perfusion imaging, stress echocardiography, exercise electrocardiography, stress cardiac 
magnetic resonance imaging), invasive tests (invasive coronary angiography, invasive fractional 
flow reserve or equivalent, optical coherence tomography, intravascular ultrasound), coronary 
revascularization procedures (coronary artery bypass graft surgery (CABG), percutaneous 
coronary intervention (PCI), number of coronary stents), and cardiac medications (beta blockers, 
aspirin, statins, antiplatelet medications). 
Confidence intervals for differences will be estimated using the bootstrap approach. Differences in 
resource use will be interpreted in the context of the trial clinical results, looking for both 
consistency and plausibility. Descriptive comparisons of intensity of care/resource consumption 
according to clinical variables defining subgroups of interest will be performed. The primary 
economic analyses will focus on the US enrollment and in secondary analyses, resource use 
patterns for all patients enrolled in the trial will be compared by intention-to-treat to develop an 
understanding of the degree to which treatment related differences in the trial are region 
dependent. 
 
Analyses of Medical Costs 
To compare medical costs between treatment arms, we must: 1) assign costs to all medical 
resources consumed during the study period; 2) compute mean costs by treatment group (defined 
by the principle of intention-to-treat); and 3) calculate the difference in mean costs between 
treatment arms and generate confidence intervals. 
A) Derivation of Cost Estimates 
The cost of US hospital-based care will be estimated by applying hospital-specific, revenue center 
level cost-to-charge ratios to empirical billing data collected during the study. This approach, which 
has been used successfully in numerous previous clinical trials including the PROMISE trial takes 
advantage of the objective, detailed account in hospital bills of services provided to patients and 
recalibrates hospital charges to more closely reflect costs. Based on experience in similar studies, 
we anticipate having complete billing data for 95% of patients treated in hospitals that generate 
bills. For patients without billing data (including patients outside US), we will impute costs using a 
generalized linear model developed using study data. In this model, the dependent variable will be 
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defined as total cost, and independent variables will include resource use elements available in 
the case report form, such as: 
Number of hospitalized nights by intensity of care and number of relevant high cost procedures. 
Coefficients for model parameters will be estimated using study data of patients with complete 
costs and then used to predict costs for patients without billing information. 
The cost of stays at non-acute care facilities will be estimated by multiplying the length of stay by 
the corresponding per-diem/reimbursement rate. 
Costs for physician services will be estimated by mapping major inpatient and outpatient 
procedures and services recorded on the case report form to appropriate CPT codes in the 
Medicare Fee Schedule. We will also assign rounding fees for inpatient stays based on type of 
unit. 
Costs for diagnostic testing procedures done in an outpatient or standalone facility will be derived 
from secondary sources available to the DCRI Outcomes Group at the time of study analysis. 
The cost of medications of interest/relevance will be estimated on the basis of medication use 
recorded in the eCRF and unit costs by medication type and class, based on current estimates of 
acquisition cost. 
B) Cost Comparisons 
Primary statistical comparisons of costs between the two treatment groups will be performed using 
the intention-to-treat principle. A nonparametric partitioned estimator will be used to estimate 
diagnostic strategy-specific, 1-year medical costs with 4 partitions corresponding to follow-up 
intervals following randomization. Comparisons between the two testing strategies will be made 
using a normal approximation with standard errors estimated using the bootstrap approach. 
Bootstrapping will be performed using 10,000 repetitions, with percentile-based confidence 
intervals reported. The primary cost comparison will be made for cumulative costs at 12 months. 
The primary effect size will be the mean cost difference between the two arms with 95% confidence 
intervals. P values will be calculated for selective comparisons, with a “significant” p value 
equivalent to a 95% confidence interval that excludes 0. No adjustment in significance levels for 
multiple comparisons will be used.  
Differences in cost will be interpreted in the context of the trial clinical results, looking for both 
consistency and plausibility. Costs will be presented both overall and by category (e.g., inpatient 
hospitalization, outpatient procedures, concomitant medications, non-acute institutional care). 
Hospitalizations will be classified as cardiovascular or non-cardiovascular by the Clinical Events 
Committee. For illustrative purposes, we will use bootstrap methods to plot the probability of a 
difference in total costs greater than arbitrary thresholds of interest (such as $500, $750, or $1000). 
C) Cost Sensitivity Analyses 
In secondary sensitivity analyses, we will compare resource use and costs between treatment 
groups in the US. In this manner, the effect of overall patterns of resource use in the US cohort 
versus ex-US on cost differences by treatment group can be assessed. We will also perform a per 
protocol analysis of costs. 
 
Analyses of Quality of Life Outcomes 
For each of the QOL measures examined in this study, we will provide simple descriptive and 
comparative analyses by intention-to-treat. To address the multiple comparisons problem arising 
from testing each individual scale and time point separately, we propose two complementary 
approaches. First, we will pre-specify the angina frequency scale from the SAQ as the primary 
QOL comparison of interest and assign all other comparisons to a secondary (supportive) status. 
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Second, we will use a repeated-measures mixed model with the baseline score as a covariate, Day 
45, Month 6, and Month 12 responses included as outcome variables, and time as a fixed variable. 
Restricted maximum likelihood estimation will be used to model all available data from each 
participant without imputing missing values. An unstructured covariance matrix will be used. 
 
Point estimates for each diagnostic strategy arm and strategy arm mean differences (precision 
strategy – usual care) with 95% confidence intervals (CIs) will be generated for each time point. 
The primary assessment will be based on the strategy arm difference at Month 12. 
Additional analyses will examine the intervention effect at the other contact time points. 
Additionally, the intervention effect will be averaged across all the follow-up time points. The 
estimated intervention difference and 95% CIs will be obtained using the ESTIMATE Statement in 
SAS PROC MIXED. 
 
We expect to have analyzable data on ≥95% of survivors at each follow-up interview, and, with 
90%+ data collection (945+ patients per treatment group), consistent with our past performance in 
trials of this size and complexity and using similar methods, even accounting for loss of data due 
to death or incapacity, we should have 90% or greater statistical power to detect clinically 
significant differences in our major QOL measures. 
 
Major QOL subgroups to be examined will be those prespecified for the clinical analysis of this trial. 
In addition, we will use baseline angina frequency from the SAQ to create a subgroup of 
participants with daily or weekly chest pain versus those with less frequent symptoms. 
 
 
IX. ETHICAL CONSIDERATIONS AND RISK ANALYSIS 
IX.A. Ethical Considerations 
 
PRECISE will be conducted in accordance with the recommendations for human research from 
the 18th World Medical Assembly, Helsinki 1964. All potential sites will obtain Institutional Review 
Board (IRB) or Ethics Committee (EC) approval of the protocol, the associated consent form and 
any participant facing recruitment tools. Written informed consent will be obtained from each 
patient before any study procedures are performed. Patients will have the option to consent for the 
study after receiving a full explanation of the risks, benefits, and available diagnostic options, with 
the right to refuse participation. Clinicians will have the option to pursue alternative diagnostic 
pathways if they deem it to be in the best interest of the patient, with the reason for study protocol 
deviation documented. Participants can withdraw from the study at any time. 
 
IX.B. Study Risks and Benefits 
 
Potential Risks 
Participation in PRECISE does not present any extra risks other than the risks associated with the 
clinically indicated care recommended by the participant’s treating physicians to evaluate and treat 
symptoms suggestive of CAD. As all approaches included in the trial are recognized as standard 
of care, the risk associated with the trial can be described in detail by the treating physician. 
Noninvasive diagnostic imaging is generally considered a safe and effective diagnostic approach. 
FFRCT does not pose any additional risk to participants beyond the performance of cCTA itself. It 
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does offer the potential benefit to participants of the recognition of hemodynamically significant 
lesions (FFR ≤0.80 or iFR ≤0.89) that may not demonstrate anatomic significance (<50% diameter 
stenosis) and avoidance of unnecessary revascularization of >50% lesions that are not 
hemodynamically significant (FFR>0.80 or iFR >0.89). 
The risks of guideline-recommended care without planned testing in the lowest risk participants 
has not been extensively studied prospectively. However, validation of the PROMISE Risk Tool in 
SCOT-HEART indicate that participants in this risk category have a CV death/MI event rate 
<1%/year, similar to the event rate observed in an age and sex matched US population. While the 
risk of guideline-recommended care without planned testing in the precision evaluation arm has 
not been quantified prospectively it is not expected to differ from the excellent outcomes noted above 
in such patients who do undergo testing. Further, participants with continued symptoms not 
controlled by medications will be permitted to cross over to the precision strategy arm and receive, 
cCTA with selective FFRCT. 
 
Potential Loss of Confidentiality 
In any clinical trial, there is a possible risk of loss of confidentiality. To prevent this from occurring, 
HeartFlow has strict procedures in place to ensure that all study data are confidential and 
anonymized except as required for centralized follow-up data collection for the US, which will be 
performed by the DCRI Outcomes Call Center. For all data transferred from enrolling sites or from 
the Call Center, participants will be identified only by unique patient identifiers. Data transmitted 
will not contain any protected health information and participants will be identified only by unique 
patient identifiers. Data transmitted will not contain any protected health information. All applicable 
study data will be transferred in a secure manner and in accordance with applicable regulations. 
 
Potential Benefits 
The PRECISE results should improve the care of future patients recommended for additional 
evaluation for suspected significant CAD. In addition, the trial will deliver high-quality data on 
radiation exposure, incidental findings, and other clinically important “side effects” of the evaluation 
and management strategies that will be examined in a large real-world experience. All participants 
may benefit from increased contact with health care providers due to study-required visits. 
 
 
X. 
DATA HANDLING AND QUALITY ASSURANCE 
X.A. Completing and Signing Case Report Forms 
 
Electronic CRFs will be employed. Trained site personnel or the trained DCRI Outcomes Group 
will enter data into the eCRFs. Data changes and corrections should be done within the electronic 
system. The audit trail will record all changes made, the date and time of the correction, the person 
making the change and a reason for the change. The appropriate electronic signature will be 
provided by the investigator as indicated. 
 
X.B. Clinical Data Management 
 
The sponsor or its designees will be responsible for the handling, processing, and quality control of 
the data in compliance with all applicable regulatory guidelines. 
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The training of clinical site personnel and the DCRI Outcomes Group on eCRF completion will be 
the responsibility of the sponsor or its designees. To ensure uniform data collection, a Case Report 
Form Guide will be created to assist with eCRF completion. All clinical site research coordinators 
will undergo site initiation training to become thoroughly familiar with the protocol, case report 
forms, and with methods of data verification. 
 
X.C. Archiving of Data 
 
All study documentation at the investigator site and sponsor site will be archived in accordance 
with ICH GCP. It is HeartFlow’s policy to retain the data collected in this clinical study for a minimum 
of 5 years after termination of the study. Clinical sites will be asked to retain the data for at least 2 
years following completion of the study or longer as required by local laws. 
 
XI. STUDY MONITORING, AUDITING, AND INSPECTING 
 
HeartFlow or its designees will monitor this clinical study to check the adequacy of clinical site staff 
and facilities, and to ensure adherence to the protocol, study procedures, and applicable 
regulations. In accordance with ICH E6 GCP guidelines, the clinical site monitor will also assess 
proper eCRF completion and source document retention. The investigator and clinical site staff are 
expected to provide adequate space for monitoring visits and to allocate sufficient time to permit 
adequate review of the study’s progress. The investigator will permit study-related monitoring, 
audits, IRB review, and regulatory inspection(s), providing direct access to source data/documents 
and study-related facilities (e.g., pharmacy, diagnostic testing and laboratories). 
 
XI.A. Study Monitoring 
 
Study monitoring will be performed in accordance with ICH E6GCP, this protocol, and applicable 
local regulations. A Clinical Monitoring Plan will be written at the outset of the study to provide 
project-specific operational guidelines for the clinical monitoring process and procedures, define 
responsibilities of the Site Management/Monitoring Team, which will in turn ensure the quality and 
integrity of data collected. 
 
XI.B. Auditing and Inspecting 
 
HeartFlow quality assurance personnel and/or their designee(s) may conduct audits at the study 
site(s). Audits may include, but not be limited to: audit trail of data handling and processes, SOPs, 
presence of required documents, the informed consent process, and comparison of case report 
forms/database with source documents. The investigator agrees to accommodate and participate 
in audits conducted at a reasonable time in a reasonable manner, as needed. 
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10.1016/j.jacc.2018.08.1038. Epub 2018 Aug 25. 
 
52. Collet D. Modeling survival data in medical research (2nd edition). London: Chapman & Hall; 
2003. 
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53. Kalbfleisch JD, Prentice RL. The Statistical Analysis of Failure Time Data. 2nd edition. 2002,
John Wiley & Sons, Inc. Hoboken, New Jersey.
54. Cox DR. Regression Models and Life-Tables. Journal of the Royal Statistical Society Series
B (Methodological). 1972;34:187-220.
55. Kaplan EL and Meier P. Nonparametric Estimation from Incomplete Observations. Journal of
the American Statistical Association. 1958;53:457-481.
56. Pocock SJ, Ariti CA, Collier TJ and Wang D. The win ratio: a new approach to the analysis
of composite endpoints in clinical trials based on clinical priorities. Eur Heart J. 2012;33:176-
82.
57. Finkelstein DM and Schoenfeld, DA. Combining mortality and longitudinal measures in
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58. Fine JP and Gray RJ. A Proportional Hazards Model for the Subdistribution of a Competing
Risk. Journal of the American Statistical Association. 1999;94:496-509.
59. Newby, D. E.; Adamson, P. D.; Berry, C.; Boon, N. A.; Dweck, M. R.; Flather, M.; Forbes, J.;
Hunter, A.; Lewis, S.; MacLean, S.; Mills, N. L.; Norrie, J.; Roditi, G.; Shah, A. S. V.; Timmis,
A. D.; van Beek, E. J. R.; Williams, M. C., Coronary CT Angiography and 5-Year Risk of
Myocardial Infarction. N Engl J Med 2018, 379 (10), 924-933.
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PRECISE Protocol
Summary of Protocol Amendments
Amendment from version 1.0 dated June 29, 2018 to version 1.1 dated July 31, 2018
Section
Version 1.0
Version 1.1
Table of Contents
Sections listed
Sections listing updated based 
on the changes
I. Study Synopsis
Secondary 
Effectiveness 
Endpoints
#2. Resource use patterns (all
patients) and medical costs (US
patients) to 12 months
#2. Resource use patterns and
medical costs
V. STUDY
PROCEDURES
V.A. Patient Screening
for Eligibility (Exclusion 
Criteria)
#3. Noninvasive CV testing within
1 year (for suspected CAD)
#3. Noninvasive CV testing
within 1 year (for suspected
CAD), including coronary artery
calcium score
V. STUDY
PROCEDURES
V.D. Participant
Follow-Up (D45)
45 (+/-14) day follow-up visit (in-
person)
45 (+/-14) day follow-up visit
(in-person, portions may be
done by phone)
V. STUDY 
PROCEDURES
V.D. Participant 
Follow-Up (D45, 6M 
and 12M)
Review and documentation of
concomitant medication changes
since enrollment
Review and documentation of
concomitant cardiovascular
medication changes since
enrollment
V. STUDY 
PROCEDURES
V.D. Participant 
Follow-Up (24M)
NA
Collection of the following:
x
Any cardiovascular test –
both written report and
test output
x
Any
cardiovascular
imaging – both written
report and image file
V.I. ADDITIONAL 
ASSESSMENTS AND 
SUBSTUDIES
V.I.A. Quality of Life 
Assessments
Quality of life (QoL) assessments
will be conducted at baseline, 45
days, 6 months and 12 months.
Quality of life (QoL) assessments
will be conducted at baseline, 45
days, 6 months, 12 months, and
24 months.
VIII.B. Statistical
Analysis Plan
C) Cost Sensitivity
Analyses
In secondary sensitivity analyses, 
we will apply US unit costs to all 
resource use of all patients and
compare costs between
treatment groups across all
patients enrolled in the trial.
In secondary sensitivity 
analyses, we will compare 
resource use and costs between 
treatment groups in the US.
XII. REFERENCES
References listed
References updated via 
EndNote
108

PRECISE Protocol
Amendment from version 1.1 dated July 31, 2018 to version 1.2 dated September 10, 2018
Section
Version 1.1
Version 1.2
Table of Contents V.E. Cross Over Participants
V.E. Testing in precision evaluation 
arm for participants assigned to no
immediate testing
I. Study
Synopsis –
Study Design 
and Methods
All subsequent decisions in the usual 
care arm regarding additional 
testing, medications, and/or
procedures will be at the discretion of 
the responsible clinical care team; 
the use of cCTA as the initial 
diagnostic strategy is not allowed in 
the usual care arm.
Usual Care: For participants 
randomized to usual care, the 
participant’s care team will select 
the specific noninvasive stress 
test (exercise electrocardiogram, 
stress nuclear imaging [including
PET], stress MR, or stress 
echocardiogram); OR invasive 
test: (direct to diagnostic 
catheterization). The use of cCTA 
as the initial diagnostic strategy is 
explicitly excluded in this arm.
All subsequent decisions in the 
usual care arm regarding additional 
testing, medications, and/or
procedures will be at the discretion 
of the responsible clinical care 
team; the use of cCTA as the initial
diagnostic strategy is not allowed in 
the usual care arm and prohibited 
as a subsequent test for the first 45
days after randomization.
Usual Care: For participants 
randomized to usual care, the 
participant’s care team will select 
the specific noninvasive stress 
test (exercise electrocardiogram, 
stress nuclear imaging [including
PET], stress MR, or stress 
echocardiogram); OR invasive 
test: (direct to diagnostic 
catheterization). The use of cCTA 
as the initial diagnostic strategy is 
explicitly excluded in this arm and 
prohibited as a subsequent test 
for the first 45 days after 
randomization.
I. Study Synopsis -
Sample Size 
Considerations
Assumed rates are based on 30% 
assigned to guideline- recommended 
care with symptom management and 
no planned testing (within which 30% 
will cross over to cCTA with selective
FFRCT); and overall 10% will not
receive assigned testing; enrolling 
1050 participants per group (2100 
total participants) would provide at 
least 90% power to demonstrate 
superiority accounting for 10% 
attrition rate.
Assumed rates are based on 20% 
assigned to guideline-
recommended care with symptom 
management and no planned 
testing (within which 30% will cross
over to cCTA with selective FFRCT);
and overall 10% will not receive
assigned testing; enrolling 1050 
participants per group (2100 total 
participants) would provide at least 
90% power to demonstrate 
superiority accounting for 10% 
attrition rate.
109

PRECISE Protocol
III.A. Prior 
Literature and 
Studies –
Rationale and 
Evidence for 
Incorporation of 
a Strategy of 
Guideline-
Recommended 
Care without 
Planned Testing
in
Low Risk patients
The Risk Tool developed using the 
PROMISE cohort employs 10 readily 
available clinical variables and has
been validated in the SCOT-HEART 
population33, 34
The Risk Tool developed using the 
PROMISE cohort employs 10 
readily available clinical variables 
(such as tobacco usage,
ethnicity/race, and age) and has 
been validated in the SCOT-
HEART population33, 34
IV.E. Rationale
for Selection of 
Testing in Each 
Arm – Usual 
Care Arm
The use of cCTA is explicitly excluded
as the initial diagnostic strategy in this 
arm.
The use of cCTA is explicitly
excluded as the initial diagnostic 
strategy in this arm and prohibited 
as a subsequent test for the first 45 
days after randomization.
IV.F.
Randomization 
Method
Risk will be classified by a risk tool
using pre-test clinical characteristics
derived in the PROMISE trial and 
validated in SCOT-HEART.
Risk will be classified by a risk tool
using pre-test clinical
characteristics (including tobacco 
usage, ethnicity/race, and age) 
derived in the PROMISE trial and 
validated in SCOT-HEART.
IV.F.
Randomization 
Method
The use of cCTA is explicitly excluded
as the initial diagnostic strategy in this 
arm.
The use of cCTA is explicitly
excluded as the initial diagnostic 
strategy in this arm and prohibited 
as a subsequent test for the first 45 
days after randomization.
V.C. Participant 
Cohort 
Assignment –
Usual Care Arm
Performance of cCTA as the initial test
is excluded in this arm.
Performance of cCTA as the initial
test is excluded in this arm and 
prohibited as a subsequent test for
the first 45 days after randomization.
V.E Cross over in
precision 
evaluation arm 
participants
Section title:
Cross over in precision evaluation arm
participants
Previous text deleted and replaced
Section title:
Testing in precision evaluation
arm for participants assigned to
no immediate testing
New text
110

PRECISE Protocol
VIII.A. Sample 
Size
Determination
and Statistical 
Power
Assuming 10% of usual care 
participants will receive angiography 
as a first test results in an 8% 
primary endpoint event rate at 1 year
in the usual care group and 5% 
(absolute) event rate in the precision 
care group (i.e., 37.5% relative effect 
size) with 30% assigned to guideline-
recommended care with symptom 
management and no planned testing.
Assuming 10% of usual care 
participants will receive 
angiography as a first test results in 
an 8% primary endpoint event rate
at 1 year in the usual care group
and 5% (absolute) event rate in the 
precision care group (i.e., 37.5% 
relative effect size) with 20% 
assigned to guideline-
recommended care with symptom 
management and no planned 
testing.
Amendment from version 1.2 dated September 10, 2018 to version 1.3 dated November 21,
2018
Section
Version 1.2
Version 1.3
Throughout 
protocol
Non hyperemic pressure ratio (NHPR)
…
NHPR… NHPR <0.90
Instantaneous wave free ratio (iFR)
…
iFR… iFR ≤0.89
I. Study Synopsis 
– Primary
Endpoint
Time to a composite of: MACE (all 
cause death, non-fatal MI) or invasive 
cardiac catheterization without 
obstructive CAD (obstructive CAD 
defined as diameter stenosis ≥50% 
according to clinical site interpretation, 
FFR≤0.80, or NHPR<0.90) at one year 
(intention to treat)
Time to a composite of: MACE (all 
cause death, non-fatal MI) or invasive 
cardiac catheterization without 
obstructive CAD (obstructive CAD 
defined as diameter stenosis ≥50% 
according to core-lab adjudicated 
quantitative coronary analysis (QCA),
FFR≤0.80, or iFR≤0.89) at one year 
(intention to treat)
I. Study Synopsis 
– Inclusion Criteria
Stable typical or atypical symptoms 
suspicious for coronary artery disease 
with further non-emergent testing or 
elective catheterization recommended 
to evaluate the presence of suspected 
coronary artery disease
Safe performance of cCTA:
Creatinine clearance ≥45 ml/min
For a female participant of 
childbearing potential, a pregnancy 
test must be performed with negative
results known within 7 days prior to 
randomization
Stable typical or atypical symptoms 
suggesting possible coronary artery 
disease (CAD) with further non-
emergent testing or elective 
catheterization recommended to 
evaluate the presence of suspected 
CAD. Stable chest pain includes those
who have fully been ruled out for Acute 
Coronary Syndrome (ACS) and for 
whom elective testing is 
recommended, regardless of the
venue in which they are seen.
Safe performance of cCTA:
Creatinine clearance ≥45 ml/min per 
most recent measurement within 90
days
For a female participant of 
childbearing potential (those who have 
not been surgically sterilized or are not 
postmenopausal), a pregnancy test
111

PRECISE Protocol
must be performed with negative 
results known within 7 days prior to 
randomization
I. Study
Synopsis –
Exclusion
Criteria
3. Noninvasive or invasive CV
testing for CAD within 1 year
4. Lifetime history of any
obstructive CAD (no prior
CABG or PCI, stenosis
≥505) or known EF ≤40% or
moderate to severe valvular or
congenital cardiac
5. Contraindications to cCTA
including but not limited to
estimated creatinine clearance
(GFR) <45 m/min measured
within 90 days.
6. Exceeds local weight or size
limit for cCTA or cardiac
catheterization
3. Noninvasive or invasive CV
testing within 1 year (for
suspected CAD). CV testing for
CAD refers to any stress tests,
ICA and cCTA (including
calcium scoring) only. Resting
ECG and resting
echocardiogram are not
exclusionary.
4. Lifetime history of known
obstructive CAD (prior
myocardial infarction, CABG or
PCI, stenosis ≥50%), known EF
≤40% or other moderate to
severe valvular or congenital
cardiac disease.
5. Contraindications to cCTA
including but not limited to
creatinine clearance (GFR) <45
ml/min as per most recent
measurement taken within 90
days.
6. Exceeds the site’s weight or
size limit for cCTA or cardiac
catheterization
IV.B.
Primary
Objective
and
Endpoints
The primary endpoint is a composite 
of: MACE (all cause death and non-
fatal MI) or invasive cardiac 
catheterization without CAD (no 
coronary stenosis
≥50%, or with FFR≤0.80, or non-
hyperemic pressure ratio (NHPR)
<0.90). The primary study 
hypothesis will be tested at one year 
using an intention to treat analysis
The primary endpoint is a composite 
of: MACE (all cause death and non-
fatal MI) or invasive cardiac
catheterization without CAD (no 
coronary stenosis ≥50% according 
to QCA by core-lab adjudication, or 
with FFR≤0.80, or instantaneous
wave free ratio (iFR) ≤0.89).
The primary study hypothesis will be 
tested at one year using an intention
to treat analysis
IV.G. Diagnostic
Evaluations and
Subsequent
Care –
Description of
Evaluations to
be performed
A pregnancy test will be required for 
female participants of childbearing 
potential, and a creatinine blood test
will be required for participants 
without a recent normal value (within 
previous 90 days).
A pregnancy test will be required for 
female participants of childbearing 
potential (those who have not been 
surgically sterilized or are not 
postmenopausal), and a creatinine
blood test will be required for 
participants without a recent normal 
value (most recent measurement 
taken within previous 90 days).
112

PRECISE Protocol
IV.G. Diagnostic 
Evaluations and 
Subsequent
Care –
Subsequent 
Care
Added text:
For patients in the Precision
Evaluation Arm, ICA cannot be 
performed unless one of the 
following criteria are met:
x
Any stenosis ≥90%
identified by cCTA
x
Left Main stenosis ≥30%
identified by cCTA
x
Plaque rupture identified by
cCTA
x
Lesion-specific FFRCT ≤0.85 
in vessels with reference
vessel size 2.0mm or 
greater in diameter
V.A. Patient
At the screening visit, patients will
At the screening visit, patients will
Screening for
undergo the following:
undergo the following:
Eligibility –
...
…
Screening visit (in-Pregnancy test (for females of child-
Pregnancy test (for females of child-
person)
bearing potential)
bearing potential – those who have
not
…
been surgically sterilized or are not
postmenopausal)
…
V.A. Patient 
Screening for 
Eligibility –
Inclusion
Criteria
2. Stable typical or atypical 
symptoms suggesting possible 
coronary artery disease (CAD) with
further non-emergent testing or 
elective catheterization 
recommended to evaluate the 
presence of suspected CAD.
3. Safe performance of cCTA:
a.
Creatinine
clearance ≥45 
ml/min
b.
For a female participant 
of childbearing potential, 
a pregnancy test must be 
performed with negative
results known within 7 
days prior to
randomization
2. Stable typical or atypical 
symptoms suggesting possible 
coronary artery disease (CAD) with
further non-emergent testing or 
elective catheterization 
recommended to evaluate the
presence of suspected CAD. Stable 
chest pain includes those who have 
fully been ruled out for Acute 
Coronary Syndrome (ACS) and for 
whom elective testing is 
recommended, regardless of the
venue in which they are seen.
3. Safe performance of cCTA:
a. Creatinine clearance ≥45
ml/min per most recent 
measurement within 90 
days
113

PRECISE Protocol
b. For a female participant of
childbearing potential
(those who have not been
surgically sterilized or are
not postmenopausal), a
pregnancy test must be
performed with negative
results known within 7 days
prior to randomization
V.A. Patient
Screening for
Eligibility –
Exclusion
Criteria
1.
Acute chest pain
2.
Unstable clinical status
3.
Noninvasive CV testing within 1
year (for suspected CAD),
including coronary artery
calcium score
4.
History of known obstructive
CAD (prior myocardial
infarction, CABG or PCI,
stenosis ≥50%), known EF≤40%
or other moderate to severe
valvular or congenital disease
5.
Contraindications to cCTA
including but not limited to
estimated creatinine clearance
(GFR) <45 ml/min
6.
Any condition leading to
possible inability to comply
with the protocol
7.
Exceeds the weight or size limit
for cCTA or cardiac
catheterization at the site
8.
Life expectancy less than 2
years due to non-cardiovascular
comorbidities
9.
Enrolled in an investigational
trial that involves a non-
approved cardiac drug or device
which has not reached its
primary endpoint
10. Any condition that might
interfere with the study
procedures or follow-up
1.
Acute chest pain
2.
Unstable clinical status
3.
Noninvasive or invasive CV
testing within 1 year for
suspected CAD, CV testing
refers to stress tests, ICA, and
cCTA (including coronary artery
calcium score) only. Resting
ECG and resting
echocardiogram are not
exclusionary.
4.
Lifetime history of known
obstructive CAD (prior
myocardial infarction, CABG or
PCI, coronaryarterystenosis
≥50%), known EF≤40% or other 
moderate to severe valvular or 
congenital cardiac disease
5.
Contraindications to cCTA
including but not limited to
creatinine clearance (GFR) <45
ml/min as per most recent
measurement taken within 90
days
6.
Exceeds the site’s weight or
size limit for cCTA or cardiac
catheterization
7.
Any condition leading to
possible inability to comply
with the protocol procedures
and follow-up
8.
Any condition that might
interfere with the study
procedures or follow-up
9.
Enrolled in an investigational
trial that involves a non-
approved cardiac drug or device
which has not reached its
primary endpoint
10. Life expectancy less than 2
years due to non-cardiovascular
114

PRECISE Protocol
comorbidities
VII.A. Primary
Endpoint
Definitions –
Cardiac
catheterization
without
obstructive
coronary artery
disease 
(diameter
stenosis <50%,
any FFR >0.80 
or
NHPR ≥0.90)
Cardiac catheterization without 
obstructive coronary artery disease 
will be defined as the absence of 
any >50% stenosis or 
hemodynamic indication of 
significance in any major epicardial 
vessel including side branches ≥2
mm in diameter, as determined by 
the clinical site interpretation.
Cardiac catheterization without 
obstructive coronary artery disease 
will be defined as the absence of 
any ≥50% stenosis or hemodynamic 
indication of significance in any 
major epicardial vessel, including
side branches, ≥2 mm in diameter, 
as determined by core-lab
adjudicated QCA or invasive FFR or 
iFR.
II.B. Secondary
Endpoint
Definitions
Myocardial infarction
Myocardial infarction will be
characterized according to Universal
MI definition subtypes as Type 1, 2, 3, 
4a,
4b, 4c, and 5.
Myocardial infarction
Myocardial infarction will be
characterized according to the 4th
Universal MI definition for 
Spontaneous MI and the
SCAI definition for periprocedural MIs.
Amendment from version 1.3 dated November 21, 2018 to version 1.4 dated February 1, 2019
Section
Version 1.3
Version 1.4
VII.A. Primary 
Endpoint
Definitions –
Myocardial
infarction
Acute
myocardial
infarction
(MI)
is
defined
as 
having 
evidence 
of 
myocardial necrosis in a clinical setting 
consistent with myocardial ischemia51.
Specifically, MI is defined as having:
1)
Typical
rise 
and/or 
gradual 
fall 
in 
cardiac 
biomarker 
level 
(cardiac 
troponin preferred) with values 
exceeding the 99th percentile
of the institutional upper limit of 
normal (ULN) (generally 2x the 
ULN)
AND either:
2)
Clinical 
presentation 
defined as 
typical 
cardiac 
ischemic type pain/discomfort
or dyspnea felt to be due to 
ischemia and consistent with 
the diagnosis of myocardial
ischemia and infarction
Acute myocardial infarction (MI) is 
defined 
as
having
evidence
of
myocardial necrosis in a clinical setting 
consistent with myocardial ischemia. 
Specifically, 
the 
Fourth 
Universal 
Definition51 of type I MI is defined as:
Detection of a rise and/or fall of cTn 
values with at least 1 value above the
99th percentile URL and with at least 1 of 
the following:
x
Symptoms of acute
myocardial ischemia;
x
New ischemic ECG changes;
x
Development of
pathological Q waves;
x
Imaging evidence of new loss
of viable myocardium or new
regional wall motion
abnormality in a pattern
consistent with an ischemic
etiology;
x
Identification of a coronary
thrombus by angiography
115

PRECISE Protocol
Or
3)
ECG manifestations of
acute myocardial ischemia (in
absence of left ventricular
hypertrophy and left bundle
branch 
block) 
including
evolving ST elevation, ST
depression, T-wave changes,
new pathological Q-waves (R
waves in V1-2) in at least two
consecutive leads or new left
bundle branch block.
A complete definition of the criteria for MI
can be found in the 2017 Cardiovascular 
and Stroke Endpoint Definitions for 
Clinical 
Trials51.
Peri-procedural 
infarctions are defined as greater than 
3x ULN for serum CK-MB for PCI and 
greater than 5x ULN for CABG.
including intracoronary
imaging or by autopsy*
cTn indicates cardiac troponin; ECG, 
electrocardiogram; URL, upper
reference limit.
*Postmortem demonstration of an
atherothrombus in the artery supplying
the infarcted myocardium, or a
macroscopically large circumscribed
area of necrosis with or without
intramyocardial hemorrhage, meets the
type 1 MI criteria regardless of cTn
values.
A complete definition of the criteria for MI
can be found in the Fourth Universal
Definition51
of Myocardial Infarction 
(2018). The exception will be for peri-
procedural 
myocardial
infarctions,
which 
are
defined
as 
biomarker 
elevation ≥10 times the upper reference
limit (URL) for creatine kinase MB
(CKMB) and/or ≥70 URL for troponin as 
outlined
in
the
most
recent
SCAI
(Society
for 
Cardiovascular
Angiography
and
Interventions) definition60.
Table of 
Abbreviations Not applicable
CAC: Coronary Artery Calcium added
Table of
Abbreviations
Not applicable
SCAI: Society for Cardiovascular 
Angiography and Interventions
Exclusi
on
criteria
Not applicable
New exclusion criteria #11 added:
11. Known CAD by coronary
calcium presence, either by prior
CAC scoring or definite coronary
calcium reported on a non-cardiac
chest CT scan.
Secondary 
Effectiveness 
Endpoints
Proportion of invasive cardiac 
catheterization patients who undergo 
revascularization (PCI or CABG) within
6 months of enrollment
“Invasive cardiac catheterization” has
been updated to invasive coronary 
angiogram.
Proportion of invasive coronary
angiogram patients who undergo 
revascularization
(PCI or CABG) within 6 months of
enrollment
116

PRECISE Protocol
V.D.
Participa
nt
Follow-
Up
For North American participants, follow-
up after 45 days will be done by phone 
interviews conducted by the DCRI 
Outcomes Call Center.
Visit 45 day has been added along with 
further clarification on site participation:
For North American participants, 
follow-up at 45 days and at 6, 12, and
24 months visits will be done by phone
interviews conducted by the DCRI 
Outcomes Call Center, unless
not allowed by their enrolling site.
IV.A
Overview of
PRECISE-
Diagram
Diagram from version 1.3.
Diagram updated to provide clarification
on the pre-randomization step.
Referral
of
precisio
n
evaluati
on cCTA
participants
for FFRCT
determination
s
Image sets showing at least one 30-90%
stenosis in epicardial vessels of 2mm 
diameter or greater will be….
Language updated to “should” from
“will”:
Image sets showing at least one 30-90%
stenosis in epicardial vessels of 2mm 
diameter or greater should be …….
IV.G.
Diagnostic
Evaluations
and
Subsequent
Care
For patients in the Precision Evaluation 
Arm, ICA cannot be performed unless 
at least one of the following criteria are
met:
With this amendment, the language
has been softened from “cannot” to 
“should not”:
For patients in the Precision Evaluation
Arm, ICA should not be performed 
unless at least one of the following
criteria are met:
IV.E.
Rationale for
Selection of
Testing in
Each Arm
Use of cCTA as the initial diagnostic 
strategy is specifically excluded in the
usual care strategy arm and prohibited 
as a subsequent test for the first 45 
days after randomization
With this amendment, “or a calcium
score” has been added to the protocol.
Use of cCTA or a calcium score as the 
initial diagnostic strategy is specifically 
excluded in the usual care strategy arm
and prohibited as a subsequent test for 
the first
45 days after randomization
117

PRECISE Protocol
IV.E.
Rationale for 
Selection of 
Testing in
Each Arm
The intervention in PRECISE will triage 
patients into two risk groups who will be
assigned to receive either guideline-
recommended medical management 
without planned testing or cCTA with 
selective FFRCT
"Including no CAC” language has been
added with this amendment:
The intervention in PRECISE will 
triage patients into two risk groups 
who will be assigned to receive either 
guideline- recommended medical 
management without planned testing
(including no CAC)
or cCTA with selective FFRCT
V.C
Participant 
Cohort 
Assignment
Performance of cCTA as the initial test is
excluded in this arm and prohibited as a 
subsequent test for the first 45 days after 
randomization.
With this amendment, “or a calcium
score” has been added to the protocol.
Performance of cCTA or a calcium
score as the initial test is excluded in 
this arm and prohibited as a subsequent 
test for the first
45 days after randomization.
V.C
Participant 
Cohort 
Assignment
Participants will be assigned to either 
guideline-recommended medical 
management without planned testing 
(low risk) or cCTA with selective FFRCT
(elevated risk).
"Including no CAC score” has been
added:
Participants will be assigned to either 
guideline-recommended medical 
management without planned testing
(low risk) including no CAC score or
cCTA with
selective FFRCT (elevated risk).
References-
51 and 60
Reference 51
51. Hicks KA, Mahaffey KW, et al.
Reference 51 is updated and reference
60 is added with the new amendment 
v1.4:
51.Thygesen K, Alpert JS, et al
60. Moussa ID, Klein LW, et al
Amendment from version 1.4 dated February 1, 2019 to version 1.5 dated October 15, 2019
Section
Version 1.4
Version 1.5
Investigator
Protocol 
Signature Page
NA
Included separate line for PI signature
Table of
Abbreviations
NA
AG: Agatston units
Table of
Abbreviations
DECISION: Decisive Evaluation
of Cardiac Ischemia, Symptoms 
and
Revascularization
Removed
Table of
Abbreviations
HU: Hounsfield units
Removed
118

PRECISE Protocol
IV. Study Overview
and Objectives -
Study duration
The anticipated total duration of 
the PRECISE study will be
approximately 48 months for 
start-up, enrollment, follow up, 
and close out. Participants will 
be followed for 24 months after 
enrollment.
Overall study duration reduced to 36
month and patient follow up to 12 
month after enrollment.
“The anticipated total duration of the 
PRECISE study will be approximately 
36 months for start-up, enrollment,
follow up, and close out. Participants
will be followed for 12 months after 
enrollment.”
IV.A. Overview
of PRECISE –
figure of the trial
design
Figure updated to remove 24 month and co-
primary endpoints of DECISION. Arrows leading
to GRMT or cCTA annotated “low risk” and 
“elevated risk” respectively. Patients with known 
nonobstructive coronary plaque or extensive 
coronary calcium randomized to the precision 
arm are mandated to undergo cCTA +/- FFRCT,
independent from PROMISE risk score strata.
IV.B. Primary
Objective and
Endpoints
Per the exclusion criteria, any
previous noninvasive or invasive 
CV diagnostic testing for 
suspected CAD must have been 
>1 year prior to enrollment.
Patients with known obstructive
CAD 
(prior 
myocardial
infarction, CABG or PCI, any
stenosis ≥50%) are ineligible
for PRECISE.
Replaced with:
“Patients with known nonobstructive 
coronary plaque or extensive coronary 
calcium randomized to the precision arm
are mandated to undergo cCTA +/-
FFRCT, independent from their
PROMISE risk score strata.”
IV.C. Secondary
Endpoints
Endpoints will be assessed at 45
days, 6 months, 1 year and 2 years.
Removed secondary endpoint assessment
at 2 years:
“Endpoints will be assessed at 45 days, 6
months and 1 year.”
IV.C. Secondary
Endpoints
9. PRECISE primary endpoint at
24 month
Removed PRECISE primary endpoint at
24 month
119