SYNTAX III REVOLUTION Trial: A Randomized Study to Evaluate the Feasibility of Heart-Team Clinical Decision Making Regarding the Optimal (Surgical or Percutaneous Based) Revascularization Strategy in Patients With Complex Coronary Artery Disease, Based on Non-invasive Coronary CT Angiography (CTA) Imaging Utilising High-definition GE RevolutionTM Multi-slice CT and HeartFlow FFRCT Compared to the Current Standard of Care With Conventional Invasive Coronary Angiography (CA)
Conditions: Coronary Artery Diseases, Multivessel Coronary Artery Disease, Heart Diseases, Cardiovascular Diseases
Sponsor: ECRI bv

 
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ECRI-004 
 
 
  
SYNTAX III REVOLUTION Trial: 
 
 
A randomized study to evaluate the feasibility of Heart-Team clinical decision making regarding 
the optimal (surgical or percutaneous based) revascularization strategy in patients with complex 
coronary artery disease, based on non-invasive coronary CT Angiography (CTA) imaging 
utilising high-definition GE RevolutionTM multi-slice CT and HeartFlow FFRCT compared to the 
current standard of care with conventional invasive coronary angiography (CA)  
 
 
 
 
 
Version 1.0, April 4th, 2016 
 
  
 
 
 
 
Sponsor: 
 
 
 
 
 
 
 
 
CRO: 
European Cardiovascular Research Institute (ECRI) 
 
 
Cardialysis  
Westblaak 98   
 
 
 
 
 
 
 
Westblaak 98  
3012 KM Rotterdam   
 
 
 
 
 
 
3012 KM Rotterdam  
The Netherlands  
 
 
 
 
 
 
 
The Netherlands  
 
 

 
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Protocol approval page  
 
A randomized clinical study investigating utilising high-definition GE-Revolution scanning to 
streamline Heart Team decision-making on the most optimal revascularization modality in 
patients with complex coronary artery disease 
 
Protocol version: 1.0, dated 04 April 2016 
 
We, the undersigned, have read and approved the protocol specified above, and agree upon the 
contents:  
 
 
 
 
 
 
____ 
Patrick W. Serruys, 
 
 
 
Date 
Prof. of Cardiology, Imperial College, London (UK) 
Chairman Steering Committee  
 
 
 
 
 
 
____ 
Gerrit-Anne van Es 
 
 
 
 
 
 
 
Date 
Managing Director, ECRI-Trials B.V. 
 
 

 
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Protocol Signature page Site Principal Investigators 
 
I have read this protocol and/or amendment and appendices and agree to adhere to the 
requirements. I will provide copies of this protocol and all pertinent information to the study 
personnel under my supervision. I will discuss this material with them and ensure they are fully 
informed regarding the device and the conduct of the study.  
 
I will conduct the study in accordance with the protocol and ISO 14155 guidelines, as well as 
local regulations. We, the undersigned, have read and approved the protocol specified above, and 
agree upon the contents. 
 
Protocol version: 1.0, dated 04 April 2016 
 
 
 
_________________________________ 
Principal Investigator 
 
_________________________________ 
 __________________ 
Principal Investigator (signature)  
Date  
 
 
 
 
_________________________________ 
Principal Investigator 
 
_________________________________ 
 __________________ 
Principal Investigator (signature)  
Date  
 
 
 
 
_________________________________ 
Principal Investigator 
 
_________________________________ 
 __________________ 
Principal Investigator (signature)  
Date  
 
 
 
_________________________________ 
Institution Name/Location 
 

 
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TABLE OF CONTENTS 
1 
PROTOOL SYNOPSIS .......................................................................................................... 6 
2 
INTRODUCTION ................................................................................................................ 12 
3 
OBJECTIVE ......................................................................................................................... 22 
4 
STUDY DESIGN.................................................................................................................. 23 
5 
ENDPOINTS ........................................................................................................................ 25 
5.1 
Primary Endpoint ............................................................................................................ 25 
5.2 
Secondary endpoints ....................................................................................................... 25 
6 
SUBJECT SELECTION ....................................................................................................... 27 
6.1 
Inclusion Criteria ............................................................................................................ 27 
6.2 
Exclusion Criteria ........................................................................................................... 28 
7 
STUDY PROCEDURES ...................................................................................................... 29 
7.1 
Screening......................................................................................................................... 29 
7.2 
Patient Information and Informed Consent..................................................................... 29 
7.3 
Baseline evaluation prior to MSCT/ Heart Team discussion.......................................... 29 
7.4 
MSCT .............................................................................................................................. 30 
7.5 
Anatomical  SYNTAX Score,  SYNTAX Score II and functional anatomy (FFRCT) .... 30 
7.6 
Randomization ................................................................................................................ 31 
7.7 
Heart Team meeting structure & organization................................................................ 31 
7.8 
Data-flow ........................................................................................................................ 33 
8 
STATISTICAL DESIGN AND ANALYSIS ....................................................................... 34 
8.1 
Introduction ..................................................................................................................... 34 
8.2 
Intent-To-Treat population.............................................................................................. 34 
8.3 
Sample size ..................................................................................................................... 34 
8.4 
Intend-to-Treat Analysis ................................................................................................. 35 
8.5 
Analysis of the Primary Endpoint ................................................................................... 35 
8.6 
Analysis of the Secondary Endpoints ............................................................................. 36 
8.7 
Descriptive statistical methodology ................................................................................ 37 
9 
QUALITY CONTROL AND QUALITY ASSURANCE .................................................... 39 
9.1 
Compliance to Standards and Regulations ..................................................................... 39 
9.2 
Quality Assurance and Monitoring ................................................................................. 39 
9.3 
Quality Assurance and Data management ...................................................................... 39 
9.4 
On-site Audits ................................................................................................................. 40 
10 ORGANISATION ................................................................................................................ 41 
10.1 
Sponsor ........................................................................................................................ 41 
10.2 
Steering Committee ..................................................................................................... 41 
10.3 
Clinical Event Committee (CEC) ................................................................................ 41 
10.4 
Data Safety Monitoring Board (DSMB) ..................................................................... 41 
10.5 
Data Management ........................................................................................................ 41 
10.6 
Site Management and Monitoring ............................................................................... 41 
10.7 
Safety Reporting .......................................................................................................... 42 
10.8 
Statistical Analysis ...................................................................................................... 42 
11 DATA HANDLING AND RECORD KEEPING ................................................................ 43 
11.1 
Source Documentation (SD) ....................................................................................... 43 
11.2 
Case Report Form Completion .................................................................................... 43 

 
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11.3 
Record Retention ......................................................................................................... 43 
12 PUBLICATION POLICY .................................................................................................... 45 
13 INVESTIGATOR RESPONSIBILITIES ............................................................................. 46 
13.1 
Investigator Responsibility/Performance .................................................................... 46 
13.2 
Required Documents ................................................................................................... 46 
13.3 
Ethics Committee (EC) / Institutional Review Board (IRB) Approval ....................... 47 
13.4 
Informed Consent ........................................................................................................ 47 
13.5 
Protocol Deviation ....................................................................................................... 47 
13.6 
Reporting Requirements .............................................................................................. 48 
13.7 
Audits / Inspection ....................................................................................................... 48 
14 SPONSOR RESPONSIBILITIES ........................................................................................ 49 
14.1 
Role of ECRI ............................................................................................................... 49 
14.2 
Supplemental Applications .......................................................................................... 50 
14.3 
Submitting Reports ...................................................................................................... 50 
14.4 
Maintaining Records ................................................................................................... 50 
14.5 
Audit ............................................................................................................................ 51 
14.6 
Confidentiality ............................................................................................................. 51 
15 REFERENCES ..................................................................................................................... 52 
16 APPENDIX I: SCHEDULE OF EVENTS ........................................................................... 58 
17 APPENDIX II: SYNTAX Score II ....................................................................................... 59 
18 APPENDIX III: DEFINITIONS ........................................................................................... 61 
19 APPENDIX IV: MSCT acquisition guidelines .................................................................... 64 
 
 
 

 
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1 
PROTOCOL SYNOPSIS 
 
Protocol Number 
ECRI-004 
 
Title 
SYNTAX III REVOLUTION Trial: a randomized clinical study utilising 
high-definition GE-Revolution scanning and HeartFlow FFRCT to 
streamline Heart Team decision-making on the most optimal 
revascularization modality in patients with complex coronary artery 
disease. 
  
Study Hypothesis 
Determination if a revascularization strategy for 3-vessel coronary artery 
disease based on non-invasive Revolution™ CT scanning and Heartflow 
FFRCT will result in similar decisions as the conventional approach based 
on invasive coronary angiography. 
 
Study design 
The SYNTAX III REVOLUTION Trial is a multicenter, all-comers trial 
(either isolated unprotected left-main or 3-vessel disease with or without 
left-main disease and candidate for either CABG or PCI treatment) aiming 
at randomizing two Heart Teams who would have to make a decision 
between surgical or percutaneous treatment according to either a 
conventional angiography or a multislice CT angiography assessment in 
approximately 223 patients in approximately 5-10 interventional 
cardiology centers in Europe. Patients with de novo 3-vessel disease or 
left-main disease (isolated or associated with 1, 2 or 3 vessel disease) will 
be eligible.  In addition, the incremental value of FFRCT in the decision 
making of the Heart Team arm allocated primarily to the assessment of the 
MSCT (CT first algorithm) will be a secondary endpoint.   
 
Patient study participation will end after final Heart Team treatment 
decision. The ultimate choice of treatment is up to the discretion of the 
physician/Heart Team.  
 
Objective 
 
 
 
 
Secondary objectives 
To compare a Heart Team clinical decision making strategy either based 
solely on non-invasive CT angiography (GE RevolutionTM) with and 
without adjunction of HeartFlow FFRCT or based solely on conventional 
invasive angiography.  
 
To evaluate in a population with multivessel disease, the outcomes 
between two strategies (non-invasive ‘CT first algorithm’ and invasive 
conventional ‘Angiography  first algorithm’) and within these two 
strategies (based on differences in availability of sources of information). 
 

 
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The sources of information are: 
- Invasive  Angiography 
- Non-invasive GE Revolution CT  
- Functional anatomy by non-invasive FFRCT (Heartflow) 
 
The results to be compared are: 
o Agreement on treatment recommendation  
o Agreement on treatment recommendation between different levels of 
available information  
o Agreement in coronary stenosis segments to be revascularized 
o Anatomical SYNTAX Score and the resulting SYNTAX Score II 
 
Number of Patients 
Approximately  223 patients in total. 
 
Investigational Sites 
Approximately  5-10 sites in Europe. 
 
Follow-up 
No follow-up assessment/visits. Study end after final Heart Team clinical  
decision making. 
 
Primary Endpoint 
Inter-rater agreement, as assessed by Cohen’s Kappa, on revascularization 
strategy of two Heart Teams using an “Angio-first” algorithm (based on 
invasive SYNTAX Score II) or a “CT-first” algorithm (based on non-
invasive SYNTAX Score II, without FFRCT). 
 
Secondary Endpoints • Level of agreement in the decision making strategy based on CT only 
without functional assessment and the decision making strategy based 
on CT with functional assessment (“CT first” algorithm group). 
• Level of agreement in the decision making strategy based on CT only 
(with functional assessment) and the decision making strategy based on 
CT with functional assessment and conventional angiography (“CT 
first” algorithm group). 
• Level of agreement in the decision making strategy based on 
conventional angiography only and the decision making strategy based 
on CT with functional assessment and conventional angiography 
(“Angio first” algorithm group). 
• Inter-rater agreement on revascularization strategy (based on 
conventional angiography and CT with functional assessment) of two 
Heart Teams using an “Angio-first” algorithm or a “CT-first” 
algorithm. 
• Anatomical SYNTAX Score calculation based on non-invasive GE 
Revolution CT (visual by Heart Team involving an experienced 
coronary CT reader) and the resulting SYNTAX Score II. 

 
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• Anatomical SYNTAX Score calculation based on non-invasive GE 
Revolution CT (visual by Core Lab) and the resulting SYNTAX Score 
II. 
• Anatomical SYNTAX Score calculation based invasive Angiography 
(visual by Heart Team) and the resulting SYNTAX Score II. 
• Anatomical SYNTAX Score calculation based on invasive 
Angiography (visual by Core Lab) and the resulting SYNTAX Score II. 
• CT based functional anatomy (FFRCT as assessed by Heartflow)  
• Concordance in SYNTAX Score(s) between and within strategies 
• Agreement in coronary stenosis segments to be revascularized between 
and within strategies. 
 
Patient population 
i). Patients with left main (isolated, or associated with 1, 2 or 3 vessel 
disease) or de novo 3-vessel coronary artery disease (DS ≥50%) who are 
able to undergo cardiac CT with a GE high-definition RevolutionTM multi-
slice CT scanner.  
 
ii). Patients can be enrolled from a referral site, externally diagnosed and 
referred to the cardiologist and/or surgeon; or patients can be diagnosed 
internally. If the patient is diagnosed internally, the physician who 
performed the diagnosis should not be involved in the Heart-Team(s).   
 
iii). The enrolment criteria will be unrestrictive all anatomical SYNTAX 
Scores are eligible for initial screening similar to the SYNTAX I and II 
studies. As per the original SYNTAX Trial, prior CABG or PCI will be 
one of the few exclusion criteria. 
 
General Inclusion 
and Exclusion 
Criteria 
Inclusion Criteria: 
1. Patients with at least 1 stenosis (angiographic, visually determined de 
novo lesions with ≥50% DS) in all 3 major epicardial territories 
(LAD and/or side branch, CX and/or side branch, RCA and/or side 
branch) supplying viable myocardium with or without left main 
involvement; 
2. Patients with hypoplastic RCA with absence of descending posterior 
and presence of a lesion in the LAD and CX territories may be 
included in the trial as a 3VD equivalent; 
3. Vessel size should be at least 1.5 mm in diameter as visually assessed 
in diagnostic angiogram; 
4. Patients with chronic stable angina or stabilized acute coronary 
syndromes (inclusion criteria of the SYNTAX I study): 
a) stable (Canadian Cardiovascular Society Class 1, 2, 3 or 4) angina 

 
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pectoris;  
b) or unstable (Braunwald class IB, IC, IIB, IIC, IIIB, IIIC) angina 
pectoris and ischemia with normal cardiac enzyme values prior to 
enrollment; 
c) or patients with atypical chest pain or those who are asymptomatic 
provided they have myocardial ischemia (e.g. treadmill exercise test, 
radionuclide scintigraphy, stress echocardiography); 
5. All anatomical SYNTAX Scores are eligible;  
6. Patient amenable to a MSCT coronary angiography (e.g. no 
claustrophobia, high heartrate not amenable to beta-blockers, poor 
renal function, etc., up to discretion of investigator); 
7. Patient has been informed of the nature of the study and agrees to its 
provisions and has provided written informed consent as approved by 
the Ethical Committee of the respective clinical site; 
 
Exclusion Criteria: 
Candidates will be ineligible for enrolment in the study if any of the 
following conditions apply: 
 
1. Under the age of 18 years; 
2. Unable to give Informed Consent; 
3. Known pregnancy at time of enrolment. Female of childbearing 
potential (and last menstruation within the last 12 months), who are 
not taking adequate contraceptives. Female who is breastfeeding at 
time of enrolment; 
4. Prior PCI or CABG; history of coronary stent implantation; 
5. Evidence of evolving or ongoing acute myocardial infarction (AMI) 
in ECG and/or elevated cardiac biomarkers (according to local 
standard hospital practice) have not returned within normal limits at 
the time of enrollment; 
6. Concomitant cardiac valve disease requiring surgical therapy 
(reconstruction or replacement); 
7. Single or two-vessel disease (at time of Heart Team consensus); 
8. Atrial fibrillation or significant arrhythmias; 
9. Known allergy to iodinated contrast; 
10. A Body Mass Index (BMI) of 35 or greater; 

 
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11. Participation in another trial with an investigational drug or device. 
Rationale for sample 
size calculation 
The SYNTAX III REVOLUTION Trial is a multicenter, all-comers trial 
aiming at randomizing two Heart Teams. Each patient will be assessed by 
two Heart Teams, the first Heart Team will perform a clinical decision 
based on SYNTAX Score II analysis with invasive angiography 
information (Angio first), the second Heart Team will perform a clinical 
decision based on SYNTAX Score II analysis with non-invasive MSCT 
information (CT first).  For both strategies the Heart Team will lead to one 
of three treatment recommendations: 
CABG-only. 
1. CABG-only. Patient should be treated by CABG due to high 4-year 
mortality of PCI according to therapeutic recommendation of 
SYNTAX Score II.  
 
PCI-only/ Equipoise. 
1. Equipoise. Patient could be treated by either CABG or PCI, 
considering that the 4-year mortality prediction is similar between 
PCI and CABG. 
2. PCI-only. Patient should be treated by PCI due to high 4-year 
mortality of CABG according to therapeutic recommendation of 
SYNTAX Score II. 
 
The SYNTAX III REVOLUTION Trial is powered to show substantial 
inter-rater agreement  between the Heart Team recommendation  (“CABG 
only” or “PCI only/Equipoise” ) based on the Angio first strategy and the 
Heart Team recommendation (“CABG only” or “PCI only/Equipoise” ) 
based on the CT first strategy.  
The inter-rater agreement will be assessed by Cohen’s Kappa, a Kappa of 
0.60 to 0.80 is considered to show substantial agreement.1  
We expect the two Heart Team decisions to reach an almost perfect 
agreement (Kappa=0.80).1 
 
Given these assumptions: 
• Both the Angio first diagnostic algorithm and the CT first diagnostic 
algorithm will result in the “CABG-Only” treatment recommendation 
decision for 30% of the patients. 
• An almost perfect agreement (Kappa=0.80)  
• 90% power to show at least substantial agreement (Kappa>=0.60).1 
• 5% two-sided alpha  
 
a sample size of 200 patients will be sufficient for achieving 90% power to 
reach a positive trial.2 Assuming an attrition rate of maximum 10%, 223 

 
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patients will be included in the study. 
Study organization/ 
Grant givers 
SYNTAX III REVOLUTION Trial is an Investigator-Sponsored-Study 
(ISS). 
Sponsor: European Cardiovascular Research Institute (ECRI). 
Scientific Grant to ECRI from GE Healthcare and Heartflow. 
 
 

 
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2 
INTRODUCTION 
 
 
For the past 50 years revascularization associated with optimal medical therapy has been the 
cornerstone of coronary artery disease (CAD) treatment.3 Since the introduction of coronary 
artery bypass surgery (CABG) in 1964 and percutaneous coronary intervention (PCI) in 1977, 
revascularization procedures have undergone rapid technological advancements that have 
markedly improved their safety and efficacy, and have lead to their widespread clinical adoption 
across the world.4,5  
 
Since the introduction of invasive coronary angiography in the 1960s, it has to the present 
day remained the gold-standard diagnostic method to visualise the coronary anatomy and guide 
revascularization procedures. Invasive coronary angiography has however three major 
limitations; firstly is the marked inter- and intra- observer variability in its interpretation, 
secondly the lack of information regarding the functional significance of coronary lesions, and 
thirdly its invasive nature.6-9 It has long been recognised that the angiographic degree of a given 
coronary stenosis to be a poor tool to ascertain its physiological impact upon blood flow – with 
simple factors such as coronary lesion location and the amount of myocardium subtended shown 
to have a significant impact on whether the lesion will be ischaemic or not.10 Moreover, 
revascularisation of coronary stenoses based upon visual assessment (diameter stenosis) alone 
has been shown to lead to inappropriate revascularisation following PCI or CABG; conversely, 
functional driven revascularisation has been proven to reduce inappropriate revascularisation 
whilst simultaneously improving clinical outcomes.10-20 
Multislice Coronary Computed Tomography Angiography (coronary CTA) 
 
In the last two decades, coronary CTA has been introduced as a non-invasive alternative 
for coronary anatomy assessment.21 Since its introduction, the technology has undergone rapid 
scientific advances with improvements in resolution, acquisition times, reduction in contrast 
volume and radiation doses, going from a eight-slice CT system in 2000, 16-slice CT in 2002, 
64-slice CT systems in 2004, and more recently 128-slice and 256-slice CT systems. The current 
new generation GE RevolutionTM multi-slice 256-slice CT system, being utilised in the present 
study, provides best-in-class technology that will enable imaging of the entire heart in a single 

 
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heart beat, with the rapid speed of the scan facilitating a substantial reduction in both contrast 
volumes and radiation dosage.22-24 
 
In the landmark multicentre CORE-64 study25 – investigating the coronary CTA 
diagnostic ability utilising 64-row scanners compared to invasive angiography in 291 
consecutive patients – coronary CTA (area under the receiver-operator curve [AUC] 0.84, 95% 
CI 0.79 to 0.88) was demonstrated to be similar to conventional invasive angiography (AUC 
0.82, 95% CI 0.77 to 0.86) in its ability to identify patients who subsequently underwent 
revascularization. Further patient-based analyses demonstrated coronary CTA to be highly 
accurate for the diagnosis of patients with at least one coronary stenosis of 50% or more, as 
assessed by invasive quantitative coronary angiography (QCA), with an AUC 0.93 (95% 
confidence interval [CI], 0.90 to 0.96). In a vessel-based analysis, the AUC was 0.91 (95% 
confidence interval [CI], 0.88 to 0.93) demonstrating the good diagnostic capacity of 64-row 
coronary CTA.  
 
 More recently, the PROMISE26 and SCOT-HEART27 trials investigating over 14000 
patients collectively, demonstrated the potential incremental value of coronary CTA over 
conventional practice in investigating patients with suspected angina due to coronary heart 
disease. In PROMISE, coronary CTA was shown to be non inferior to functional testing over a 
median follow up of 2 years, and allowed for better understanding of the coronary anatomy and 
presence of obstructive disease before the patient got to the catheterisation lab. This in turn was 
shown to reduce the likelihood of the patient undergoing invasive angiography demonstrating no 
obstructive CAD, as well as better directing of secondary prevention medication, such as statins. 
In SCOT-HEART, similar findings were shown to PROMISE, namely, that the addition of 
coronary CTA to standard medical therapy lead to an incremental benefit; in particular, for 
gaining an understanding of the presence of obstructive disease before the patient got to the 
catheterisation lab, thus reducing the likelihood of the patient undergoing invasive angiography 
demonstrating no obstructive CAD and allowing for the appropriate immediate targeting of 
revascularisation strategies and other secondary prevention care.  
Anatomical SYNTAX Score, Functional SYNTAX Score and SYNTAX Score II  
 
Decision-making between surgery and percutaneous based revascularisation  

 
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strategies in complex CAD has historically remained difficult.28 To aid this process, European 
revascularisation guidelines currently advocate a multidisciplinary “Heart-Team” approach – 
consisting of at least a cardiologist and cardiac surgeon – and clinical tools, such as the 
anatomical SYNTAX Score and SYNTAX Score II, to objectively quantify CAD burden and 
clinical co-morbidity.7-9,29-38  
Anatomical SYNTAX Score 
 
The anatomical SYNTAX Score (www.syntaxscore.com) was developed during the 
design of the SYNTAX Trial as a tool to force the interventional cardiologist and cardiac 
surgeon to systematically analyse the coronary angiogram and to specify the number of coronary 
lesions requiring treatment, their angiographic location and anatomical complexity.7,34-36,39-41 The 
anatomical SYNTAX Score combines the importance of a diseased coronary artery segment in 
terms of its severity (i.e. obstructive or occlusive), anatomical location and importance in 
supplying blood to the myocardium (‘vessel-segment weighting’ based on the Leaman Score42), 
adverse characteristics of the coronary lesion for revascularisation (ACC/AHA lesion 
classification),43,44 the Medina Classification System for bifurcation lesions,45 and total occlusion 
characteristics from the European TOTAL Surveillance Study46 (Fig. 1). Each vessel segment, 
1.5mm in diameter or greater (Fig. 1, labelled 1 through 16), with a ≥50% diameter stenosis by 
visual estimation, is awarded a multiplication factor related to coronary lesion location and 
severity. Further characterisation of the coronary lesions leads to the addition of more points, 
which includes features of total occlusions (duration, length, blunt stump, presence of bridging 
collaterals or side branch), presence of bifurcation (based on the MEDINA classification45) or 
trifurcation disease (number of diseased branches involved), side branch angulation, aorto-ostial 
lesion, severe tortuosity, lesion length >20 mm, heavy calcification, thrombus and diffuse or 
small vessel disease. An online SYNTAX Score algorithm41 automatically summates each of 
these features to calculate the final total SYNTAX Score. 
Based primarily on the results of the SYNTAX Trial,40,47,48 both European and US guidelines on 
coronary revascularization now recommend the use of the anatomical SYNTAX score to aid 
cardiologists in selecting the most appropriate revascularization modality in patients with 
complex CAD.3,49,50 Specifically, current European revascularisation guidelines32 gives subjects 

 
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with 3VD and low SYNTAX Scores (0-22) a level of evidence of IA for CABG and IIa B for 
PCI. In subjects with ULMCA disease and low to intermediate SYNTAX Scores (<33), a level 
of evidence of IA is given for CABG and IIb B for PCI.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 1 
Coronary tree segments and their importance in supplying blood flow to the left ventricle (vessel segment weighting 
- Leaman score34,42) based on the presence of a left or right dominant system (upper images). In a right dominant 
system, the right coronary artery (RCA) supplies approximately 16% and the left coronary system 84% of the flow 
to the left ventricle. Hence the left main has a weighting factor of x5, the left anterior descending (LAD) x3.5, the 
left circumflex (LCX) x1.5, and RCA x1. In a left dominant system, the RCA contribution of blood flow to the LV 
is supplied by the left circumflex, thus the left coronary system supplies 100% of the blood to the left ventricle 
(LAD 58%, LCX 42%). Thus the weighting factor for the left main is increased to x6, the LAD unaltered at x3.5, 
and LCX increased to x2.5. A multiplication factor of 2 is used for non-occlusive lesions (50-99% diameter stenosis) 
and 5 for occlusive (100% diameter stenosis) lesions. Other adverse lesion characteristics considered in the 
SYNTAX score have an additive value (lower image). Images used with permission from the SYNTAX Trial 
Investigators.  
 
 
Functional SYNTAX Score 
 
Percutaneous coronary intervention guided by the assessment of the functional 
significance of a lesion using fractional flow reserve (FFR) has been shown to reduce 
inappropriate revascularization whilst simultaneously improving clinical outcomes.10-20,51-53 The 
Functional SYNTAX Score uses the principle of the functional assessment of coronary lesions to 

 
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determine the SYNTAX Score, rather than the angiographic determination of the SYNTAX 
Score based upon visual assessment, as is undertaken in conventional anatomical SYNTAX 
Score calculations. In a retrospective sub-analysis of almost 500 patients (n=497) from the FFR-
guided arm of the FAME (Fractional Flow Reserve Versus Angiography for Multivessel 
Evaluation) study, the primary benefit appeared in reclassifying higher-risk groups into lower 
risk categories without any adverse sequelae in terms of major adverse cardiac events (MACE) 
and death or myocardial infarction (MI) at 1 year.11 It should be emphasized that subjects in the 
FAME Study had substantially less complex coronary artery disease (mean SYNTAX Score 
14.8±6.0) compared to the PCI arm of the SYNTAX Trial (mean SYNTAX Score 28.4±11.5). 
Prospective validation of the functional SYNTAX Score in complex coronary artery disease is 
currently ongoing in the SYNTAX II (ClinicalTrials.gov Identifier: NCT02015832) and FAME 
III (ClinicalTrials.gov Identifier: NCT02100722) clinical trials.  
SYNTAX Score II 
 
The SYNTAX Score II combines anatomical and clinical characteristics to guide decision 
making between CABG and PCI.37,38 The European Society of Cardiology/European Association 
for Cardio-thoracic Surgery guidelines on myocardial revascularization29 currently gives the 
SYNTAX Score II a recommendation of IIa (weight of evidence/opinion in favour of 
usefulness/efficacy – should be considered), level of evidence B.  
 
During development of the SYNTAX Score II, it was hypothesised that the category 
based system of the anatomical SYNTAX Score (low <23, intermediate 23-32, high ≥33) was 
potentially concealing higher (or lower) risk patients in lower (or higher) risk groups.54 The 
SYNTAX Score II was developed to overcome this limitation by allowing for individualised 
decision making, and was shown to identify subsets of patients in all tertiles (low [<23], 
intermediate [23-32], high [>32]) of the SYNTAX Score in which CABG or PCI would confer a 
long term mortality benefit or offer equipoise for long term prognosis. 37 
 
In SYNTAX, the combination of the anatomical SYNTAX Score with ACEF (age, 
creatinine clearance and left ventricular ejection fraction) was shown to contain the bulk of the 
prognostic information in predicting mortality after CABG (excluding the anatomical SYNTAX 

 
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Score54-57) or PCI (including the anatomical SYNTAX Score58). The SYNTAX Score II was 
therefore built on the ACEF ‘skeleton,’ with the addition of risk factors that were shown to 
directly affect decision making between CABG and PCI. Clinical factors that were shown to 
directly affect decision making between CABG and PCI were selected based on their ‘interaction 
effect,’ i.e. if a clinical factor was more predictive of mortality in patients undergoing PCI 
compared to CABG, or vice versa. For example, the anatomical SYNTAX Score aids decision-
making between CABG and PCI because it is more predictive of clinical outcomes in patients 
undergoing PCI, compared to patients undergoing CABG (where it is not predictive).7,54 Based 
on this principle, younger age, female gender and reduced LVEF favoured CABG compared to 
PCI on long-term prognostic grounds. Thus, in such patients a LOWER anatomical SYNTAX 
Score would be required in order for the long-term mortality risk to be similar between CABG 
and PCI. By contrast, older age, chronic obstructive pulmonary disease or ULMCA disease 
favoured PCI compared to CABG and thus, in this type of patient, a HIGHER anatomical 
SYNTAX Score would be needed for the long-term mortality risks to be similar.  A nomogram 
was developed (Fig. 2) that allowed for an accurate individualised prediction of 4-year mortality 
in patients proposing to undergo CABG or PCI to objectively aid decision making. The online 
version of the SYNTAX Score II will appear shortly after recruitment of patients in the ongoing 
SYNTAX II trial (ClinicalTrials.gov Identifier: NCT02015832) has been completed 
(www.syntaxscore.com).  
The SYNTAX Score II was developed in 1800 patients from the randomised SYNTAX 
Trial. The design of SYNTAX was all-comers in order to reduce selection bias and therefore 
adds to the robustness of the SYNAX Score II in application to contemporary clinical practice. 
External validation of the SYNTAX Score II37 was performed in the multinational Drug Eluting 
stent for Left main coronary Artery disease (DELTA) Registry (14 centres in Europe, US and 
South Korea),59 composed of subjects with ULMCA disease associated with or without 
multivessel disease (26% of the study population had 3 vessel disease [3VD]) (n=2891). Further 
retrospective validation of the SYNTAX Score II has recently been undertaken in 3,896 
patients with 3-vessel and/or ULMCA disease undergoing PCI (n=2,190) or CABG (n=1,796) 
from the Japanese Coronary REvascularization Demonstrating Outcome Study in Kyoto 
(CREDO-Kyoto) PCI/CABG multicenter registry.60  

 
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Prospective validation of the SYNTAX Score II is currently occurring in 2 separate 
studies. 
Firstly, in the international multicenter EXCEL Trial (Evaluation of XIENCE PRIME™ 
or XIENCE V® Everolimus Eluting Stent System Versus Coronary Artery Bypass Surgery for 
Effectiveness of Left Main Revascularization) Trial (ClinicalTrials.gov Identifier: 
NCT01205776) having recently completely recruitment of patients. EXCEL recruited 1905 
patients with ULMCA disease and investigator reported SYNTAX Scores <33, randomised to 
CABG (n=957) or PCI with contemporary stents (n=948). The Primary Endpoint is a composite 
measure of all-cause death, MI, or stroke at 3 years post revascularisation.61 As part of the 
prospective validation of the SYNTAX Score II in EXCEL, the SYNTAX Score II has been used 
to forecast and compare 4-year mortality in the PCI and CABG arms of EXCEL, and has 
predicted at least an equipoise for long-term mortality between CABG and PCI in subjects 
with ULMCA disease up to an intermediate anatomical complexity (anatomical SYNTAX 
Score <33).62  
Secondly in the ongoing SYNTAX II Trial (ClinicalTrials.gov Identifier: 
NCT02015832), where the SYNTAX Score II is being used as a clinical tool to recruit subjects 
with de novo three vessel disease (without left main involvement) on the grounds of patient 
safety, i.e. subjects with a similar long term mortality between CABG and PCI, in conjunction 
with the Heart Team. Notably subjects from all tertiles (low <23, intermediate 23-32, high ≥33) 
of the anatomical SYNTAX Score will be eligible. The PCI procedure will be guided by a 
functional assessment of all three vessels37, a newer generation stent platform with a 
biodegradable polymer,11 and intravascular ultrasound (IVUS) guided stent implantation.63,64 The 
PCI and CABG arms of the SYNTAX Trial48,65 will act as control arms.  
 
 
 
 

 
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Figure 2: The SYNTAX Score II nomogram for bedside application. Total number of points for 8 factors can be 
used to accurately predict 4-year mortality for the individual patient proposing to undergo for CABG or PCI. For 
example, a 60 year old male with an anatomical SYNTAX Score of 30, ULMCA disease, CrCl 60 ml/min, a LVEF 
of 50%, and COPD, would have 41 points (predicted 4-year mortality: 16·3%) and 33 points (predicted 4-year 
mortality: 8·7%) to undergo CABG and PCI respectively. The same example, without COPD included, would lead 
to identical points (29 points) and 4-year mortality predictions (6.3%) for CABG and PCI.  
*Due to the rarity of complex coronary artery disease in pre-menopausal women, mortality predictions in younger 
women are predominantly based on the linear relationship of age with mortality. The differences in mortality 
predictions in younger woman between CABG and PCI, will therefore be affected by larger 95% confidence 
intervals (CIs) but be equally valid. 
Courtesy of Farooq et al.37 
 
 
Non-invasive SYNTAX score 
A limitation of the anatomical SYNTAX Score is the inter-observer variability in its 
calculation from the coronary angiogram, and the lack of information regarding the functional 
Abbreviations: CABG coronary artery bypass graft surgery, PCI percutaneous coronary intervention; CrCl creatinine 
clearance (Cockcroft and Gault formula)20; LVEF left ventricular ejection fraction; Left Main: unprotected left main 
coronary artery disease, COPD chronic obstructive pulmonary disease (long term use of bronchodilators or steroids for 
lung disease [EuroSCORE definition11]); PVD peripheral vascular disease (aorta and arteries other than coronaries, with 
exercise related claudication, and/or revascularisation surgery and/or reduced or absent pulsation and/or angiographic 
stenosis of more than 50% [ARTS I definiton19]). 

 
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significance of coronary lesions.6-9 Although appropriate training has been shown to improve the 
reproducibility of anatomical SYNTAX Score interpretation by clinicians, differences still 
persisted in the interpretation of several lesion types, in particular coronary bifurcations.6 The 
need to develop a more objective, rapidly calculated anatomical SYNTAX Score has become 
increasingly apparent.8,9 The development of a non-invasive anatomical SYNTAX Score will 
therefore potentially streamline the Heart Team process and allow for more objective decision-
making by allowing for a non-invasive, less biased, anatomical and physiological assessment of 
the coronary anatomy in combination with clinical factors utilising the SYNTAX Score II.  
Multislice Coronary CTA SYNTAX score  
Papadopoulou et al66 first described the feasibility and reproducibility of a MSCT-derived 
SYNTAX Score in 80 consecutive patients with symptomatic angina, using definitions of the 
angiographically defined SYNTAX Score adapted for the MSCT capabilities. The underlying 
concept being to allow for the anatomical SYNTAX Score to be calculated prior to the 
intervention, to potentially aid decision making and optimise patient management. Within this 
study, the MSCT SYNTAX Score was shown to be feasible, with results comparable to the  
anatomical SYNTAX Score calculated with conventional invasive coronary angiography. Whilst 
this study was shown to be highly reproducible,66 a subsequent validation study of similar size 
numbers (n=104) was met with only fair agreement between MSCT and angiography derived 
SYNTAX Scores,67 although this did improve substantially when analyses were restricted to 
good quality MSCT. Notably, both studies investigated subjects with predominantly less 
complex coronary artery disease (low SYNTAX Scores <23).66,67 Larger scale validation studies, 
particularly in more complex ‘SYNTAX-like’ patients, are awaited. 
The addition of a non-invasive fractional flow reserve (FFR) component (Heartflow, 
Redwood City, California, USA) has the potential to allow for the non invasive calculation of a 
functional based MSCT SYNTAX Score. This technology is based upon utilizing computational 
fluid dynamic techniques applied to the MSCT angiography.66 Validation data of the non-
invasive FFR MSCT has been reported in the DISCOVER FLOW36,68 and multicentre 
DeFACTO (Determination of Fractional Flow Reserve by Anatomic Computed Tomographic 
Angiography)69 and NXT (Diagnostic performance of noninvasive fractional flow reserve 

 
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derived from coronary computed tomography angiography in suspected coronary artery disease: 
the NXT trial (Analysis of Coronary Blood Flow Using CT Angiography: Next Steps)70 trials.  
As of present the MSCT substudy in the ongoing SYNTAX Trial II (ClinicalTrials.gov 
Identifier: NCT02015832) is currently developing a non invasive functional MSCT SYNTAX 
Score using the HeartFlow technology. It is expected that the present study will allow validation 
of the non invasive functional MSCT SYNTAX Score developed in SYNTAX II. 
MSCT SYNTAX Score II 
In the MSCT substudy of the ongoing SYNTAX II Trial, 68 patients had SYNTAX Score II 
calculations performed with both invasive coronary angiography and coronary CTA. The mean 
difference in SYNTAX score II PCI between ICA and coronary CTA was 0.5 ± 2.1 (limits of 
agreement -3.8 to 4.7). The intraclass correlation coefficient was 0.97 (95%CI 0.95 to 0.99) 
(unpublished data). 
Purpose of Study 
The purpose of the SYNTAX III trial is to investigate whether the Heart Team decision making 
regarding the choice of revascularization strategy based on non-invasive coronary CTA 
assessment of CAD (GE RevolutionTM) and non-invasive HeartFlow FFRCT is at least 
comparable to the standard-of-care assessment based on invasive coronary angiography, in 
patients with complex CAD. The Heart Team decision making process will be compared 
between the two modalities of assessment (invasive vs. non-invasive) regarding the chosen 
revascularization strategy (PCI or CABG), the number of vessels requiring treatment and the 
coronary segments in need of revascularization. 
 
 

 
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3 
OBJECTIVE  
 
Primary Objective: to compare a Heart-Team clinical decision making strategy either based 
solely on non-invasive CT angiography (GE RevolutionTM) with and without adjunctive 
HeartFlow FFRCT or based solely on conventional invasive angiography.  
 
Secondary objectives: 
To evaluate in a population with multivessel disease, the outcomes between two strategies (non-
invasive ‘CT first algorithm’ and invasive conventional ‘Angiography first algorithm’) and 
within these two strategies (based on differences in availability of sources of information). 
The sources of information are: 
• Invasive Angiography 
• Non-invasive GE Revolution CT 
• Functional anatomy by non-invasive FFRCT (Heartflow) 
 
The results of information are: 
• Agreement on treatment recommendation 
• Agreement on treatment recommendation between different levels of available 
information  
• Agreement in coronary stenosis segments to be revascularized 
• Anatomical SYNTAX Score and the resulting SYNTAX Score II 

 
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4 
STUDY DESIGN  
 
The SYNTAX III REVOLUTION Trial is a multicenter, all-comers* trial aiming at randomizing 
two Heart Teams who would have to make a decision between surgical or percutaneous 
treatment according to either an invasive conventional angiography or a non-invasive multislice 
CT angiography assessment in approximately 223 patients in approximately 5-10 interventional 
cardiology centers in Europe. *Patients with de novo 3-vessel disease or left-main disease 
(isolated or associated with 1, 2 or 3 vessel disease) will be eligible. 
 
   
 
For each given patient the Heart Team is randomly assigned to an “Angio-First” or a “CT-First” 
decision algorithm. There will be two (2) independent Heart Teams per hospital, and each patient 
will be assessed by both teams. The concordance or discordance of decision makings based on 

 
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either conventional angiography (Angio first algorithm) or MSCT angiography (CT first 
algorithm) will be assessed and constitute the primary endpoint of the trial. In addition, the 
incremental value of FFRCT in the decision making of the Heart Team arm allocated primarily to 
the assessment of the MSCT (CT first algorithm) will be a secondary endpoint.   
 
Patient study participation will end after final Heart Team treatment decision. The ultimate 
choice of treatment is up to the discretion of the physician/Heart Team. 
 
 
 

 
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5 
ENDPOINTS 
 
5.1 
Primary Endpoint 
 
Inter-rater agreement, as assessed by Cohen’s Kappa, on revascularization strategy of two Heart 
Teams using an “Angio-first” algorithm (based on invasive SYNTAX Score II) or a “CT-first” 
algorithm (based on non-invasive SYNTAX Score II, without FFRCT). 
 
The Heart Team consensus on therapeutic strategy is made according to the following 3 options: 
  
CABG-only. 
1. CABG-only. Patient should be treated by CABG due to high 4-year mortality of PCI 
according to therapeutic recommendation of SYNTAX Score II.  
 
PCI-only/ Equipoise. 
1. Equipoise. Patient could be treated by either CABG or PCI, considering that the 4-year 
mortality prediction is similar between PCI and CABG. 
2. PCI-only. Patient should be treated by PCI due to high 4-year mortality of CABG 
according to therapeutic recommendation of SYNTAX Score II 
 
*The Heart Team can overrule the SYNTAX Score II therapeutic recommendation whenever the 
Heart Team identifies significant additional clinical risks which are not addressed in the 
SYNTAX Score II. 
 
5.2 
Secondary endpoints 
 
Secondary endpoints of this study are to assess: 
• Level of agreement in the decision making strategy based on CT only without functional 
assessment and the decision making strategy based on CT with functional assessment 
(“CT first” algorithm group). 
• Level of agreement in the decision making strategy based on CT only (with functional 
assessment) and the decision making strategy based on CT with functional assessment 
and conventional angiography (“CT first” algorithm group). 

 
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• Level of agreement in the decision making strategy based on conventional angiography 
only and the decision making strategy based on CT with functional assessment and 
conventional angiography (“Angio first” algorithm group). 
• Inter-rater agreement on revascularization strategy (based on conventional angiography 
and CT with functional assessment) of two Heart Teams using an “Angio-first” algorithm 
or a “CT-first” algorithm. 
• Anatomical SYNTAX Score calculation based on non-invasive GE Revolution CT 
(visual by Heart Team involving a radiologist) and the resulting SYNTAX Score II. 
• Anatomical SYNTAX Score calculation based on non-invasive GE Revolution CT 
(visual by Core Lab) and the resulting SYNTAX Score II. 
• Anatomical SYNTAX Score calculation based invasive Angiography (visual by Heart 
Team) and the resulting SYNTAX Score II. 
• Anatomical SYNTAX Score calculation based on invasive Angiography (visual by Core 
Lab) and the resulting SYNTAX Score II. 
• CT based functional SYNTAX Score (FFRCT as assessed by Heartflow)  
• Concordance in SYNTAX Score(s) between and within strategies 
• Agreement in coronary stenosis segments to be revascularized between and within 
strategies. 
 
 
 

 
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6 
SUBJECT SELECTION   
 
i). Patients with left main (isolated, or associated with 1, 2 or 3 vessel disease) or de novo 3-
vessel coronary artery disease (DS ≥50%) who are able to undergo cardiac CT with a GE high-
definition RevolutionTM multi-slice CT scanner.  
 
ii). Patients can be enrolled from a referral site, externally diagnosed and referred to the 
cardiologist and/or surgeon; or patients can be diagnosed internally. If the patient is diagnosed 
internally, the physician who performed the diagnosis should not be involved in the Heart-
Team(s).  
 
iii). The enrolment criteria will be unrestrictive all anatomical SYNTAX Scores are eligible for 
initial screening similar to the SYNTAX I and II studies. As per the original SYNTAX Trial, 
prior CABG or PCI will be one of the few exclusion criteria. 
 
6.1 
Inclusion Criteria 
 
1. Patients with at least 1 stenosis (angiographic, visually determined de novo lesions with 
≥50% DS) in all 3 major epicardial territories (LAD and/or side branch, CX and/or side 
branch, RCA and/or side branch) supplying viable myocardium with or without left main 
involvement; 
2. Patients with hypoplastic RCA with absence of descending posterior and presence of a 
lesion in the LAD and CX territories may be included in the trial as a 3VD equivalent; 
3. Vessel size should be at least 1.5 mm in diameter as visually assessed in diagnostic 
angiogram; 
4. Patients with chronic stable angina or stabilized acute coronary syndrome (inclusion criteria 
of the SYNTAX I study): 
a) stable (Canadian Cardiovascular Society Class 1, 2, 3 or 4) angina pectoris;  
b) or unstable (Braunwald class IB, IC, IIB, IIC, IIIB, IIIC) angina pectoris and ischemia 
with normal cardiac enzyme values prior to enrollment; 

 
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c) or patients with atypical chest pain or those who are asymptomatic provided they have 
myocardial ischemia (e.g. treadmill exercise test, radionuclide scintigraphy, stress 
echocardiography); 
5. All anatomical SYNTAX Scores are eligible; 
6. Patient amenable to a MSCT coronary angiography (e.g. no claustrophobia, high heartrate 
not amenable to beta-blockers, poor renal function, etc., up to discretion of investigator); 
7. Patient has been informed of the nature of the study and agrees to its provisions and has 
provided written informed consent as approved by the Ethical Committee of the respective 
clinical site; 
 
6.2 
Exclusion Criteria 
 
Candidates will be ineligible for enrolment in the study if any of the following conditions apply: 
 
1. Under the age of 18 years; 
2. Unable to give Informed Consent; 
3. Known pregnancy at time of enrolment. Female of childbearing potential (and last 
menstruation within the last 12 months), who are not taking adequate contraceptives. Female 
who is breastfeeding at time of enrolment; 
4. Prior PCI or CABG; history of coronary stent implantation; 
5. Evidence of evolving or ongoing acute myocardial infarction (AMI) in ECG and/or elevated 
cardiac biomarkers (according to local standard hospital practice) have not returned within 
normal limits at the time of enrollment; 
6. Concomitant cardiac valve disease requiring surgical therapy (reconstruction or 
replacement); 
7. Single or two-vessel disease (at time of Heart Team consensus); 
8. Atrial fibrillation or significant arrhythmias; 
9. Known allergy to iodinated contrast; 
10. A Body Mass Index (BMI) of 35 or greater; 
11. Participation in another trial with an investigational drug or device. 

 
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7 
STUDY PROCEDURES   
 
7.1 
 Screening 
 
To assess the eligibility of the patient according to the inclusion/exclusion criteria, the presence 
of left main disease (isolated, or associated with 1, 2 or 3 vessel disease) or de novo 3-vessel 
coronary artery disease must be diagnosed on conventional angiography and/ or MSCT before 
randomization.  
 
7.2 
Patient Information and Informed Consent 
 
If the eligibility of the patient is confirmed according to inclusion and exclusion criteria, patients  
must be consented prior to undergoing any study-specific procedures. Once the patient’s general 
eligibility for the study is met, the background of the proposed study and the benefits and risks of 
the study must be explained to the patient prior to obtaining informed consent. Only those 
patients who sign the Ethics Committee approved informed consent form prior to any study-
specific procedures (MSCT scanning with GE 256-slice REVOLUTION scanner) are candidates 
for actual enrolment in the study. Failure to provide written informed consent renders the patient 
ineligible for the study. 
The investigator and/or designee must also clearly document the process of obtaining informed 
consent in the subject’s source documents. The voluntary process of obtaining informed consent 
confirms the subject’s willingness to participate in the study. It is the investigator’s responsibility 
to ensure that the informed consent process is performed in accordance with ISO14155, EC 
requirements and country specific regulations.  
 
7.3 
Baseline evaluation prior to MSCT/ Heart Team discussion 
 
As part of good clinical practice, the following routine laboratory tests must be performed prior 
to MSCT scanning/Heart Team randomization: 
- creatinine clearance (Cockcroft-Gault71); 
 

 
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According to good routine local clinical practice, left ventricular ejection fraction (percentage) 
should be assessed quantitatively by either echo-cardiography, or conventional left 
ventriculography or other modalities. In addition, the history of chronic obstructive pulmonary 
disease, peripheral artery disease should be evaluated according to the EuroScore (I) definition.  
 
7.4 
MSCT  
 
Prior to the Heart Team randomization, a MSCT scan must be obtained utilizing the 256-slice 
GE Revolution* CT scanner.  Refer to Appendix IV for MSCT acquisition guidelines.  
*A patient may be diagnosed/enrolled based on previously performed MSCT (but solely, if that CT was performed 
with the 256-slice GE Revolution CT scanner and within 1 month prior to patient enrolment. 
FFRCT will be used in the incremental process of Heart Team discussion (= secondary endpoint). 
The MSCT-derived FFR (FFRCT) will only be disclosed after the first decision making has been 
concluded.  
 
7.5 
Anatomical  SYNTAX Score,  SYNTAX Score II and functional anatomy (FFRCT) 
 
The baseline anatomical SYNTAX Score for angiography and for MSCT and SYNTAX Score II 
should be calculated  prior to the start of the Heart Team meeting(s) and must be recorded in the 
eCRF.  
The diagnostic angiograms and acquired and reconstructed MSCT images should be transferred 
automatically using AG Mednet to the independent Core Lab (Cardialysis, B.V., Rotterdam, NL) 
and to HeartFlow Inc. (Redwood city, California, USA) for the functional assessment derived 
from MSCT (FFRCT).   
Additionally, anatomical SYNTAX Score (angiography and CT) will be performed by the Core 
Laboratory. The site/Heart Team may consult the Core Lab SYNTAX Score (I and II) during the 
Heart Team meeting/treatment decision-making process.  
The site/Heart Team may consult the Core Lab SYNTAX Score (I and II) during the Heart Team 
meeting/treatment decision-making process.  
The site/Heart Team will also receive the functional anatomy (FFRCT) for consultation. 

 
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7.6 
Randomization 
 
Before the start of enrolment, two Heart Teams (A and B) are formed and registered at each site, 
including at least one physician from each sub-speciality (i.e., radiologist, cardiac surgeon and 
interventional cardiologist). When a patient is enrolled, the algorithm of decision making is 
randomly allocated to two Heart Teams (i.e. Heart Team A: CT first, Heart Team B: 
Angiography first, or Heart Team A: Angiography first, Heart Team B: CT first) in order to 
ensure that the two Heart Teams experience both decision-making processes equally (e.g. CT 
based or Angio based). According to the allocated sequence, two Heart Teams discuss and make 
a treatment decision independently (blinded to the decision made by the other Heart Team).  
In case any member of the Heart Team is not available due to logistical (e.g. on-call, congress, 
holiday) or other reasons (e.g. pre-exposure to angiography or MSCT)  the site is allowed to have 
‘back-up physicians’ for Heart Team A and Heart Team B.  In other words, in order to prevent 
any delay in clinical decision making, the Heart Team can still proceed with the discussion as 
long as at least one physician from all three specialities is available.  
7.7 
Heart Team meeting structure & organization 
 
The Heart Team should involve an interventional cardiologist, cardiac surgeon, radiologist 
(experienced coronary CT reader) and study coordinator.  
It is recommended to execute the different levels of decision making during one Heart Team 
session. In other words, one should start the Heart Team meeting only when all information is 
available and accessible, i.e. anatomic SYNTAX Score by Angio and CT (by site and by Core 
Lab), SYNTAX Score II and functional anatomy (FFRCT).  Randomization is performed via the 
eCRF module. The Heart Teams are randomized to one of two groups (1:1) to either ‘Angio-first 
algorithm’ or ‘MSCT-first’ algorithm. 
   
Angio first algorithm: Screen the patients first by means of conventional invasive angiography 
(i.e. anatomical SYNTAX Score [visual] and SYNTAX Score II) and record the first decision 
making on choice of revascularization (PCI or CABG), planning of revascularization measures 
(# of stents / # of grafts), and localization of diseased segments needing revascularization in the 

 
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eCRF. As an external reference, the independent Core Lab also provides anatomical SYNTAX 
Score for consultation. After the first decision making recording, the additional information of 
CT and the functional severity assessment is disclosed and the Heart Team completes the second 
decision based on information derived from both modalities. 
  
CT first algorithm: Screen the patients first by means of non-invasive CT (i.e. anatomic 
SYNTAX Score [visual by experienced coronary CT reader/radiologist] and SYNTAX Score II 
and record the first decision making on choice of revascularization (PCI or CABG), planning of 
revascularization measures (# of stents / # of grafts), and localization of diseased segments 
needing revascularization in the eCRF. The radiologist of the Heart Team provides anatomical 
SYNTAX Score on MSCT, which is primarily used for decision making. As an external 
reference, the independent Core Lab also provides anatomical SYNTAX Score on MSCT for 
consultation.  
After the first decision making recording the functional anatomy (FFRCT) is disclosed to the 
Heart Team. The Heart Team recalculates the SYNTAX Score (I and II) by subtracting the 
(SYNTAX Score) points of non-flow limiting lesions (>0.80) and makes the second decision  
(incremental value FFRCT). Next, the additional information of conventional angiography is 
disclosed and the Heart Team makes the third decision based on information derived from both 
modalities. 
 
For the first, second and third decision making, the Heart Team records following items in the 
eCRF (as well as for the final/actual treatment): 
a. choice of revascularization mode: PCI/CABG; 
b. number of diseased vessels/diseased lesions; 
c. diseased segment numbers 
 
Final decision of treatment recommendation will be left at the discretion of the Heart Team after 
formal dialogue with the patient and provision of the prognostic information. The Heart Team 
may overrule the treatment recommendation made by the online calculator whenever the Heart 

 
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Team identifies significant additional clinical risks which are not addressed in the SYNTAX 
Score II. Reasons for undertaking this should be clearly documented in the eCRF 
 
Note: the Heart Team must co-sign and document in the eCRF (including date and time) each 
decision-making following the assigned algorithm prior to the unblinding with the 
complementary information (either Angio or MSCT, or functional anatomy).  
Note: the physicians involved in the initial angiography/catherization or MSCT acquisition are 
not ‘blind’ for both imaging modalities and as a consequence cannot be part of the study Heart 
Team (randomisation).  
 
7.8 
Data-flow 
 
The data-flow, the export of images, and the access to Core Lab SYNTAX Scores and FFRCT 
will be described in a separate manual. 
 
 

 
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8 
STATISTICAL DESIGN AND ANALYSIS 
 
8.1 
Introduction 
 
The SYNTAX III REVOLUTION Trial is a multicenter, all-comers trial aiming at randomizing 
two Heart Teams. Each patient will be assessed by two Heart Teams, the first Heart Team will 
perform a clinical decision based on SYNTAX Score II analysis with angiographic information 
(Angio first), the second Heart Team will perform a clinical decision based on SYNTAX Score 
II analysis with MSCT information (CT first).  For both strategies the Heart Team will lead to 
one of three treatment recommendations: 
CABG-only. 
1. CABG-only. Patient should be treated by CABG due to high 4-year mortality of PCI 
according to therapeutic recommendation of SYNTAX Score II.  
PCI-only/ Equipoise. 
1. Equipoise. Patient could be treated by either CABG or PCI, considering that the 4-year 
mortality prediction is similar between PCI and CABG. 
2. PCI-only. Patient should be treated by PCI due to high 4-year mortality of CABG 
according to therapeutic recommendation of SYNTAX Score II. 
 
8.2 
Intent-To-Treat population 
 
The ‘Intend-to-Treat’ population consists of all patients having a GE Revolution CT scan 
performed and for whom the Heart Team is randomly assigned to an “Angio-First” or a “CT-
First” decision algorithm. 
 
8.3 
Sample size 
 
The SYNTAX III REVOLUTION Trial is powered to show substantial inter-rater agreement  
between the Heart Team recommendation (“CABG only” or “PCI only/Equipoise” ) based on the 
Angio first algorithm and the Heart Team recommendation (“CABG only” or “PCI 
only/Equipoise” ) based on the CT first algorithm.  

 
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The inter-rater agreement will be assessed by Cohen’s Kappa, on revascularization strategy of 
two Heart Teams using an “Angio-first” algorithm (based on invasive SYNTAX Score II) or a 
“CT-first” algorithm (based on non-invasive SYNTAX Score II, without FFRCT). 
A Kappa of 0.60 to 0.80 is considered to show substantial agreement.1  We expect the two Heart 
Team decisions to reach an almost perfect agreement (Kappa=0.80).1 
 
Given these assumptions: 
• Both the Angio first diagnostic algorithm and the CT first diagnostic algorithm will result 
in the “CABG-Only” treatment decision for 30% of the patients, 
• An almost perfect agreement (Kappa=0.80),  
• 90% power to show at least substantial agreement (Kappa>=0.60) 
• and a 5% two-sided alpha  
 
a sample size of 200 patients will be sufficient for achieving 90% power to reach a positive trial.2 
Assuming an attrition rate of maximum 10%, 223 patients will be included in the study. 
 
8.4 
Intend-to-Treat Analysis 
 
All analyses will be performed for the Intend-to-Treat population only. 
 
8.5 
Analysis of the Primary Endpoint 
 
The inter-rater agreement will be assessed by Cohen’s Kappa, on revascularization strategy of 
two Heart Teams using an “Angio-first” algorithm (based on invasive SYNTAX Score II) or a 
“CT-first” algorithm (based on non-invasive SYNTAX Score II, without FFRCT).  A 95% two-
sided confidence interval will be calculated for Kappa, using the asymptotic variance of the 
Kappa coefficient and applying the standard normal distribution.72 
If the lower limit of this confidence interval is 0.6 or higher the trial is considered to be positive. 
If the lower limit of this confidence interval is less than 0.6 the trial is considered to be negative.  

 
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8.6 
Analysis of the Secondary Endpoints 
 
No formal testing will take place for the secondary endpoints. 
 
Secondary Endpoints measuring Inter-Rater agreement 
 
Secondary Endpoints that measure inter-rater agreement are for the following situations: 
• A comparison between the treatment recommendation between two diagnostic algorithms 
(CT only versus Angio only)  at the same decision moment  
• A comparison between the treatment recommendation for the same diagnostic algorithm 
(e.g. CT only) but for different levels of available information 
Agreement is reached when both algorithms recommend “CABG only” or both algorithms 
recommend “PCI only/Equipoise”. 
 
In both cases the inter-rater agreement will be measured by: 
 
• 2*2 tables showing the treatment recommendations (“CABG only”/”PCI 
only/Equipoise”) for the compared situations. 
• The percentage of patients with agreement between the algorithms and its 95% two-sided 
Confidence Interval (using the Clopper-Pearsons (Exact) approach). 
• The inter-rater agreement as measured by Cohen’s Kappa and its 95% two-sided 
Confidence Interval for Kappa using the asymptotic variance of the Kappa coefficient  
and applying the standard normal distribution.72  
 
Additionally these endpoints measuring agreement will be reported. 
  
• Concordance in SYNTAX Score(s) between and within strategies, measured as the 
difference in SYNTAX Score(s) points. 
• Agreement in coronary stenosis segments to be revascularized between and within 
strategies (using AHA 16 segment model).73,74  
• An ad-hoc defined composite endpoint combining   
-Concordance in SYNTAX Score(s) 
-Agreement in coronary stenosis segments to be revascularized 

 
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-Agreement between treatment recommendation. 
 
Continuous secondary endpoints 
 
• Anatomical SYNTAX Score calculation based on non-invasive GE Revolution CT 
(visual by Heart Team involving a radiologist) 
• Anatomical SYNTAX Score calculation based on non-invasive GE Revolution CT 
(visual by Core Lab) 
• Anatomical SYNTAX Score calculation based on invasive Angiography (visual by Heart 
Team) 
• Anatomical SYNTAX Score calculation based on invasive Angiography (visual by Core 
Lab) 
• Functional SYNTAX Score by non-invasive FFRCT (Heartflow)  
• SYNTAX Score II derived from either conventional angiography (CA) or non-invasive 
angiography (CTA) by Heart Team 
 
8.7 
 Descriptive statistical methodology 
 
All statistical analyses will be done using the SAS System software, version 9.3 or above (SAS 
Institute Inc., SAS Campus Drive, Cary, North Carolina 27513, USA. All rights reserved). 
 
Inter-rater agreement will be assessed by Cohen’s Kappa.  A 95% two-sided confidence interval 
will be calculated, using the asymptotic variance of the Kappa coefficient and applying the 
standard normal distribution.72 
 
 Continuous endpoints will be summarized by their mean, standard deviation, number of 
observations, median, minimum, maximum and interquartile range. The variable means are 
evaluated by a paired t-test, the difference between treatments and its 95% confidence interval 
will be reported. 
 
Categorical variables are summarized by frequencies and percentages. Baseline Characteristics 

 
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Demographics, medical history and other clinically relevant baseline variables will be tabulated. 
In principal patient oriented percentages refer to the proportion of patients with the characteristic 
present.  
 
 
 
 
 
 
 

 
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9 
QUALITY CONTROL AND QUALITY ASSURANCE 
 
9.1 
Compliance to Standards and Regulations 
The protocol, informed consent form and other study-related documents will be submitted to the 
Ethics Committee (EC) / Institutional Review Board (IRB). The study will be performed in 
accordance with the Declaration of Helsinki and Good Clinical Practices (GCP). 
 
The trial will only start at a clinical site after written approval of the study has been obtained 
from the appropriate national EC/IRB.  
 
9.2 
Quality Assurance and Monitoring  
Monitoring the clinical investigation at the study site is the responsibility of the monitoring 
organisation through trained and qualified Clinical Research Associates (CRAs).  
The study Sponsor, or designee, will monitor the study to ensure proper conduct and progress of 
the study including adequate protection of human subjects and the integrity of the clinical study 
data.  It may include initiation and close-out visits. This will also include routine, periodic visits 
to study sites to confirm reported results are consistent with source documentation, appropriate 
subject enrollment, compliance with all applicable laws and regulations, and compliance with the 
protocol.  Remote monitoring may also occur.  The frequency of monitoring visits will be based 
upon enrollment, data integrity, and site compliance.  A Monitoring Plan will be written for the 
study and will be kept separate from the protocol. Each study site will allow monitoring activities 
to be conducted at their site, including visits by the study Sponsor and/or their designee.  
Therefore, access to the patients’ files must be allowed as per the informed consent at the 
Investigator's site. 
 
9.3 
Quality Assurance and Data management 
 
The data collection will be performed through an electronic CRF (eCRF). The investigator or an 
authorised member of the investigational team must sign all completed eCRFs by using an 

 
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electronic signature (a password will be provided by the data management centre at the start of 
the study).  
 
Clinical data management will be performed in accordance with data cleaning procedures. This 
is applicable for data recorded in the eCRF as well as for data from other sources (e.g. 
angiographies, CTs, etc.). Appropriate computer edit programs will be run to verify the accuracy 
of the database. The investigator will be queried on incomplete, inconsistent or missing data. 
 
9.4 
On-site Audits 
 
To ensure compliance with GCP and regulatory requirements, a member of the Sponsor’s (or a 
designated CRO’s) quality assurance unit, may arrange to conduct an audit to assess the 
performance of the study at the study site and of the study documents originating there. The 
investigator agrees to cooperate with the Sponsor and/or its designee in the conduct of these 
audits and provide access to medical records and other relevant documentation, as required. The 
investigator/institution will be informed of the audit outcome.  
 
Regulatory authorities worldwide may inspect the investigator during and after the study. The 
investigator should contact the sponsor immediately if this occurs, and must cooperate with the 
regulatory authority inspections as required.  
 

 
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10 
ORGANISATION  
 
10.1 Sponsor 
In this investigator-initiated trial, the European Cardiovascular Research Institute (ECRI) will act 
as Sponsor (ECRI-Trials B.V., PO Box 2125, 3000 CC Rotterdam, The Netherlands,). The 
Sponsor’s responsibilities are described in chapter 14. 
 
10.2 Steering Committee 
The Steering Committee is responsible of the overall management of the study. The Steering 
Committee is comprised of a Chairman, PIs, co-PIs, and ECRI. Their names, roles and 
responsibilities are described in a separate Steering Committee Charter. 
 
10.3 Clinical Event Committee (CEC) 
Not applicable. 
 
10.4 Data Safety Monitoring Board (DSMB) 
Not applicable. 
 
10.5 Data Management 
Data management will be conducted by the Clinical Research Organisation (CRO) Cardialysis 
(Cardialysis B.V., PO Box 2125, 3000 CC Rotterdam, The Netherlands). 
 
10.6 Site Management and Monitoring 
The CRO Cardialysis (Cardialysis B.V., PO Box 2125, 3000 CC Rotterdam, The Netherlands) 
will be responsible for site management and monitoring.  
 
 

 
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10.7 Safety Reporting 
For the study patient, this study is ended after the MSCT acquisition has been performed. The 
clinical treatment decision-making and patient treatment is up to investigators’ discretion and no 
follow-up investigation is implemented. Serious Adverse Events occurring between the moment 
the subject gave Informed Consent until the MSCT acquisition has been performed must be 
documented in the eCRF if considered related to study procedures within 24 hours. The 
investigator must inform Ethical Committee and manufacturers conform local practice. 
 
10.8 Statistical Analysis 
The CRO Cardialysis (Cardialysis B.V., PO Box 2125, 3000 CC Rotterdam, The Netherlands) is 
responsible for the statistical analysis. 

 
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11 
DATA HANDLING AND RECORD KEEPING 
11.1 Source Documentation (SD) 
Regulations require that investigators maintain information in the patient’s medical records that 
corroborate data collected in the electronic Case Report Form (eCRF). In order to comply with 
these regulatory requirements, at minimum, the following is a list of information that should be 
maintained and made available as required by monitors and/or regulatory inspectors:  
• Medical history/physical condition of the study patient before involvement in the study 
sufficient to verify investigational plan entry criteria;  
• Dated and signed notes on the day of entry into the study, protocol number, clinical site, 
patient number assigned and a statement that informed consent was obtained; 
• Notations on abnormal lab results; 
 
11.2 Case Report Form Completion 
All required data will be accurately recorded by authorised personnel documented on the 
authorised signature log in the eCRF.  
 
11.3 Record Retention  
All eCRF information, study records, reports and source documents that support the eCRF must 
be retained in the files of the responsible investigator according to the national requirements 
following notification by the Sponsor or designee that all investigations have been completed, 
and will further be retained in accordance with local and international guidelines as identified in 
the Investigator Site Agreement. This documentation must be accessible upon request by 
international regulatory authorities or the Sponsor (or designee). The Sponsor or designee must 
approve archiving or transfer of the documentation for relocation purpose of premises, in writing, 
prior to the actual file transfer. The investigator must notify the Sponsor, in writing, of transfer 
location, duration, and the procedure for accessing study documentation. The investigator must 
contact the Sponsor, or designee, before the destruction of any records and reports pertaining to 
the study to ensure they no longer need to be retained.  
 

 
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If the investigator retires, relocates, or for other reasons withdraws from assuming primary 
responsibility for keeping the study records, custody per written notice must be submitted to the 
Sponsor, or designee, indicating the name and address of the person accepting primary 
responsibility. The EC/IRB must be notified in writing of the name and address of the new 
custodian.  
 

 
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12 
PUBLICATION POLICY 
The Steering Committee and investigators are committed to the publication and widespread 
dissemination of the results of the study. Data from this study will not be withheld regardless of 
the findings.  
 
The SYNTAX III REVOLUTION trial is an investigator-initiated and scientifically driven study 
nested within the European Cardiovascular Research Institute (ECRI) and set up in collaboration 
with GE Healthcare and Heartflow. All public presentations and manuscript generation and 
submissions will be led under the auspices of the Study Chairman who will organise and lead a 
Publications Committee. However, this study represents a joint effort between investigators, 
ECRI and collaborators, and as such, the parties agree that the recommendation of any party 
concerning manuscripts or text shall be taken into consideration in the preparation of final 
scientific documents for publication or presentation. 
 
The final locked database will be housed at the data management centre, Cardialysis. Cardialysis 
will not publicly release data or study-related material, presentations, or manuscripts without the 
express permission of the Principal Investigators. All Principal Investigators will be listed as 
authors on all abstracts and publications, and as such must agree to their submission. The 
publication and/or presentation of results from a single trial site are not allowed until publication 
and/or presentation of the multi-centre results. All single site data for public dissemination must 
be generated from the central database – local database projects are not permitted. All proposed 
publications and presentations resulting from or relating to the study (whether from multicenter 
data or single site analysis) must be submitted to the Publications Committee for review and 
approval prior to submission for publication or presentation. 
 
The Steering Committee will receive any proposed publication and/or presentation materials 
prior to submission of the presentation or the initial submission of the proposed publication in 
order for the materials to be timely reviewed by all parties.  
 

 
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13 
INVESTIGATOR RESPONSIBILITIES 
13.1 Investigator Responsibility/Performance 
Prior to starting enrolment of patients, the investigator must read and understand this study 
protocol, and must sign and date the Protocol Signature page. The Investigator Site Agreement 
documents, agreement to all conditions of the study protocol and agreement to conduct the study 
accordingly. This study will be conducted in accordance the Declaration of Helsinki and other 
applicable regulatory requirements or any conditions of approval imposed by the IRB/EC or 
regulatory authorities.  
 
13.2 Required Documents 
The following documents must be submitted to Sponsor, or designee prior to patient enrolment:  
• Signed protocol signature page.  
• Recent signed and dated English Curriculum Vitae (CVs) of the Investigators participating in 
the Heart Team meetings (i.e. interventional cardiologists, radiologists and cardio-thoracic 
surgeons). These CVs should clearly show the investigator’s qualifications and experience.  
• Copy of the written confirmation of the EC/IRB regarding approval of the protocol including 
version number and date, patient information sheet and informed consent form, including 
version and date and other adjunctive patient material.  
• List of EC/IRB members, including name, title, occupation and any institutional affiliation of 
each member. If the EC/IRB member list is not available, the General Assurance or EC/IRB 
Recognition Number should be provided.  
• Signed Investigator Site Agreement. 
 

 
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13.3 Ethics Committee (EC) / Institutional Review Board (IRB) Approval 
According to the local regulations, the investigator must have all necessary approvals, including 
written approval from the EC/IRB of the clinical site or other accepted EC/IRB prior to enrolling 
patients in the study. A copy of the written approval must be provided to Sponsor and should 
include the following:  
• Statement of EC/IRB approval for the proposed study at the clinical site  
• Date the study was approved and the duration of the approval  
• Listing of any conditions attached to the approval  
• Identification of the approved Primary Investigator  
• Signature of the EC/IRB chairperson  
• Acknowledgement of the Co-Investigators  
• EC/IRB approval of the informed consent form (if applicable)  
• EC/IRB approval of the final protocol (if applicable).  
 
Any substantial amendments to the protocol, as well as associated consent form changes, will be 
submitted to the EC/IRB and written approval obtained prior to implementation. Minor changes 
which do not affect the subject’s safety will be subject to notification.  
 
13.4 Informed Consent 
Study patients must provide written informed consent using an EC/IRB-approved informed 
consent form. The study must be explained to the study patients in lay language. The investigator, 
or representative, must be available to answer all of the study subject’s study-related questions. 
Study patients will be assured that they may withdraw from the study at any time for any reason.  
 
13.5 Protocol Deviation 
The CRA/monitor will report all protocol deviations to the Sponsor. The investigator will review 
all protocol deviations  and will inform the EC/IRB according to the EC/IRB requirement.  
 

 
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13.6 Reporting Requirements 
The investigator should notify the EC/IRB in writing within three months after completion, 
termination, or discontinuation of the study at the site.  
 
Site responsibilities for submitting data and reports:  
Type of CRF/Report  
Completed by Site Within  
Process  
eCRF notification of study procedure 
related SAEs 
24 hours  
Enter eCRF pages within 
24 hours of knowledge of 
event  
eCRF (e.g. baseline assessments, 
SYNTAX Score, Heart Team decisions, 
final treatment (i.e. diseased vessels, 
segments) 
Ongoing basis  
Collected in the eCRF 
Angiographic Films, MSCT scans. 
Ongoing basis  
Transferred to Core Lab 
using AG Mednet 
Annual Reports  
Forward as requested by 
EC/IRB  
Copy provided by 
Sponsor to be send to 
EC/IRB (if required by 
national/local 
regulations) 
Final Report  
Forward within 3 months of 
study completion or 
termination  
Copy provided by  
Sponsor to be send to 
EC/IRB (if required by 
national/local 
regulations) 
 
13.7 Audits / Inspection 
In the event that audits are initiated by the Sponsor (or its designee) or national/international 
regulatory authorities, the investigator allows access to the original medical records and provides 
all requested information. In the event that audits are initiated by a regulatory authority, the 
investigator will immediately notify the Sponsor. 
 
 

 
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14 
SPONSOR RESPONSIBILITIES  
 
14.1 Role of ECRI 
As Sponsor, ECRI has the overall responsibility for the conduct of the study, including assurance 
that the study satisfies international standards and the regulatory requirements of the relevant  
authorities.  
 
General duties  
Prior to allowing the sites to start enrolling patients into the study, the Sponsor is responsible for 
selecting investigators, ensuring EC/IRB approvals are obtained where applicable, and signing 
the Investigator Site Agreement with the investigators and/or hospitals. It is the Sponsor’s 
responsibility to ensure that the study is conducted according to ISO 14155, the Declaration of 
Helsinki, and other applicable regulatory requirements, the study protocol, and any conditions of 
approval imposed by the EC/IRB or regulatory authorities. Additionally, the Sponsor will ensure 
proper clinical site monitoring.  
 
Selection of clinical investigators and sites  
The Sponsor together with the Steering Committee and Grant giver (GE) will select qualified 
investigators and facilities which have suitable equipment (GE 256-slice Revolution scanner) 
and adequate study patient population to meet the requirements of the investigation.  
 
Training of investigator and site personnel and site monitoring  
The training of the investigator and appropriate clinical site personnel will be the responsibility 
of the Sponsor, or designee, and may be conducted during an investigator meeting, a site 
initiation visit, or other appropriate training sessions.  
Periodic monitoring visits will be conducted frequently enough to ensure that all clinical patient 
data are properly documented and that the study is properly conducted.  
 
 
 

 
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Documentation  
The Sponsor will collect, store, guard and ensure completion by the relevant parties of the 
following documents;  
• All study relevant documents (protocol, EC/IRB approval and comments, patient information 
and informed consent template, relevant correspondence, etc.)  
• Signed and dated Case Report Form  
• Any statistical analyses and underlying supporting data  
• Final report of the clinical investigation  
 
 
14.2 Supplemental Applications 
As appropriate, the Sponsor will submit changes to the study protocol to the investigators to 
obtain EC/IRB re-approval. 
 
14.3 Submitting Reports 
The Sponsor will submit the appropriate reports identified by the regulations. This includes 
withdrawal of any EC/IRB approval, interim (if any) and final reports. 
 
14.4 Maintaining Records 
The Sponsor will maintain copies of correspondence, data,  and other records related to the 
clinical study. The Sponsor will maintain records related to the signed Investigator Site 
Agreements according to requirements set forth by ISO14155.  
 
All Core Laboratories and clinical sites will maintain study records according to local 
requirements for this type of study. 
 
 

 
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14.5 Audit 
The Sponsor is responsible for auditing the study to ensure compliance with GCP and regulatory 
requirements, a member of the Sponsor’s (or a designated CRO’s) quality assurance unit and 
may arrange to conduct an on-site audit to assess the performance of the study at the study site 
and of the study documents originating there.  
 
14.6 Confidentiality  
All data and information collected during this study related to the participating subject will 
comply with the standards for protection of privacy based on applicable local/ national 
requirements for subject’s confidentiality. All data used in the analysis and summary of this 
study will be anonymous, and without reference to specific study patients’ names. Access to 
study subject files will be limited to authorised personnel of the Sponsor, the investigator, and 
research staff. Authorised regulatory personnel have the right to inspect and copy all records 
pertinent to this study, but all efforts must be made to remove the subject’s personal data. 

 
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15 REFERENCES 
1. 
Landis JR, Koch GG. The measurement of observer agreement for categorical data. 
Biometrics. 1977;33(1):159-174. 
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Sim J, Wright CC. The kappa statistic in reliability studies: use, interpretation, and 
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3. 
Windecker S, Kolh P, Alfonso F, et al. 2014 ESC/EACTS Guidelines on myocardial 
revascularization: The Task Force on Myocardial Revascularization of the European 
Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery 
(EACTS)Developed with the special contribution of the European Association of 
Percutaneous Cardiovascular Interventions (EAPCI). Eur Heart J. 2014;35(37):2541-
2619. 
4. 
Head SJ, Kieser TM, Falk V, Huysmans HA, Kappetein AP. Coronary artery bypass 
grafting: Part 1--the evolution over the first 50 years. Eur Heart J. 2013;34(37):2862-
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5. 
Gruntzig A. Transluminal dilatation of coronary-artery stenosis. Lancet. 
1978;1(8058):263. 
6. 
Genereux P, Palmerini T, Caixeta A, et al. SYNTAX score reproducibility and variability 
between interventional cardiologists, core laboratory technicians, and quantitative 
coronary measurements. Circ Cardiovasc Interv. 2011;4(6):553-561. 
7. 
Serruys PW, Onuma Y, Garg S, et al. Assessment of the SYNTAX score in the Syntax 
study. EuroIntervention. 2009;5(1):50-56. 
8. 
Farooq V, Head SJ, Kappetein AP, Serruys PW. Widening clinical applications of the 
SYNTAX Score. Heart. 2014;100(4):276-287. 
9. 
Head SJ, Farooq V, Serruys PW, Kappetein AP. The SYNTAX score and its clinical 
implications. Heart. 2014;100(2):169-177. 
10. 
Wijns W, Bruyne B, Vanhoenacker P. What does the clinical cardiologist need from 
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Hillis LD, Smith PK, Anderson JL, et al. 2011 ACCF/AHA Guideline for Coronary 
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Foundation/American Heart Association Task Force on Practice Guidelines and the 
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patients with stable, complex coronary artery disease. Eur Heart J. 2013;34(32):2510-
2518. 
34. 
Sianos G, Morel MA, A.P. K, et al. The SYNTAX Score: an angiographic tool grading 
the complexity of coronary artery disease. EuroIntervention. 2005 1:219-227. Europa 
Edition 2005. All rights reservedEuroPCRonline.com. 
35. 
Farooq V, Brugaletta S, Serruys PW. The SYNTAX score and SYNTAX-based clinical 
risk scores. Semin Thorac Cardiovasc Surg. 2011;23(2):99-105. 
36. 
Farooq V, Brugaletta S, Serruys PW. Contemporary and evolving risk scoring algorithms 
for percutaneous coronary intervention. Heart. 2011;97(23):1902-1913. 
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Farooq V, van Klaveren D, Steyerberg EW, et al. Anatomical and clinical characteristics 
to guide decision making between coronary artery bypass surgery and percutaneous 
coronary intervention for individual patients: development and validation of SYNTAX 
score II. Lancet. 2013;381(9867):639-650. 
38. 
Farooq V, van Klaveren D, Steyerberg EW, Serruys PW. SYNTAX score II - Authors' 
reply. Lancet. 2013;381(9881):1899-1900. 
39. 
Head SJ, Farooq V, Serruys PW, Kappetein AP. The SYNTAX score and its clinical 
implications. Heart. 2013. 
40. 
Serruys PW, Morice MC, Kappetein AP, et al. Percutaneous coronary intervention versus 
coronary-artery bypass grafting for severe coronary artery disease. N Engl J Med. 
2009;360(10):961-972. 
41. 
SYNTAX score calculator: http://www.syntaxscore.com. SYNTAX working-group. 
Launched 19th May 2009. 
42. 
Leaman DM, Brower RW, Meester GT, Serruys P, van den Brand M. Coronary artery 
atherosclerosis: severity of the disease, severity of angina pectoris and compromised left 
ventricular function. Circulation. 1981;63(2):285-299. 
43. 
Smith SC, Jr., Feldman TE, Hirshfeld JW, Jr., et al. ACC/AHA/SCAI 2005 guideline 
update for percutaneous coronary intervention: a report of the American College of 
Cardiology/American Heart Association Task Force on Practice Guidelines 
(ACC/AHA/SCAI Writing Committee to Update the 2001 Guidelines for Percutaneous 
Coronary Intervention). J Am Coll Cardiol. 2006;47(1):e1-121. 
44. 
Scanlon PJ, Faxon DP, Audet AM, et al. ACC/AHA guidelines for coronary 
angiography: executive summary and recommendations. A report of the American 
College of Cardiology/American Heart Association Task Force on Practice Guidelines 
(Committee on Coronary Angiography) developed in collaboration with the Society for 
Cardiac Angiography and Interventions. Circulation. 1999;99(17):2345-2357. 
45. 
Medina A, Suarez de Lezo J, Pan M. [A new classification of coronary bifurcation 
lesions]. Rev Esp Cardiol. 2006;59(2):183. 

 
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46. 
Hamburger JN, Serruys PW, Scabra-Gomes R, et al. Recanalization of total coronary 
occlusions using a laser guidewire (the European TOTAL Surveillance Study). Am J 
Cardiol. 1997;80(11):1419-1423. 
47. 
Kappetein AP, Feldman TE, Mack MJ, et al. Comparison of coronary bypass surgery 
with drug-eluting stenting for the treatment of left main and/or three-vessel disease: 3-
year follow-up of the SYNTAX trial. Eur Heart J. 2011;32(17):2125-2134. 
48. 
Mohr FW, Morice MC, Kappetein AP, et al. Coronary artery bypass graft surgery versus 
percutaneous coronary intervention in patients with three-vessel disease and left main 
coronary disease: 5-year follow-up of the randomised, clinical SYNTAX trial. Lancet. 
2013;381(9867):629-638. 
49. 
Levine GN, Bates ER, Blankenship JC, et al. 2011 ACCF/AHA/SCAI Guideline for 
Percutaneous Coronary Intervention: a report of the American College of Cardiology 
Foundation/American Heart Association Task Force on Practice Guidelines and the 
Society for Cardiovascular Angiography and Interventions. Circulation. 
2011;124(23):e574-651. 
50. 
Hillis LD, Smith PK, Anderson JL, et al. 2011 ACCF/AHA Guideline for Coronary 
Artery Bypass Graft Surgery. A report of the American College of Cardiology 
Foundation/American Heart Association Task Force on Practice Guidelines. Developed 
in collaboration with the American Association for Thoracic Surgery, Society of 
Cardiovascular Anesthesiologists, and Society of Thoracic Surgeons. J Am Coll Cardiol. 
2011;58(24):e123-210. 
51. 
Tonino PA, Fearon WF, De Bruyne B, et al. Angiographic versus functional severity of 
coronary artery stenoses in the FAME study fractional flow reserve versus angiography 
in multivessel evaluation. Journal of the American College of Cardiology. 
2010;55(25):2816-2821. 
52. 
Pijls NH, Fearon WF, Tonino PA, et al. Fractional flow reserve versus angiography for 
guiding percutaneous coronary intervention in patients with multivessel coronary artery 
disease: 2-year follow-up of the FAME (Fractional Flow Reserve Versus Angiography 
for Multivessel Evaluation) study. Journal of the American College of Cardiology. 
2010;56(3):177-184. 
53. 
Tonino PA, De Bruyne B, Pijls NH, et al. Fractional flow reserve versus angiography for 
guiding percutaneous coronary intervention. N Engl J Med. 2009;360(3):213-224. 
54. 
Serruys PW, Farooq V, Vranckx P, et al. A global risk approach to identify patients with 
left main or 3-vessel disease who could safely and efficaciously be treated with 
percutaneous coronary intervention: the SYNTAX Trial at 3 years. JACC Cardiovasc 
Interv. 2012;5(6):606-617. 
55. 
Ranucci M, Castelvecchio S, Menicanti L, Frigiola A, Pelissero G. Risk of assessing 
mortality risk in elective cardiac operations: age, creatinine, ejection fraction, and the law 
of parsimony. Circulation. 2009;119(24):3053-3061. 
56. 
Ranucci M, Castelvecchio S, Conte M, et al. The easier, the better: age, creatinine, 
ejection fraction score for operative mortality risk stratification in a series of 29,659 
patients undergoing elective cardiac surgery. J Thorac Cardiovasc Surg. 
2011;142(3):581-586. 
57. 
Ranucci M, Castelvecchio S. The ACEF score one year after: a skeleton waiting for 
muscles, skin, and internal organs. EuroIntervention. 2010;6(5):549-553. 

 
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58. 
Farooq V, Vergouwe Y, Raber L, et al. Combined anatomical and clinical factors for the 
long-term risk stratification of patients undergoing percutaneous coronary intervention: 
the Logistic Clinical SYNTAX score. Eur Heart J. 2012;33(24):3098-3104. 
59. 
Chieffo A, Meliga E, Latib A, et al. Drug-Eluting Stent for Left Main Coronary Artery 
Disease: The DELTA Registry: A Multicenter Registry Evaluating Percutaneous 
Coronary Intervention Versus Coronary Artery Bypass Grafting for Left Main Treatment. 
JACC Cardiovasc Interv. 2012;5(7):718-727. 
60. 
Campos CM, van Klaveren D, Iqbal J, et al. Predictive Performance of SYNTAX Score 
II in Patients With Left Main and Multivessel Coronary Artery Disease. Circ J. 
2014;78(8):1942-1949. 
61. 
Farooq V, Serruys PW, Stone GW, Virmani R, Chieffo A, Fajadet J. Left main coronary 
artery disease. Percutaneous Interventional Cardiovascular Medicine. The PCR-EAPCI 
Textbook.  PCR publishing / EUROPA EDITION, Toulouse, France, 2012: Part 3, 
Chapter 12: 407-445. 
62. 
Campos CM, van Klaveren D, Farooq V, et al. Long-term forecasting and comparison of 
mortality in the Evaluation of the Xience Everolimus Eluting Stent vs. Coronary Artery 
Bypass Surgery for Effectiveness of Left Main Revascularization (EXCEL) trial: 
prospective validation of the SYNTAX Score II. Eur Heart J. 2015. 
63. 
Wilson GJ, Huibregtse BA, Pennington DE, Dawkins KD. Comparison of the 
SYNERGY with the PROMUS (XIENCE V) and bare metal and polymer-only Element 
control stents in porcine coronary arteries. EuroIntervention. 2012;8(2):250-257. 
64. 
Meredith IT, Verheye S, Dubois CL, et al. Primary endpoint results of the EVOLVE trial: 
a randomized evaluation of a novel bioabsorbable polymer-coated, everolimus-eluting 
coronary stent. J Am Coll Cardiol. 2012;59(15):1362-1370. 
65. 
Zhang Y, Farooq V, Garcia-Garcia HM, et al. Comparison of intravascular ultrasound 
versus angiography-guided drug-eluting stent implantation: a meta-analysis of one 
randomised trial and ten observational studies involving 19,619 patients. 
EuroIntervention. 2012;8(7):855-865. 
66. 
Papadopoulou SL, Girasis C, Dharampal A, et al. CT-SYNTAX score: a feasibility and 
reproducibility Study. JACC Cardiovasc Imaging. 2013;6(3):413-415. 
67. 
Kerner A, Abadi S, Abergel E, et al. Direct comparison between coronary computed 
tomography and invasive angiography for calculation of SYNTAX score. 
EuroIntervention (In Press). 2013. 
68. 
Serruys PW, Girasis C, Papadopoulou SL, Onuma Y. Non-invasive fractional flow 
reserve: scientific basis, methods and perspectives. EuroIntervention. 2012;8(4):511-519. 
69. 
Koo BK, Erglis A, Doh JH, et al. Diagnosis of ischemia-causing coronary stenoses by 
noninvasive fractional flow reserve computed from coronary computed tomographic 
angiograms. Results from the prospective multicenter DISCOVER-FLOW (Diagnosis of 
Ischemia-Causing Stenoses Obtained Via Noninvasive Fractional Flow Reserve) study. J 
Am Coll Cardiol. 2011;58(19):1989-1997. 
70. 
Nørgaard BL, Leipsic J, Gaur S, et al. Diagnostic performance of noninvasive fractional 
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71. 
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. 
Nephron. 1976;16(1):31-41. 
72. 
Fleiss JL, Cohen J, Everitt BS. Large sample standard errors of kappa and weighted 
kappa. Psychological Bulletin. 1969;72(5):323-327. 
73. 
Austen WG, Edwards JE, Frye RL, et al. A reporting system on patients evaluated for 
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Artery Disease, Council on Cardiovascular Surgery, American Heart Association. 
Circulation. 1975;51(4 Suppl):5-40. 
74. 
Serruys PW, Unger F, van Hout BA, et al. The ARTS study (Arterial Revascularization 
Therapies Study). Semin Interv Cardiol. 1999;4(4):209-219. 
75. 
Roques F, Michel P, Goldstone AR, Nashef SA. The logistic EuroSCORE. European 
heart journal. 2003;24(9):881-882. 
76. 
Serruys PW, Unger F, Sousa JE, et al. Comparison of coronary-artery bypass surgery and 
stenting for the treatment of multivessel disease. The New England journal of medicine. 
2001;344(15):1117-1124. 
 

 
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16 APPENDIX I: SCHEDULE OF EVENTS 
 
EVENT 
SCREENING ENROLMENT
HEART 
TEAM 
Preparation 
HEART 
TEAM 
Meeting 
Diagnostic Angiography¹ 
X 
 
  
  
Cardiac history and anginal status 
X 
 
  
  
Informed Consent 
X 
 
  
  
GE Revolution MSCT 
  
X 
  
  
Heart Team Randomization 
  
X 
  
  
Anatomical SYNTAX Score by Angio² ³  
  
  
X 
  
Anatomical SYNTAX Score by MSCT² ³ 
  
  
X 
  
SYNTAX Score II by Angio² ³ 
  
  
X 
  
SYNTAX Score II by MSCT² ³ 
  
  
X 
  
Functional Anatomy (FFRCT) ² ⁴ 
  
  
X 
  
Consult combined information modality 1 
  
  
  
X 
Document treatment recommendation 1 Heart Team 
  
  
  
X 
Consult combined information modality 2 
  
  
  
X 
Document treatment recommendation 2 Heart Team 
  
  
  
X 
Consult combined information modality 3 
  
  
  
X 
Document final Heart Team treatment 
recommendation  
  
  
  
X 
 
¹ Index angiograms for anatomical SYNTAX Score assessment both the right coronary artery (RCA) and left coronary artery (LCA, incl. LAD 
and LCX) must be imaged. 
² Collect and forward to central Core Lab. 
³ By site and Core Lab 
⁴ By HeartFlow 
 
 
 
 

 
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17 APPENDIX II: SYNTAX SCORE II 
 
SYNTAX Score II nomogram for bedside application. An online version will be made available 
online at the original SYNTAX Score website (www.syntaxscore.com).41 
Total number of points for 8 factors can be used to accurately predict 4-year mortality for the 
individual patient proposing to undergo for CABG or PCI. For example, a 60 year old man with 
an anatomical SYNTAX score of 30, unprotected left main coronary artery disease, creatinine 
clearance of 60 mL/min, an LVEF of 50%, and COPD, would have 41 points (predicted 4-year 
mortality 16·3%) to undergo CABG and 33 points (predicted 4-year mortality 8·7%) to undergo 
PCI respectively. The same example without COPD included would lead to identical points (29 
points) and 4-year mortality predictions (6·3%) for CABG and PCI. 
COPD defined with EuroSCORE definition,75 long-term use of bronchodilators or steroids for 
lung disease. PVD defined according to ARTS I definition,76 aorta and arteries other than 
coronaries, with exercise-related claudication, or revascularisation surgery, or reduced or absent 
pulsation, or angiographic stenosis of more than 50%, or combinations of these characteristics.  
Adapted from Farooq et al.37 
 
 
 
 

 
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*Because of the rarity of complex coronary artery disease in premenopausal women, mortality predictions in 
younger women are predominantly based on the linear relation of age with mortality. The differences in mortality 
predictions in younger women between CABG and PCI will therefore be affected by larger 95% CIs than those in 
older women.  

 
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18 APPENDIX III: DEFINITIONS 
 
 
ADVERSE EVENT DEFINITIONS 
Adverse Event (AE) 
An adverse event (AE) is any untoward medical occurrence in a subject or clinical investigation 
when subject was treated with a study product and which does not necessarily have a causal 
relationship with the treatment. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with the 
use of an investigational product whether or not related to the investigational device. 
 
Serious Adverse Event (SAE) 
If an adverse event meets any of the criteria below, it is regarded as a serious adverse event 
(SAE).  
• Led to death; 
• Led to serious deterioration in the health of a patient that: 
o Resulted in a life threatening illness or injury; 
o Resulted in a permanent impairment of a body structure or a body function; 
o Required in patients hospitalisation or prolongation of existing hospitalisation; 
o Resulted in medical or surgical intervention to prevent permanent impairment to a body 
structure or a body function. 
• Led to foetal distress, foetal death or a congenital abnormality or birth defect. 
 
Relationship of Adverse Event to the investigational treatment and/or procedure 
• Certain: Event or laboratory test abnormality, with plausible time relationship to treatment 
and/or procedure. It cannot be explained by disease or other drugs.  
• Probable: Event or laboratory test abnormality, with plausible time relationship to treatment 
and/or procedure. Unlikely to be attributed to disease or other drugs.  
• Possible: Event or laboratory test abnormality, with plausible time relationship treatment 
and/or procedure. Could also be explained by disease or other drugs. 

 
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• Unlikely: Event or laboratory test abnormality, with a time to treatment and/or procedure that 
makes a relationship improbable (but not impossible). 
• Unassessable: Event or laboratory test abnormality, more data is needed for proper 
assessment. 
 
ANGINA PECTORIS 
 
Braunwald Classification of Unstable Angina: 
  
  
Severity 
Clinical Circumstances
A
B
C
Develops in presence of 
extracardiac condition that 
intensifies myocardial 
ischemia (secondary UA) 
Develops in the absence 
of extracardiac condition 
(primary UA) 
Develops within 2 
weeks after acute 
myocardial infarction 
(postinfarction UA) 
I 
New onset of severe 
angina or accelerated 
angina; no rest pain 
IA 
IB 
IC 
II 
Angina at rest within past 
month but not within 
preceding 48 hr (angina at 
rest, subacute) 
IIA 
IIB 
IIC 
III 
Angina at rest within 48 hr 
(angina at rest, acute) 
IIIA 
IIIB Troponin negative 
IIIB Troponin positive 
IIIC 
 
Canadian Cardiovascular Society (CCS) Classification of Stable Angina: 
CLASS 
 
0 
Asymptomatic
I 
Angina with strenuous exercise (ordinary physical activity does not cause angina; for 
example walking or climbing stairs, angina occurs with strenuous or rapid or prolonged 
exertion at work or recreation) 
II 
Angina with moderate exertion (slight limitation of ordinary activity; for example, angina 
occurs walking or stair climbing after meals, in cold, in wind, under emotional stress or only 
during the few hours after awakening, walking more than two blocks on the level or 
climbing more than one flight of ordinary stairs at a normal pace and in normal conditions) 
III 
Angina with mild exertion (marked limitation of ordinary activity; for example, angina 
occurs walking one or two blocks on the level or climbing one flight of stairs in normal 
conditions and at a normal pace) 
IV 
Angina at any level of physical exertion (inability to carry on any physical activity without 
discomfort - angina syndrome may be present at rest). 
 
 
 
 

 
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CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) 
[EuroScore definition] 
Long term use of bronchodilators or steroids for lung disease. 
 
PERIPHERAL VASCULAR DISEASE (PVD) 
[EuroScore definition] 
Aorta and other arteries than coronary arteries, with exercise related claudication, or reduced or 
absent pulsation, or angiographic stenosis of more than 50%. 
 

 
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19 APPENDIX IV: MSCT ACQUISITION GUIDELINES 
 
Introduction 
• Utilize 256-slice GE Revolution CT Scanner. 
• Imaging the entire coronary tree allows for the most accurate FFRCT computation. 
 
Preparation 
• Assess heart rate and rhythm. Heart rate control (below 65 beats per minute) reduces 
motion artifacts. 
• Heart rate modulation for heart rates >60/min during breath holding. 
o Oral: metoprolol tartrate 100 mg, one hour before the exam. 
          atenolol 50 mg, one hour before the exam. 
o IV:    metoprolol 5 mg, repeated up to 5 times. 
o Contraindications: conduction delays, hypotension, severe asthma, allergy to 
betablockers, reduced left ventricle ejection fraction. 
o Consider ivabradin for patients with contra-indications to betablockers (in case of 
ivabradine the dosage suggested is 5 mg twice a day for at least 3-4 days before the 
scan) 
• Full explanation of exam, and practice breath hold. Ensure breath hold time will be 
sufficient for scan time. Evaluate impact of breath holds on heart rate. 
 
• Nitrates and FFRCT.  
• use NTG preferably 3 minutes prior to CT image acquisition; 
• use 1-2 sprays (0.4mg-0.8mg) 
• use beta-blocker with it to avoid reflex tachycardia/vasoconstriction 
• additional Beta blockade may be given after nitroglycerin to counteract the reflex 
tachycardia 
 
• Confirm absence of allergy to contrast media (consider prophylaxis for patients with 
doubtful or mild reactions to contrast in the past). 
 
Patient installation 
• Attach ECG leads, avoid respiratory muscles, check signal stability during breath hold. 
• Placement of an IV catheter that allows a flow of at least 5 ml/sec 
 
Data acquisition: 
1) Overview/scout of the entire chest. 
2) Contrast enhancement:  
• ≥300 g/L iodine contrast medium. 
• Injection rate: 5-6 ml/s. 
• Total amount depends on the patient size, the scan mode and the scan duration.  
• Contrast-scan timing: 
o Test/Timing Bolus: 15-20 ml of contrast is injected, preferably followed by a 
bolus chaser. Place the localizer line one centimeter below the carina and just 

 
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CIP Version 1.0 – 04 April 2016 
 
above the base of the heart, the optimal location to find the ascending aorta for a 
timed contrast injection. The time of (maximum) enhancement is used as the 
delay of the data acquisition after start of contrast injection.   
o Bolus tracking/Smart Prep: arrival of the (entire) bolus is monitored by using a 4-
chamber view.  
• A saline bolus of ≈50 ml is injected after the contrast medium at the same rate. 
3) Scan mode : 
• ECG-triggered one-beat scan mode should be used.  For HR <65, 75% of the R-R cycle 
is appropriate.  For HR>65 or variable heart rates, 40-80% of the R-R cycle is appropriate 
with ECG mA modulation. Consider use of Auto-Gating functionality on the system. 
4) Acquisition parameters: 
• Thinnest detector width. 
• For patients acquired in standard mode we suggest 100 kVp/500 mA  for BMI<25; 100 
kVp/550 mA for BMI included between 25 and 30 and 120 kVp/600 mA for BMI>30; 
for HD mode we suggest 100 kVp for BMI<25, together with 550 mA  
• Scan range: from 1-2 cm below the carina until the caudal border of the heart. 
• High Definition Mode should be used preferably except in patients with BMI > 25 
 
Alternate Data Acquisition protocols may be applicable based on local experience and expertise. 
These alternative protocols will be reviewed and approved by the Steering Committee including 
potential review of sample clinical cases. 
 
Image reconstruction (appropriately labelled): 
• 0.625mm slice thickness 
• ASIR-V 50% in all cases should be provided. Additional ASIR-V levels may be provided 
if ASIR-V 50% is inadequate. 
• Field-of-view enclosing the entire heart (cover inferior carina to lower heart border) 
(approx. 18 x 18 cm). 
• Standard kernel reconstructions of at least three different phases. Depending on the scan 
protocol both diastolic and systolic reconstructions should be performed.  
• Reconstructions should be optimized for the segments of interest (ROI). In case of 
suboptimal image quality other phases should be explored.  
• Additional high-definition reconstructions should be provided at the optimal phase(s). If 
High Definition mode was not performed, then Detail kernel reconstructions should be 
provided 
• If motion artifacts persist in the optimal phase images, the standard and high definition 
(or detail) reconstructions should be done with “Temporal Enhanced” enabled and 
SnapShot Freeze processing should be performed on the Advantage Workstation. 
 
DVD/USB recording:  
• Scout images 
• ECG trace 
• Standard kernel reconstructions for at least one (or the same) optimal phase for each 
diseased coronary segment, preferably three or more datasets including both systolic and 

 
SYNTAX III REVOLUTION
Protocol 
Protocol ECRI-004
Version 1.0
Page 66 of 66
 
 
Confidential and Proprietary 
Do not distribute or reproduce without the prior written permission of ECRI. 
CIP Version 1.0 – 04 April 2016 
 
diastolic phases. SnapShot Freeze processed images should be provided if any motion 
persists in the optimal phases (the accuracy of FFR-CT need to be evaluated for images 
reconstructed with SSF). 
• HD or Detail reconstructions for at least one (or the same) optimal phase for each 
diseased segment. SnapShot Freeze processed images should be provided if any motion 
persists in the optimal phases (the accuracy of FFR-CT need to be evaluated for images 
reconstructed with SSF).